1. health and fitness
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2012 Annual Meeting of the
American Neurological Association
in partnership with
Association of British Neurologists
October 7–9, 2012
Marriott Copley Place Boston
Poster Listings
Poster Session Abstracts
Works in Progress Abstracts
Career Development Abstracts
Author Index
Subject Index
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1–31
32–151
152–163
164–179
180–200
201–204
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Poster Listings
Sunday, October 7, 2012
Posters
Poster Listing Pages
Topic
Abstract Pages
S101-S161
1–4
32–47
Education
S201-S209
4
47–49
Neuro-oncology
S301-S309
4
49–51
Sleep Disorders and Circadian Rhythm
S401-S407
5
51–53
Neurogenetics
S501-S521
5–6
53–58
Neuroinfectious Disease
S601-S608
6
58–60
Neuro-opthalmology
S701-S714
6–7
60–63
Pediatric Neurology
S801-S806
7
63–64
Rehabilitation and Regeneration
S901-S914
7–8
64–68
8
68–70
Trauma/Injury
S1001-S1007
Monday, October 8, 2012
Posters
Poster Listing Pages
Topic
Abstract Pages
Dementia and Aging
M1101-M1162
8–11
70–86
Epilepsy
M1201-M1232
11–13
86–93
Neurology Critical Care
M1301-M1306
13
94–95
Neuromuscular Disease
M1401-M1474
13–17
95–113
Tuesday, October 9, 2012
Posters
Poster Listing Pages
Topic
Abstract Pages
Behavioral Neurology
T1501-T1522
17–18
113–118
Headache and Pain/Neuro-otology
T1601-T1613
18
118–122
Movement Disorder
T1701-T1780
19–22
122–141
Autoimmune Neurology
T1801-T1840
22–24
141–151
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Poster Listings
Cerebrovascular Disease
J_ID: ZAY Customer A_ID: BKLT2012_Poster_Sessions Cadmus Art: ANS9 Date: 14-September-12
2012 Annual Meeting Sunday,
October 7, 2012
Poster Session
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S108 Brain and Abdominal Aneurysm Study (BAAS):
Interim Analysis
Kevin M. Barrett, Sothear M. Luke, Albert G. Hakaim, Rabih
G. Tawk, Ricardo A. Hanel, Bradford B. Worrall, William D.
Freeman, Thomas G. Brott and James F. Meschia; Jacksonville,
FL and Charlottesville, VA
Posters will be displayed in Gloucester, located on the
3rd floor in the Back Bay Hall of the Marriott Copley
Place from 11:30 am – 7:00 pm, with authors present
from 5:30 pm – 7:00 pm.
NOTE: An asterisk designates a resident/fellow travel award
winner. Two asterisks designates an abstract selected for oral
presentation in the Derek Denny-Brown New Member Symposium.
S109 Revising the Model of Vascular Homeostasis:
Mechanotransduction Is Opposed by a Novel
Electrical Force
Darshan P. Trivedi and Peter R. Bergethon; Boston, MA
S110 Does the NMDA Receptor Biomarker Predict
Impaired Cerebral Vascular Function in Diabetes?
Kerstin Bettermann, Julia E. Slocomb, Mary E.J. Lott and
Svetlana Dambinova; Hershey, PA and Atlanta, GA
Cerebrovascular Disease
S101 The Expression of Individual Genes in Acute
Stroke Differs across Leukocyte Subsets
Mateusz G. Adamski, Erin Wagenr, Yan Li, Hua Yu, Steven
A. Soper and Alison E. Baird; Brooklyn, NY; Krakow, Poland
and Baton Rouge, LA
S111 Neurophysiological Identification of Two
Independent Generators Causing Oculofaciopalatal and
Lingual Myoclonus
Rony Dekermenjian, Nancy Gadallah, Sushanth Bhat,
Sumaiya Salim, Liudmila Lysenko, Michael Rosenberg
and Sudhansu Chokroverty; Edison, NJ
S102 Genetic Risk in Cerebral Small Vessel Disease
(SVD): 17q25 Locus Associates with White Matter
Lesions but Not Lacunar Stroke
Poneh Adib-Samii, The International Stroke Genetics Consortium
and METASTROKE Consortium; London, United Kingdom
S112 Evaluation of Gender Disparities in
Hemicraniectomy Utilization in the United States
Mahmoud Rayes, Seemant Chaturvedi and Pratik
Bhattacharya; Detroit, MI
S103 The Untreated Clinical Course of Cerebral
Cavernous Malformations: A Prospective,
Population-Based Cohort Study
Rustam Al-Shahi Salman, Julie M. Hall, Margaret A. Horne,
Fiona A. Moultrie, Colin B. Josephson, Jo J. Bhattacharya,
Carl E. Counsell, Gordon Murray, Vakis Papanastassiou,
Vaughn Ritchie, Richard C. Roberts, Robin J. Sellar and
Charles P. Warlow; Edinburgh, United Kingdom; Newcastleupon-Tyne, United Kingdom; Glasgow, United Kingdom;
Aberdeen, United Kingdom; Fauldhouse, United Kingdom and
Dundee, United Kingdom
S113 Functional Weakness in tPA Candidates:
Challenges and NIHSS-Minus
Ilya Bragin, Mirret M. El-Hagrassy and Adham Kamel;
Syracuse, NY
S114 Cognitive Outcomes of Acute Ischemic Stroke
Patients: Association with Concentrations of Thyroid
Axis Hormones and C-Reactive Protein
Adomas Bunevicius, Henrikas Kazlauskas, Nijole Raskauskiene,
Rima Radziuviene, Audra Anskoliene, Vinsas Janusonis and
Robertas Bunevicius; Palanga, Lithuania; Klaipeda, Lithuania
and Chapel Hill, NC
S104 Characteristic Distributions of Intracerebral
Hemorrhage-Associated Microinfarcts
Eitan Auriel, Mahmut Edip Gurol, Alison Ayers, Andrew
Dumas, Kristin Schwab, Anastasia Vashkevich, Sergi
Martinez-Ramirez, Jonathan Rosand, Anand Viswanathan
and Steven M. Greenberg; Boston, MA
S115 Angioplasty and Stenting of Patients with Carotid
Artery or Vertebral Artery Stenosis: Experience from
Lithuania
Adomas Bunevicius, Donatas Cerniauskas, Rytis S. Kaupas and
Edvardas Vaicekavicius; Kaunas, Lithuania and Chapel Hill, NC
S105 Effect of Leukoaraiosis on Neglect Performance in
Acute Stroke Patients
Zainab Bahrainwala, Argye E. Hillis, Jennifer Dearborn and
Rebecca F. Gottesman; Baltimore, MD
S116 Risk Factors for Stroke in South Asians across
Two Continents
Zhongbo Chen, Muhammad S. Khan, Sunaina Yadav, Ankita
Maheshwari, Tharushi Fernando, Ranil de Silva, Ranjani
Gamage, Kameshwar Prasad and Pankaj Sharma; London,
United Kingdom; New Delhi, India; Nugegoda, Sri Lanka
and Colombo, Sri Lanka
S106 First Mexican Family with CADASIL: A Novel
Mutation in the NOTCH3 Gene
Fernando Barinagarrementeria, Antonio Arauz and Manuele
Minw; Queretaro, Mexico; Mexico City, Mexico and Paris, France
S107 Prolyl 4-Hydroxylase Inhibition (GSK360A)
Increases Hypoxia Inducible Factor (HIF)-Regulated
Transcripts and Improves Post-Stroke Sensory-Motor
and Cognitive Functions
Frank C. Barone, Jin Zhou, Jie Lie, Robert N. Willette, John
Lapore, Erding Hu and Daniel M. Rosenbaum; Brooklyn, NY
and King of Prussia, PA
S117 Withdrawn.
S118 A Fulminant Case of Atypical Posterior Reversible
Encephalopathy Syndrome Associated with Status
Epilepticus
Bhavpreet Dham, Usman Moghal, Yadira Velazquez, Tapan
Kavi, Luis Zayas and Akbar Umer; Camden, NJ
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S119 Quality of Life after Lacunar Stroke: The
Secondary Prevention of Small Subcortical
Strokes (SPS3)
Mandip S. Dhamoon, Leslie A. McClure, Carole L. White,
Oscar Benavente and Mitchell S.V. Elkind; New York, NY;
Birmingham, AL; San Antonio, TX and Vancouver, BC,
Canada
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S130 No Significant Association of Aspirin Use with
Cerebral Microbleeds in the Asymptomatic Elderly
Chi Kyung Kim, Hyuk Tae Kwon, Jong-Ho Park and
Hyung-Min Kwon; Seoul, Korea and Koyang, Korea
S131 A Population-Based Study of Pre-Morbid Blood
Pressure in Patients with Small Vessel TIA and Stroke
Linxin Li, Nicola L.M. Paul, Linda Bull, Ziyah Mehta and
Peter M. Rothwell; Oxford, United Kingdom
S120 Primary/Familial CAA and Maeda-Type
Cerebral Small-Vessel Disease: Clinicopathological
Diferential Diagnosis and Role of Amyloid
Deposition Diseases
A.N. Viswanathan, S.M. Greenberg and Sabino Guillermo
Echebarria; Boston, MA and Las Arenas, Bizkaia, Spain
S132 Is the Susceptibility to Carotid Atherosclerosis
Reduced in Small Vessel Disease? Evidence from a
Population-Based Study
Linxin Li, Ziyah Mehta, Ursula Schulz and Peter M.
Rothwell; Oxford, United Kingdom
S121 TIA with New Ischemic Lesion: Clinical Features
and Stroke Risk for Patients with Different TIA
Subtypes
Olena Y. Fartushna; Kiev, Ukraine
S133 The Secondary Degeneration in Red Nuclei
Following Striatum Infarction Revealed by
Diffusion Tensor Imaging
Zijun Wang, Chao Qin, Zhijian Liang, Xuean Mo, Daobin
Cheng, Yajuan Chen, Wei Ye and Yi Dai; Nanning, Guangxi,
China
S122 Risk Factors for Intracranial Haemorrhage
in Acute Ischaemic Stroke Patients Treated
with rtPA
William N. Whiteley, Karsten Bruins-Slot, Peter M.
Fernandes, Peter A.G. Sandercock and Joanna Wardlaw;
Edinburgh, United Kingdom and Oslo, Norway
S134 Early Plasma Biomarkers of Ischemic Penumbra
in Acute Stroke
Svetlana Lorenzano, Natalia S. Rost, Hens B. Brouwers,
Alfredo J. Caceres, Matthew S. Siket, Octavio M. Pontes Neto,
Hua Li, Rebecca E. Green, Tijy Thankachan, Allison J.
Dipietro, Brenda J. Thornell, Ona Wu, Ken Arai, Sophia
Hartdegen, Angel T. Som, Loc-Duyen D. Pham, Peter J. Kelly,
Gordon J. Harris, Eng H. Lo, Steven K. Feske and
Karen L. Furie; Boston, MA and Dublin, Ireland
S123 Reversible Cerebral Vasoconstriction in
Pre-Eclampsia
Pablo Garcia-Reitboeck, Phil Rich and Ali Al-Memar;
London, United Kingdom
S124 Endothelial Engulfment of Emboli ‘‘Angiophagy’’
Is a Fundamental Mechanism of Microvascular
Recanalization
Jaime Grutzendler; New Haven, CT
S135 Elevated Factor IX and XI Activities May Not
Be a Risk Factor for Ischemic Stroke
Jennifer J. Majersik, George M. Rodgers, Kevin D. Call, Jana
J. Wold, Ronda A. Crist, Anna M. Sherr, Elaine J. Skalabrin
and Kristi J. Smock; Salt Lake City, UT; Provo, UT and
Springfield, OR
S125 Chronic Inflammatory Diseases and Stroke:
Evidence for Heterogeneous Mechanisms
Jose Gutierrez and Mitchell S.V. Elkind; New York, NY
S136 Partial to Complete Recanalization in Middle
Cerebral Artery Occlusion Following Intra-Arterial
tPA and Transcranial Doppler Monitoring
Amer M. Malik, Krislynn Barnhart and Yince Loh; Seattle, WA
S126 Dabigatran Etexilate: Management in Acute
Ischemic Stroke
Parisa P. Javedani, B. Zane Horowitz, Wayne M. Clark and
Helmi L. Lutsep; Portland, OR
S137 Clinical and Radiologic Significance of Dilated
Perivascular Spaces in Patients with Cognitive
Impairment
Sergi Martinez-Ramirez, Amy Halpin, Megan Quimby,
Andrew P. Dumas, Mahmut Edip Gurol, Eithan Auriel,
Steven M. Greenberg and Anand Viswanathan; Boston, MA
S127 High Resolution Magnetic Resonance Imaging
(HRMRI) in Intracranial Atherosclerosis
Tanya N. Turan, Truman R. Brown, Zoran Rumboldt and
Robert J. Adams; Charleston, SC
S128 Outcomes of Perfusion Based Endovascular
Therapy in Witnessed Onset and Unwitnessed
Onset of Stroke
Deependra Khanal, Pratik Bhattacharya and Seemant
Chaturvedi; Detroit, MI
S138 Protective Association between ACE Inhibitors
and Lobar Intracerebral Hemorrhage
Sharyl R. Martini, Matthew L. Flaherty, William M. Brown,
Charles J. Moomaw, Mary E. Comeau, Mary Haverbusch,
Dawn O. Kleindorfer, Brett M. Kissela, Joseph P. Broderick,
Carl D. Langefeld and Daniel Woo; Cincinnati, OH and
Winston-Salem, NC
S129 A Retrospective Study of Complications and
Discharge Dispositions after Treatment for Acute
Ischemic Stroke Based on the Nationwide Inpatient
Sample from 2006-2009
Tobias B. Kulik, Kate C. Young, Ann M. Leonhardt, Babak S.
Jahromi and Curtis G. Benesch; Rochester, NY
S139 Heparin May Not Improve Recanalization of
Intraluminal Thrombi in Acute Stroke Patients
Haris Kamal, Ping Li, Mohammed Shafie, Max Mokin and
Bijal K. Mehta; Buffalo, NY and Torrance, CA
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S140 Cerebral Vasospasm and Anterior Circulation
Stroke Secondary to an Exacerbation of Hereditary
Corproporphyria – First Reported Case
Stephen Mullin, Andrew Platts and Kashmir Randhawa;
London, United Kingdom
S150 Comparative Gene Expression Profiling of
Simvastatin Single and Vytorin Combination Therapy
in Hypercholesterolemic Subjects
Zohara Sternberg, Trevor Chichelli, David Hojnacki, Alison
Drake and Frederick Munschauer; Buffalo
S141 Physiologic Device-Based Diagnosis of Stroke in
Acute Vertigo: Proof-of-Concept
Ali S. Saber Tehrani, Georgios Mantokoudis, John H. Pula,
Cindy Guede, Kevin A. Kerber, Richard Rothman, Daniel F.
Hanley, David S. Zee, Jorge C. Kattah and David E.
Newman-Toker; Baltimore, MD; Peoria, IL and Ann Arbor, MI
S151 Immune Inflammatory Cross-Talk
between Carotid Plaque and Peripheral
Circulation
Zohara Sternberg, Husam Ghanim, Elad Levy, Adnan
Siddiqui and Paresh Dandona; Buffalo, NY
S142 Ischemic Burden in Relation to Apolipoprotein B/
AI Ratio in Intracranial Atherosclerotic Stenosis
Jong-Ho Park; Goyang, Republic of Korea and Seoul, Republic
of Korea
S152 A Comparative Study of Immune
Cells, and Their Activation State, in the
Carotid Plaque and in the Peripheral
Circulation
Zohara Sternberg, Kristen Glotti, Joseph Tario, Richard Curl,
Sonya Noor, Paul Wallace, Frederick Munschauer and Paresh
Dandona; Buffalo, NY
S143 Lipid Measurements and Risk of Ischemic Vascular
Events: Framingham Study
Aleksandra Pikula, Alexa S. Beiser, Jayandra J. Himali,
Margaret Kelly-Hayes, Carlos S. Kase, Sudha Seshadri and
Philip A. Wolf; Boston, MA and Framingham, MA
S153 Dissection in the Veterans’ Administration (DIVA):
Re-Examining Spinal Manipulation and Cervical Artery
Dissection
David E. Thaler, Xuemei Cai, Ali Razmara, Karen
Switkowski, Sergey D. Goryachev, Leonard D’Avolio, Pari J.
Fariborz and Edward Feldmann; Boston, MA
S144 Transient Aura Attacks in Cerebral Amyloid
Angiopathy Respond to Migraine Prophylactics
Patrick Pullicino, Ross W. Paterson and Ken Uchino;
Canterbury, Kent, United Kingdom and Cleveland, OH
S154 Lobar Microbleeds without Intracerebral
Hemorrhage: A Clinical, Genetic and Neuroimaging
Analysis
Ellis S. van Etten, Eitan Auriel, Alison M. Ayers, Anastasia
Vashkevich, Kristin M. Schwab, Jonathan Rosand, Anand
Viswanathan, Steven M. Greenberg and M. Edip Gurol;
Boston, MA
S145 Superposition of Stents in the Management of
Intracranial Aneurysms in Arterial Bifurcations
Ricardo A. Rangel-Guerra and Alberto Garcia-de la Fuente;
Monterrey, NL, Mexico and Monterrrey, NL, Mexico
S146 A Recombinant Human Neuron-Binding IgM
Protects the Brain Against Experimental Stroke by
Improving Motor Function, Reducing Infarct Volume
and Preserving Tissue Integrity
Bharath Wootla, Aleksandar Denic, Makoto Eriguchi, Istvan
Pirko and Moses Rodriguez; Rochester, MN
S155 A New Mouse Model for Central Post-Stroke
Pain
Simon Gritsch, Rohini Kuner and Daniel Vardeh; Heidelberg,
Germany and Boston
S147 Acute Ischemic Stroke Caused by Thrombotic
Thrombocytopenic Purpura without Significant
Hematologic Abnormalities
Julio C. Rojas, Fazeel Siddiqui, Bardia Nourbakhsh,
Chirantan Banerjee and Craig Powell; Dallas, TX
S156 The Third International Stroke Trial (IST-3) of
Intravenous rt-PA: Effect of Age and Time among
3035 Patients Randomised
Graham Venables, Richard Lindley, Peter Sandercock, Joanna
Wardlow and Geoff Cohen; Sheffield, United Kingdom;
Sydney, Australia and Edinburgh, United Kingdom
S148 Genetic Variants Associated with Severity of
Leukoaraiosis Predict Ischemic Stroke Risk
Natalia S. Rost, William J. Devan, Jing Wang, Guido
Falcone, Poneh Adib-Samii, Matthew Traylor, Alesandro Biffi,
Kaitlin M. Fitzpatrick, Valerie Valant, Alexa Beiser, Steven
Bevan, Bradford B. Worrall, Christopher Levi, Cathie Sudlow,
Peter Rothwell, Giorgio Boncoraglio, Martin Dichgans, James
Meschia, Philip A. Wolf, Hugh Markus, Karen L. Furie,
Qiong Yang, Sudha Seshadri and Jonathan Rosand; Boston;
London, United Kingdom; Charlottsville; Newcastle, Australia;
Edinburgh, United Kingdom; Oxford, United Kingdom;
Milan, Italy; Munich, Germany and Jacksonville
S157 Should We Thrombolyse the Oldest Old?
Julio R. Vieira, Shankar Awasthi and Barbara Koppel; New
York, NY
S158 Early Arrival to Stroke Centers Should
Be Most Emphasized in Public Education
Concerning Strokes
Kuniyasu Wada, Tadashi Terasaki, Yasuhiro Ogata and Yukio
Ando; Kumamoto, Japan
S159 Recurrent Brain Hemorrhage Caused by Cerebral
Vasculitis Due to Ulcerative Colitis: A Case Report and
Review
Heisuke Mizukami, Toshiyuki Yanagisawa, Hisanao Akiyama,
Yuta Hagiwara, Takahiro Shimizu, Makoto Shiraishi and
Yasuhiro Hasegawa; Kawasaki, Kanagawa, Japan
S149 Body Mass Index and Mortality in Acute Ischemic
Stroke
Lesli E. Skolarus, Brisa N. Sanchez, Deborah A. Levine, Kevin
A. Kerber, Lewis B. Morgenstern, Melinda A. Smith and
Lynda D. Lisabeth; Ann Arbor
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S160 Genetic Variants on 9p21.3 Are Associated with
Brain Arteriovenous Malformations with Associated
Flow-Related Arterial Aneurysms
Helen Kim, Nasrine Bendjilali, Jeffrey Nelson,
Shantel M. Weinsheimer, Mark Segal, Charles E.
McCulloch, Ludmila Pawlikowska and William L.
Young; San Francisco, CA
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S209 Churg–Strauss Syndrome in a Patient Previously
Diagnosed with Multiple Sclerosis: A Case Report
Pamela Sarkar, Richard T. Ibitoye and Douglas A. Promnitz;
London, United Kingdom; Preston, United Kingdom and
Ipswich, United Kingdom
Neuro-oncology
S161 Impact of Acute Ischemic Stroke Treatment in
Patients over Age 80: The SPOTRIAS Consortium
Experience
Joshua Z. Willey, Santiago Ortega-Gutierrez, Nils Petersen,
Pooja Khatri, Andria L. Ford, Natalia S. Rost, Latisha K. Ali,
Nichole R. Gonzales, Jose G. Merino, Brett C. Meyer and
Randolph S. Marshall; New York, NY; Cincinnati, OH; St.
Louis, MO; Boston, MA; Los Angeles, CA; Houston, TX;
Bethesda, MD and San Diego, CA
S301 Cerebrospinal Fluid and MRI Analysis in
Leptomeningeal Carcinomatosis
Ameya Save, Nicholas Blondin and Joachim Baehring; New
Haven, CT
S302 Emerging Therapeutic Targets in Merlin-Deficient
Tumors
Clemens O. Hanemann, Sylwia Ammoun and Lu Zhou;
Plymouth, United Kingdom
Education
S303 Ataxia, Ophthalmoplegia and Areflexia: What
Would You Think?
Nazia Karsan, Phillip Fletcher, Istvan Bodi and Bridget K.
Macdonald; London, United Kingdom
S201 Competency-Based Curricula in Neuromodulation
Device Therapies
Bruce Bellande, Zev Winicur, John Huffman, Maged Hamza,
David Caraway, Michael Saulino, Michael Turner, David
Charles, Bruno Gallo, Kevin Benson, Steven Siegel, Mary
Elizabeth Nelson, Susan Bennett, Susan Heath, Gail
McGlothlen, Myra Joseph-Gonzales, Glenn Sulley, Cynthia
Reese, Suzanne Dawidowicz, Kathleen Cox, Jamie Boche,
Andrea Larson and Peter Scott; Carmel, IN; Silver Spring,
MD; Richmond, VA; Huntington, WV; Philadelphia, PA;
Indianapolis, IN; Nashville, TN; Miami, FL; Sioux Falls,
SD; Woodbury, MN; Milwaukee, WI; Buffalo, NY;
San Francisco, CA; Napa, CA; San Antonio, TX;
Oklahoma City, OK and Minneapolis, MN
S304 Use of Rituximab in a Case of Paraneoplastic
Sensorimotor Neuropathy with Positive ANNA-1
Antibodies
Inhyup Kim, Shyla Kodi and Etta Eskridge; Valhalla, NY
S305 Use of Body-CT and PET-CT in the
Investigation of Paraneoplastic Neurological Syndromes:
Retrospective Audit of Practice in a UK Neuro-Science
Unit
Deacon Z.J. Lee, Ammar Kheder, Mhairi Forbes, Ian Craven
and Marios Hadjivassiliou; Sheffield, South Yorkshire, United
Kingdom
S202 Improved Timeliness of Neurology Consults in the
Emergency Department
Marius Birlea*, Charles Braun, Drew Kern, William Jones,
Steven P. Ringel and Kenneth L. Tyler; Aurora, CO
S306 Widespread Intracerebral Metastases from
Prostate Adenocarcinoma
Devin D. Mackay, Eli L. Diamond and Joshua P. Klein;
Boston, MA and New York, NY
S203 What? No Ascending Paralysis?
Joseph Khalil and Frank Hrisomalos; Indianapolis, IN
S307 Evaluating Corneal Innervation as a
Surrogate for Skin-Biopsy Diagnosis of Small-Fiber
Polyneuropathy
Giulio Ferrari, Nambi Nallassamy, Heather Downs, Reza
Dana and Anne Louise Oaklander; Boston, MA
S204 A Survey To Identify Neurology Education in
Africa
Heather Koons and Gretchen Birbeck; Nashville, TN and East
Lansing, MI
S205 Withdrawn.
S308 Neurophysiologic Tests Do Not Correlate Well
with Pain Measures and Quality of Life in Taxane
Neuropathy
Harry Openshaw, Karen Knight, Wei Ye, Gloria Juarez, Paul
Frankel and George Somlo; Duarte, CA
S206 Neurological Diagnoses among the Uninsured
Farrah J. Mateen; Baltimore, MD
S207 The Neurology Boot Camp: Tackling the ‘July
Phenomenon’
Wazim Mohamed, Maysa M. Basha and Benjamin
E. Atkinson; Detroit, MI
S309 Leveraging Expression of the GABA-A Receptor,
alpha 5 in Medulloblastoma as a Novel Therapeutic
Target
Soma Sengupta, Shyamal D. Weeraratne, Hongyu Sun, Bela
Kosaras, Jillian Phallen, Natalia Teider, Sundari Rallapalli,
Mirna Lechpammer, Dimitrios Mathios, Vlad Amani, Jessica
Pierre-Francois, Tenley Archer, James Cook, Frances Jensen,
Michael Lim, Scott Pomeroy and Yoon-Jae Cho; Boston;
Baltimore; Milwaukee and Stanford
S208 Who Needs Us Most? – Seeking out Those
Needing Rapid Neurological Assessment
Catriona L. Gribbin, Edward J. Newman,
Paul Gallagher and John Paul Leach; Glasgow,
United Kingdom
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S503 Subarachnoid Hemorrhage and Acute
Hydrocephalus in a Patient with Familial
Transthyretin Type Amyloidosis
Matthew B. Bevers, Nivedita U. Jerath and Patricia L.
Musolino; Boston, MA
Sleep Disorders and Circadian Rhythm
S401 Polysomnographic and Polymyographic
Characteristics of Painful/Painless Limbs Moving
Toes Syndrome (PPLMTS) Syndrome
Rony Dekermenjian, Nancy Gadallah, Sushanth Bhat, Phillip
Hanna, Fouzia Siddiqui and Sudhansu Chokroverty; Edison
and Harrisonburg, VA
S504 Exome Sequencing Identifies Two Separate
Mutations in a Novel Gene as Cause of Autosomal
Dominant Cervical Dystonia in Two Families
Gavin Charlesworth, Jose M. Bras, Rita Guerreiro, Una M.
Sheerin, Kailash Bhatia and Nicholas W. Wood; London,
United Kingdom
S402 Complex Sleep Behavior with Multiple Etiologies:
A Diagnostic Challenge
Rony Dekermenjian, Nancy Gadallah, Sushanth Bhat,
Sumaiya Salim, Luidmila Lysenko, Disha Patel and Sudhansu
Chokroverty; Edison, NJ
S505 Withdrawn.
S506 Progressive Supranuclear
Palsy Genetic Risk Variants Associate with Brain
Gene Expression and Neuropathology
Endophenotypes
Nilufer Ertekin-Taner, Mariet Allen, Melissa Murray, Julia
Crook, Daniel Serie, Fanggeng Zou, High Seng Chai, Curtis
Younkin, Shane Pankratz, Minerva Carrasquillo, Christopher
Rowley, Asha Nair, Sumit Middha, Sooraj Maharjan, Thuy
Nguyen, Li Ma, Kimberly Malphrus, Ryan Palusak, Sarah
Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri,
Christopher Kolbert, Jin Jen, Gerard Schellenberg, Ronald
Petersen, Neill Graff-Radford, Steven Younkin and Dennis
Dickson; Jacksonville; Rochester and Philadelphia
S403 Sleep and Circadian Rhythm Disruption in
Incident Parkinson’s Disease – A Multimodal Analysis
David P. Breen, Romina Vuono, Kate Fisher, Shani
Nawarahtna, John M. Shneerson, Akhilesh B. Reddy and
Roger A. Barker; Cambridge, United Kingdom
S404 The Tuberous Sclerosis Complex-Mammlian Target
of Rapamycin (mTOR) Pathway Regulates Mammalian
Circadian Rhythms
Jonathan Lipton, Elizabeth Yuan, Ashwin Nathan, Jarrett Leech,
Juliette Han, Fred Davis and Sahin Mustafa; Boston, MA
S405 A Longitudinal Study of 322 Individuals with
Narcolepsy
Maurice M. Ohayon; Palo Alto, CA
S507 Hexanucleotide Repeat Expansion in c9orf72 Is
Associated with Increased Risk of Bulbar Amyotrophic
Lateral Sclerosis (ALS)
Paloma Gonzalez-Perez, Peter Sapp, Zack C. Kennedy, Diane
McKenna-Yasek, Ru-Ju Chian, Andrew Fox and Robert H.
Brown; Worcester, MA
S406 Medical Conditions and Psychiatric Disorders
Associated with Narcolepsy
Maurice M. Ohayon; Palo Alto, CA
S508 Infrequent NaV1.7 Mutation in Insensitivity to
Pain, Erythromelalgia and Small Fiber Neuropathy
Christopher J. Klein, Dean H. Kilfoyle, Yanhong Wu, Paola
Sandroni, Phillip A. Low, Mark D. Davis and Peter J. Dyck;
Rochester, MN and Epsom, Aucklund, New Zealand
S407 Bmal1 Provides a Molecular Link between
Circadian Clock Function, Brain Metabolism, and
Neurodegeneration
Erik S. Musiek, Miranda M. Lim, Adam Q. Bauer, Guangrui
Yang, Jee Hoon Roh, Benoit I. Giasson, David M. Holtzman
and Garret A. FitzGerald; St. Louis, MO; Philadelphia, PA
and Gainesville, FL
S509 Improvement of Learning and Memory in
Ts65Dn Mouse Model of Down Syndrome (DS) by
GABAB Receptor Antagonists: DS-Specific and
Non-Specific Mechanisms
Francisco Madamba, Yasaman Pirahanchi, Brett Rasmussen
and Alexander Kleschevnikov; La Jolla, CA
Neurogenetics
S501 Nonsyndromic and Syndromic Polymicrogyria:
Illustration of Clinical, Radiological and Genetic
Heterogeneity in a Cohort of 50 Patients
Dina R. Amrom, Jacques Michaud, Grant Mitchell, Emmanuelle
Lemyre, Annapurna Poduri, Jennifer Partlow, Vijay Ganesh,
Bernard Dan, Giorgi Kuchukhidze, Ingrid Unterberger, Eugen
Trinka, Nicolas Deconinck, Catherine Christophe, Benoıˆt Pichon,
François Dubeau, Donatella Tampieri, Jean-Claude De´carie,
William B. Dobyns, Frederick Andermann, Christopher A. Walsh
and Eva Andermann; Montreal, QC, Canada; Boston, MA;
Brussels, Belgium; Innsbruck, Austria; Salzburg, Austria; Seattle,
WA and Montreal, QC
S510 PRRT2 Mutations in Japanese PKC Cases
Mitsuya Morita and Imaharu Nakano; Shimotsuke, Tochigi,
Japan
S511 C9ORF72 Hexanucleotide Repeat Expansion
Analysis in Multiple System Atrophy and Progressive
Supranuclear Palsy
Karen E. Morrison, Rachel V. Denyer, Gilbert Bensimon,
Albert Ludolph, Yves Agid, P. Nigel Leigh, Ammar Al-Chalabi
and on Behalf of NNIPPS Consortium; Birmingham, United
Kingdom; Paris, France; Ulm, Germany; Falmer, Brighton,
United Kingdom and London, United Kingdom
S502 The Phenotypic Spectrum of Subcortical Band
Heterotopia in Patients Negative for DCX/LIS1 Gene
Mutations
Eva Andermann, Dina Amrom, François Dubeau, Maria D.
D’Agostino, William B. Dobyns and Frederick Andermann;
Montreal, QC, Canada and Seattle, WA
S512 No Association of CETP Genotypes with Evolution
of Dementia Due to Alzheimer’s Disease
Fabricio F. Oliveira, Paulo H. Bertolucci, Marilia A. Smith
and Elizabeth S. Chen; Sa˜o Paulo, SP, Brazil
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S513 GLRB Is the 3rd Major Gene-of-Effect in
Hyperekplexia
Charlotte Hunt, Anna Derrick, Thomas Cushion, Sian Wood,
Cheney Drew, Owain W. Howells, Rhys H. Thomas, Seo
Kyung Chung and Mark I. Rees; Swansea, Wales, United
Kingdom and, Wales, United Kingdom
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Neuroinfectious Disease
S601 Spiroplasma Biofilm on Stainless Steel Is a Model
for Iatrogenic Transmission of CJD Via Surgical
Instruments
Frank O. Bastian, Xiaochu Wu and Philip H. Elzer; Baton
Rouge, LA
S514 Neuronal Loss of Tuberous Sclerosis
Complex Activity Results in Increased
Autophagosome Accumulation Despite
mTOR Activation
Alessia Di Nardo, Mary H. Wertz, Jarrett Leech, Emily
Greene-Colozzi, June Goto, Dennis Wall, David J.
Kwiatkowski and Mustafa Sahin; Boston, MA
S602 Upstate Eastern Equine Encephalitis: A Case
Report
Mirret M. El-Hagrassy and Yaman Eksioglu; Syracuse, NY
S603 HIV-1 Exposure Affects Neural Progenitor Cell
Renewal and Accelerates Astrocyte Differentiation in
Human Brain Slices
Ricardo Martinez, Rebeca Geffin and Micheline McCarthy;
Miami, FL
S515 Homozygous Nonsense Mutations of C12orf65 in
Patients with Spastic Paraplegia, Optic Atrophy and
Neuropathy
Haruo Shimazaki; Shimotsuke, Tochigi, Japan
S604 Anti-Ganglioside Antibodies Positive Influenza
Encephalopathy
Hitoshi Mori and Katuro Shindo; Kurashiki,
Okayama, Japan
S516 Hyperekplexia Phenotypes Associated with GLRB
Mutations
Rhys H. Thomas*, Cheney J. Drew, Owain W. Howell,
Thomas Cushion, Sian E. Wood, Jonathan G. Mullins,
SeoKyung Chung and Mark I. Rees; Swansea, United
Kingdom
S605 A Severe Case of Recurrent Coccidioidal
Meningitis Complicated by Hydrocephalus
Sarah Nelson and Michal Vytopil; Burlington, MA
S517 Increased Cancer Incidence in LRRK2-G2019S
Mutation Carriers
Bjørg Johanne Warø, Krisztina K. Johansen and Jan Olav
Aasly; Trondheim, Norway
S606 A Mouse Model of Arachnoid Granulation
Obstruction by Cryptococcus
Jeffrey A. Rumbaugh, Angela Pool, Lindsey Gainey and Yu
Hui Wu; Atlanta, GA
S518 Detailed Phenotype of a Novel Allelic Form of
Spinocerebellar Ataxia Type 13
Michael F. Waters, Kristina Santiago, Alexis K.
Harmeling and Richard P. Morse; Gainesville, FL and
Lebanon, NH
S607 Pathways to Neurodegeneration: The Effects of
HIV & Aging on Resting State fcMRI
Jewell B. Thomas, Matthew R. Brier, Florin F. Vaida,
Abraham Z. Snyder and Beau M. Ances; St. Louis, MO and
San Diego, CA
S519 A Meta-Analysis of Genome Wide Association
Studies To Identify Loci Associated with Brain Atrophy
in Multiple Sclerosis
Zongqi Xia*, Nikolaos Patsopoulos, Charles Guttmann, PierreAntoine Gourraud, Sergio Baranzini, Jorge Oksenberg, Jeroen
Geurts, Bernard Uitdehaag, Raija Lindberg, Yvonne Naegelin,
Stephen Hauser, Ludwig Kappos, Chris Polman, Howard
Weiner and Philip De Jager; Boston, MA; Cambridge, MA;
San Francisco, CA; Amsterdam, Netherlands and Basel,
Switzerland
S608 Clearance of Low Copy JC Virus from CSF of MS
Patients on Natalizumab
Gloria von Geldern, Caroline Ryschkewitsch, Peter Jensen,
Avindra Nath and Eugene O. Major; Bethesda, MD
Neuro-ophthalmology
S701 Withdrawn.
S702 3-Tesla MRI of the Optic Nerve: A Pilot Study
David Bradley, Iqbal Mudassir, Gerard O’Connor, Lisa
Costelloe, Derbhail O’Driscoll, Andrew Fagan, Jim Meaney
and Janice Redmond; Dublin, Ireland
S520 Engineering Mouse Chromosomes
To Facilitate Genetic Analysis of Down
Syndrome
Xiaoling Jiang, Chunhong Liu, Li Zhang, Pavel V.
Belinchenko, Alexander M. Kleschevnikov, Annie
Pao, William C. Mobley and Y. Eugene Yu; Buffalo,
NY and La Jolla, CA
S703 The Lone Abducting Eye and Laterality of Motor
Control: Congresswoman Giffords’ ‘‘Wrong-Way Eyes’’
Denotes Crossed Right Hemisphere Syndrome in
a Right Hander
Iraj Derakhshan; Veckeley, WV and Cleveland, OH
S521 Body-Wide Correction of Myotonic Dystrophy
Type 1 (DM1) in Transgenic Mice by RNase H-Active
Antisense Oligonucleotides (ASOs)
Thurman M. Wheeler, Andrew J. Leger, Sanjay K. Pandey, A.
Robert MacLeod, Masayuki Nakamori, Seng H. Cheng, Bruce
M. Wentworth and C. Frank Bennett; Rochester, NY;
Framingham, MA and Carlsbad, CA
S704 MOG Antibody Positive Optic Neuritis in Adults
Jithin S. George, Joanna Kitley, Mark Woodhall, John Elston,
Maria I. Leite, Angela Vincent and Jacqueline Palace; Oxford,
Oxfordshire, United Kingdom
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S705 Longitudinally Extensive Optic Neuritis in
Pediatric Patients
Jennifer Graves, Verena Kraus, Bruno Soares, Jonathan Strober
and Emmanuelle Waubant; San Francisco and Munich, Germany
Stage:
Page: 7
S804 Visual Function and Optical Coherence
Tomography in Pediatric Demyelinating
Diseases
Amy T. Waldman, Girish Hiremath, Robert A. Avery, Amy
Conger, Michael Loguidice, Lauren S. Talman, Kristin M.
Galetta, Michael J. Shumski, James Wilson, E’tona Ford,
Benjamin M. Greenberg, Jonas Ellenberg, Elliot M. Frohman,
Laura J. Balcer and Peter A. Calabresi; Philadelphia, PA;
Baltimore, MD and Dallas, TX
S706 Hypertrophic Perioptic Neuritis (HPN) in Wegener
Granulomatosis (WG)
Ken Ikeda, Takanori Takazawa, Tetsuro Nagaoka, Takehisa
Hirayama, Osamu Kano, Kiyokazu Kawabe and Yasuo
Iwasaki; Tokyo, Japan
S805 Epidermal Growth Factor Treatment Rescues
Neonatal White Matter Injury
Joseph Scafidi, Maria Roncal, Tamas L. Horvath,
Robert J. McCarter and Vittorio Gallo; Washington,
DC and New Haven, CT
S707 Is This the Tolosa-Hunt Syndrome?
Ulya S. Malik and Odai Jumma; Birmingham, United Kingdom
S708 Ethambutol Induced Optic Chiasmopathy
Subin Mathew, Raghavendra Seetharam, Ravindra Kamble
and Rajani Battu; Bangalore, Karnataka, India
S806 Drosophila Peroxisomal Biogenesis Defects
Produce Shortened Lifespan and Excess Cystene-String
Protein at the Synapse
Michael F. Wangler, Lucy Liu, Nikolaos Giagtzoglou, Vafa
Bayat, Joseph Faust, James McNew and Hugo J. Bellen;
Houston, TX
S709 Optic Disc Edema Does Not Always Correlate with
Retinal Nerve Fiber Layer (RNFL) Thickening
Mark J. Morrow; Torrance, CA
S710 Syphilitic Optic Neuritis: Possibly Forgotten but
Not Gone
Robert K. Shin, Marc A. Malouf, Shalom E. Kelman, Larysa
D. Kwintkiewicz and Stephen G. Reich; Baltimore, MD
Rehabilitation and Regeneration
S901 Time Limited Functional Properties of
Transplanted Neural Stem Cells
Nina Fainstein, Ofira Einstein, Mikhal Cohen and Tamir
Ben-Hur; Jerusalem, Israel
S711 Correlation of the Retinal Ganglion Cell Complex
and Contrast Sensitivity in Parkinson Disease
Eric M. Shrier, Christopher R. Adam, Yin Ding, Sophya
Glazman and Ivan Bodis-Wollner; Brooklyn, NY
S902 Recovery of Motor Function after Complete
Unilateral Injury of the Corticospinal Tract Using
Electrical Stimulation of Motor Cortex on the
Uninjured Hemisphere in Rats
Jason B. Carmel, Hiroki Kimura, Gabriel Felder, Ashley
Khalili, Melissa Lopresti, Chelsea Jin and John H. Martin;
White Plains, NY and New York, NY
S712 Late Diffusion Changes in Optic Radiations
Predicted by Early Optic Nerve Structure after Optic
Neuritis, Suggesting Trans-Synaptic Effects
Olivia Goodkin, Olga Ciccarelli, Daniel Altmann, Camilla
Fini, Alessia Mirigliani, Thomas M. Jenkins, Alan J.
Thompson and Ahmed T. Toosy; London, United Kingdom
S713 Cerebellar Esotropia Misdiagnosed as VI Nerve
Paresis: A Case Series
Sui H. Wong, Leena Patel and Gordon T. Plant; London,
United Kingdom and London, United Kingdom
S903 Synergic Effects of Enriched Environment and
Mesenchymal Stem Cells in Hypoxic-Ischemic Brain
Injury through FGF-2 Dependent Mechanism
Jung Hwa Seo, Ji Hea Yu, Yang Hyun Cho and Sung-Rae
Cho; Seoul, Republic of Korea
S714 Withdrawn.
S904 OnabotulinumtoxinA Plus Rehabilitation Improves
Functional Outcome in Post-Stroke Upper Limb
Spasticity: A Single-Blind, Randomized Trial
Deidre J. Devier, JoAnn Harnar, Leandro M. Lopez, Allison
Brashear and Glenn D. Graham; New Orleans, LA;
Albuquerque, NM; Albuqueruque, NM; Winston Salem, NC
and Washington, DC
Pediatric Neurology
S801 Elevated Immune Response to Gliadin in Autism:
Association with Gastrointestinal Symptoms but Not
Celiac Disease
Nga M. Lau, Peter H. Green, Donald D. Kasarda, Luan To,
Abhishek Chandra, Barry E. Kosofsky, Joseph J. Higgins, Anjali
M. Rajadhyaksha and Armin Alaedini; New York, NY and
Albany, CA
S905 Peripheral and Cutaneous Nerve Fiber
Regeneration in the Distal Foot of Macaques
after Spinal Nerve Ligation (SNL)
Gigi J. Ebenezer, Jasenka Borzan, Matthias Ringkamp, Lun
Chen, Justin C. McArthur, Peter Hauer, James N. Campbell,
Richard A. Meyer, John W. Griffin and Michael Polydefkis;
Baltimore
S802 Cognitive Assessment in Rett Syndrome: A Pilot
Study of Eyetracking
Aleksandra Djukic, Maria Valicenti-McDermott, Kathleen
Mavrommatis and Cristina Martins; Bronx, NY
S803 Asymptomatic Abnormalities in the White Matter
of Patients with CMT-X
Amy R. Viehoever, Linda Schimmoeller, Tammie Benzinger,
Soe Mar and Amy Viehoever; St. Louis, MO
S906 Vestibular Rehabilitation and Multiple Sclerosis:
Do Patients with Infratentorial Lesions Benefit More?
Jeffrey R. Hebert; Aurora, CO
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S907 Effects of Vestibular Rehabilitation on Multiple
Sclerosis-Related Fatigue and Upright Postural
Control: A Randomized Controlled Trial
Jeffrey R. Hebert, John R. Corboy, Mark M. Manago and
Margaret Schenkman; Aurora, CO
Stage:
Page: 8
S1003 Widely Used Clinical Predictors Do Not Account
for Outcome Variability in Mild Traumatic Brain Injury
Paolo Moretti, Stephen McCauley, Elisabeth Wilde and Harvey
Levin; Houston
S1004 Systematic Review and Meta-Analysis of Glasgow
Coma Scale and Simplified Motor Scale in Predicting
Traumatic Brain Injury Outcomes
Balwinder Singh, M. Hassan Murad, Larry J. Prokop, Patricia
J. Erwin, Zhen Wang, Shannon K. Mommer, Sonia S.
Mascarenhas and Ajay K. Parsaik; Rochester, MN and
London, United Kingdom
S908 RTMS in Treatment of Poststroke Aphasia
Wolf-Dieter Heiss, Alexander Hartmann, Josef Kessler, Nora
Weiduschat, Ilona Rubi-Fessen, Carole Anglade and Alexander
Thiel; Cologne, Germany and Montreal, Canada
S909 Regulatory Experience with Orphan Disorders of
the Nervous System
Orest Hurko, Andra E. Miller, Ruth Wolff and James G.
Kenimer; Alexandria, VA
S1005 Headaches and Cognitive Performance after
Combat Mild Traumatic Brain Injury (mTBI) Correlate
with Episodes of Loss of Consciousness (LOC),
Post-Traumatic Stress Disorder (PTSD) and
Impaired Sleep (IS)
Ronald G. Riechers, Robert L. Ruff, Xiao-Feng Wang, Suzanne
S. Ruff and Traci Piero; Cleveland, OH
S910 Examining Driving Ability in Multiple
Sclerosis
Maria Schultheis, Chelsea Morse, Josh McKeever, Lisa Zhao
and Thomas Leist; Philadelphia, PA
S1006 Delayed Imaging Findings in Delayed
Posthypoxic Leukoencephalopathy
Kevin A. Shapiro, Mai Anh Huynh, Riley M. Bove´, Stephanie
L. Cincotta and Jeffrey M. Ellenbogen; Boston, MA
S911 Shefstim: Automated Setup of Functional Electrical
Stimulation for Drop Foot Using a 64 Channel
Prototype Stimulator and Electrode Array
Ben W. Heller, Alison J. Clarke, Timothy R. Good, Jamie
Healey, Krishnan P.S. Nair, Emma J. Pratt, Mark L. Reeves,
Jill M. van der Meulen and Anthony T. Barker; Sheffield,
South Yorkshire, United Kingdom
S1007 When Mild Traumatic Brain Injury Isn’t so Mild
Latha G. Stead, Aakash N. Bodhit, Keith R. Peters, Lawrence
Lottenberg and Bayard D. Miller, Sr; Gainesville, FL
2012 Annual Meeting Monday,
October 8, 2012 Poster Session
S912 Deconditioning in Patients with Orthostatic
Intolerance
Ajay K. Parsaik, Thomas G. Allison, Wolfgang Singer, David
M. Sletten, Michael J. Joyner, Eduardo E. Benarroch, Phillip
A. Low and Paola Sandroni; Rochester, MN
Posters will be displayed in Gloucester, located on the
3rd floor in the Back Bay Hall of the Marriott Copley
Place from 11:30 am – 6:30 pm, with authors present
from 5:30 pm – 6:30 pm.
NOTE: An asterisk designates a resident/fellow travel award
winner.
S913 Orthostatic Intolerance with or without Postural
Orthostatic Tachycardia
Ajay K. Parsaik, Thomas G. Allison, Wolfgang Singer, David
M. Sletten, Michael J. Joyner, Eduardo E. Benarroch, Phillip
A. Low and Paola Sandroni; Rochester, MN
Dementia and Aging
M1101 Epigenetics of Induced Neuronal Cells to Model
Neurologic Diseases
Andy J. Liu, Bradley T. Hyman, Asa Abeliovich, Benjamin S.
Bleier and Mark W. Albers; Boston, MA; North Chicago, IL
and New York, NY
S914 Efficacy of Vitamin E Supplementation in
Cisplatin-Induced Neuropathy: A Meta-Analysis of
Randomized Controlled Trials
Rechilda Rhea P. Reyes, Rechilda Rhea Reyes, Rechilda Rhea
Reyes, Rechilda Rhea Reyes and Rechilda Rhea Reyes; Davao
City, Davao, Philippines
M1102 Family History of Alzheimer Disease Disrupts
Functional Connectivity between the Hippocampus and
Posterior Cingulate Cortex
Liang Wang, Abraham Z. Snyder, Matthew Brier, Jewell
Thomas and Beau M. Ances; Saint Louis, MO
Trauma/Injury
S1001 Preliminary Clinical Utility of Advanced SpinalCord MRI
Julien Cohen-Adad, Wei Zhao, Lawrence L. Wald, Bradley
Buchbinder and Anne Louise Oaklander; Charlestown, MA
and Boston, MA
M1103 Interactive Visual Analysis of Diffusion-Tensor
MRI Data Using the Expectation Maximization
Algorithm
Jian Chen, Andrew Maxwell, Haipeng Cai and Alexander P.
Auchus; Hattiesburg and Jackson
S1002 Neuregulin-1 Effects on Endothelial and
Blood-Brain Barrier Permeability after Experimental
Injury
Josephine Lok, Song Zhao, Wendy Leung, Ji Hae Seo, Deepti
Navaratna, Xiaoying Wang and Lo Eng; Boston, MA and
Jilin, China
M1104 The Hypothalamus in Alzheimer’s Disease: A
Golgi and Electron Microscope Study
Stavros J. Baloyannis, Ioannis Mavroudis and Ioannis S.
Baloyannis; Thessaloniki, Greece
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M1105 Mixed-Risk Vascular Cognitive Impairment:
Hypertension Plus Hypoperfusion Decrease Cognition
and Gait and Increase Fiber Tract Pathology and
Inflammation
Frank C. Barone, Jin Zhou, Jie Li, Alison E. Baird, Adamski
G. Mateusz, Diana L. Dow-Edwards, Peter J. Bergold, Samah
G. Abdel Baki, Howard Crystal and Daniel M. Rosenbaum;
Brooklyn, NY
Stage:
Page: 9
M1114 Cognitive, Functional, and Neuropsychiatric
Trajectories before and after an Alzheimer’s Disease
Diagnosis
Joseph E. Gaugler, David L. Roth, Robert Kane, Martha
Hovater, Joseph Johnston and Khaled Sarsour; Minneapolis,
MN; Baltimore and Indianapolis
M1115 Hippocampal Volumes Predict Response to
Acetylcholinesterase Inhibitors in Patients with
Dementia with Lewy Bodies
Jonathan Graff-Radford*, Bradley F. Boeve, Otto Pedraza,
Tanis J. Ferman, Scott Przybelsk, Timothy Lesnick, Matthew
Senjem, Glenn E. Smith, David S. Knopman, Clifford R.
Jack, Jr, Ronald C. Petersen and Kejal Kantarci; Rochester
and Jacksonville
M1106 Excessive Trk-B Signaling in GABAeric Synapses
Revealed by Array Tomography in the Ts65Dn Mouse
Model of Down Syndrome
Rachel L. Nosheny, Pavel V. Belichenko, Brad Busse, Kristina
D. Micheva, Stephen J. Smith and William C. Mobley; La
Jolla, CA and Stanford, CA
M1116 Sustained Cognitive Improvement with
Extended-Release Memantine (28 mg, Once Daily) in
Moderate to Severe Alzheimer’s Disease
Michael Tocco, Suzanne Hendrix, Michael L. Miller, Vojislav
Pejovic and Stephen M. Graham; Jersey City, NJ; Salt Lake
City, UT and Chicago, IL
M1107 Degeneration of Brainstem Respiratory Nuclei in
Dementia with Lewy Bodies
Michael F. Presti, Ann M. Schmeichel, Phillip A. Low, Joseph
E. Parisi and Eduardo E. Benarroch; Rochester, MN
M1108 Pathological Accumulation of a-Synuclein and
Ab in Dementia Associated with Parkinson Disease
Meghan C. Campbell, Paul T. Kotzbauer, Nigel J. Cairns,
Allison W. Willis, Brad A. Racette, Samer D. Tabbal and Joel
S. Perlmutter; St. Louis, MO
M1117 Response across Multiple Outcome Measures in
Patients with Moderate to Severe Alzheimer’s Disease
Taking Extended-Release Memantine (28 mg, Once
Daily)
Stephen M. Graham, Suzanne Hendrix, Michael L. Miller,
Vojislav Pejovic and Michael Tocco; Jersey City, NJ; Salt Lake
City, UT and Chicago, IL
M1109 Impaired Default Network Functional
Connectivity in Autosomal Dominant Alzheimer’s
Disease: Findings from the DIAN Study
Jasmeer P. Chhatwal*, Aaron P. Schultz, Keith A. Johnson,
Tammie L.S. Benzinger, Clifford R. Jack, Stephen Salloway,
John M. Ringman, Robert A. Koeppe, David L. Marcus, Paul
M. Thompson, Andrew J. Saykin, Sonia C. Correia, Peter R.
Schofield, Christopher C. Rowe, Nick C. Fox, Adam M.
Brickman, Richard Mayeux, Miroslava Rimajova, Chester A.
Mathis, Eric M. McDade, William E. Klunk, Michael W.
Weiner, Randall J. Bateman, Alison M. Goate, Chengjie
Xiong, Virginia Buckles, Krista L. Moulder, John C. Morris
and Reisa A. Sperling; Boston, MA; St. Louis, MO; Rochester,
MN; Providence, RI; Los Angeles, CA; Ann Arbor, MI; New
York, NY; Indianapolis, IN; Coimbra, Portugal; Randwick,
Australia; Melbourne, Australia; London, United Kingdom;
Perth, Australia; Pittsburgh, PA and San Francisco, CA
M1118 Retinal Degeneration in FTLD Patients and
PGRN-Deficient Mice Preceded by TDP-43
Mislocalization
Michael E. Ward*, Alice Taubes, Bruce L. Miller, Jeffrey M.
Gelfand, Li Gan and Ari J. Green; San Francisco, CA
M1119 Cerebral Amyloid Angiopathy Independently
Contributes to Ischemic White Matter Disease: A PET/
MRI Correlative Study
Edip M. Gurol, Christopher Gidicsin, Andrew Dumas, Trey
Hedden, Alison Ayres, Alex Becker, Anastasia Vashkevich, Sergi
R. Martinez, Eitan Auriel, Kristen Schwab, Anand
Viswanathan, Jonathan Rosand, Keith A. Johnson and Steven
M. Greenberg; Boston, MA
M1110 Apples Far from the Tree: Clinical and
Electrophysiologic Variability in a Family with c9FTD/
ALS
Elizabeth A. Coon, Jasper R. Daube, Mariely DeJesusHernandez, Anahita Adeli, Rodolfo Savica, David S.
Knopman, Josephs E. Parisi, Rosa Rademakers and Bradley F.
Boeve; Rochester, MN and Jacksonville, FL
M1120 Gephyrin Plaques Identified in Frontal Cortex
of Alzheimer’s Disease Brains
Chadwick M. Hales, Howard Rees, James J. Lah, Allan I.
Levey and Thomas Wingo; Atlanta, GA
M1121 Clinical, Imaging and Pathologic Features of
C9ORF72 Hexanucleotide Expansion in ALS and FTLD
David J. Irwin, Corey T. McMillan, Johannes Brettschneider,
David J. Libon, Ashley Boller, John Powers, Keerthi
Chandrasekaran, Elisabeth McCarty Wood, Jon B. Toledo,
Leslie Shaw, Katya Rascovsky, John H. Woo, David A. Wolk,
Steven E. Arnold, Vivianna Van Deerlin, Leo F. McCluskey,
Lauren Elman, Virginia M.Y. Lee, John Q. Trojanowski and
Murray Grossman; Philadelphia, PA
M1111 Withdrawn.
M1112 Neural Correlates of Face-Name Encoding Using
Simultaneous Eye-Tracking and ERP
Ali Ezzati, Meghan B. Mitchel, Steven D. Shirk, Donald G.
Mclaren, Brandon A. Ally and Alireza Atri; Boston, MA;
Bedford, MA and Nashville, TN
M1122 Inflammatory Cerebral Amyloid Angiopathy: An
Unrecognized Cause of Reversible Dementia
Nivedita Jerath, Aarti Jerath, Keri Oxley, Matt Bevers, Shelley
Waite and Steve Greenberg; Boston, MA
M1113 Efficacy of a Brain/Cognitive Training
Therapeutic Program for Diagnosed Dementia
Barbara C. Fisher and Danielle M. Garges; Shelby Township, MI
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M1123 Inclusion of Axial Rigidity May Improve
Diagnostic Accuracy for Dementia with Lewy Bodies
Fariha Zaheer, John T. Slevin, Erin L. Abner, Peter T. Nelson
and Gregory A. Jicha; Lexington, KY
M1134 Decreased Life Expectancy When Seizures
Develop in Alzheimer’s
Lauren R. Moo and Steven D. Shirk; Bedford, MA and
Boston, MA
M1124 Quantitative Neurofibrillary Tangle Density and
Brain Volumetric MRI Analyses in Alzheimer’s Disease
Presenting as Progressive Fluent Aphasia
Keith A. Josephs, Dennis W. Dickson, Melissa E. Murray,
Matthew L. Senjem, Joseph E. Parisi, Ronald C. Petersen,
Clifford R. Jack and Jennifer L. Whitwell; Rochester, MN and
Jacksonville, FL
M1135 Comparison of the Impact of Alzheimer’s
Disease on Medicare and Medicaid
Lisa Mucha, Amanda Forys, Huai-Che Shih, Joel Bobula,
Trent McLaughlin, Kara Suter, Machaeon Bonafede and
Robert Fowler; Collegeville, PA; Arlington, VA; Abbott Park,
IL and Cambridge, MA
M1125 Hippocampal CA1 Apical Neuropil Atrophy
and Memory Performance in Alzheimer Disease
Geoffrey A. Kerchner, Gayle K. Deutsch, Michael Zeineh,
Robert F. Dougherty and Brian K. Rutt; Stanford, CA
M1136 Optineurin Immunoreactivity in Neuronal and
Glial Intranuclear Inclusions in Adult-Onset Neuronal
Intranuclear Inclusion Disease
Masataka Nakamura, Melissa E. Murray, Wen-Lang Lin,
Hirofumi Kusaka and Dennis W. Dickson; Jacksonville, FL
and Moriguchi, Osaka, Japan
M1126 Dimensions of Dementia: Item Response
Analysis of the Alzheimer’s Disease Assessment Scale
(ADAS-Cog)
Christian Yavorsky, Anzalee Khan, Mark Opler, Guillermo
DiClemente and Sofija Jovic; New York, NY; Hamilton, NJ
and Orangeburg, NY
M1137 Redistribution of Memory Load in Temporal
Association Tracts in Mild Cognitive Impairment
Claudia Metzler-Baddeley, Sarah Hunt, Derek K. Jones, John
P. Aggleton and Michael J. O’Sullivan; Cardiff, United
Kingdom and London, United Kingdom
M1127 Quantifying Differences in the Shape
Complexity of the Cerebral Cortex across the Adult
Lifespan
Richard D. King, Sourav Kole and Nikhil Singh; Salt Lake
City, UT
M1138 Cingulum Bundle Microstructure Predicts
Cognitive Control in Ageing and Mild Cognitive
Impairment
Michael J. O’Sullivan, Claudia Metzler-Baddeley, Derek K.
Jones, Jessica Steventon, Laura Westacott and John P. Aggleton;
London, United Kingdom and Cardiff, United Kingdom
M1128 Treatment of Primary Progressive Aphasia with
Rivastigmine
Hisatomo Kowa, Tsuneyoshi Seki, Mikiko Yamamoto, Fumio
Kanda and Tatsushi Toda; Kobe, Japan
M1139 Alzheimer’s Disease Progression Rates: New
Estimates
Natalia Olchanski, Pei-Jung Lin, Joshua T. Cohen and
Peter J. Neumann; Boston, MA
M1129 Rest/Activity Fragmentation and the Risk of AD
in Older Adults
Andrew S. Lim, Matthew Kowgier, Lei Yu, Aron S. Buchman
and David A. Bennett; Toronto, ON, Canada and
Chicago, IL
M1140 Impact of Cerebrovascular Risk over
Age of Onset of Dementia Due to Alzheimer’s
Disease in a Sample of Patients with Low Schooling
from Brazil
Fabricio F. Oliveira, Paulo H. Bertolucci, Marilia A. Smith
and Elizabeth S. Chen; Sa˜o Paulo, SP, Brazil
M1130 Does Sporadic Atonia Occur in Alzheimer
Disease?
Leopold Liss; Columbus, OH
M1141 Repurposing Anti-Hypertensive Drugs for
Alzheimer’s Disease
Giulio M. Pasinetti and Paul Rosenberg; New York, NY and
Baltimore, MD
M1131 Diminished Thalamocortical Feedforward
Inhibition in an Aging Mouse Model of Chronic
Tinnitus: Implications for Deafferentation Syndromes
and Aging
Daniel A. Llano, Jeremy Turner and Don Caspary; Urbana,
IL; Jacksonville, IL and Springfield, IL
M1142 Changes in Specific Resting State Brain
Networks Correlate with Clinical Measures in PSP and
CBD
Timothy Rittman, Boyd Ghosh, William R. Shirer, Michael D.
Greicius and James B. Rowe; Cambridge, Cambridgeshire,
United Kingdom and Stanford, CA
M1132 Does Education Slow Functional Decline in
Alzheimer’s Disease? Revisiting the Reserve Hypothesis
Meghan B. Mitchell, Steven D. Shirk and Alireza Atri;
Boston, MA and Bedford, MA
M1143 Patterns of Longitudinal Brain Atrophy
in the Logopenic Variant of Primary Progressive
Aphasia
Jonathan D. Rohrer, Francesca Caso, Colin Mahoney, Maya
Henry, Howard Rosen, Martin N. Rossor, Bruce Miller, Jason
D. Warren, Gerard R. Ridgway and Maria Luisa
Gorno-Tempini; London, United Kingdom and San Francisco
M1133 Predictive Value of the MemoryImpairment-Screen Test in Subjects with Subjective
Memory Loss
Pedro J. Modrego, Jose´ Gazulla and Pedro J. Modrego;
Zaragoza, Spain
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M1144 Differential Patterns of White Matter
Degeneration as a New Biomarker for Dementia
Seyed Ahmad Sajjadi, Julio Acosta-Cabronero and Peter J.
Nestor; Cambridge, Cambridgeshire, United Kingdom
Stage:
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M1154 Gait and Balance Dysfunction in Dementia
Yutaka Tanaka, Masao Miyazaki and Lisa T. Connor; IkomaGun, Nara, Japan; Ise, Mie, Japan and St. Louis, MO
M1145 Souvenaid Improves Memory in Mild
AD – Results from the Clinical Study Program
P. Scheltens, R. Shah, D.A. Bennett, R.L. Wieggers, T.
Hartmann, H. Soininen and P.J.G.H. Kamphuis; Amsterdam,
Netherlands; Chicago, IL; Wageningen, Netherlands; Homburg,
Germany and Kuopio, Finland
M1155 Pharmacodynamic and Pharmacokinetic
Properties of Novel gamma-Secretase Modulators in
Multiple Animal Model Systems
Brian S. Bronk, Timonthy D. McKee, Robyn M.B. Louriero,
JoAnn Dumin, Vladislav Zarayskiy, Wesley F. Austin, Nathan
O. Fuller, Jed L. Hubbs, Ruichao Shen, Paul Pearson, Jeffrey
Ives, Jeffrey Jonker and Barbara Tate; Cambridge, MA
M1146 Relationship between ß-Amyloid Retention and
Ischemia in the Patients with Subcortical Vascular
Cognitive Impairment
Young Noh*, Sang Won Seo, Geon Ha Kim, Seun Jeon, Jong Min
Lee, Seung Jun Oh, Jae Seung Kim, Yearn Seong Choe, KyungHan Lee, Jae-hong Lee and Duk L. Na; Seoul, Republic of Korea
M1156 Effects of Extended-Release Memantine (28 mg,
Once Daily) on Language and Communication Abilities
in Patients with Moderate to Severe Alzheimer’s Disease
Michael Tocco, Suzanne Hendrix, Michael L. Miller, Vojislav
Pejovic and Stephen M. Graham; Jersey City, NJ; Salt Lake
City, UT and Chicago, IL
M1147 Prefrontal Cortex: Unilateral Disruption
Differentially Affects Verbal Working Memory in Young
and Older Adults
Jessica A. Shields, Jeffrey Mock and Anne L. Foundas; New
Orleans, LA
M1157 Ile143Thr Presenilin 1 Mutation in Sporadic
Atypical Early-Onset Alzheimer’s Disease
Maria Travasarou, Stella Marousi, Vasiliki Kyrimi and
Clementine E. Karageorgiou; Athens, Greece
M1158 Brain Imaging and Cognitive Predictors of
Incident Stroke, Dementia and Alzheimer’s Disease (AD)
Galit Weinstein, Alexa Beiser, Charles DeCarli, Rhoda Au,
Philip A. Wolf and Sudha Seshadri; Boston, MA and
Sacramento, CA
M1148 Normative Scores and Calculator for the NACC
UDS Neuropsychological Test Battery
Steven D. Shirk, Meghan B. Mitchell, Joseph J. Locascio,
Sandra Weintraub and Alireza Atri; Bedford, MA; Boston,
MA and Chicago, IL
M1159 Beyond the Myths: Forgetting the Fictions of
Alzheimer’s and Facing the Facts
Peter J. Whitehouse; Cleveland, OH
M1149 Integrating Human and Fly Genetics To
Understand Alzheimer’s Disease Susceptibility
Joshua M. Shulman, Selina Imboywa, Allison E. Diamond,
Portia Chipendo, Philip L. De Jager and Mel B. Feany;
Boston, MA
M1160 Baseline Characteristics of Subjects with
Prodromal Alzheimer’s Disease: The LipiDiDiet Study
Y. Freund-Levi, P.J. Visser, M. Kivipelto, R.L. Wieggers, T.
Hartmann and H. Soininen; Huddinge, Sweden; Maastricht,
Netherlands; Amsterdam, Netherlands; Stockholm, Sweden;
Wageningen, Netherlands; Homburg, Germany and Kuopio, Finland
M1150 Genetic Susceptibility for Amyloid Pathology in
Alzheimer’s Disease
Joshua M. Shulman, Kewei Chen, Brendan T. Keenan, Lori
B. Chibnik, Pradeep Thiyyagura, Cristin McCabe, Jason J.
Corneveaux, Lei Yu, Matthew J. Huentelman, Denis A. Evans,
Julie A. Schneider, Eric M. Reiman, Philip L. De Jager and
David A. Bennett; Boston, MA; Phoenix, AZ and Chicago, IL
M1161 Pellagra: The Forgotten American Neurological
Epidemic
Adrian C. Williams; Birmingham, United Kingdom
M1151 Impaired Nutritional Status in Patients with
Mild Alzheimer’s Disease Compared to Healthy AgeMatched Controls
J.W. Sijben, M.G.M. Olde Rikkert, P. Scheltens, A.M.J. van
Hees, M. Groenendijk and P.J.G.H. Kamphuis; Wageningen,
Netherlands; Nijmegen, Netherlands and Amsterdam, Netherlands
M1162 Induction of Autophagy Protects Against
TDP43-Mediated Neurodegeneration
Sami Barmada, Aaron Daub, Michael Ando, Andrea Serio,
Andrey Tsvetkov, Arpana Arjun, Siddharthan Chandran and
Steve Finkbeiner; San Francisco, CA and Edinburgh, United
Kingdom
M1152 Supporting Synapse Formation and Function in
Alzheimer’s Disease: Mechanism of Action of the Specific
Nutrient Combination FortasynTM Connect
John W. Sijben, Patrick J. Kamphuis, Martijn C. de Wilde,
Robert J. Hageman, Laus M. Broersen and Martine
Groenendijk; Wageningen, Netherlands and Utrecht, Netherlands
Epilepsy
M1153 A Return to Clinical Skills in the Early
Diagnosis of Alzheimer’s Disease
Cassandra Szoeke, Kathryn Ellis, Ping Zhang, Christopher Rowe,
Ralph Martin, Colin Masters, David Ames and AIBL Research
Group; Melbourne, VIC, Australia and Melbourne, Australia
M1202 Pharmacokinetics of Extended- and
Immediate-Release Topiramate at Steady State and after
Formulation Switch
Tricia L. Braun, Lawrence J. Lambrecht, Wesley M. Todd and
Mark B. Halvorsen; Maple Grove, MN
M1201 Extended-Release Topiramate Exhibits Linear
and Dose-Proportional Pharmacokinetics
Tricia L. Braun, Lawrence J. Lambrecht, Wesley M. Todd,
Mark B. Halvorsen and T.L. Braun; Maple Grove, MN
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M1203 Magnetic Resonance Volumetry Reveals Focal
Brain Atrophy in Transient Epileptic Amnesia
Christopher R. Butler, Willemijn van Erp, Amit Bhaduri,
Alexander Hammers, Rolf Heckemann and Adam Z. Zeman;
Oxford, United Kingdom; Nijmegen, Netherlands; London,
United Kingdom; Lyon, France and Exeter, United Kingdom
Stage:
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M1216 Dravet Syndrome Patient-Derived Cells and
Mouse Model Suggest SUDEP Mechanisms
David Auerbach, Huilin Shi, Yu Liu, Julie M. Jones, Miriam
H. Meisler, Lori L. Isom and Jack M. Parent; Ann Arbor, MI
M1217 Hypothermia Attenuates Glial Injury and
Prevents EEG Progression during Status Epilepticus
Sandipan Pati, J.X. Yin, Y. Gan, J. Georges, F.D. Shi, M.
Maalouf and D.M. Treiman; Phoenix, AZ
M1204 SOS for Seizures in SESA
Mirret M. El-Hagrassy and Robert Beach; Syracuse, NY
M1205 Reduced GABAA Receptor Endocytosis in a
Mouse Model of Absence Epilepsy
Chengwen Zhou, Li Ding and Martin J. Gallagher; Nashville, TN
M1218 Weight Change Associated with Anti-Epileptic
Drugs
W.O. Pickrell, A.S. Lacey, R.H. Thomas, M.I. Rees and P.E.M.
Smith; Swansea, United Kingdom and Cardiff, United Kingdom
M1206 Leucine Has Anticonvulsant Effects in Acute
Seizure Tests
Adam L. Hartman, Polan Santos and J. Marie Hardwick;
Baltimore, MD
M1219 Mutations in the Novel Protein PRRT2 Cause
Infantile Convulsions with Paroxysmal Kinesigenic
Dyskinesia
Hsien-Yang Lee, Yong Huang, Nadine Bruneau, Patrice Roll,
Elisha D.O. Roberson, Mark Hermann, Emily Quinn, James
Maas, Robert Edwards, Tetsuo Ashizawa, Betul Baykan,
Kailash Bhatia, Susan Bressman, Michiko K. Bruno, Ewout R.
Brunt, Roberto Caraballo, Bernard Echenne, Natalio
Fejerman, Steve Fruct, Christina A. Gurnett, Edouard Hirsch,
Henry Houlden, Joseph Jankovic, Wei-Ling Lee, David R.
Lynch, Shehla Mohammed, Ulrich Mu¨ller, Mark P. Nespeca,
David Renner, Jacques Rochette, Gabrielle Rudolf, Shinji
Saiki, Bing-Wen Soong, Kathryn J. Swoboda, Sam Tucker,
Nicholas Wood, Michael Hanna, Anne M. Bowcock, Pierre
Szepetowski, Ying-Hui Fu and Louis J. Ptacek; San Francisco,
CA; Marseille, France; Saint Louis, MO; Gainesville, FL;
Istanbul, Turkey; London, United Kingdom; New York, NY;
Honolulu, HI; Groningen, Netherlands; Buenos Aires,
Argentina; Montpellier, France; Strasbourg, France; Houston,
TX; Novena, Singapore; Philadelphia, PA; Giessen, Germany;
San Diego, CA; Salt Lake City, UT; Amiens, France;
Ishikawa, Japan and Taipei, Taiwan
M1207 Withdrawn.
M1208 Antiphospholipid Syndrome Presenting as
Epilepsia Partialis Continua
Fenella F. Johnstone and Odai Jumma; Birmingham, United
Kingdom
M1209 Race and Sex Differences in Characteristics of
Temporal Lobe Epilepsy
Robert Knowlton, Suzanne Miller, Maria Pisu, Lawrence Ver
Hoef, Kristen Riley and Nita Limdi; Houston, TX and
Birmingham, AL
M1210 A Higher Hurdle? Baseline Frequency and
Severity of Seizures in Trials of Perampanel, a New AED,
Compared with Previously Approved AEDs
Gregory L. Krauss, Frank Kerling, Vicente Villanueva, David
Squillacote, Haichen Yang, Jin Zhu and Antonio Laurenza;
Baltimore, MD; Ulm, Germany; Valencia, Spain and
Woodcliff Lake, NJ
M1220 Appropriate Drug Treatment for Status
Epilepticus Does Not Influence Its Prognosis
Andrea O. Rossetti, Vicent Alvarez, Jean-Marie Januel and
Bernard Burnand; Lausanne, Switzerland
M1211 Optogenetic Treatment Approaches for Focal
Neocortical Epilepsy
Laura Mantoan, Rob Wykes, Stephanie Schorge, Matthew C.
Walker and Dimitri M. Kullmann; London, United Kingdom
M1221 Planes Trains and Automobiles: Neurologic
Disorders and the Workforce. A Systematic Review
Eva Pilcher, Maria Baldwin and Michael J. Schneck;
Maywood, IL and Pittsburgh, PA
M1212 Effect of Ocimum basilicum Extract Against
Pentylenetetrazole-Induced Seizure in Mice
Mehrdad Modaresi and Arezoo Pouriyanzadeh; Isfahan,
Islamic Republic of Iran
M1222 Electroconvulsive Therapy Induced Absence
Status Epilepticus
Umang Shah, Evren Burakgazi and Usman Mogul; Camden, NJ
M1213 MRI Volumetry of the Temporal Lobe in Sudan;
Comparative Study between Epileptics and Matching
Control
Mohamed A. Nurein, Mohamedsalah M. Magzoub, Tahir O.
Ali, Abdullah M. Jabir and Abdulrahman M. Fadlalmola;
Umdurman, Khartoum, Sudan and Khartoum, Sudan
M1223 The Role of RhoA, Filamin and Formin in
Cortical Development
Gewei Lian, Markus Dettenhofer, Russell Ferland and Volney
Sheen; Boston, MA and Albany, NY
M1214 Epileptic Aphasia as an Initial Manifestation of
Lyme Meningoencephalitis
Dipakkumar P. Pandya, Anery Patel, Jennie Luna, Megan
McGarry and Sourav Sen; Paterson, NJ
M1224 Seizure Etiology & Outcome in HIVþ Zambian
Adults
Omar K. Siddiqi, Melissa Elafros, Izukanji Sikazwe, Chris
Bositis, Michael J. Potchen, Igor J. Koralnik, William
Theodore and Gretchen L. Birbeck; Boston, MA; Lusaka,
Zambia; East Lansing, MI; Baltimore, MD; Lawrence, MA
and Bethesda, MD
M1215 Synaptic Reporter Labeling of Adult-Born
Hippocampal Neurons in Experimental Epilepsy
Alison L. Althaus, Helen Zhang, Hisashi Umemori and Jack
M. Parent; Ann Arbor, MI
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M1225 Ketamine in the Treatment of Refractory Status
Epilepticus
Andrea S. Synowiec, Deepinder S. Singh, Vamsi Yenugadhati,
James P. Valeriano, Carol J. Schramke and Kelly M. Kevin;
Pittsburgh, PA and Philadelphia, PA
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M1304 Serum Sodium Values and Their Association
with Adverse Outcomes in Moderate-Severe Traumatic
Brain Injury (TBI)
Lucia Rivera-Lara, Raphael Carandang, Wiley Hall, Cynthia
Ouillette, Frederick A. Anderson, Robert J. Goldberg and
Susanne Muehlschlegel; Worcester, MA
M1226 Self Reported Anger and Depression in Patients
on Levetiracetam in Mono and Polytherapy
Udo C. Wieshmann and Gus Baker; Liverpool, United
Kingdom
M1305 Impact of Medical and Neurological ICU
Complications on Moderate-Severe Traumatic Brain
Injury (TBI)
Susanne Muehlschlegel, Raphael Carandang, Wiley Hall, Fred
A. Anderson and Robert J. Goldberg; Worcester, MA
M1227 Intravenous Sodium Valproate for Status
Epilepticus
Yuan Wu, Xiaofei Liu, ZiBin Chen, MeiGang Ma and Li Su;
Nanning, Guangxi, China
M1306 Incidence Rates of ICU Complications in
Moderate-Severe Traumatic Brain Injury (TBI)
Susanne Muehlschlegel, Raphael Carandang, Cynthia Ouillette,
Wiley Hall and Robert J. Goldberg; Worcester, MA
M1228 Protective Effect of Alpha -Asarone in Sombati’s
Cell-Based Model of Epilepsy
Yuan Wu, Xiao-Fei Liu, Yue-Juan Wu, Jie Su and Mei-Gang
Ma; Nanning, Guangxi, China
Neuromuscular Disease
M1401 Novel Choline Kinase Beta Gene Mutation
Associated with Exercise Induced Myalgia and
Mitochondrial Changes
Hena Ahmad, Aleksander Radunovic, Angharad Davis, Sylvia
Marino, Heinz Jungbluth, Chieko Aoyama, Steve Abbs and
David Moore; London, United Kingdom and Tochigi, Japan
M1229 The Syndrome of Transient Epileptic Amnesia
(TEA)
Adam Zeman and Christopher R. Butler; Exeter, Devon,
United Kingdom and Oxford, Oxfordshire,
United Kingdom
M1402 Might Sodium Phenylbutyrate (PBA)
Be a Drug for Sporadic Inclusion-Body Myositis
(s-IBM)?
Anna Nogalska, Carla D’Agostino, W. King Engel and Valerie
Askanas; Los Angeles, CA
M1230 Oxygen-Enhanced MRI: A New Imaging
Tool for Localization of Focal Epilepsy and Eloquent
Cortex
Giridhar P. Kalamangalam, Timothy M. Ellmore, Nelson T.
Nelson and Narayana A. Ponnada; Houston, TX
M1231 Attenuated and Augmented Emotional
Face Processing Networks in Temporal Lobe
Epilepsy
Brett W. Fling, Jeff Riley and Jack J. Lin; Irvine, CA
M1403 Chaperone-Mediated Autophagy (CMA) in
Sporadic Inclusion-Body Myositis (s-IBM)
Muscle Fibers
Mafalda Cacciottolo, Anna Nogalska, Carla D’Agostino, W.
King Engel and Valerie Askanas; Los Angeles, CA
M1232 Microelectrodes Produce Unreliable EEG
Recordings
William Stacey, Spencer Kellis, Christopher Butson, Paras Patil,
Trevor Assaf, Temenuzhka Mihaylova and Simon Glynn; Ann
Arbor, MI; Pasadena, CA and Milwaukee, WI
M1404 Is the Familial Amyotrophic Lateral Sclerosis
(ALS) Classification Fit for Purpose?
Rubika Balendra and Ammar Al-Chalabi; London, United
Kingdom
M1405 Putative Mechanisms Involved in Primary
Hyperoxaluria Type 1 Polyneuropathy
Sarah E. Berini, JaNean K. Engelstad, Jennifer A. Tracy,
Dawn S. Milliner, P. James B. Dyck and Peter J. Dyck;
Rochester, MN
Neurology Critical Care
M1301 Fatal Hyperammonemic Brain Injury from
Valproic Acid Exposure
Danny Bega, Henrikas Vaitkevicius, Torrey Boland, Rebecca
Folkerth, Michael Murray, Katia Meirelles and Sherry Chou;
Boston, MA
M1406 Cachexia in Two Adults with Single
Mitochondrial DNA Deletions Is Due to
Dysphagia
Sergiu C. Blumen, Ron Dabby, Yaron River, Esther
Leshinsky-Silver and Itzhak Braverman; Hadera, Israel and
Holon, Israel
M1302 A Population-Based Study of Aetiology
and Outcome in Acute Neuromuscular Respiratory
Failure
Aisling S. Carr, Anne I. Hoeritzaur, Rachel Kee, Michael
Kinney, Aoibhean Hutchinson and Gavin V. McDonnell;
Belfast, Northern Ireland, United Kingdom
M1407 Slowly Progressing Familial ALS with Bulbar
Onset Due to a Novel VCP Mutation
Sergiu C. Blumen, Paloma Gonzales-Perez, Vivian
E. Drory, Ron Dabby, Diane McKenna-Yasek and Robert H.
Brown, Jr; Hadera, Israel; Worcester; Tel Aviv, Israel and
Holon, Israel
M1303 Rapid High Volume CSF Loss – A New
Cause of Coma
Minjee Kim, Rose Du and Sherry H.-Y. Chou; Boston, MA
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M1416 Withdrawn.
M1408 Bulbar Speech-Articulation/Swallowing Rate
Changes Measured in Amyotrophic Lateral Sclerosis
(ALS) Patients Treated with Dextromethorphan/
Quinidine(Nuedexta) for Pseudobulbar Affect
(PBA) – Determination of Treatment Effect Size for
Future Clinical Trials
Benjamin Rix Brooks, Elena Bravver, Urvi G. Desai, K. Amy
Wright, Velma L. Langford, Nicole M. Williams, Mohammed S.
Sanjak and Richard A. Smith; Charlotte, NC and La Jolla, CA
M1417 Often-Treatable
‘‘Multi-Microcramps’’ (MMCs) Are Common and
Frequently Overlooked Manifestations of Peripheral
Neuropathy
W. King Engel; Los Angeles, CA
M1418 Q-Fever IgM-Positivity in 3/5 sALS Patients:
Any Pathogenic Significance Regarding the XYZ
Hypothesis?
W. King Engel; Los Angeles, CA
M1409 Assessment of Clinical Disease Trajectory [CDT]
in Amyotrophic Lateral Sclerosis [ALS] Patients by ‘ALS
Dashboard’ Containing Cognitive- Behavior
(Depression-Pseudobulbar Affect (PBA)-BulbarRespiratory-Arm-Leg Domains – Longitudinal Validation
over Time and by El Escorial/Awaji Shima Criteria
[EEC/ASC] Clinically-Definite [EECD/ASCD]
Classification at Diagnosis
Benjamin Rix Brooks, Mohammed S. Sanjak, Elena K. Bravver,
William L. Bockenek, Urvi G. Desai, Scott S. Lindblom,
Thomas J. Paccio, Nicole M. Williams, Mindy S. Nichols,
Amber L. Ward, K. Amy Wright, Velma L. Langford, Michael
P. Fischer, Kristy L. Walgren, Louise H. Frumkin, Priscilla C.
Russo, Anne S. Blythe, Nicole P. Smith, Jessica N. Scrmina,
Scott E. Holsten and Heather L. Oplinger; Charlotte, NC
M1419 Disruption of Intracellular Redox Homeostasis by
Mutant CUG-RNA in Myotonic Dystrophy Type 1 (DM1)
Xiang Fang, Rui Gao, Arpita Chatterjee, Tapas K. Hazra,
Robert Glen Smith and Partha S. Sarkar; Galveston, TX
M1420 Expanded CUG-RNA Suppresses PGC-1a
Transcription Via Activating DNA Damage
Response ATM Signaling in Myotonic Dystrophy
Type 1 (DM1)
Xiang Fang, Rui Gao, Arpita Chatterjee, Tapas K. Hazra,
Robert Glen Smith and Partha S. Sarkar; Galveston, TX
M1421 A Common Link between Three Sporadic
Amyotrophic Lateral Sclerosis Cases in Annapolis, MD
Nicholas C. Field, Sandra Banack, Tracie A. Caller, James
Metcalf, Paul A. Cox and Elijah W. Stommel; Lebanon, NH
and Jackson, WY
M1410 Peripheral Nerve Function Following Treatment
with Tanezumab
Mark T. Brown, William J. Litchy, David N. Herrmann,
Mark Goldstein, Aimee M. Burr, Michael D. Smith, Christine
R. West, Kenneth M. Verburg and Peter J. Dyck; Groton, CT;
Rochester, MN; Rochester, NY and Atlantis, FL
M1422 Infections in Myasthenia Gravis (MG)
Raghav Govindarajan, Dennys Reyes, John Morren, Evelio
Velis and Nestor Galvez; Weston, FL and Miami
M1411 Evaluation of Neuropathy: Tests and
Expenditures by Provider Type
Brian C. Callaghan, Ann Rodgers, Kevin Kerber, Ken Langa
and Eva L. Feldman; Ann Arbor, MI
M1423 Anti Acetylcholine Receptor Antibodies in a
Patient with LEMS and Idiopathic Thromobocytopenic
Purpura
Raghav Govindarajan and Virgilio Salanga; Weston, FL
M1412 Clinical, Neurophysiological and Histological
Differentiators of Congenital Myasthenic Syndromes
from the General Neuromuscular Disease Cohort
Aisling S. Carr, Estelle Healy, Brian Herron, Stephen Haffey,
Kiang Pang, Jacqueline Palace, David Beeson and John
McConville; Belfast, Northern Ireland, United Kingdom and
Oxford, United Kingdom
M1424 Blockade of Matrix Metalloproteinase-3 after
Traumatic Nerve Injury Preserves the Motor End Plate
Tom Chao, Derek Frump, Vincent J. Caiozzo, Tahseen
Mozaffar and Ranjan Gupta; Orange, CA
M1413 High Fat Diet Induces Impaired Glucose
Tolerance and Painful Peripheral Neuropathy
Hsinlin T. Cheng, Jacqueline R. Dauch, John M. Hayes,
Sangsu Oh and Eva L. Feldman; Ann Arbor, MI
M1425 Transgenic Mouse Models of
FUS/TLS-Mediated ALS
Lawrence J. Hayward, Hongru Zhou, Guohong Gao and
Robert H. Brown; Worcester, MA
M1414 Iatrogenic Mitochondrial Disease Emerging Years
after Stopping Anti-HIV Treatment: The Tip of the
Iceberg in 2012?
Brendan Payne, David A. Price, David Samuels, Ian Wilson,
Kris Gardner, Michael Trenell, Mauro Santibanez-Koref and
Patrick F. Chinnery**; Newcastle upon Tyne, United Kingdom
and Nashville
M1426 A Novel Mutation in the CACNA1S Gene in a
Japanese Family with Hypokalemic Periodic Paralysis
Makito Hirano, Yosuke Kokunai, Yusaku Nakamura,
Kazumasa Saigoh, Susumu Kusunoki and Masanori P.
Takahashi; Sakai, Osaka, Japan; Suita, Osaka, Japan and
Osakasayama, Osaka, Japan
M1427 Pathological Involvement of ubiquilin2 in
Autophagy in Sporadic Amyotrophic Lateral Sclerosis
Makito Hirano, Keiji Shimada, Tatsuki Itoh, Yoshiyuki
Mitsui, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno,
Takao Satou, Noboru Konishi, Yusaku Nakamura and Susumu
Kusunoki; Sakai, Osaka, Japan; Kashihara, Nara, Japan and
Osakasayama, Osaka, Japan
M1415 Development of C9orf72 ALS Biomarkers and
Therapeutics
Christopher J. Donnelly, Lyle W. Ostrow, Ying Li, Svetlana
Vidensky, Pingwu Zhang, Alan E. Renton, Rita G. Sattler,
Bryan J. Traynor and Jeffery D. Rothstein; Baltimore, MD
and Bethesda, MD
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M1428 An Unbiased Phenotypic Screen Identifies
Ethoxyquin as an hsp90 Activity Modulating
Neuroprotective Compound for Peripheral Neuropathies
Jing Zhu, Weiran Chen and Ahmet Hoke; Baltimore, MD
Stage:
Page: 15
M1438 Psoriatic Myopathies: The Mayo Clinic
Experience
Teerin Liewluck and Jennifer A. Tracy; Rochester, MN
M1439 Dynactin Mutations in HMN7B Disrupt
Initiation of Retrograde Transport at NMJ Terminal
Boutons
Thomas E. Lloyd, James Machamer, Sarah H. Collins,
Yunpeng Yang and Alex L. Kolodkin; Baltimore, MD
M1429 Zonisamide (ZNS) Treatment Attenuates Motor
Neuron Degeneration and Astrocytosis in the Wobbler
Mouse
Ken Ikeda, Yasuhiro Yoshii, Takehisa Hirayama, Kiyokazu
Kawabe, Osamu Kano and Yasuo Iwasaki; Tokyo, Japan
M1440 Phenotypic Diversity of Mutations
in the Ryanodine Receptor (RYR1): A Series
of Six Cases
Charles Marshall, Hena Ahmad, Nicholas Parkin, Stephen
Abbs, Silvia Marino, Sujit Vaidya, Heinz Jungbluth and
Aleksandar Radunovic; London, United Kingdom
M1430 Serum Lipid, Creatinine, Urate and Ferritin
Levels at the First Time Diagnosed with Amyotrophic
Lateral Sclerosis (ALS) Contribute to Disease
Progression
Ken Ikeda, Takehisa Hirayama, Kiyokazu Kawabe, Osamu
Kano and Yasuo Iwasaki; Tokyo, Japan
M1441 Advanced Neuroimaging Study of
Molecularly Defined Hereditary Spastic Paraplegias
(HSPs)
Andrea Martinuzzi, Domenico Montanaro, Nicola Martino,
Hana Hlavata, Giuseppe Rossi, Gabriella Paparella, Francesca
Peruch, Maria G. Rossetto, Alessandra T. Baratto and Maria
T. Bassi; Conegliano and Bosisio Parini, Italy; Pisa-Massa,
Italy and Conegliano, Italy
M1431 Protective Effect of Erythropoietin on
Glutamate-Mediated and Axotomy Induced Motor
Neuron Death
Yasuo Iwasaki, Ken Ikeda, Kiyokazu Kawabe and Osamu
Kano; Tokyo, Japan
M1432 Denervation Causes Lower Expression of
Insulin-Like Growth Factor (IGF) mRNA in
Regenerating Skeletal Muscle
Takahiro Jimi, Yoshiriro Wakayama and Hiroo Ichikawa;
Yokohama, Japan
M1442 The Use of Non-Invasive Ventilation for Patients
with Motor Neurone Disease: Patient and Carer
Perceptions of Obstacles and Outcomes
Susan K. Baxter, Wendy O. Baird, Sue Thompson, Stephen
Bianchi, Stephen Walters, Sam H. Ahmedzai, Alison Proctor,
Pamela J. Shaw and Christopher J. McDermott; Sheffield,
United Kingdom
M1433 Quantitative Image Analysis of Brain
Abnormality in Myotonic Dystrophy
Nam-Hee Kim, Dong-Eog Kim, Sang-Wuk Jeong, Ho Jin Kim
and Kyung Seok Park; Goyangsi, Korea and Bundang, Korea
M1443 Steroid Responsive Anti-GAD Antibody Positive
Spino-Cerebellar Ataxia
Shri K. Mishra, Yama Akbari and Parampreet Singh; Los
Angeles, CA; Baltimore, MD and Sylmar, CA
M1434 Prolonged High Frequency Electrical Nerve
Stimulation Precipitates Motor Axon Degeneration in
Presymptomatic SOD1G127X Mutant Mice
Susana Alvarez, Alexandru Calin, Stefan Marklund, Karin
Graffmo, Mihai Moldovan and Christian Krarup;
Copenhagen, Denmark; Bucharest, Rwanda and Umea˚,
Sweden
M1444 Confocal Microscopy Analysis of Altered
TDP-43 Expression in Peripheral Blood Lymphocytes
from ALS Patients
Jean-Luc C. Mougeot, Sriparna Ghosh, Anne C. Lutin,
Andrea E. Price, Richelle A. Hemendinger, Edward J.
Armstrong and Benjamin R. Brooks; Charlotte, NC
M1435 More MS Patients Remain Free from Disease
Activity with Teriflunomide Versus Placebo in TEMSO,
a Phase III Trial
Marcelo Kremenchutzky, Paul W. O’Connor, Jerry Wolinsky,
Christian Confavreux, Giancarlo Comi, Ludwig Kappos,
Tomas P. Olsson, Philippe Truffinet, Deborah Dukovic and
Aaron Miller; London, ON, Canada; Toronto, Canada;
Houston; Lyon, France; Milan, Italy; Basel, Switzerland;
Stockholm, Sweden; Chilly-Mazarin, France; Bridgewater and
New York
M1445 Myasthenia Gravis Associated with Graves’
Disease
Hiroyuki Murai, Natsumi Yamashita and Jun-ichi Kira;
Iizuka, Fukuoka, Japan; Matsuyama, Ehime, Japan and
Fukuoka, Japan
M1446 Effects of Small-Fiber Polyneuropathy
(SFPN) on Bone Mineral Density and Skeletal
Microarchitecture
Benjamin Z. Leder, Ruchit Khumbani, Erica Siwila-Sackman,
Heather Downs and Anne Louise Oaklander; Boston, MA
M1436 Anxiety in Benign Fasciculation Syndrome
Alexandra LaMela, Stephanie Scala, Ioannis Karakis, James A.
Russell and Doreen T. Ho; Biddeford, ME and
Burlington, MA
M1447 Mononeuropathy of the Lateral Cutaneous Nerve
of the Calf (LCNC) in Patients Previously Labeled with
‘‘Complex Regional Pain Syndrome-I’’
Anne Louise Oaklander and Jose´ Ochoa; Boston, MA and
Portland, OR
M1437 Myositis with Autoantibodies to c/d Sarcoglycan:
A New Disease
Russell Lane, Chiara Marini-Bettolo, Peter Charles and
Federico Roncaroli; London, United Kingdom
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M1448 The Incidence and Prevalence of CIDP in
Iceland
Brynhildur Hafsteinsdottir, Elias Olafsson and Sigurjon
Stefansson; Reykjavik, Iceland
Stage:
Page: 16
M1459 Confocal Microscopy Is a Reliable Measure of
Corneal Innervation
A. Gordon Smith, Gene Kim, Michael Porzio, Blaine Allen,
Kathleen Digre, Mark Mifflin and Rob Singleton; Salt Lake
City, UT
M1449 Abundant FUS-Immunoreactive Pathology
in the Skin in Sporadic Amyotrophic Lateral
Sclerosis
Seiitsu Ono, Takahiko Yamano, Hirotsugu Mikami, Takeshi
Watanabe, Tomomi Tsukie, Hiroyuki Fukazawa, Kazuhiro
Higashida, Yoshihiko Oketa, Hiroaki Ishikawa, Kanako Yasui,
Makoto Nomura and Megumi Suzuki; Ichihara, Chiba, Japan
M1460 In Sensory Neuropathy Contact Heat Evoked
Potential Stimulation (CHEPS) Small Fiber Conduction
Velocity (CV) Is Faster in Peripheral Than in Central
Spinothalamic Pathways
Benn E. Smith, Mark A. Ross, Brent P. Goodman, E.P. Bosch
and Lyell K. Jones, Jr; Scottsdale, AZ and Rochester, MN
M1450 Brown Sequard Syndrome as an Initial
Manifestation of Idiopathic Spinal Cord Herniation
Dipakkumar P. Pandya, Anery Patel, Jennie Luna, Megan
McGarry, Sourav Sen and Gaetan Moise; Paterson, NJ
M1461 Bortezomib Alters Microtubule Localization and
Mitochondrial Dynamics in Rat Dorsal Root Ganglion
Neurons
Nathan P. Staff, Jewel L. Podratz, Lukas Grassner, Miranda
Lange, Justin Paz, Andrew M. Knight, Charles L. Loprinzi,
Eugenia Trushina and Anthony J. Windebank; Rochester, MN
M1451 Sub-Regional Dual-Energy X-Ray
Absorptiometry (DEXA) Analysis: A Potential Endpoint
Measure for Therapeutic Trials in Myotonic Dystrophy
Type 1 (DM1)
Araya Puwanant, Noya Rackovsky, Jeffrey M. Statland, Katy J.
Eichinger, Richard T. Moxley, III and Charles A. Thornton;
Rochester, NY
M1462 Facioscapulohumeral Dystrophy (FSHD):
D4Z4 Fragment Size in Patients with Coat’s
Syndrome
Jeffrey M. Statland and Rabi Tawil; Rochester, NY
M1452 A Recombinant Human Neuron-Binding IgM
Promotes Survival and Protects Spinal Cord Anterior
Horn Cells in a Transgenic Murine Model of
Amyotrophic Lateral Sclerosis
Aleksandar Denic, Laurie Zoecklein, Bharath Wootla, Arthur
E. Warrington and Moses Rodriguez; Rochester, MN
M1463 SMN May Have Multiple Functions
Necessitating Widespread Restoration for Maximal
Therapeutic Benefit in SMA
Tara L. Martinez, Lingling Kong, James P. Van Meerbeke,
Rebecca Gibbs, Crystal Davis, Heather L. Plaster, Chien Ping
Ko, James R. Rusche, Cathleen M. Lutz, Mark M. Rich and
Charlotte J. Sumner; Baltimore, MD; Dayton, OH; Bar
Harbor, ME; Waltham, MA and San Diego, CA
M1453 A Clinical Study of the Distal Hereditary Motor
Neuropathies
Alexander M. Rossor, Henry Houlden and Mary M. Reilly;
London, United Kingdom
M1464 A Multicenter Phase II Open-Label Trial of
Valproic Acid and L-Carnitine in Infants with
SMA Type I
Kathryn J. Swoboda, Kristin Krosschell, Thomas Crawford,
Charles Scott, John Kissel, Mary K. Schroth, Gyula Acsadi,
Priya Kishnani, Jurgen-Christoph von Kleist-Retzow, Guy
D’Anjou, Edward C. Smith, Bakri Elsheik, Louise R. Simard,
Thomas W. Prior and Sandra P. Reyna; Salt Lake City, UT;
Chicago, IL; Baltimore, MD; Fort Washington, PN;
Columbus, OH; Madison, WI; Detroit, MI; Durham, NC;
Cologne, Germany; Montreal, QC, Canada and Winnepeg,
MB, Canada
M1454 Withdrawn.
M1455 Electrical Impedance Alterations in Muscle
Induced by Hindlimb Unloading
Jia Li, Andrew Spieker, Glenn D. Rosen and Seward B.
Rutkove; Boston, MA
M1456 SMN Controlled MiR-183 Regulates Neuronal
Morphology Via mTOR and Akt1
Min J. Kye, Mary H. Wertz, Bikem Akten, Pierre Neveu,
Kenneth S. Kosik and Mustafa Sahin**; Boston, MA; Santa
Barbara, CA and Heidelberg, Germany
M1465 Fetal Stem Cells in Duchenne’s Muscular
Dystrophy (DMD)
Nataliia S. Sych, Mariya O. Klunnyk, Olena V. Ivankova and
Iryna G. Matiyaschuk; Kiev, Ukraine
M1457 Clinical, Molecular and Muscle
Histopathological Features in Myotonic Dystrophy
Type 1 (DM1) Associated with Variant CCG
Expansions
Marcella Masciullo, Massimo Santoro, Giulia Conte, Roberta
Pietrobono, Anna Modoni, Maria Laura E. Bianchi,
Valentina Rizzo, Maria Grazia Pomponi, Enzo Ricci,
Giovanni Neri and Gabriella Silvestri; Rome, Italy
M1466 The Survival Motor Neuron (SMN)
Gene as a Therapeutic Target in Amyotrophic Lateral
Sclerosis
Kevin Talbot, Neza Alfazema, Kay E. Davies and
Bradley J. Turner; Oxford, United Kingdom and Melbourne,
Australia
M1458 Metabolic Syndrome Reduces Cutaneous Nerve
Regenerative Capacity
J. Robinson Singleton, Robin Marcus, Collin J. Arsenault,
Michael Porzio, Justin E. Jackson and A. Gordon Smith; Salt
Lake City, UT
M1467 Quantitative Analysis of FLAIR Images in ALS
Has Diagnostic Potential
Jez Fabes, Lucy Matthews, Nicola Fillipini, Kevin Talbot,
Mark Jenkinson and Martin R. Turner; Oxford, United
Kingdom
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M1468 Complexity-Based Classification of Resting-State
fMRI in Amyotrophic Lateral Sclerosis
Tomer Fekete, L. R. Mujica-Parodi and Martin R. Turner;
Stony Brook, NY and Oxford, United Kingdom
Stage:
Page: 17
T1503 From Molecule to Mechanism: How Listening to
Synapses Reveals Novel Insights to OCD Pathogenesis
Nicole Calakos, Yehong Wan, Meng Chen, Kristen Ade,
William Wetsel and Guoping Feng; Durham, NC and Boston,
MA
M1469 Congenital Amyelinating Neuropathy: A
Genetically Heterogeneous Syndrome
Jean-Michel Vallat, Pierre-Marie Gonnaud, Philippe Latour,
Federico Garcia Bragado and Benoit Funalot; Limoges, France;
Pierre Benite, France; Lyon, France and Pamplona, Spain
T1504 Brainstem Lesions and Central Auditory
Processing
Gastone G. Celesia; Chicago, IL
T1505 Frequency of Elevated ASO Titer in Children and
Adolescents at Onset or Exacerbation of Tic, OCD or
Aggression and Symptomatic Effect of Antibiotic
Treatment
Brittany M. DiVito, Karen D. Ellis and Drake D. Duane;
Scottsdale, AZ and Tempe, AZ
M1470 Cerebral Metabolic Features of Clinically
Heterogenous A3243G Mitochondrial DNA Mutation
Carriers: Prognostic Implications
Nora Weiduschat, Petra Kaufmann, Xiangling Mao, Kristin
Engelstad, Vanessa Battista, Mary Sano, Michio Hirano,
Salvatore DiMauro, Darryl C. DeVivo and Dikoma C.
Shungu; New York, NY
T1506 Modulation and Assessment of the CerebelloCortical Connectivity through Transcranial Magnetic
Stimulation (TMS) Combined with
Electroencephalography (EEG)
Faranak Farzan, Mark A. Halko, Andrea Pousada-Casal,
Jeremy D. Schmahmann and Alvaro Pascual-Leone;
Boston, MA
M1471 The Role for Macrophages in Nerve Repair in
an Animal Model of Autoimmune Neuropathy
Gang Zhang, Nataliia Bogdanova, Lixia Gao and Kazim A.
Sheikh; Houston, TX
M1472 Comprehensive Genetic Screening of a Large
ALS Cohort Using Pooled-Sample Sequencing
Matthew B. Harms, Janet Cady, Peggy Allred, Taha Bali,
Ryan T. Libby, Alan Pestronk, John Ravits and Robert H.
Baloh; Saint Louis, MO; La Jolla, CA and Los Angeles, CA
T1507 Changes in Cortical Functional Connectivity
Introduced with Intermittent Theta Burst TMS to the
Cerebellum Assessed with fMRI
Mark A. Halko, Faranak Farzan, Andrea Pousada-Casal,
Jeremy Schmahmann and Alvaro Pascual-Leone; Boston, MA
M1473 Optimizing the Total Neuropathy Score for
HIV-Associated Distal Symmetric Polyneuropathy
Jessica Robinson-Papp, Sandeep Sharma, David M. Simpson
and Susan Morgello; New York, NY
T1508 PRISM Registry: A Novel Tool To Determine the
Prevalence of Pseudobulbar Affect
Daniel Kantor, Jonathan Fellus and Randall E. Kaye; Ponte
Vedra Beach, FL; Secaucus, NJ and Aliso Viejo, CA
M1474 Motor Neuron Disease-Associated Mutations in
p150/Glued Disrupt the Initiation of Retrograde Axonal
Transport at Synaptic Termini
Thomas E. Lloyd, James Machamer, Sarah Collins and Alex L.
Kolodkin; Baltimore, MD
T1509 Effects of the Dopamine Agonist Rotigotine on
Hemispatial Neglect Following Stroke
Nikos Gorgoraptis, Yee-Haur Mah, Bjoern Machner, Victoria
Singh-Curry, Paresh Malhotra, Maria Hadji-Michael, David
Cohen, Robert Simister, Ajoy Nair, Elena Kulinskaya, Nick
Ward, Richard Greenwood and Masud Husain; London,
United Kingdom; Lübeck, Germany and Norwich, United
Kingdom
2012 Annual Meeting Tuesday,
October 9, 2012 Poster Session
Posters will be displayed in Gloucester, located on the
3rd floor in the Back Bay Hall of the Marriott Copley
Place from 11:30 am – 7:00 pm, with authors present
from 5:30 pm – 7:00 pm.
NOTE: An asterisk designates a resident/fellow travel award
winner.
T1510 Sudden Visual Spatial Memory Loss as Presenting
Manifestation of CJD
Nivedita Jerath, Aarti Jerath, Shelley Waite, Deborah Forst,
Shivraj Sohur and Jeremy Schmahmann; Boston, MA
T1511 Inflammation and Cognitive Decline in Normal
Elderly
Joel H. Kramer, Brianne Bettcher, Ralph Green and Josh
Miller; San Francisco, CA and Davis, CA
Behavioral Neurology
T1501 Metabolic Abnormalities in the Caudate in
Patients with Mitochondrial Disorders Measured Using
Proton Magnetic Resonance Spectroscopy
Rebecca Anglin, Patricia Rosebush, Michael Noseworthy, Mark
Tarnopolsky and Michael Mazurek; Hamilton, Canada
T1512 Acute Impairments of Empathy
Richard Leigh and Argye E. Hillis; Baltimore, MD
T1513 Evolution of Psychiatric Co-Morbidity in the
Transition Phase in a Cohort of Patients with
Neurological Perinatal Disability
Sara Piccoli, Gianni De Polo and Andrea Martinuzzi;
Conegliano, Italy
T1502 Antipsychotic Drug Effects at Nicotinic AChRs
Studied in a Novel Model System
Tai-Xiang Xu, Limin Hao, Bruce M. Cohen and Edgar A.
Buttner; Belmont, MA
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T1514 fMRI Study of Yogic Meditation
Shri K. Mishra, Manbir Singh and Parampreet Singh; Los
Angeles, CA and Sylmar, CA
Stage:
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T1602 Analysis of the Development of Allodynia:
Correlation between Migraine Duration and Severity
Biao Lu, Xiaodong Li, Songyang Zhao, Emilee Connors and
Shashidhar Kori; Mountain View, CA
T1515 Withdrawn.
T1603 Is Lack of Habituation of Somatosensory
Evoked Potential (SEP) a Biological Marker of
Migraine?
Jayantee Kalita, Sanjeev K. Bhoi and Usha K. Misra;
Lucknow, UP, India
T1516 A Randomised Controlled Trial of Cognitive
Behaviour Intervention for Impulse Control Behaviours
Affecting Parkinson’s Disease Patients and Their
Caregivers
David Okai, Sally Askey-Jones, Michael Samuel, Sean S.
O’Sullivan, Ray Chaudhuri, Anne Martin, Joel Mack, Richard
G. Brown and Anthony David; London, United Kingdom;
Ashford, United Kingdom and Portland, OR
T1604 Dextromethorphan Plus Quinidine for Headache
Prophylaxis: The First Case Report
Daniel Kantor; Ponte Vedra, FL
T1517 Characteristics of Subjects with Chronic Low
Back Pain-Related Neuropathic Pain (CLBP-NeP) in the
US: BEAT Neuropathic Pain Observational Study
Alesia Sadosky, Caroline Schaefer, Bruce Parsons, Rebecca Baik,
Rachael Mann, Felicia Bergstrom, Gergana Zlateva, Brett
Stacey, Srivinas Nalamachu, Michael Tuchman and Edward
Nieshoff; New York, NY; Gaithersburg, MD; San Diego, CA;
Portland, OR; Leawood, KS; Palm Beach Gardens, FL and
Detroit, MI
T1605 Sustained Pain Relief with Dihydroergotamine
in Migraine Is Potentially Due to Persistent Binding
to 5-HT1B/5-HT1D Receptors
Shashidhar Kori, Jian Zhang, Donald Kellerman, Thomas
Armer and Peter J. Goadsby; Mountain View, CA and San
Francisco, CA
T1606 Valsalva Test Responses in Cough Headache
Patients
Russell J.M. Lane and Paul T.G. Davies; London, United
Kingdom and Oxford, United Kingdom
T1518 Characteristics of Subjects with Painful Diabetic
Neuropathy (PDN) in the US: BEAT Neuropathic Pain
Observational Study
Felicia Bergstrom, Rachael Mann, Alesia Sadosky, Bruce
Parsons, Caroline Schaefer, Rebecca Baik, Gergana Zlateva,
Brett Stacey, Srivinas Nalamachu, Edward Nieshoff and
Michael Tuchman; Gaithersburg, MD; San Diego, CA; New
York, NY; Portland, OR; Leawood, KS; Detroit, MI and Palm
Beach Gardens, FL
T1607 Comparative Efficacy of Triptans for the Abortive
Treatment of Migraine: A Multiple Treatment
Comparison Meta-Analysis (MTC)
Edward J. Mills, Kristian Thorlund, Ping Wu and Anjan
Chatterjee; Ottawa, ON, Canada; Hamilton, ON, Canada
and New York, NY
T1519 Increased Phosphorylation of the MAPK/ERK
Pathway Is Associated with Social Impairment in BTBR
Mice
Alireza Faridar, Dorothy M. Jones-Davis, Mu Yang, Adam M.
Katz, Michael D. Weber, Eric Rider, Saunak Sen, Jacqueline
Crawley and Elliott H. Sherr; San Francisco, CA and
Bethesda, MD
T1608 Repetitive Transcranial Magnetic Stimulation
(rTMS) Results in Elevation of b Endorphin Level and
Relief of Migraine Headache
Usha K. Misra, Jayantee Kalita, Gyanesh M. Tripathi and
Sanjeev K. Bhoi; Lucknow, UP, India
T1520 Stepwise Onset of Memory Impairment,
Encephalopathy and Hearing Loss Presenting as Susac
Syndrome
Alvin Shrestha, Tatiana Mihalova, Daniel Burns and Mark
Willmot; Birmingham, United Kingdom
T1609 Alice in Wonderland Syndrome: Epilepsy,
Migraine or Both?
W.O. Pickrell, R.H. Thomas, J.A. Johnston, C.P. White and
M.I. Rees; Swansea, United Kingdom and Cardiff, United
Kingdom
T1521 The Effect of a Family History of Major
Depression on the Outcome of Electroconvulsive
Therapy
Ceri A. Smith; Cardiff, Wales, United Kingdom
T1610 Analysis of EEG and MRI for
Localization of Structures Affected in Temporal Lobe
Epilepsy
Ildefonso Rodrı´guez-Leyva, Ana A. Renterı´a Palomo, Luis
Concha-Loyola and Adriana Martı´nez-Mayorga; San Luis
Potosi, Mexico
T1522 Syphilitic Polyradiculoneuropathy in an
Immunocompetent Patient
Safaa Zahlane, Nissrine Louhab and Najib Kissani;
Marrakesh, Morocco
T1611 Direct Conversion of Fibroblasts into Functional
Nociceptors
Brian J. Wainger, Amy J. Wang, Lee Barrett, Justin Ichida,
Qiufu Ma, Lee L. Rubin, Kevin Eggan and Clifford J. Woolf;
Boston, MA and Cambridge, MA
Headache and Pain/Neuro-otology
T1601 Lidocaine Desensitizes TRPA1 Receptors in
Human Sural Nerves
Anupam Bhattacharjee, Lionel Ginsberg, Richard Orrell,
Saqiba Jadoon and Reginald Docherty; London,
United Kingdom
T1612 The Prevalance of Anxiety and Depression in
Migraine Patients
Hakan Balibey, Halit Yasar, Nalan Bayar and Hakan Tekeli;
Ankara, Turkey and Istanbul, Turkey
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T1713 Identification of Axonal Transport Biomarkers in
Parkinson’s Disease
Christine W. Chadwick, Michael J. Aminoff, Po- Yin A.
Wong, Kristofor H. Husted, Shanshan Liu, Victoria M. Liu,
Lori A. Kohlstaedt, Johan Protasio, Timothy Riff, Drina
Boban, Maudi Killian, Lorrie Epling, Elisabeth Sinclair, Julia
Peterson, Richard Price, Marc K. Hellerstein and Patrizia
Farnara; San Francisco; Emeryville, CA and Berkeley
Movement Disorder
T1701 PARK2 Mutant hiPSC-Derived Neural
Progenitors Exhibit Altered Sensitivity and
Mitochondrial Dysfunction to Neurotoxic Metal
Exposure
Asad A. Aboud, Andrew M. Tidball, Kevin K. Kumar, M.
Diana Neely, Michael Litt, Peter Hedera, Charles C. Hong,
Kevin C. Ess and Aaron B. Bowman; Nashville, TN
T1714 Predictors of Cognitive Performance Following
Bilateral Subthalamic Nucleus Deep Brain Stimulation
Lidia Yaguez, Angela Costello, John Moriarty, Natasha Hulse,
Richard Selway, Chris Clough, Michael Samuel and
Keyoumars Ashkan; London, United Kingdom and Kent,
United Kingdom
T1702 Amyloid Profiles of Subjects with Lewy Body
Disease
Rizwan S. Akhtar, Laura Brennan, Daniel Weintraub and
Andrew D. Siderowf; Philadelphia, PA
T1703 Reversal of Levodopa-Induced Dyskinesia
Mathew Alias and Mohamed Hassan; Farmington, CT
T1715 What Patient Factors Associate with Inaccuracies
in Reporting of Parkinsonian Signs?
Nabila Dahodwala, Andrew Siderowf and Jason Karlawish;
Philadelphia
T1704 L-Dopa Induced Dystonia, Dyskinesia in
Juvenile Parkinson’s Disease
Sarah M. Misbah El-Saadig; Khartoum, Sudan
T1716 Previously Unspecified SETX Mutation
Producing AOA2 in Two Siblings
Neil Datta and Anna Hohler; Boston, MA
T1705 Amelioration of Somatic and Autonomic
Neuropathy in Patients with Idiopathic Parkinson’s
Disease Following Cobalamin Therapy
Sabrina Apel and Cory Toth; Calgary, AB, Canada
T1717 Directional EEG Connectivity Method
Demonstrates Complex, Reciprocal Information Flows
during Praxis Performance
Joshua B. Ewen, Balaji M. Lakshmanan, Stewart H.
Mostofsky, Nathan E. Crone and Anna Korzeniewska;
Baltimore, MD
T1706 Low Frequency DBS in PD Patients with Gait
and Speech Problems
Diana Apetauerova, Janet W. Zani and Stephanie A. Scala;
Burlington, MA
T1718 Clinical Assessment of the Effect of Tetrabenazine
on Motor Function in Moderate Huntington Disease
Robert Fekete, Anthony Davidson and Joseph Jankovic;
Valhalla, NY and Houston, TX
T1707 Chronic Parkinsonism Associated with Liver
Cirrhosis
Diana Apetauerova, Peter G. Hildenbrand, Janet W. Zani and
Stephanie A. Scala; Burlington, MA
T1719 Identification of Individualized Cortical Targets
for Focal Brain Stimulation Based on Intrinsic
Functional Connectivity
Michael D. Fox, Randy L. Buckner and Alvaro Pascual-Leone;
Boston, MA
T1708 A Genetic Study of Wilson Disease in the UK
Oliver Bandmann, Alison Coffey, Magnus Rattray and Ann Dalton;
Sheffield, United Kingdom and Cambridge, United Kingdom
T1709 Metronidazole-Induced Reversible Ataxia and
Numbness
Chirantan Banerjee, Fazeel Siddiqui and Jessica Lee; Dallas, TX
T1720 Does Iron Play Different Roles in Various
Neurodegenerations?
Andrzej Friedman and Jolanta Galazka-Friedman; Warsaw,
Poland
T1710 Striatal Functional Connectivity during Rest in
Parkinson’s Disease
Brian D. Berman, Erika Shelton, Mark Hallett and Tor
Wager; Denver, CO; Bethesda, MD and Boulder, CO
T1721 Asymmetric Upper Motor Neuron Disease (Mills’
Syndrome) Presenting as Corticobasal Syndrome
Shinsuke Fujioka, Masataka Nakamura, Melissa E. Murray,
Zbigniew K. Wszolek and Dennis W. Dickson; Jacksonville, FL
T1711 Short Hairpin RNA Targeting Endogenous
a-Synuclein Prevents Degeneration of Dopaminergic
Neurons in the Rat Rotenone Model of Parkinson’s
Disease
Jason R. Cannon, Qing Bai, Maxx Horowitz, Victor Tapias, J.
Timothy Greenamyre and Edward A. Burton; Pittsburgh, PA
and West Lafayette, IN
T1722 Progressive Ataxia and Palatal Tremor Syndrome
(PAPTS): Clinical and Radiological Findings
Pablo Garcia-Reitboeck, Marie-Helene Marion and Salah
Omer; London, United Kingdom
T1712 Effect of Deep Brain Stimulation on Autonomic
Function in Early Parkinson’s Disease
Anna L. Molinari, Fenna T. Phibbs, Lily Wang, Yanna Song,
Amanda Currie, Maxim Turchan, Danielle S. Cherdak and
David Charles; Nashville, TN
T1723 Progressive Bilateral Parkinsonism Secondary
to a Unilateral Midbrain Lesion
Maiya R. Geddes, A. Jon Stoessl, Alain Dagher, Jean-Paul
Soucy and Anne-Louise Lafontaine; Montreal, QC, Canada
and Vancouver, BC, Canada
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T1735 Randomized, Double-Blind, Double-Dummy
Study of Levodopa-Carbidopa Intestinal Gel in Patients
with Advanced Parkinson’s Disease: Functional and
Quality-of-Life Outcomes
K. Kieburtz, A. Antonini, C.W. Olanow, H.H. Fernandez,
A.J. Espay, D.G. Standaert, S. Hass, K. L. Widnell, W.Z.
Robieson, Y. Pritchett, K. Chatamra and J. Benesh; Rochester,
NY; Padua, Italy; New York, NY; Cleveland, OH; Cincinnati,
OH; Birmingham, AL and Abbott Park, IL
T1724 Rapid Onset Dystonia-Parkinsonism Associated
with the I758S ATP1A3 Mutation: A Neuropathologic
Study of Three Affected Siblings
Bernardino Ghetti, Matthew C. Hagen, Joseph Maldjian,
Christopher T. Whitlow, Laurie J. Ozelius, Kathleen J.
Sweadner and Allison Brashear; Indianapolis, IN;
Cincinnati, OH; Winston-Salem, NC; New York, NY and
Boston, MA
T1725 Alcoholic Cerebellar Degeneration: Not All
Due to Alcohol
Marios Hadjivassiliou, Stuart Currie, David Sanders and
Nigel Hoggard; Sheffield, United Kingdom
T1736 Videotape Assessments of Psychogenic Movement
Disorders Subjects Following Immediate Versus Delayed
Treatment with Short Term Psychodynamic
Psychotherapy: Randomized Parallel Trial
Katie Kompoliti, Vanessa K. Hinson, Burgess Wilson and Glen
T. Stebbins; Chicago, IL and Charleston, SC
T1726 GABA Receptor Changes and Functional
Connectivity Abnormalities in Focal
Hand Dystonia
Cecile Gallea, Priyantha Herath, Valerie Voon, Alicja Lerner
and Mark Hallett; Bethesda, MD
T1737 Binding of the Alpha-Synuclein Radioligand
SIL-23 Reflects the Level of Aggregated Alpha-Synuclein
in Parkinson’s Disease Brain tissue
Paul T. Kotzbauer, Devika Bagchi, Maria Udan, Lihai Yu,
Robert H. Mach and Zhude Tu; St. Louis, MO
T1727 What Issues Face Parkinson’s Patients at Ten
Years and beyond?
Anhar Hassan, Samuel Wu, Peter Schmidt, Irene A. Malaty,
Yun Feng Dai, Janis Miyasaki and Michael S. Okun;
Gainesville, FL; Miami, FL and Toronto, Canada
T1738 An Unexpected Cause of Altered Mental State in
a Presumed Healthy Caucasian Male
Tobias B. Kulik and Irene H. Richard; Rochester, NY
T1739 Withdrawn.
T1728 Dysphagia i Spinocerebellar Ataxia Type 3 and
Type 6
Chiharu Isono, Makito Hirano, Hikaru Sakamoto, Shuichi
Ueno, Susumu Kusunoki and Yusaku Nakamura; Sakai,
Osaka, Japan and Osakasayama, Osaka, Japan
T1740 An Unsupported Exploratory Clinical Trial on
Tremor
Gian L. Lenzi, Laura Troilo and Francesca Puledda; Rome, Italy
T1741 4-aminopyridine for Gait Dysfunction in
Parkinson’s Disease
Corneliu C. Luca and Carlos Singer; Miami, FL
T1729 Multiple System Atrophy with Inappropriate
Secretion of Antidiuretic Hormone
Makoto Samukawa, Makito Hirano, Hikaru Sakamoto, Mari
Kitada, Susumu Kusunoki and Yusaku Nakamura; OsakaSayama, Osaka, Japan and Sakai, Osaka, Japan
T1742 Risk Factors for Cardiac Arrhythmia and
Syncope through QTc Prolongation in Parkinson’s
Disease
Naveed Malek, Katherine A. Grosset, David Stewart, Graeme
J. Macphee and Donald G. Grosset; Glasgow, United Kingdom
T1730 Higher Iron in the Red Nucleus Marks
Parkinson’s Dyskinesia
Mechelle M. Lewis, Guangwei Du, Michal Kidachi,
Nisargkumar Patel, Michele L. Shaffer, Richard B. Mailman
and Xuemei Huang; Hershey, PA
T1743 Effects of Green Tea Extract (GTE) on
Haloperidol (HAL) Induced Neuroleptic Anxiety
Syndrome (NAS) in Rat Model of Extrapyramidal
Syndrome (EPS)
Tafheem Malik and Darakhshan J. Haleem; Karachi, Sind,
Pakistan
T1731 Side of Parkinson’s Disease Onset Predicts Gray
Matter Loss and Cognitive Impairments
Suman Sen, Paul J. Eslinger, Daymond Wagner, Michele L.
Shaffer, Mechelle M. Lewis, Guangwei Du and Xuemei
Huang; Hershey, PA
T1744 Innovative Web-Based Matching Service, Fox
Trial Finder, as a Mechanism To Improve Clinical Trial
Recruitment
Claire C. Meunier, Sohini Chowdhury, Todd Sherer and
Deborah W. Brooks; New York, NY
T1732 Patient Expectations and Outcome after DBS
Nasrin Esnaashari, Jospehine Hwu, Jennifer S. Hui and
Daniel Togasaki; Los Angeles, CA
T1733 Lewy Body Negative Idiopathic Parkinsonism
Fariha Zaheer, John T. Slevin, Erin L. Abner, Peter T. Nelson
and Gregory A. Jicha; Lexington, KY
T1745 LIVECHART: A System for Recording,
Evaluating and Monitoring Botulinum Toxin Treatments
for Any Condition
Austen P. Moore; Liverpool, Merseyside, United Kingdom
T1734 Comparison of In Vivo PET with In Vitro
Measures of Pre-Synaptic Nigrostriatal Neurons
Morvarid Karimi, LinLin Tian, Christopher A. Brown,
Hubert P. Flores, Susan K. Loftin, Tom O. Videen, Steve M.
Moerlein and Joel S. Permutter; St. Louis, MO
T1746 C9ORF72 Hexanucleotide Repeat Expansion
Analysis in Patients with Parkinson’s Disease
Joanne D. Stockton, Catriona Moorby, Rachel V. Denyer,
Caroline Rick, Keith Wheatley, Carl E. Clarke and Karen E.
Morrison; Birmingham, United Kingdom
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T1747 Cannabinoid CB2 Receptor Gene and Protein
Expression Differences in Parkinson’s Disease PostMortem Brain Samples and Lymphocytes from Recently
Diagnosed and Non-Treated Patients
Francisco Navarrete, Marı´a Salud Garcı´a-Gutie´rrez, Jose´
Antonio Molina, Carlos Leiva and Jorge Manzanares; San
Juan de Alicante, Spain; Madrid, Spain and Alicante,
Spain
Stage:
Page: 21
T1754 Role of the Subthalamic Nucleus in Modulating
Cognitive Functions. A Viewpoint Based on Recordings
from DBS Electrodes
Ivan Rektor, Marek Bala´z, Martina Bockova´ and Irena
Rektorova; Brno, Czech Republic
T1755 The Addenbrooke’s Cognitive Examination in
Parkinsonian Disorders at Baseline and 18 Months
Timothy Rittman, Boyd C.P. Ghosh, Jonathan R. Evans, Peter
McColgan, David P. Breen, Roger A. Barker and James B.
Rowe; Cambridge, Cambridgeshire, United Kingdom
T1748 Randomized, Double-Blind, Double-Dummy
Study of Levodopa-Carbidopa Intestinal Gel in Patients
with Advanced Parkinson’s Disease: Efficacy and Safety
C.W. Olanow, A. Antonini, K. Kieburtz, H.H. Fernandez,
A.J. Espay, D.G. Standaert, A. Vanagunas, K. L. Widnell, S.
Freeman, W.Z. Robieson, Y. Pritchett, K. Chatamra, J. Benesh
and R.A. Lenz; New York, NY; Padua, Italy; Rochester, NY;
Cleveland, OH; Cincinnati, OH; Birmingham, AL; Chicago,
IL and Abbott Park, IL
T1756 Alpha-Synuclein Expression in the Epidermis and
Epithelial Tissue in Parkinsonism
Ildefonso Rodriguez-Leyva, Ana Laura Calderon-Garcidueñas,
Ana Arely Renteria-Palomo, Rodrigo Valdez-Rodriguez, Julio
Sepulveda and Juan Pablo Castanedo-Cazares; San Luis Potosı´,
Mexico; Jalapa, VER, Mexico and Monterrey, NL, Mexico
T1757 Paradigm for Neuroprotection in Presymptomatic
Huntington’s Disease
H. Diana Rosas, Gheorghe Doros, Sona Gevorkian, David H.
Salat, Martin Reuter, Bruce Fischl, Keith Malarick, Wayne R.
Matson, Clemens R. Scherzer, Robert J. Ferrante and Steven
M. Hersch; Charlestown, MA; Boston, MA; Bedford, MA;
Cambridge, MA and Pittsburgh, PA
T1749 A Prospective, Observational Trial Evaluating
Xeomin (incobotulinumtoxinA) for Cervical Dystonia
(CD) or Blepharospasm in the United States –
Preliminary Baseline Results on the Health Impact of
CD on Patients Using the Cervical Dystonia Impact
Profile (CDIP)
Joseph Jankovic, Madhavi Thomas, Alberto Vasquez, Kapil D.
Sethi, Amit Verma, Eric J. Pappert and Hubert H. Fernandez;
Houston, TX; St. Petersburg, FL; Greensboro, NC and
Cleveland, OH
T1758 Withdrawn.
T1759 Diagnostic Error in Primary Torsion Dystonia
Caroline M. Tanner, Stephen K. Van Den Eeden, Samuel
Goldman, Raymond Y. Lo, Connie Marras, Kathleen B.
Albers, Amethyst D. Leimpeter, Robin Fross, Kathleen Comyns,
Zhuqin Gu, Robin Smit, Annelie de Kleijn, Laurie Ozelius,
Susan Bressman, Rachel Saunders-Pullman, Cynthia Comella,
Lorene M. Nelson and Jeffrey Klingman; Sunnyvale, CA;
Oakland, CA; Taiwan, Taiwan; Toronto, ON, Canada;
BeiJing, China; Nijmegen, Netherlands; New York City, NY;
Chicago, IL and Palo Alto, CA
T1750 A Prospective, Observational Trial Evaluating
Xeomin [IncobotulinumtoxinA] for Cervical Dystonia or
Blepharospasm in the US – Preliminary Baseline Results
for Patients with Blepharospasm
Mark S. LeDoux, Joseph Jankovic, Kapil D. Sethi, Amit
Verma, Eric J. Pappert and Hubert H. Fernandez; Memphis,
TN; Houston, TX; Greensboro, NC and Cleveland, OH
T1751 A Prospective, Observational Trial Evaluating
Xeomin [IncobotulinumtoxinA] for Cervical Dystonia
(CD) or Blepharospasm in the United States –
Preliminary Baseline Results for Patients with CD
Daniel D. Truong, Fabio O. Danisi, Kapil D. Sethi, Amit
Verma, Eric J. Pappert and Hubert H. Fernandez; Fountain
Valley, CA; Kingston, NY; Greensboro, NC and Cleveland,
OH
T1760 Analysis of Wave III of Brain Stem
Auditory Evoked Potential during Microvascular
Decompression of Cranial Nerve VII for Hemifacial
Spasm
Balaji Krishnaiah, Parthasarathy D. Thirumala, Miguel
Habeych, Donald Crammond and Jeffrey Balzer;
Pittsburgh, PA
T1752 Rapid Generation of iPSCs from Lymphoblastoid
Cell Lines Using an Episomal Plasmid Containing
Multi-Reprogramming Factors in a Single Cassette
Sharan Paul, Warunee Dansithong, Karla Figueroa and Stefan
M. Pulst; Salt Lake City, UT
T1761 Establishing Baseline Values for Brainstem
Auditory Evoked Potentials (BAEP) during
Microvascular-Decompression for Hemifacial Spasm
Santhosh Kumar Mohanraj, Parthasarathy D. Thirumala,
Miguel Habeych, Donald Crammond and Jeffrey Balzer;
Pittsburgh, PA
T1753 Is Psychiatric Disease a Core Phenotype of
Myoclonus Dystonia Syndrome Caused by SGCE
Mutations?
Kathryn J. Peall, Manju A. Kurian, Mark Wardle, Martin
Smith, Hardev Pall, Jean-Pierre Lin, Tammy Hedderly, Alan
Whone, Cathy White, Andrew Lux, Adrian J. Waite, Michael
Samuel, Timothy Lynch, Patrick F. Chinnery, George Kirov,
Mary King, Derek J. Blake, Huw R. Morris, Daniel J. Smith
and Michael J. Owen; Cardiff, United Kingdom; London,
United Kingdom; Birmingham, United Kingdom; Bristol,
United Kingdom; Swansea, United Kingdom; Dublin, Ireland
and Newcastle, United Kingdom
T1762 Proteomic Analysis of Serum Microvesicles in
Parkinson’s Disease
Paul R. Tomlinson, Samuel Evetts, Michele Hu, Chris
Gradner, Benedikt Kessler, Kevin Talbot and George K.
Tofaris; Oxford, United Kingdom
T1763 Examining Memory Subtypes in Huntington’s
Disease Using the Montreal Cognitive Assessment
Charles P. Van Liew, Shea Gluhm, Daniel Brown, Jody L.
Goldstein and Jody Corey-Bloom; San Diego, CA
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T1764 Inhibitory Neurons In the Ventral Medial
Medulla Modulate Gait and Tone
Veronique G. VanderHorst, Brian Ellison and Clifford B.
Saper; Boston, MA
Stage:
Page: 22
T1774 Evaluation of Smelling Function,
F-DOPA PET Study and Transcranial Sonography of
Substantia Nigra in Asymptomatic Carriers of
Common LRRK2 Risk Variants: A Longitudinal
Case-Control Study
Ruey-Meei Wu, Chin-Yi Yu, Kai-Yuan Tzen and Meng-Ling
Chen; Taipei, Taiwan
T1765 Genetic Association Studies (Single Nucleotide
Polymorphisms) in South Indian Parkinson’s Disease
Patients and Controls
Padmaja M. Vishwanathan, Devaprasad Markandeyan,
Meenakshi Jayaraman, Srikumari C.R. Srisailapathy, Bhanu
K. Murthy, Srinivasan A. Venkatesan and Ramesh
Arabandi; Chennai, Tamilnadu, India and Chennai, Tamil
Nadu, India
T1775 Modulation of 14-3-3 Proteins in the MPTP
Parkinson’s Disease Model
Huiping Ding, Sunny Slone and Talene Yacoubian;
Birmingham, AL
T1766 REM Sleep without Atonia and Freezing of Gait
in Parkinson’s Disease
Aleksandar Videnovic, Clare C. Marlin, Joni Planetta, Laila
Alibiglou, David E. Villancourt and Colum D. MacKinnon;
Chicago, IL and Gainesville, FL
T1776 Short Latency Afferent Inhibition:
A Biomarker for Mild Cognitive Impairment in
Parkinson’s Disease?
Alison J. Yarnall, Lynn Rochester, Rachel David, Tien K.
Khoo, Gordon W. Duncan, Brook Galna, Mark R. Baker and
David J. Burn; Newcastle, United Kingdom
T1767 Clinical and Immunological Features with
Glycine Receptor Antibodies
Angela Vincent, M. Isabel Leite, Alexander Carvajal,
Patrick Waters and Mark Woodhall; Oxford,
United Kingdom
T1777 Normal Striatal D1 Dopamine Receptor Binding
in Primary Focal Dystonias
Morvarid Karimi, Joanne Markham, Hubert Flores, Stephen
Moerlein, Tom Videen and Joel S. Perlmutter; St. Louis, MO
T1778 Dopaminergic Modulation of Basal Ganglia
Connectivity in Parkinson’s Disease
Kathleen L. Poston, William Shire, Richard Joseph, Vinod
Menon and Michael Greicius; Stanford, CA
T1768 Short Latency Cortical Activation during
Clinically Effective Ventral Intermediate Nucleus Deep
Brain Stimulation for Essential Tremor
Harrison C. Walker, He Huang, Christopher L. Gonzalez,
James E. Bryant, Jeffrey Killen, Robert C. Knowlton, Erwin B.
Montgomery, Gary C. Cutter, Abidin Yildirim, Barton L.
Guthrie and Ray L. Watts; Birmingham, AL
T1779 Alpha Synuclein as a Cutaneous Biomarker of
Parkinson Disease
Christopher H. Gibbons, Ningshan Wang and Roy Freeman;
Boston, MA
T1769 Can Proton and Phosphorus MR
Spectroscopy Be Used for Early Diagnosis
in Parkinson’s Disease?
Nora Weiduschat, M. Flint Beal, Xiangling Mao, Melissa J.
Nirenberg, Dikoma C. Shungu and Claire Henchcliffe; New
York, NY
T1780 Circadian Rhythm of Melatonin Secretion Is
Altered in Parkinson’s Disease
Aleksandar Videnovic, Angelica Marconi, Charleston Noble,
Katherine Reid, Teresa Kuhta, Tanya Simuni, Cindy Zadikoff
and Phyllis Zee; Chicago, IL
T1770 Structural Abnormalities in the Brain Associated
with Rapid Onset Dystonia-Parkinsonism: A Preliminary
Investigation
Christopher T. Whitlow, Allison Brashear, Bernardino Ghetti,
Matthew C. Hagen, Kathleen J. Sweadner and Joseph A.
Maldjian; Winston-Salem, NC; Indianapolis, IN; Cincinnati,
OH and Boston, MA
Autoimmune Neurology
T1801 A Case of Bilateral Horizontal Gaze
Ophthalmoplegia: The 1þ1 Syndrome
Nadeem Akhtar and Sumeet Singhal; Nottingham, United
Kingdom
T1771 MRI Comparison of Primary Progressive Apraxia
of Speech and PSP
Jennifer L. Whitwell, Joseph R. Duffy, Edythe A. Strand, Mary
M. Machulda, Matthew L. Senjem, Jeffrey L. Gunter, Kejal
Kantarci, Scott D. Eggers, Clifford R. Jack and Keith A.
Josephs; Rochester, MN
T1802 Chronic Microglial Encephalomyelitis
(CME)
Allen J. Aksamit, Brian G. Weinshenker and Joseph E. Parisi;
Rochester, MN
T1803 Elevated IFNa Activity in Patients with a History
of Lyme Disease and Persistent Symptoms
Elzbieta Jacek, Brian Fallon, Mary K. Crow and Armin
Alaedini; New York, NY
T1772 Subacute Combine Degeneration of the Cord
Due to Functional B12 Deficiency
Subhashie Wijemanne, Sui Li and Michal Vytopil;
Boston, MA
T1804 Anti-NMDA Receptor Antibody Encephalitis
Presenting as Acute Psychosis
Matthew B. Bevers, Isabel C. Arrillaga-Romany and Bradford
C. Dickerson; Boston, MA
T1773 MRI Signal Intensity in Dystonic Muscle
Kathleen V. Woschkolup, Gonzalo J. Revuelta and Kenneth
Spicer; Charleston, SC
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T1805 Patients Can Adequately Report Their MS
Severity Online; Implications for Online Research
Platforms
Riley Bove, Timothy Vaughan, Brian C. Healy, Elizabeth
Secor, Alexander Musallam, Bonnie Glanz, Howard Weiner,
Paul Wicks, Tanuja Chitnis and Philip L. De Jager; Boston,
MA and Cambridge
Stage:
Page: 23
T1816 Intrathecal Autologous Mesenchymal
Stem Cell Transplantation in Patients with Amyotrophic
Lateral Sclerosis: A Four Year Case Control Follow-Up
Study
Clementine E. Karageorgiou, Ioanna Chatzi, Athanasia
Alexoudi, George Gortzolidis, Elissaios Karageorgiou, Helen
Papageorgiou, George A. Tagaris, Theofanis Chatzistamatiou,
Aikaterini Stavropoulou-Gioka and Aikaterini StavropoulouGioka; Athens, Greece and Minneapolis
T1806 Comparison of Disease Activity in
SPMS and PPMS in the Context of Multicenter
Clinical Trials
Diego Cadavid, Rotem Orbach and Zhenming Zhao;
Cambridge, MA and Tal Hashomer, Israel
T1817 Chronic Pain as a Manifestation of Potassium
Channel-Complex Autoimmunity
Christopher J. Klein, Vanda A. Lennon, Paula A. Aston,
Andrew McKeon and Sean J. Pittock; Rochester, MN
T1807 The MS-STAT Trial: A Phase II Trial of High
Dose Simvastatin for Secondary Progressive Multiple
Sclerosis (SPMS): Initial Results
Jeremy S. Chataway, Ali Alsanousi, Dennis Chan, David
MacManus, Kelvin Hunter, Jo Foster, Charles Bangham,
David Wilkie, Jennifer Nicholas, Virginia Calder, John
Greenwood, Chris Frost and Richard Nicholas;
London, United Kingdom and Brighton,
United Kingdom
T1818 Targeting Innate Receptors with MIS416
Reshaped Autoimmune T Cell Responses and Suppressed
CNS Inflammation and Disease
Anne C. La Flamme, Gill Webster, David O’Sullivan,
Madeleine White and Sarrabeth Stone; Wellington, New
Zealand and Auckland, New Zealand
T1819 Treatment of MS with ACTHar Gel – Clinical
Experience and Case Presentation
Gerard M. Lehrer; New York, NY
T1808 Seasonal Variation of Relapses in Neuromyelitis
Optica
Peter Chater-Lea, Joanna Kitley, Liene Elsone, Yoshiki Takai,
Anu Jacob, Ichiro Nakashima, M. Isabel Leite, Kazuo
Fujihara and Jackie Palace; Oxford, United Kingdom;
Liverpool, United Kingdom and Sendai, Japan
T1820 Blood Brain Barrier Changes Prior
to Lesion Formation in a Primate Model of Multiple
Sclerosis
Pietro Maggi, Emily Leibovitch, Maria I. Gaita´n, Jillian
Wholer, Govind Nair, Luca Massacesi, Steve Jacobson, Afonso
Silva and Daniel S. Reich; Bethesda, MD
T1809 PK11195-PET Enhancement in Black Holes
Correlates with Disability and Outcome in Progressive
Multiple Sclerosis
Paolo Giannetti, Marios Politis, Paul Su, Federico E.
Turkheimer, Omar Malik, Shiva Keihaninejad, Kit Wu,
Richard Reynolds, Richard Nicholas and Paola Piccini;
London, United Kingdom
T1821 Phase Imaging in Marmoset EAE
at 7T Demonstrates Heterogeneity within
Focal Lesions
Pietro Maggi, Pascal Sati, Emily Leibovitch, Maria I. Gaita´n,
Jillian Wholer, Sheila Macri, Luca Massacesi, Susan
Westmoreland, Steve Jacobson, Afonso Silva and Daniel S.
Reich; Bethesda, MD and Boston, MA
T1810 Withdrawn.
T1811 Natal Natalizumab
Daniel Lashley, Kevin Gormley and Timothy Harrower;
Exeter, United Kingdom
T1822 Cognitive Function and Visual outcome
Measures in Patients with Early MS
Amir H. Maghzi, Laura Julian, Jackie Marcus, Jennifer
Graves, Ellen M. Mowry, Rebecca Spain, Ari Green, Michelle
K. Mass, Daniel Pelletier and Emmanuelle Waubant; San
Francisco, CA; Baltimore; Prtland and New Haven
T1812 Brain-Infiltrating Inflammatory Monocytes Injure
the Hippocampus and Induce Seizures during Acute
Picornavirus Infection of the CNS
Charles L. Howe; Rochester, MN
T1823 Clinical Information of Four Men
with Anti-N-Methyl D-Aspartate Receptor
Encephalitis
Makoto Samukawa, Makito Hirano, Hikaru Sakamoto,
Shuichi Ueno, Toshiharu Maekura, Harutoshi Fujimura,
Susumu Kusunoki and Yusaku Nakamura; Osaka-Sayama,
Osaka, Japan; Sakai, Osaka, Japan and Toyonaka, Osaka,
Japan
T1813 Faciobrachial Dystonic Seizures Are
Immunotherapy-Responsive and Treatment May Prevent
Amnesia
Sarosh R. Irani*, Susanne A. Schneider, Rosemary Pettingill,
Philippa Pettingill, Bethan Lang, Shelagh J.M. Smith, Michael
R. Johnson and Angela Vincent; Oxford, United Kingdom and
London, United Kingdom
T1824 Connexin Astrocytopathy in Multiple
Sclerosis, Baló’s Disease and Neuromyelitis
Optica
Katsuhisa Masaki, Satoshi O. Suzuki, Takuya Matsushita,
Takeshi Matsuoka, Toshihiko Suenaga, Takeshi Tabira, Toru
Iwaki and Jun-ichi Kira; Fukuoka, Japan; Nara, Japan and
Tokyo, Japan
T1814 Withdrawn.
T1815 Evaluation of Blood Anti-JCVirus Antibodies of
Natalizumab Treated Multiple Sclerosis Patients
Themistoklis Kalamatas, Nikolaos Protopapas, Ioannis Doumos,
Aimilia Lafioniati, Athina Nella, Anastasios Graigos and
Klimentini Karageorgiou; Athens, Attiki, Greece
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T1825 The Role of Manganese Enhanced MRI
(MEMRI) in Theiler’s Murine Encephalitis Virus
(TMEV) Induced CNS Inflammatory Disease Models
Istvan Pirko, Jeffrey Gamez, Emily R. Shearier, Mekala
Raman, Aaron J. Johnson and Slobodan I. Macura; Rochester,
MN
Stage:
Page: 24
T1833 Profound Alternating Corticospinal Tract
Enhancement in Neuro-Behcet’s Disease
April A. Erwin, Carlo Tornatore and Mark Lin; Washington,
DC
T1834 Anti-CD52 Therapy in Experimental
Autoimmune Encephalomyelitis
Michael J. Turner, Nathalie Chretien, Evis Havari, Michael
LaMorte, Bruce Roberts, Johanne Kaplan and William M.
Siders; Framingham, MA
T1826 Pilot Clinical Trial of Eculizumab in
AQP4-IgG-Positive NMO
Sean J. Pittock**, Andrew McKeon, Jay N. Mandrekar, Brian
G. Weinshenker, Claudia F. Lucchinetti and Dean M.
Wingerchuk; Rochester, MN and Scottsdale, AZ
T1835 MOG Antibodies in Adult and Pediatric
Demyelinating Diseases
Joanna Kitley, Mark Woodhall, Patrick Waters, M. Isabel
Leite, Jackie Palace and Angela Vincent; Oxford, United
Kingdom
T1827 Growth Factors PDGF and FGF-2 Are Required
for Human Recombinant IgM-Mediated Stimulation of
Oligodendrocyte Proliferation and Survival
Jens O. Watzlawik, Arthur E. Warrington and Moses
Rodriguez; Rochester, MN
T1836 Serum Proteomic Analysis of a Presymptomatic
MS Cohort
Mitchell Wallin, Unsong Oh, Julius Nyalwidhe, Thomas
Kislinger, O. John Semmes, John Kurtzke, Parisa Coffman and
Steven Jacobson; Washington, DC; Richmond, VA; Norfolk,
VA; Bethesda, MD and Toronto, ON, Canada
T1828 Does ‘‘Fulminant’’ Multiple Sclerosis Exist?
Loren A. Rolak and Susan Anderson; Marshfield, WI
T1829 Demographic and Clinical Features of
Participants in a VA Longitudinal Study of MS
Walter Royal, Mitchell Wallin, Terry Lee-Wilk, Heidi Maloni,
William J. Culpepper, Joseph Finkelstein, Jong-Chaur Shieh,
Michael Levin, Micheline McCarthy, William Tyor, Jonathan
Leigh, Min Zhan, Robert Kane and Christopher Bever;
Baltimore, MD; Washington, DC; Buffalo, NY; Memphis,
TN; Miami, FL; Atlanta, GA and Cleveland, OH
T1837 Guillain-Barré Syndrome and Its Association
with the 1976 ‘Swine Flu’ Immunisation Programme
James N.R. Wyatt; Liverpool, United Kingdom
T1838 Leveraging Electronic Health Records for
Studying Multiple Sclerosis
Zongqi Xia, Tianxi Cai, Suchun Cheng, Raul N.G. Perez,
Vivian S. Gainer, Shwan N. Murphy, Pei J. Chen, Guergana
K. Savova, Katherine P. Liao, Elizabeth W. Karlson, Ashwin
N. Ananthakrishnan, Peter Szolovitis, Susanne E. Churchill,
Issac S. Kohane, Robert M. Plenge and Philip L.
De Jager; Boston, MA; Cambridge, MA and
Charlestown, MA
T1830 Unusual Presentation of Paraneoplastic StiffPerson Syndrome with Underlying Breast Cancer
Alvin Shrestha, Tatiana Mihalova, Daniel Burns, Hannah
Jennens and Roland Etti; Birmingham, West Midlands, United
Kingdom
T1831 The Prevalence of Cardiovascular Risk Factors in
Multiple Sclerosis Patients
Zohara Sternberg, Christopher Leung, Daniel S. Sternberg and
Elad Levy; Buffalo
T1839 The First Nationwide Survey of Hypertrophic
Pachymeningitis in Japan
Tomomi Yonekawa, Katsuhisa Masaki, Takuya Matsushita,
Shinya Sato and Jun-ichi Kira; Fukuoka, Japan
T1832 Akt1, Not Ak2 or Akt3, Regulates
Oligodendrocyte Maturation In Vitro
Jennifer A. Minarcik, Mary V. Reid, Morris J. Birnbaum,
Chen Po, Judith B. Grinspan and Gihan I. Tennekoon;
Philadelphia, PA and Baltimore, MD
T1840 Caspr2 Autoantibodies Target CNS and PNS
Axons
Eric Lancaster, Josep Dalmau and Steven S. Scherer;
Philadelphia, PA and Barcelona, Spain
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2012 Annual Meeting Works in
Progress Poster Session
WIP202 Quantifying Neurologist Outpatient Test
Utilization and Costs
James F. Burke, Brian Callaghan, Lesli E. Skolarus and Kevin
A. Kerber; Ann Arbor, MI
Posters will be displayed in Arlington, located on the
3rd floor in the Back Bay Hall of the Marriott
Copley Place from 11:30 am – 7:00 pm.
Authors will be present during the following times:
WIP100-WIP1001: Sunday, October 7, 5:30 – 7:00 pm
WIP1100-WIP1409: Monday, October 8, 5:30 – 6:30 pm
WIP1500-WIP1804: Tuesday, October 9, 5:30 – 7:00 pm
The Works in Progress category emphasizes ongoing clinical or basic research of an extraordinary nature, which warrants expediated presentation. These abstracts were selected
based on scientific merit, timeliness, and anticipated interest
to the membership. Key aspects of research must have been
conducted after the regular abstract deadline.
NOTE: Two asterisks designates an abstract selected for oral presentation in the Derek Denny-Brown New Member Symposium.
Neuro-oncology
WIP301 Malignant Glioma Genotyping by
CSF 2-Hydroxyglutarate Oncometabolite and IDH1
Mutation Analysis
Leonora Balaj, Edwin Lok, Kenneth D. Swanson, John M.
Asara, Clark C. Chen, Fred Hochberg, Xandra O.
Breakefield and Eric T. Wong; Boston, MA and
San Diego, CA
WIP302 Genetic Modifiers Affecting Neurofibromatosis
(GMAN): Cutaneous Tumor Burden in
Neurofibromatosis Type 1
Fawn Leigh, Lan Kluwe, Victor Mautner, Douglas R. Stewart,
Conxi Lazaro, Neale Benjamin, Bergen Sarah, Scott R.
Plotkin, Alexander Pemov, Jennifer Sloan, Lee Kaplan,
Maragaret P. Wallace, Meena Upadhyaya, Ludwine Messiaen,
Bruce Korf, Andre Bernards and James Gusella; Boston, IL;
Hamburg, Germany; Rockville, MD; Barcelona, Spain;
Gainesville, FL; Birmingham, AL and Cardiff, United
Kingdom
Cerebrovascular Disease
WIP101 The Detrimental Effect of Aging on
Leptomeningeal Collaterals in Ischemic Stroke
Atay Vural, Murat E. Arsava, Erhan Akpinar, Rahsan
Gocmen, Seray Akcalar, Kader K. Oguz and Akif M.
Topcuoglu; Ankara, Turkey
Neurogenetics
WIP102 The Association between Non-Alcoholic Fatty
Liver Disease and Intracranial Atherosclerotic Disease
Hyun-Suk Jung, Byung-Su Kim and Yoon Ho Choi; Seoul,
Republic of Korea
WIP501 Dark Xavier, Zebrafish Model of MADD
Seok-Hyung Kim, Robert Carson, Michael J. Bennett, Sarah
A. Scott, H. Alex Brown and Kevin C. Ess; Nashville, TN
and Philadelphia, TN
WIP103 Hydrogen Sulfide Increases Angiogenesis and
Improves Functional Outcome after Stroke
Mi-Young Oh, Hyunduk Jang, Wi-Sun Ryu, Seung-Hoon Lee
and Byung-Woo Yoon; Seoul, Korea
WIP502 Driving Selection Against Heteroplasmic
Mitochondrial DNA Mutations by Rapamycin
Ying Dai, Kangni Zheng, Joanne Clark, Russell H. Swerdlow,
Stefan M. Pulst, James P. Sutton, Leslie A. Shinobu and David
K. Simon; Boston, MA; Kansas City, KS; Salt Lake City, UT;
Oxnard, CA and Fujisawa, Kanagawa, Japan
WIP104 Retinal Microvascular Abnormalities Predict
Brain Microvascular Disease Progression: An ARIC
Study
Thomas C. Hanff, A. Richey Sharrett, Tom H. Mosley, Dean
Shibata, David S. Knopman, Ronald Klein, Barbara Klein
and Rebecca F. Gottesman; Baltimore, MD; Jackson, MS;
Seattle, WA; Rochester, MN and Madison, WI
WIP503 Voxel Based Morphometry and Voxel Based
Relaxometry in Neuroferritinopathy
Michael J. Keogh, Andrew M. Blamire and Patrick F.
Chinnery; Newcastle upon Tyne, Tyne and Wear, United
Kingdom
WIP105 Racial and Ethnic Differences in Post-Stroke
Depression among Community Dwelling Adults
Lesli Skolarus, Lynda Lisabeth, Lewis Morgenstern, Deborah
Levine and Devin Brown; Ann Arbor
WIP504 Early Neuropsychiatry Features in
Neuroferritinopathy
Michael J. Keogh, Baldev Singh and Patrick F. Chinnery;
Newcastle upon Tyne, Tyne and Wear, United Kingdom
WIP106 Association between TBI and Ischemic Stroke
James F. Burke, Jessica L. Stulc, Lesli E. Skolarus, Darin B.
Zahuranec and Lewis B. Morgenstern; Ann Arbor, MI
Pediatric Neurology
WIP801 Anti-NMDA Receptor Encephalitis, a Series of
208 Children
Maarten J. Titulaer**, Lindsey McCracken, Thais Armangue,
Inigo Gabilondo, Eugenia Martinez-Hernandez, Takahiro
Iizuka, Lawrence S. Honig, Susanne Benseler, Myrna R.
Rosenfeld, Rita Balice-Gordon, Francesc Graus, Carol Glaser
and Josep Dalmau; Barcelona, Spain; Philadelphia, PA;
Sagamihara, Japan; New York, NY; Toronto, Canada and
Richmond, CA
Education
WIP201 The Association of Non-Clinical Factors with
Head CT Use in Emergency Department Dizziness
Visits: A Population-Based Study
Kevin A. Kerber, James F. Burke, Lesli E. Skolarus, Brian C.
Callaghan, Devin L. Brown, William J. Meurer, Lynda D.
Lisabeth, A. Mark Fendrick and Lewis B. Morgenstern; Ann
Arbor, MI
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WIP802 Tolerability and Efficacy of rTMS in Children
with ASD
Lindsay M. Oberman, Brittany Irish, Lidya Poni, Alvaro
Pascual-Leone and Alexander Rotenberg; Boston, MA
Stage:
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Trauma/Injury
WIP1404 Completion and Outcomes of a Phase 1
Intraspinal Stem Cell Transplantation Trial for ALS
Eva L. Feldman, Nicholas M. Boulis, Karl Johe, Seward B.
Rutkove, Thais Federici, Meraida Polak, Crystal Kelly and
Jonathan D. Glass; Ann Arbor, MI; Atlanta, GA; Rockville,
MD and Boston, MA
WIP1001 Predicting Return to Functional-Independence
by 12-15 Months after Severe Traumatic Brain Injury on
Discharge from Inpatient-Rehabilitation
David S. Kushner, Jasmine Martinez-Barrizonte and Myrlynn
Delille; Miami, FL
WIP1405 Congenital Myasthenic Syndrome (CMS),
Autophagic Myopathy, and Cognitive Dysfunction
Caused by Mutations in DPAGT1
Duygu Selcen**, XinMing Shen, Ying Li, Eric Wieben and
Andrew G. Engel; Rochester, MN and Rochester
Dementia and Aging
WIP1406 Withdrawn.
WIP1101 Dementia Hospital Length-of-Stay and Cost
Leslie S. Wilson; San Francisco, CA
WIP1407 Withdrawn.
WIP1408 DNA Replication, but Not Chromosomal
Unequal Exchange, as an Alternative Mechanism That
Results in CMT1A Mutation
Brett A. Parker, Ryan Alexander, Xingyao Wu, Michael Shy,
Nathalie Schnetz-Boutaud, Jonathan Haines, Jun Li and
Bryan Burnette; Nashville, TN and Iowa City, IA
WIP1102 The Auditory Event-Related Oscillations Are
Diminished, and Correlate with Hippocampal Volumetry
in Mild Cognitive Impairment
Gorsev G. Yener, Pinar Kurt, Berrin Cavusoglu, Derya D.
Emek, Gulsah Aktas, Emel Ada, Bahar Guntekin and Erol
Basar; Izmir, Turkey and Istanbul, Turkey
WIP1409 Prevalence of Small-Fiber Polyneuropathy in
Fibromyalgia
Anne Louise Oaklander, Daniela Herzog, Heather Downs and
Siena Napoleon; Boston, MA
WIP1103 Biomarkers of Neuroinflammation in
Subcortical Ischemic Vascular Disease
Gary A. Rosenberg, Yi Yang, Richard R. Reichard, Jillian
Prestopnik and John C. Adair; Albuquerque, NM and
Albququerque, NM
Behavioral Neurology
WIP1501 Cognitive Remediation (CR) Combined with
Transcranial Magnetic Stimulation (TMS) in Alzheimer’s
Disease (AD)
Lukas Schilberg, Anna-Katharine Brem, Catarina Freitas,
Natasha Atkinson, Ilya Vidrin, Leonie Asboth, Daniel Z. Press
and Alvaro Pascual-Leone; Boston, MA
WIP1104 Behavioral Deficits in APP Transgenic Mice
Reversed by mGluR Inhibitor with Pro-Neurogenic,
Ab-Reducing, and Anxiolytic Properties
Sam Gandy, John W. Steele, Star W. Lee, Dane Clemenson,
Reto Gadient, Pam Wedel, Charles Glabe, Carrolee Barlow,
Michelle Ehrlich, Fred H. Gage and Soong Ho Kim; New
York, NY; La Jolla, CA and Irvine, CA
Movement Disorder
WIP1701 A Diagnostic Questionnaire Discriminates
between Psychogenic and Neurogenic Movement
Disorders
David S. Glosser, Nathan A. Taylor, Lori Sheehan, Daniel
Kremens and Tsao-Wei Liang; Philadelphia, PA
WIP1105 Transcranial Magnetic Stimulation of Deep
Brain Regions in Alzheimer’s Disease: A Pilot Study
Elissa L. Ash, Veronika Vakhapova, Irena Bova, Ely Simon,
Moran Korem, Moran Eldad, Amos D. Korczyn and Avraham
Zangen; Tel Aviv, Israel and Beersheva, Israel
WIP1702 Resting State Functional Connectivity
Pharmaco-MRI of Parkinson’s Disease
Peter S. Pressman, Darren R. Gitelman and Tanya Simuni;
San Francisco, CA and Chicago, IL
Neuromuscular Disease
WIP1401 Non-Human Primate Model of Amyotrophic
Lateral Sclerosis with Cytoplasmic Mislocalization of
TDP-43
Takuya Ohkubo, Mio Tajiri, Azusa Uchida, Hiroki Kimura,
Nobuyuki Sasaguri, Toshiki Uchihara, Hidehiro Misusawa
and Takanori Yokota; Tokyo, Japan and Tsukuba, Japan
WIP1703 Distinct Progressive Genotype-Related
Neurodegeneration in Spinocerebellar Ataxia
Types 1, 3 and 6 – A Longitudinal Study
Kathrin Reetz, Shahram Mirzazade, Anna Lehmann, Agnes Juzek,
Anna Costa, Till K. Hauser, Heike Jacobi, Thomas Klockgether,
Jorg B. Schulz and On Behalf of the Ataxia Study Group; Aachen,
Germany; Tu¨bingen, Germany and Bonn, Germany
WIP1402 Regional Spread of ALS Lesion – Multifocal
Hits and Local Propagation?
Teruhiko Sekiguchi, Tadashi Kanouchi, Kazumoto Shibuya,
Yuichi Noto, Masanori Nakagawa, Satoshi Kuwabara,
Hidehiro Mizusawa and Takanori Yokota; Tokyo, Japan;
Chiba, Japan and Kyoto, Japan
WIP1704 Cerebellar Ataxia with Neuronopathy and
Bilateral Vestibular Areflexia Syndrome (CANVAS)
David J. Szmulewicz, John A. Waterston, Hamish G.
MacDougall, Stuart Mossman, Andrew M. Chancellor,
Catriona A. McLean, Saumil Merchant, Peter Patrikios, Leslie
Roberts, Elsdon Storey and G. Michael Halmagyi; Melbourne,
Australia; Sydney, Australia; Wellington, New Zealand; Boston
and Brisbane, Australia
WIP1403 Miller-Fisher Variant of Guillain-Barre: Is
Treatment Cost-Effective?
Li Yang, Harrison X. Bai, Li-Ming Tan and Bo Xiao;
Changsha, Hunan, China and New Haven, CT
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WIP1705 N-Acetylcysteine Increases Cerebral
Glutathione as Measured by 7T Magnetic Resonance
Spectroscopy in Patients with Gaucher or Parkinson’s
Disease
Mary J. Holmay, Melissa Terpstra, Lisa Coles, Usha Mishra,
Matthew Ahlskog, Gulin Oz, James C. Cloyd and Paul J.
Tuite; Minneapolis, MN
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Autoimmune Neurology
WIP1801 Elevated Micro RNAs in Cerebrospinal Fluid
of Multiple Sclerosis Patients Contribute to Neuronal
Injury
Neha Patel, Elliot Choi, Marie Medynets, Scott Newsome,
Peter Calabresi, Avindra Nath and Tongguang Wang;
Bethesda, MD and Baltimore, MD
WIP1706 Changes in D1 Receptor Are
Associated with the Potentiation of Response to
Levodopa Following Subthalamotomy in Parkinsonian
Monkeys
Vincent A. Jourdain, Laurent Gregoire, Marc Morissette,
Nicolas Morin, Martin Parent and Therese Di Paolo; Quebec,
QC, Canada
WIP1802 Encephalitis and Antibodies to DPPX, a
Regulatory Subunit of Kv4.2 Potassium Channels
Anna Boronat, Jeffrey M. Gelfand, Nuria Gresa-Arribas, HyoYoung Jeong, Michael Walsh, Kirk Roberts, Eugenia MartinezHernandez, Myrna R. Rosenfeld, Rita Balice-Gordon, Francesc
Graus, Bernardo Rudy and Josep Dalmau; Barcelona, Spain;
San Francisco; New York; Brisbane, Australia and Philadelphia
WIP1707 A Novel Alpha-Synuclein Missense Mutation
in Parkinson’s Disease
Christos Proukakis, Maria Katsianou, Angelika Hummel,
Timothy Brier, Henry Houlden, Jonathan Mark Cooper and
Anthony H. Schapira; London, United Kingdom and London,
United Kingdom
WIP1803 Human Aquaporin 4 281-300 Is the
Immunodominant Linear Determinant in the Context
of HLA-DRB1*03:01 – Relevance for Diagnosing and
Monitoring Patients with Neuromyelitis Optica
Benjamin Arellano, Rehana Hussain, Tresa Zacharias, Doris
Lambracht-Washington and Olaf Stuve; Dallas, TX
WIP1708 The Discharge of Striatal Neurons Is
Profoundly Altered in Patients with Parkinson’s
Disease
Arun Singh, Lisa F. Potts, Klaus Mewes, Robert Gross, Mahlon
R. DeLong and Stella M. Papa; Atlanta, GA
WIP1804 Treatment Patterns in Co-Occurring
Multiple Sclerosis and Sarcoidosis
Dorlan J. Kimbrough, Justin C. McArthur and
Carlos A. Pardo; Baltimore, MD
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NINDS/ANA Career Development
Symposium Poster Session
Stage:
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CD508 Sex Chromosomes Modulate Longevity and
Susceptibility to Alzheimer Disease
Dena B. Dubal, Nino Devidze, Kurtresha Worden, Daniel
Kim, Julie Harris, Gui-Qiu Yu, Jorge Palop, Art Arnold,
Bruce Miller and Lennart Mucke; San Francisco, CA and Los
Angeles, CA
Each year, recipients of K awards are invited to attend the
NINDS/ANA Career Development Symposium, designed to
provide them with the essential tools to enhance their ability
to write successful grant proposals and to obtain grant funding from the NIH and other institutions. The NINDS/ANA
Career Development Symposium was set up to foster the
success of young members of the faculty who had obtained
career development awards (K08, K12, or K23) from the
NIH. Career Development posters will be presented during
the wine and cheese reception of the Career Development
Symposium from 5:00 pm – 7:00 pm on Saturday, October
6. The K-awardee participant’s name is in bold.
CD509 Genome-Wide Scan for Copy Number Variation
Association with Age at Onset of Alzheimer’s Disease
Kinga Szigeti, Deepika Lal, Yanchun Li, Rachelle S. Doody
and Li Yan; Buffalo, NY and Houston, TX
CD510 Video-EEG Monitoring of Lithium PilocarpineInduced Status Epilepticus in Postnatal Day 7 Rats
Using a Novel Miniature Telemetry System
Erika A. Scholl, Andrew Zayachkivsky, Mark J. Lehmkuhle,
Fisher H. John, F. E. Dudek and Jeffrey J. Ekstrand; Salt
Lake City, UT
CD501 Directional EEG Connectivity Method
Demonstrates Complex, Reciprocal Information Flows
during Praxis Performance
Joshua B. Ewen, Anna Korzeniewska, Balaji M. Lakshmanan,
Stewart H. Mostofsky and Nathan E. Crone; Baltimore, MD
CD511 Leucine Has Anticonvulsant Effects in Acute
Seizure Tests
Adam L. Hartman, Polan Santos and J. Marie Hardwick;
Baltimore, MD
CD512 Oxygen-Enhanced MRI: A New Imaging Tool
for Localization of Focal Epilepsy and Eloquent Cortex
Giridhar P. Kalamangalam, Timothy M. Ellmore, Nelson T.
Nelson and Narayana A. Ponnada; Houston, TX
CD502 Genetic Variants on 9p21.3 Are Associated with
Brain Arteriovenous Malformations with Associated
Flow-Related Arterial Aneurysms
Helen Kim, Nasrine Bendjilali, Jeffrey Nelson, Shantel M.
Weinsheimer, Mark Segal, Charles E. McCulloch, Ludmila
Pawlikowska and William L. Young; San Francisco, CA
CD513 Attenuated and Augmented Emotional Face
Processing Networks in Temporal Lobe Epilepsy
Brett W. Fling, Jeff Riley and Jack J. Lin; Irvine, CA
CD503 Metabolomics Identifies Alterations in the
Tricarboxylic Acid Cycle in Acute Ischemic Stroke
W. Taylor Kimberly, Yu Wang, Ly Huong Pham and Robert
E. Gerszten; Boston, MA
CD514 Seizure Recurrence and Remission after
Switching Antiepileptic Drugs
Scott Mintzer, Sophia P. Wang, Christopher T. Skidmore,
Tingting Zhan, Erika Stuckert, Maromi Nei and Michael R.
Sperling; Philadelphia, PA
CD504 Perception among African Americans towards
Calling 911 for Acute Stroke
Lesli E. Skolarus, Jillian S. Murphy, Marc A. Zimmerman,
Sarah Bailey, Sophronia Fowlkes and Lewis B. Morgenstern;
Ann Arbor and Flint
CD515 Combined Therapy with Clonazepam and
Tiagabine Is Protective Against Febrile Seizures in a
Mouse Model of Dravet Syndrome and Has Reduced
Toxicity Compared with Monotherapy
John C. Oakley, Christine Cheah, Franck Kalume, Ruth
Westenbroek and William Catterall; Seattle, WA
CD505 High Resolution Magnetic Resonance Imaging
(HRMRI) in Intracranial Atherosclerosis
Tanya N. Turan, Truman R. Brown, Zoran Rumboldt and
Robert J. Adams; Charleston, SC
CD516 Microelectrodes Produce Unreliable EEG
Recordings
William Stacey, Spencer Kellis, Christopher Butson, Paras
Patil, Trevor Assaf, Temenuzhka Mihaylova and Simon Glynn;
Ann Arbor, MI; Pasadena, CA and Milwaukee, WI
CD506 Impact of Acute Ischemic Stroke Treatment in
Patients over Age 80: The SPOTRIAS Consortium
Experience
Joshua Z. Willey, Santiago Ortega-Gutierrez, Nils Petersen,
Pooja Khatri, Andria L. Ford, Natalia S. Rost, Latisha K. Ali,
Nichole R. Gonzales, Jose G. Merino, Brett C. Meyer and
Randolph S. Marshall; New York, NY; Cincinnati, OH; St.
Louis, MO; Boston, MA; Los Angeles, CA; Houston, TX;
Bethesda, MD and San Diego, CA
CD517 High Fat Diet Induces Impaired Glucose
Tolerance and Painful Peripheral Neuropathy
Hsinlin T. Cheng, Jacqueline R. Dauch, John M. Hayes,
Sangsu Oh and Eva L. Feldman; Ann Arbor, MI
CD518 Endogenous l-Opioid System as a Research and
Therapeutic Target in Migraine
Alexandre F. DaSilva, Thiago D. Nascimento, Tiffany Love,
Marcos F. DosSantos, Ilkka K. Martikainen, Misty DeBoer,
Chelsea M. Cummiford, Felipe Fregni, Yolanda R. Smith, Eric
Maslowski and Jon-Kar Zubieta; Ann Arbor, MI and Boston,
MA
CD507 Induction of Autophagy Protects Against
TDP43-Mediated Neurodegeneration
Sami Barmada, Aaron Daub, Michael Ando, Andrea Serio,
Andrey Tsvetkov, Arpana Arjun, Siddharthan Chandran and
Steve Finkbeiner; San Francisco, CA and Edinburgh, United
Kingdom
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CD519 Adiponectin (ADP) & ADP Oligomers Are
Differentially Modulated by Treatment Response in
Episodic Migraineurs
B. L. Peterlin, G. E. Tietjen, B. A. Gower, L. W. White, E.
Hammond, P. D. Dash, T. N. Ward, S. J. Tepper and J. A.
Haythornthwaite; Baltimore, MD; Toledo, OH; Birmingham,
AL; Lebanon, NH and Cleveland, OH
Stage:
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CD531 Caspr2 Autoantibodies Target CNS and PNS Axons
Eric Lancaster, Josep Dalmau and Steven S. Scherer;
Philadelphia, PA and Barcelona, Spain
CD532 Vitamin D Levels Are Associated with Disability
and Brain Volume in Multiple Sclerosis
Ellen M. Mowry, Emmanuelle Waubant, Charles E. McCulloch,
Mehul Sampat, Pamela Qualley, Robin Lincoln, Pierre-Antoine
Gourraud, Alan Evangelista, Don Brenneman, Azadeh
Beheshtian, Sara Llufriu, Stephen Hauser and Daniel Pelletier;
San Francisco, CA; Baltimore, MD and New Haven, CT
CD520 Obesity Increases Nociceptive Activation of the
Trigeminal System
Ana Recober, Sang Luu, Jennika DeVilbiss and Heather
Rossi; Iowa City, IA
CD533 fMRI Findings Using the Immediate Memory
Task/Delayed Memory Task and Correlation with
Neuropsychological Assessment of Cognitive Function in
Multiple Sclerosis Patients
Flavia Nelson, Edward Zuniga, Zahra Kamdar, Muhammad
Akhtar, Jeffrey Wilken, Jerry Wolinsky, Ponnada Narayana and
Joel Steinberg; Houston, TX and Washington, DC
CD521 Feasibility of Electrogastrography in Parkinson
Disease
Samay Jain, Peter J. Gianaros and Max E. Levine;
Pittsburgh, PA and Loudonville, NY
CD522 Normal Striatal D1 Dopamine Receptor Binding
in Primary Focal Dystonias
Morvarid Karimi, Joanne Markham, Hubert Flores, Stephen
Moerlein, Tom Videen and Joel S. Perlmutter; St. Louis, MO
CD534 Decreased Inflammation in Response to
sarA-Mediated Biofilm Formation in a Model
of CNS Catheter Infection
Jessica Snowden; Omaha, NE
CD523 The Transcription Factor ATF4 as a
Neuroprotective Target in Parkinson Disease
Xiaotian Sun, Lloyd A. Greene and Oren A. Levy; New York,
NY
CD535 Leveraging Electronic Health Records for
Research in Multiple Sclerosis
Zongqi Xia, Riley Bove, Tianxi Cai, Suchun Cheng, Raul
N.G. Perez, Vivian S. Gainer, Shawn N. Murphy, Pei J.
Chen, Guergana K. Savova, Katherine Liao, Elizabeth W.
Karlson, Stanley Shaw, Ashwin N. Ananthkrishnan, Peter
Szolovits, Susanne E. Churchill, Issac S. Kohane, Robert M.
Plenge and Philip L. De Jager; Boston, MA; Cambridge, MA
and Charlestown, MA
CD524 Rab Protein Expression Alters alpha-Synuclein
Oligomer Formation and Cytotoxicity
Nikolaus R. McFarland and Tomoko Sahara; Gainesville, FL
CD525 Dopaminergic Modulation of Basal Ganglia
Connectivity in Parkinson’s Disease
Kathleen L. Poston, William Shire, Richard Joseph, Vinod
Menon and Michael Greicius; Stanford, CA
CD536 Toxoplasma Co-Opts Host Cells It Does Not
Invade
Anita A. Koshy, Hans K. Dietrich, Patrick K. House, Robert
Sapolsky and John C. Boothroyd; Stanford, CA
CD526 Circadian Rhythm of Melatonin Secretion Is
Altered in Parkinson’s Disease
Aleksandar Videnovic, Angelica Marconi, Charleston Noble,
Katherine Reid, Teresa Kuhta, Tanya Simuni, Cindy Zadikoff
and Phyllis Zee; Chicago, IL
CD537 Problematic Initial Shunt Placement and Initial
Infection Are Associated with Reinfection
Tamara D. Simon, Nicole Mayer Hamblett, Kathryn B.
Whitlock, Marcie Langley, John R.W. Kestle, Jay RivaCambrin, Margaret Rosenfeld and Emily A. Thorell; Seattle,
WA and Salt Lake City, UT
CD527 Modulation of 14-3-3 Proteins in the MPTP
Parkinson’s Disease Model
Huiping Ding and Talene Yacoubian; Birmingham, AL
CD538 JC Virus Infection in a Humanized Mouse Model
Chen S. Tan, Thomas A. Broge Jr, Edward Seung, Vlad
Vrbanac, Raphael Viscidi, Jennifer Gordon, Andrew M. Tager
and Igor J. Koralnik; Boston, MA; Baltimore, MD and
Philadelphia, PA
CD528 Genome-Wide Association Study of Tourette
Syndrome
Jeremiah M. Scharf and TS GWAS Consortium; Boston, MA
and Bayside, NY
CD529 Body-Wide Correction of Myotonic Dystrophy
Type 1 (DM1) in Transgenic Mice by RNase H-Active
Antisense Oligonucleotides (ASOs)
Thurman M. Wheeler, Andrew J. Leger, Sanjay K. Pandey,
A. Robert MacLeod, Masayuki Nakamori, Seng H. Cheng,
Bruce M. Wentworth and C. Frank Bennett; Rochester, NY;
Framingham, MA and Carlsbad, CA
CD539 Comprehensive Genetic Screening of a Large
ALS Cohort Using Pooled-Sample Sequencing
Matthew B. Harms, Janet Cady, Peggy Allred, Taha Bali,
Ryan T. Libby, Alan Pestronk, John Ravits and Robert H.
Baloh; Saint Louis, MO; La Jolla, CA and Los Angeles, CA
CD540 Motor Neuron Disease-Associated Mutations in
p150/Glued Disrupt the Initiation of Retrograde Axonal
Transport at Synaptic Termini
Thomas E. Lloyd, James Machamer, Sarah Collins and Alex
L. Kolodkin; Baltimore, MD
CD530 Timed-25 Foot Walk & The Real World
Myla D. Goldman, John Scagnelli, Robert W. Motl, John
Pula and Jacob J. Sosnoff; Charlottesville, VA and Urbana, IL
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CD541 Validation of the Pediatric CMT Quality of Life
Outcome Measure
Sindhu Ramchandren, Richard Finkel, Cathey Boyer,
Thomas Templin, Carly Siskind, Mary Reilly and Michael
Shy; Detroit, MI; Philadelphia, PA; Palo Alto, CA; London,
United Kingdom and Iowa City, IA
CD551 Drosophila Peroxisomal Biogenesis Defects
Produce Shortened Lifespan and Excess Cystene-String
Protein at the Synapse
Michael F. Wangler, Lucy Liu, Nikolaos Giagtzoglou, Vafa
Bayat, Joseph Faust, James McNew and Hugo J. Bellen;
Houston, TX
CD542 Optimizing the Total Neuropathy Score
for HIV-Associated Distal Symmetric
Polyneuropathy
Jessica Robinson-Papp, Sandeep Sharma, David M. Simpson
and Susan Morgello; New York, NY
CD552 Glial Restricted Precursor and
Oligodendrocyte Progenitor Cell Transplantation
in an Ischemic Perinatal White Matter
Injury Model
Ali Fatemi, Andre W. Phillips, Michael Porambo, Mary Ann
Wilson, Joel Marx, Jeffrey D. Rothstein and Michael V.
Johnston; Baltimore
CD543 TGF-b Signaling in Glioma Microenvironment
Inhibits Engraftment and Differentiation of Oncogenic
Neural Stem/Progenitor Cells
Sabah O. Ghazi, Laura D. Hover, Michelle Stark, Alex
Munden and Ty W. Abel; Nashvill, TN
CD553 Epidermal Growth Factor Treatment Rescues
Neonatal White Matter Injury
Joseph Scafidi, Maria Roncal, Tamas L. Horvath, Robert J.
McCarter and Vittorio Gallo; Washington, DC and New
Haven, CT
CD544 Hexokinase-2-Mediated Aerobic
Glycolysis as a Novel Target for Medulloblastoma
Therapy
Timothy R. Gershon, Andrew Crowther, Andrey Tikunov,
Hong Yuan, Jeffrey Macdonald and Mohanish Deshmukh;
Chapel Hill, NC
CD554 Visual Function and Optical Coherence
Tomography in Pediatric Demyelinating
Diseases
Amy T. Waldman, Girish Hiremath, Robert A. Avery, Amy
Conger, Michael Loguidice, Lauren S. Talman, Kristin M.
Galetta, Michael J. Shumski, James Wilson, E’tona Ford,
Benjamin M. Greenberg, Jonas Ellenberg, Elliot M. Frohman,
Laura J. Balcer and Peter A. Calabresi; Philadelphia, PA;
Baltimore, MD and Dallas, TX
CD545 Reversible Opening of the Blood-Brain Barrier
by Targeted Suppression of Claudin 5 To Enhance
Drug Delivery into Brain Tumors
Gerald A. Grant, Christy Wilson, Matthew Campbell,
Shuqin Li, Peter Humphries, Allan Johnson, Mark Dewhirst
and Darell Bigner; Durham, NC and Dublin, Ireland
CD555 Impact of Acute Hypoxia on the Developing
Mouse EEG
Santina A. Zanelli, Samuel Kowalski and Jaideep Kapur;
Charlottesville
CD546 A New Genetic Model of Sporadic
Medulloblastoma Reveals Heterogeneity of the Sonic
Hedgehog Tumor Subtype
G. Praveen Raju, Giselle A. Suero-Abreu, Diane Pham, Luis
Barazza, Brandon Wainwright, Marc K. Rosenblum, Daniel
H. Turnbull and Alexandra L. Joyner; New York, NY and
Brisbane, Queensland, Australia
CD556 Recovery of Motor Function after Complete
Unilateral Injury of the Corticospinal Tract Using
Electrical Stimulation of Motor Cortex on the
Uninjured Hemisphere in Rats
Jason B. Carmel, Hiroki Kimura and John H. Martin;
White Plains, NY and New York, NY
CD547 Regulation and Impact of HSF1 in Malignant
Human Cancers
Sandro Santagata, Marc L. Mendillo, Rulla M. Tamimi,
Tan A. Ince, Chengkai Dai, Luke Whitesell and Susan
Lindquist; Cambridge, MA; Boston, MA; Miami, FL and Bar
Harbor, ME
CD557 Bimanual Dexterity and Interhemispheric
Interactions in Musicians
Alex R. Carter, Kristi Zinn, Jennifer Rengachary and
Maurizio Corbetta; Saint Louis, MO
CD548 MicroRNA 218a Acts as a Tumor Suppressor in
Medulloblastoma
Sujatha Venkataraman, Diane K. Birks, Irina Alimova, Peter
Harris and Rajeev Vibhakar; Aurora, CO
CD558 Probing for Hemispheric Specialization for
Motor Skill Learning: A Transcranial Direct Current
Stimulation Study
Heidi M. Schambra, Mitsunari Abe, David A.
Luckenbaugh, Janine Reis, John W. Krakauer and
Leonardo G. Cohen; New York, NY; Bethesda, MD
and Baltimore, MD
CD549 Alpha Synuclein as a Cutaneous Biomarker of
Parkinson Disease
Christopher H. Gibbons, Ningshan Wang and Roy Freeman;
Boston, MA
CD559 Bmal1 Provides a Molecular Link between
Circadian Clock Function, Brain Metabolism, and
Neurodegeneration
Erik S. Musiek, Miranda M. Lim, Adam Q. Bauer,
Guangrui Yang, Jee Hoon Roh, Benoit I. Giasson, David M.
Holtzman and Garret A. FitzGerald; St. Louis, MO;
Philadelphia, PA and Gainesville, FL
CD550 Erythropoietin Alters Cell Fate of Subventricular
Zone Progenitor Cells at Early and Late Time Points
after Neonatal Stroke
Fernando Gonzalez, Patrick McQuillen, Amara
Larpthaveesarp, Nikita Derugin, Michael Wendland and
Donna Ferriero; San Francisco, CA
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CD560 Neuregulin-1 Effects on Endothelial and BloodBrain Barrier Permeability after Experimental Injury
Josephine Lok, Song Zhao, Wendy Leung, Ji Hae Seo, Deepti
Navaratna, Michael J. Whalen, Xiaoying Wang and Eng H.
Lo; Boston, MA; Charlestown, MA and Changchun, Jilin,
China
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CD561 Acetyl-L-Carnitine (ALCAR) Provides
Long-Term Neuroprotection after Traumatic Brain
Injury in Immature Rats
Susanna Scafidi, Su Xu, Shruti V. Kabadi, JayLyn Waddell,
Rao Gullapalli, Alan Fadan, Mary C. McKenna and Gary
Fiskum; Baltimore, MD
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2012 Annual Meeting Sunday,
October 7, 2012
Poster Session Abstracts
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expect it to associate with lacunar stroke. Therefore, we also
tested this hypothesis.
Methods: Association between six single nucleotide polymorphisms (SNPs) at 17q25 and WMHV measured in
2504 ischaemic stroke cases was assessed. These SNPs were
also investigated for association with lacunar stroke in 1886
SVD strokes and 52277 controls.
Results: All six SNPs associated with WMHV (risk alleles
concordant with previous reports). The most significant
SNP was rs11869977 (p ¼ 0.00031) and accounted for
0.5% of WMHV variability. Conditional analysis did not
reveal other independent signals within the region. In contrast, no SNPs associated with lacunar stroke.
Conclusion: This study further supports the association
between 17q25 locus and WMH, but not with lacunar
stroke. This suggests that its effects are mediated via brain
responses to injury rather than promoting small vessel
arteriopathy.
Study supported by: The principal funding for this
study was provided by the Wellcome Trust, the Intramural
Research Program of the National Institute on Aging
(NIH), National Institute for Neurological Disorders and
Stroke (NINDS), the National Institutes of Health Genes,
Environment and Health Initiative (GEI), National Health
& Medical Research Council (Australia), Annual Research
Funding of the Italian Ministry of Health, National
Human Genome Research Institute (NIH), National
Heart, Lung, and Blood Institute, Henry Smith
Charity, the Medical Research Council (UK) and the British Council (UKIERI).
Posters will be displayed in Gloucester, located on
the 3rd floor in the Back Bay Hall of the Marriott
Copley Place from 11:30 am – 7:00 pm, with
authors present from 5:30 pm – 7:00 pm.
NOTE: An asterisk designates a resident/fellow travel award
winner. Two asterisks designates an abstract selected for oral
presentation in the Derek Denny-Brown New Member
Symposium.
Cerebrovascular Disease
S101. The Expression of Individual Genes in Acute
Stroke Differs across Leukocyte Subsets
Mateusz G. Adamski, Erin Wagenr, Yan Li, Hua Yu, Steven
A. Soper and Alison E. Baird; Brooklyn, NY; Krakow, Poland
and Baton Rouge, LA
In prior microarray studies overlapping gene expression panels for acute ischemic stroke were developed. In these studies
mRNA was isolated either from whole blood or from
peripheral blood mononuclear cells (PBMC). We aimed to
validate individual genes from these published panels and to
determine the cellular sources of alterations in acute stroke
patients.
Peripheral blood was obtained from 12 acute stroke
patients within 48 hours from symptom onset and from 12
age, race and sex matched control subjects. The expression
of five genes previously found to be substantially altered in
ischemic stroke (IL1R2, S100A9, FDFT1, C3AR1 and
RNASE2) was measured in four leukocyte subsets: CD14þ
monocytes, CD4þ T, CD20þ B cell lymphocytes and
PBMCs. The expression of these five 5 genes was measured
using qPCR and compared between stroke patients and control subjects.
S100A9 was significantly (p<0.05) overexpressed in
CD4þ and CD20þ lymphocytes whereas FDFT1 expression was significantly (p<0.05) decreased in CD20þ
lymphocytes.
These results show the potential diagnostic value of genes
identified in prior microarray studies in stroke patients.
They also emphasize the potential and added value of studying gene expression in specific leukocyte subsets.
Study supported by: S. A. Soper: Research Grant; NIH
funded grant # 1 R01
EB010087-01A1.
A. E. Baird: Research Grant; NIH funded grant # 1 R01
EB010087-01A1.
S103. The Untreated Clinical Course of Cerebral
Cavernous Malformations: A Prospective,
Population-Based Cohort Study
Rustam Al-Shahi Salman, Julie M. Hall, Margaret A. Horne,
Fiona A. Moultrie, Colin B. Josephson, Jo J. Bhattacharya,
Carl E. Counsell, Gordon Murray, Vakis Papanastassiou,
Vaughn Ritchie, Richard C. Roberts, Robin J. Sellar and
Charles P. Warlow; Edinburgh, United Kingdom; Newcastleupon-Tyne, United Kingdom; Glasgow, United Kingdom;
Aberdeen, United Kingdom; Fauldhouse, United Kingdom and
Dundee, United Kingdom
Background: Cerebral cavernous malformations (CCM) are
prone to bleeding but the risk of intracranial haemorrhage
and other complications, as well as their predictors, are
unclear.
Methods: We conducted a population-based study using
multiple overlapping sources of case ascertainment and prospective follow-up.
Findings: During 1,177 person-years of follow-up (completeness 97%), the five-year risk of a first haemorrhage was
lower than the risk of recurrent haemorrhage (24% [95%
confidence interval (CI) 0-57] versus 295% [95% CI
41-550], p<00001). Considering a composite endpoint
of intracranial haemorrhage or focal neurological deficit
definitely or possibly related to CCM, the five-year risk of a
first event was again lower than the risk of recurrence (93%
[95% CI 31-154] versus 424% [95% CI 268-580],
p<00001); the annual risk of recurrence declined from
198% (95% CI 61-334) in year one to 50% (95% CI
00-148) in year five, and it was higher for women than
men (p ¼ 001).
Interpretation: The risk of recurrent intracranial haemorrhage or focal neurological deficit from CCM is greater
than the risk of a first event, is greater for women than for
men, and declines over five years.
S102. Genetic Risk in Cerebral Small Vessel Disease
(SVD): 17q25 Locus Associates with White Matter
Lesions but Not Lacunar Stroke
Poneh Adib-Samii, The International Stroke Genetics
Consortium and METASTROKE Consortium; London, United
Kingdom
Background: Recently, CHARGE consortium identified a
novel locus at 17q25 associated with white matter hyperintensities (WMH) on MR-imaging in stroke-free individuals.
In stroke, WMH are linked to SVD; therefore, we aimed to
replicate the association with WMH volume (WMHV) in
stroke. If the locus acts by promoting SVD, one might
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Study supported by: This study was supported by the
UK Medical Research Council, the Chief Scientist Office
of the Scottish Government, and the UK Stroke
Association.
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infarct size. Further studies of the possible mechanism
behind this association are needed.
Study supported by: NINDS R01 NS047691
S106. First Mexican Family with CADASIL: A Novel
Mutation in the NOTCH3 Gene
Fernando Barinagarrementeria, Antonio Arauz and Manuele
Minw; Queretaro, Mexico; Mexico City, Mexico and Paris,
France
S104. Characteristic Distributions of Intracerebral
Hemorrhage-Associated Microinfarcts
Eitan Auriel, Mahmut Edip Gurol, Alison Ayers, Andrew
Dumas, Kristin Schwab, Anastasia Vashkevich, Sergi
Martinez-Ramirez, Jonathan Rosand, Anand Viswanathan
and Steven M. Greenberg; Boston, MA
We report the first Mexican family affected with CADASIL.
Material and methods: DNA was extracted from whole
blood using standard procedures.
Results: The family is a native Mexican family settled
in Sinaloa, Northwestern part of the Country. The proband is a female seen at age of 48 years with history of
migraine. Recently developed depression. An MRI disclosed white matter and periventricular abnormalities as
well temporal anterior poles and basal ganglia. Her father
died at age 63 after 6 years history of repeated strokes and
dementia and two paternal uncles with history of multiple
strokes and dementia. She had fourteen siblings. Six of
them with history of depression, multiple strokes and
dementia. Five of them are alive and with abnormal MRI.
One nephew with migraine and and one brother with
CADASIL spectrum were evaluated in search of notch 3
mutation.We identified a heterozygous point mutation in
exon 3 of NOTCH3 (c .304T>A. This mutation, was
detected in all 3 patients. It is a mutation typical of
CADASIL.
Conclusion: Clinical, imaging and genetic characteristics
of the first Mexican Family with CADASIL are similar to
other races with the disease.
Study supported by: None
Clinically silent cerebral microinfarcts have been observed
with high incidence on diffusion-weighted imaging of
patients with primary intracerebral hemorrhage (ICH). We
examined the timing and spatial distribution of cerebral
microinfarcts in patients with lobar and deep ICH.
We retrospectively analyzed 458 MRI scans from 392
subjects with lobar (n ¼ 276) and deep (n ¼ 116) ICH
(48.7% females; mean age 72.8611.7 years) and identified
103 DWI-hyperintense lesions on 62 MRI scans, located
mostly in lobar brain regions (90/103, 87.4%). The lesions
were not uniformly distributed throughout the brain lobes
and specifically differed between the lobar and deep ICH
patients (p ¼ 0.002). Although the frequency of DWI
lesions tended to be greater on scans performed within 7
days after ICH (39/214, 18.2%), they continued at high
frequency in the non-acute (>14 days post-ICH) period as
well (23/178, 12.9%, OR 1.5, 95% CI 0.86-2.6 for acute
vs. nonacute).
The characteristic distributions of incident microinfarcts
and their high frequency even outside the acute post-ICH
period suggest that they are products of the underlying
small vessel disease. These findings also support the possibility that cortical microinfarcts are numerous enough to
make important contributions to small vessel-related cognitive impairment.
Study supported by: None
S107. Prolyl 4-Hydroxylase Inhibition (GSK360A)
Increases Hypoxia Inducible Factor (HIF)-Regulated
Transcripts and Improves Post-Stroke Sensory-Motor
and Cognitive Functions
Frank C. Barone, Jin Zhou, Jie Lie, Robert N. Willette, John
Lapore, Erding Hu and Daniel M. Rosenbaum; Brooklyn,
NY and King of Prussia, PA
S105. Effect of Leukoaraiosis on Neglect Performance
in Acute Stroke Patients
Zainab Bahrainwala, Argye E. Hillis, Jennifer Dearborn and
Rebecca F. Gottesman; Baltimore, MD
Hypoxia inducible factor (HIF) is upregulated by decreased
oxygen tension and ischemic preconditioning. GSK360A is
a prolyl 4-hydroxylase (PHD) inhibitor that increases HIF1a. Here we evaluated an optimum, pharmacodynamically
determined dose in focal stroke over 3 weeks. Rats
received reperfusion stroke. Vehicle (1% Methyl cellulose)
or GSK360A (30 mg/kg) was administered by oral gavage
at 18 and 5 hr prior to stroke. Measurements were made
of circulating and tissue erythropoietin (EPO) mRNA and
protein, sensory-motor and cognitive (Active Avoidance;
AA) functions, and terminal brain tissue loss due to infarction. GSK360A increased circulating and tissue EPO
mRNA and protein up to 80-fold (p<0.01) by 5 hr poststroke. Stroke increased sensory-motor deficits that were
reduced (20-31%, p<0.05) by GSK360A. Stroke decreased
AA performance that was improved (p<0.01) by
GSK360A. GSK360A also reduced terminal brain tissue
loss (30%, p<0.05). These data demonstrate GSK360A
brain protection and long-term functional improvement in
post-stroke function. PHD inhibition can stimulate
HIF-induced transcription and might be useful for highstroke-risk situations and/or prior to surgery to reduce
post-surgical cognitive decline.
Study supported by: GlaxoSmithKline and SUNY Downstate Medical Center
Background: Leukoaraiosis is longitudinally associated with
cognitive decline and dementia, but how it interacts with
the brain’s response to acute ischemia is less understood. We
hypothesized that acute ischemic stroke patients with a
higher burden of leukoaraiosis would perform worse on tests
of cognitive performance, specifically neglect, when controlling for infarct size.
Methods: 261 patients with an acute ischemic right-hemispheric stroke at The Johns Hopkins Hospital underwent
brain MRI and cognitive assessment for hemispatial neglect,
within 5 days of symptom onset. Acute infarcts were measured volumetrically on DWI images and FLAIR images
were reviewed for white matter hyperintensities (WMH),
using the Cardiovascular Health Study (CHS) scale (0-9,
with 9 being most extensive).
Results: Each one-point increase in CHS category was
associated with a 1.17-fold increased odds (95% CI 0.991.37) of having any neglect and a 1.19-fold increased odds
(95% CI 1.02-1.40) of having severe neglect, after adjusting
for DWI volume, age, sex and race. Neglect scores were
markedly worse in individuals with both severe WMH and
large infarcts (p-interaction<0.05).
Conclusion: More severe leukoaraiosis is associated with
worse neglect after acute ischemic stroke, independent of
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S108. Brain and Abdominal Aneurysm Study (BAAS):
Interim Analysis
Kevin M. Barrett, Sothear M. Luke, Albert G. Hakaim, Rabih
G. Tawk, Ricardo A. Hanel, Bradford B. Worrall, William D.
Freeman, Thomas G. Brott and James F. Meschia; Jacksonville,
FL and Charlottesville, VA
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unknown whether the NR2 peptide, a breakdown product
of brain specific NMDA receptors, which is released into
the bloodstream during acute cerebral ischemia, is elevated
in diabetics and how it may correlate with cerebrovascular
function.
Methods: NR2 peptide plasma concentrations were measured in 27 diabetics, 14 prediabetics and 9 healthy controls
and correlated with cerebrovascular function. Middle cerebral artery (MCA) vasoreactivity was measured using Transcranial Doppler Ultrasound at rest and following inhalation
of 5%CO2.
Results: NR2 levels were significantly different between
all groups (p ¼ 0.033). Diabetics had increased NR2 peptide levels (0.24 lg) compared to prediabetics (0.07 lg/l)
and healthy controls (0.09lg/l), but prediabetics had no significant peptide elevations compared to controls (p ¼ 0.99).
Regression analysis showed that increased NR2 peptide levels were significantly associated with increased MCA pulsatility (p< 0.001) and resistance (p< 0.001) indices, and
possibly with impaired cerebral vasoreactivity (p ¼ 0.056).
Conclusion: The NR2 peptide may indicate injury to
cerebral vessels in patients with diabetes and may predict
risk of cerebrovascular disease.
Study supported by: Funding of this study was partially
provided by a grant from Pennsylvania Tobacco Settlement
Funds, Human Health Services
The relationship between intracranial and aortic aneurysms
has not been well quantified. Evidence of shared genetic risk
factors suggests screening for abdominal aortic aneurysms
(AAA) may be warranted in patients with aneurysmal subarachnoid hemorrhage. BAAS (NCT01420991) is a prospective study designed to obtain an estimate of the proportion
of patients with aneurysmal subarachnoid hemorrhage who
are found to have AAA by screening ultrasonography.
Thirty-eight subjects have been screened for eligibility; 18
subjects enrolled as of 3/27/12. One (6%) was excluded
from enrollment for pre-existing diagnosis of AAA. Sixteen
subjects have completed 30 day follow-up. Mean age was
50.2 yrs (range 33 to 69 yrs); 72% were women. Sixty-seven
percent were active cigarette smokers. Five (28%) subjects
had more than one intracranial aneurysm. Aneurysm treatment: 13 (72%) endovascular coiling, 5 (28%) clipping.
Subjects with mild (<6), moderate (6-13), and severe (>13)
baseline NIHSS was 12 (67%), 2 (11%), and 4 (22%).
One (6%) had an aortic aneurysm (5.9 cm) detected by
ultrasonography. In this population of aneurysmal subarachnoid hemorrhages, 2 (5%) of the 38 subjects had AAA.
Updated results will be presented.
Study supported by: Mayo Jacksonville Intramural Funds
S111. Neurophysiological Identification of Two
Independent Generators Causing Oculofaciopalatal
and Lingual Myoclonus
Rony Dekermenjian, Nancy Gadallah, Sushanth Bhat,
Sumaiya Salim, Liudmila Lysenko, Michael Rosenberg and
Sudhansu Chokroverty; Edison, NJ
S109. Revising the Model of Vascular Homeostasis:
Mechanotransduction Is Opposed by a Novel Electrical
Force
Darshan P. Trivedi and Peter R. Bergethon; Boston, MA
Oculofaciopalatal myoclonus, characterized by rhythmic,
pendular vertical eye movements with synchronous contraction of the soft palate, is often seen in brainstem infarction
or hemorrhage with damage to the Guillian-Mollaret triangle. Lingual myoclonus occurs in an idiopathic fashion,
with Arnold-Chiari malformations, brainstem tumors or as
an epileptic phenomenon. We report a case of oculopalatofacial myoclonus secondary to brainstem stroke with independent lingual myoclonus.
A 52 year old man suffered brainstem infarction, with a
one and a half syndrome, left sided lower motor nerve facial
palsy, quadriplegia, and sensory loss in the right hemibody
and left face. Rhythmic ocular bobbing with synchronous
palatal and facial contractions were noted, as well as independent tongue myoclonus. Polymography of multiple cranial and limb muscles revealed synchronous, rhythmic myoclonic bursts at a frequency of 1.5-2 Hz in the orbicularis
oculi, mentalis, palatal and sternocleidomastoid muscles.
However, the lingual myoclonic bursts occurred asynchronously, at the same frequency but with variable latency.
The neurophysiological evaluation demonstrates a second
generator causing rhythmic tongue movements, completely
independent and asynchronous from the classic generator of
oculofaciopalatal myoclonus, a novel description in our
patient.
Study supported by: N/A
Blood flow is controlled by local mechanisms including
mechanotransduction. Vascular endothelial cells (VEC) are
exposed to a ubiquitous yet unexamined flow-induced electrical force, the electrostatic vascular streaming potential
(EVSP). Previously membrane potential and nitric oxide production in cultured VEC were shown to respond to isolated
EVSP-modeled electric fields. We test the hypothesis that the
EVSP and mechanical shearing forces are separable and act in
homeostatic opposition. Using a laminar flow chamber,
VECs were exposed to shearing forces including the EVSP.
With flow (shear and EVSP), the membrane potential hyperpolarized within 100 seconds and then depolarized back to
baseline. With the EVSP neutralized, flow induced a persistent hyperpolarization (8 mV) without subsequent depolarization. Isolated electrical field exposure induced depolarization
(2 mV). Application of channel blocking agents showed the
EVSP effect attributable to a flow-sensitive chloride channel.
The production of NO was proportional to flow but with
the EVSP neutralized the NO signal was potentiated.
We conclude that mechanotransduction and EVSP show
biologically independent effects and that the EVSP has a
homeostatic role in vascular biology. Its derangement may
contribute to cerebrovascular disease.
Study supported by: NIH
S110. Does the NMDA Receptor Biomarker Predict
Impaired Cerebral Vascular Function in Diabetes?
Kerstin Bettermann, Julia E. Slocomb, Mary E.J. Lott and
Svetlana Dambinova; Hershey, PA and Atlanta, GA
S112. Evaluation of Gender Disparities in
Hemicraniectomy Utilization in the United States
Mahmoud Rayes, Seemant Chaturvedi and Pratik
Bhattacharya; Detroit, MI
Background: Diabetes is a risk factor for stroke, chronic
ischemic white mater disease and vascular dementia causing
endothelial dysfunction and structural vascular damage. It is
Randomized trials suggest a robust survival benefit from
hemicraniectomy in malignant infarctions 60 years. We
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have previously shown a gender disparity favoring men in
the nationwide utilization of this procedure. In the present
study we analyzed data from ischemic stroke discharges in
the Nationwide Inpatient Sample (NIS) years 2007-2009, to
explain these differences. 328937 ischemic stroke discharges
were included; of which 384 (0.12%) received hemicraniectomies. Males (0.15%) were more likely to receive the
procedure than females(0.09%, p<0.0001). Females were
significantly older (p<0.0001); received tPA less often
(p<0.0001); less likely to be in the highest income quartile
(p<0.0001); more likely to have Medicare (p<0.0001) and
less likely to have Medicaid (p<0.0001) or private insurance
(p<0.0001)-even in the 60 years group; less likely to be
treated at urban teaching centers (p<0.0001) and less likely
to be transferred (p<0.0001). Upon adjustment of the gender-hemicraniectomy association by age, income quartile,
primary insurance type, and urban location/teaching status
of the hospital; the gender disparity was no longer significant. Many reasons for this gender disparity are physician
and system-centered. Addressing these factors can extend the
benefit of this potentially lifesaving procedure to more
women with stroke.
Study supported by: none
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Methods: Eighty-eight patients (57 men and 31 women;
mean age 72611 years) diagnosed with an acute ischemic
stroke within 24 hours of admission to the stroke unit were
evaluated for stroke severity using the Scandinavian Stroke
Scale and Glasgow Coma Scale, and for serum concentrations of free tri-iodothyronine (T3), free thyroxin, thyroid
stimulating hormone and C-reactive protein (CRP). At discharge, cognitive outcome was evaluated using the Mini
Mental State Examination (MMSE).
Results: In univariate regression analyses higher free T3
concentrations (b ¼ .332, p ¼ .006) and lower CRP
concentrations (b ¼ -.348, p ¼ .005) were associated with
better cognitive outcomes (higher MMSE score) at discharge. In multivariate analyses higher free T3 concentrations was associated with better cognitive outcome (b ¼
.252, p ¼ .011) after adjustment for age, gender, stroke
severity on admission and CRP condentrations.
Conclusions: In acute ischemic stroke patients higher
free T3 concentration on admission is independently associated with better cognitive outcome at discharge.
Study supported by: Funding internal.
S115. Angioplasty and Stenting of Patients with Carotid
Artery or Vertebral Artery Stenosis: Experience from
Lithuania
Adomas Bunevicius, Donatas Cerniauskas, Rytis S. Kaupas and
Edvardas Vaicekavicius; Kaunas, Lithuania and Chapel Hill, NC
S113. Functional Weakness in tPA Candidates:
Challenges and NIHSS-Minus
Ilya Bragin, Mirret M. El-Hagrassy and Adham Kamel;
Syracuse, NY
Objective: To evaluate initial and long term outcomes of
angioplasty with stenting for stenosis of carotid and vertebral arteries.
Methods: From 2003 until 2006 a total of 45 consecutive patients (n ¼ 39 men; mean age 6268 years) underwent angioplasty and stenting for documented stenosis of
carotid or vertebral arteries. Long term outcomes were evaluated in 26 patients 2.461.1 years after the procedure.
Results: There were no complications during the procedure.
During in-patient period 3 (7%) patients developed ischemic
complications: 1 ipsilateral stroke, 1 contralateral stroke and 1
transient ischemic attack. At discharge, clinical status was considered as improved in 33 (73%) patients, as not changed in
10 (22%) patients and as worsened in 2 (4%) patients.
During follow-up period 4 (18%) patients died due to suicide (n ¼ 2), stroke (n ¼ 1) and lung embolism (n ¼ 1).
Eighteen (69%) patients were compliant with prophylactic
treatment regimen. At follow-up clinical status improved in
18 (82%) patients and did not-change in 4 (18%) patients.
Conclusions: Angioplasty and stenting of vertebral and
carotid arteries due to stenosis are safe and effective treatment
modality, however, suicide rate was high in our cohort of
patients.
Study supported by: No external funding
Introduction: Thrombolytic associated symptomatic intracranial hemorrhage rates range 2.1% – 9.4%. Thrombolytic
administration is based on the NIHSS. No formal NIHSS
component accounts for functional symptomatology or
malingering.
Cases: A 56 year old male presented with pleuritic chest
pain and hemiparesis. He claimed to be a factor V Leiden
‘‘heterozygote’’ smoker arriving from a cross-country flight.
He knew the exact time of onset. NIHSS was 10. He
received tPA, but was subsequently found to be a fraud.
Workup was negative.
A 54 year old female schizophrenic with vascular risk factors presented with acute unresponsiveness, collapse and
possible left sided weakness. NIHSS was 16. She received
tPA; workup was negative.
Discussion: Stroke mimics are frequently encountered. In
one study, rt-PA was administered to 193 cases, 30 of which
proved to be mimics. Hoover’s sign in the legs and arms for
functional weakness has been tested in small studies, and
can be quickly performed. We propose that positive results
cancel NIHSS Motor Leg/Arm scores (NIHSS-Minus),
reducing the overall score. This could reduce inappropriate
tPA administration.
Conclusions: The NIHSS can be refined to address nonorganic weakness and better direct management.
Study supported by: N/A
S116. Risk Factors for Stroke in South Asians across
Two Continents
Zhongbo Chen, Muhammad S. Khan, Sunaina Yadav, Ankita
Maheshwari, Tharushi Fernando, Ranil de Silva, Ranjani
Gamage, Kameshwar Prasad and Pankaj Sharma; London,
United Kingdom; New Delhi, India; Nugegoda, Sri Lanka
and Colombo, Sri Lanka
S114. Cognitive Outcomes of Acute Ischemic Stroke
Patients: Association with Concentrations of Thyroid
Axis Hormones and C-Reactive Protein
Adomas Bunevicius, Henrikas Kazlauskas, Nijole Raskauskiene,
Rima Radziuviene, Audra Anskoliene, Vinsas Janusonis and
Robertas Bunevicius; Palanga, Lithuania; Klaipeda,
Lithuania and Chapel Hill, NC
Background: Stroke in South Asians remains poorly characterised. We assessed stroke risk factors in South Asians in
the Indian subcontinent (SA) and British Asians (BA), with
comparison to Europeans.
Methods: This hospital-based case-control study used
neuroimaging-confirmed stroke. Subjects were recruited
from India, Sri Lanka and the UK.
Objective: To evaluate in acute ischemic stroke patients the
association of concentrations of thyroid axis hormones and
CRP on admission with cognitive outcome at discharge.
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Outcomes: 1030 SA stroke cases and 546 controls, 654
Europeans, and 200 BAs were recruited. SAs had strokes at
a younger mean age (52.4 years) than BAs (61.6years)
(p<0.001) and earlier than Europeans (68.5years)
(p<0.001). SAs had a higher proportion of haemorrhagic
stroke compared to Europeans (p ¼ 0.001). In SAs,
adjusted Odds Ratios (OR) and Population Attributable
Risk (PAR) for established risk factors in cases compared to
controls were: hypertension (OR 10.7, 95%CI 7.7–14.8,
PAR 51.8%); diabetes (OR 3.5, 2.3–5.2; PAR 13.5%);
hypercholesterolaemia (OR 14.4, 8.3–25.0, PAR 28.0%);
atrial fibrillation (OR 8.0, 3.3–21.1); and migraine with
aura (OR 4.8, 2.8–8.2). SAs had a higher proportion of left
ventricular hypertrophy on echocardiography compared to
Europeans (p<0.001). BAs had higher mean fasting glucose6SEM (7.5mmol/l 60.3) compared to Europeans
(6.560.2): p ¼ 0.007; and SAs (6.660.1): p ¼ 0.018.
Conclusions: Three modifiable risk factors, hypertension,
diabetes and hypercholesterolaemia, account for 90% of
stroke in South Asians.
Study supported by: Department of Health; The Henry
Smith Charity; British Council (UKIERI)
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Methods: QOL was assessed annually in SPS3 using the
Stroke Specific QOL scale (range 1-5). We fit linear mixed
models to assess the trend in QOL over time, assuming linearity of time, and adjusted for demographic, medical, and
cognitive factors and functional status.
Results: Among 2870 participants (mean follow-up 3.5
years), mean age was 63.4 years (SD 10.7); 63% were male;
10% had prior stroke. Factors associated with decline in
QOL over time included age (-0.0003 per year, p<0.0001),
any college education (-0.0013 per year, p ¼ 0.01), prior
stroke (-0.004 per year, p < 0.0001), and Barthel score
(-0.0002 per year, p < 0.0001). In age-stratified models,
prior stroke had a significant effect on change in QOL
among the three older quartiles.
Conclusion: In this well-defined cohort of lacunar stroke
patients, age, education, prior stroke, and functional status
predicted changes in QOL over time. Prior subcortical stroke
may worsen decline in QOL, especially among the elderly,
perhaps due to loss of functional reserve, subclinical progressive vascular disease, or reversible cerebral dysfunction.
Study supported by: SPS3 is an investigator initiated study
funded by a cooperative agreement from the National Institute of Neurological Disorders and Stroke of United States
(Grant #2 U01 NS38529-04A1). The clopidogrel and
matching placebo have been donated by Sanofi-Aventis and
Bristol-Myers Squibb. Neither company has any involvement
with the design, execution, or analysis of the trial.
S117. Withdrawn.
S118. A Fulminant Case of Atypical Posterior Reversible
Encephalopathy Syndrome Associated with Status
Epilepticus
Bhavpreet Dham, Usman Moghal, Yadira Velazquez, Tapan
Kavi, Luis Zayas and Akbar Umer; Camden, NJ
S120. Primary/Familial CAA and Maeda-Type Cerebral
Small-Vessel Disease: Clinicopathological Diferential
Diagnosis and Role of Amyloid Deposition Diseases
A.N. Viswanathan, S.M. Greenberg and Sabino Guillermo
Echebarria; Boston, MA and Las Arenas, Bizkaia, Spain
Introduction: Posterior Reversible Encephalopathy Syndrome (PRES) is a clinico-radiological diagnosis associated
with headaches, seizures, visual complaints and radiological
findings of vasogenic edema predominantly in the white
matter of parieto-occipital lobes. Treatment of underlying
etiologies often leads to spontaneous resolution of symptoms
and imaging findings.
Case: A 72-year old man with hypertension presented
with a 2-week history of generalized malaise, headaches,
vomiting and intermittent blurry vision. Systolic blood pressure was over 200 but the remainder of the physical examination was normal. Initial head CT was also unremarkable.
Hospital course was complicated by a progressive decline in
mental status. Brain MRI 3-days after a normal head CT
showed development of extensive regions of vasogenic
edema in the parieto-occipital lobes, basal ganglia and cerebellum with associated acute infarctions and extensive multifocal hemorrhages. Hospital course was further complicated
by prolonged status epilepticus, requiring pharmacologic
coma. Comfort care measures were instituted per family’s
request and the patient passed away soon thereafter.
Summary: Although generally reversible, PRES can rarely
have devastating clinical outcome with development of
extensive cerebral hemorrhages and infarctions with associated status epilepticus, as described in this case.
Study supported by: N/A
Introduction: Recent series have enhanced the imnportance
and frequency of the association CAA/primary cerebral vasculitis, defined as Ab -related arteritis (ABRA) with descriptives extensive to cerebral amyloid angiopathy related
inflammation (CAAi).
Leukoencephalopathies defined in these series may be
compared with small vessel meningocortical CAAs.
Methods: Comparatives in microscopic and ultrastructural neuropathological markers and diagnostic features in:
-Diffuse type of CAA with leukoencephalopathy (primary
cerebrovascular amyloidosis, familial CAA with nonneuritic
amyloid).
-Non CADASIL forms of cerebral small-vessel disease.
Results: Fibronectin and carvertin deposits (TGF-b products) in tunica intima/media of autosomal recessive small-vessel disease would be a descriptive hallmark, in which extracellular matrix protein expression would be decissive (COL4A1
vascular diseases); comparable, also to demyelinating forms of
subcortical amyloid with leukoencephalopathy.
Conclusions: Descriptional sampling showing leukoencephalopathy commonalities between diffuse hemorrhagic
CAA and Binswanger subcortical encephalopathy, may be
connected with definitions derived from WM description in
diffuse forms of CAA and Maeda-type small vessel disease
of the brain with demyelination predominance.
Study supported by: ------------
S119. Quality of Life after Lacunar Stroke: The
Secondary Prevention of Small Subcortical Strokes
(SPS3)
Mandip S. Dhamoon, Leslie A. McClure, Carole L. White,
Oscar Benavente and Mitchell S.V. Elkind; New York, NY;
Birmingham, AL; San Antonio, TX and Vancouver, BC,
Canada
S121. TIA with New Ischemic Lesion: Clinical Features
and Stroke Risk for Patients with Different TIA
Subtypes
Olena Y. Fartushna; Kiev, Ukraine
Background: We sought to determine predictors of longterm decline in quality of life (QOL) after lacunar stroke.
Transient symptoms do not exclude the possibility of associated acute ischemic lesion (AIL) on neuroimaging.
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Aim is to study the causes and character of AIL and
stroke risk in TIA patients with AIL and without it according to the TIA subtypes (as to TOAST criteria).
Methods: DW-MRI has been performed within the first
24 h for 178 patients with acute TIA, which were divided
into 2 groups according to the MRI results: 1-TIA with AIL
on DWI (n ¼ 66(37.0%)) and 2-without it (n ¼
112(63.0%)).
Results: Stroke developed in 27(40.9%) patients after
TIA with AIL and in 18(16.1%) cases - without it
(OR(95% CI) ¼ 19,6(19.09-20.1),p<0.001). TIA patients
with AIL had a significantly greater volume (p<0.05) and
duration (p< 0.001) of neurological deficit compared with
persons with TIA without AIL. The diameter of AIL ranged
from 1.5 to 26mm (13.461.2mm) and as well as localization it was significantly different of TIA subtypes
(p<0.001). Most often AIL were determined for cardioembolic (39.4%) TIA.
Conclusions: The duration and volume of the neurological deficit as the risks of stroke were much higher in
patients with TIA with AIL than without it and differ
depending on TIA subtypes.
Study supported by: Bogomolets National Medical
University
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We present a 41-year-old lady who underwent caesarean
section following the development of pre-eclampsia 30
weeks into her pregnancy. 2 days after delivery she developed sudden onset total visual loss followed by weakness of
her left leg. MRI brain revealed areas of hyperintensity with
restricted diffusion in both parieto-occipital cortices consistent with acute infarction. Imaging of intracranial vessels
with MRA and CTA demonstrated marked diffuse vasoconstriction involving both the anterior and posterior circulation. Vasculitic screen was negative. The patient’s vision
started to return within 24 hours and her symptoms almost
completely resolved over the following days. A repeat MRI
4 weeks after the event showed evolution of the hyperintense signal in both parieto-occipital cortices with scarring
and volume loss, consistent with recent infarction. MRA
revealed complete resolution of the vasoconstriction.
This case illustrates the spectrum of reversible cerebral
vasoconstriction syndromes and highlights the importance
of (repeated) cerebral vascular imaging in the diagnosis of
women presenting with neurological symptoms in association with (pre)-eclampsia or shortly after delivery.
Study supported by: none
S124. Endothelial Engulfment of Emboli ‘‘Angiophagy’’
Is a Fundamental Mechanism of Microvascular
Recanalization
Jaime Grutzendler; New Haven, CT
S122. Risk Factors for Intracranial Haemorrhage in
Acute Ischaemic Stroke Patients Treated with rtPA
William N. Whiteley, Karsten Bruins-Slot, Peter M.
Fernandes, Peter A.G. Sandercock and Joanna Wardlaw;
Edinburgh, United Kingdom and Oslo, Norway
We have found a mechanism of recanalization in the cerebral microcirculation independent of the fibrinolytic system.
This involves endothelial engulfment of emboli followed by
their transendothelial translocation into the perivascular
space. Here we compare the efficacy of this mechanism of
microvascular clearance with that of the fibrinolytic system
and determine if it is unique to the brain or if it occurs in
other microvascular beds. Mice expressing GFP in endothelial cells were embolized with fibrin microclots and studied
with high-resolution confocal, two-photon, and transmission
electron microscopy. In the first 6-hours, endogenous fibrinolysis and hemodynamic forces cleared a significant portion of emboli but clearance dropped dramatically 6-hours
post-occlusion. Tissue plasminogen activator had a modest
additional effect that was limited to the first 6-hours postembolization. Emboli that failed to be washed-out underwent transendothelial translocation 2-7 days postocclusion.
This occurred in the brain as well as the microvasculature of
the heart, retina and skeletal muscle. Thus endothelial
engulfment of emboli,’’angiophagy’’, is a robust mechanism
of microvascular clearance likely to be important at
maintaining vessel patency throughout life and could have
important implications in the pathogenesis of a variety of
embolic disorders.
Study supported by: NIH/NIA
Intravenous thrombolysis with recombinant tissue plasminogen activator is an effective treatment for acute ischaemic
stroke, but is associated with an increased risk of fatal or
disabling intracranial haemorrhage (ICH). We sought to
identify the risk factors for ICH with a comprehensive systematic review of the published literature.
We searched for relevant studies of stroke patients treated
with rtPA that reported an association between a variable
measured before rtPA infusion and subsequent, significant
ICH. We calculated associations between baseline variables
and ICH.
We identified 55 studies that measured 43 baseline variables in 65,264 stroke patients. Post-rtPA ICH was associated
with higher age (odds ratio [OR] 1.03 per year;
95%CI:1.01-1,04), higher stroke severity (OR 1.08 per
NIHSS point; 95%CI:1.06-1.11), and higher glucose (OR
1.10 per mmol/L, 95%CI :1.05-1.14). There was approximately a doubling of the odds of ICH with the presence of
atrial fibrillation, congestive heart failure, renal impairment,
prior antiplatelet agents, leukoariaosis and a visible acute
ischaemic lesion on pre-treatment brain imaging.
Individual baseline variables are modestly associated with
post-rtPA ICH. Prediction of post-rtPA ICH is therefore
likely to be difficult if based on individual clinical or imaging factors alone.
Study supported by: MRC Clinician Scientist Fellowship
G0902303 to Dr. Will Whiteley
S125. Chronic Inflammatory Diseases and Stroke:
Evidence for Heterogeneous Mechanisms
Jose Gutierrez and Mitchell S.V. Elkind; New York, NY
Background: Increased inflammatory markers predict cardiovascular events. The relationship between chronic inflammatory diseases, inflammatory markers and stroke has been
less well characterized.
Methods: Using data from the 2005-2010 NHANES (n
¼ 2210), we calculated odds ratios and 95% confidence
intervals (OR, 95% CI) for the association of inflammatory
diseases with stroke before and after adjusting for demographics, risk factors and inflammatory markers.
S123. Reversible Cerebral Vasoconstriction
in Pre-Eclampsia
Pablo Garcia-Reitboeck, Phil Rich and Ali Al-Memar;
London, United Kingdom
Postpartum angiopathy forms part of the spectrum of reversible cerebral vasoconstriction syndromes, and typically
presents with severe headaches, neurological deficits secondary to stroke or seizures.
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Results: Stroke was associated with arthritis (OR 4.83,
3.82-6.09). Asthma was only associated with stroke in participants 55 years (2.25, 1.71-3.32), while hepatitis B
and hepatitis C were associated with stroke in those < 55
years (OR 7.22, 2.76-18.87; and OR 9.57, 2.77-33.04,
respectively). Adjusting for demographics and cardiovascular
risks attenuated the association of stroke with asthma (OR
1.88, 0.93-3.81) and arthritis (OR 1.81, 0.90-3.65) and
further controlling for inflammation did not modify the
odds. The association of stroke with hepatitis B (OR 19.40,
4.82-77.90) and hepatitis C (OR 9.61, 2.58-35.78) persisted after adjusting for all potential confounders.
Conclusions: The associations of asthma and arthritis
with stroke prevalence may be confounded by cardiovascular
risk factors, while viral hepatitis may be associated with
stroke through other direct mechanisms.
Study supported by: No support or finantial disclosure
received for this workl
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using a grading scale based on visualization of the vessel
wall, lumen, and plaque components.
Results: The final imaging protocol was selected from
the sequences that provided the best image quality without
unacceptable scan duration. The final sequences include 3D
acquisition of T1 weighted images (pre- and post-contrast),
T2 weighted images, and FLAIR sequences.
Summary: HRMRI can be used to identify IPH, fibrous
cap, and lipid rich core in ICAS. Further studies are
planned using this protocol to determine inter-rater reliability and the prognostic value of these plaque features in
ICAS.
Study supported by: NIH/NINDS 1K23NS069668
S128. Outcomes of Perfusion Based Endovascular
Therapy in Witnessed Onset and Unwitnessed
Onset of Stroke
Deependra Khanal, Pratik Bhattacharya and Seemant
Chaturvedi; Detroit, MI
S126. Dabigatran Etexilate: Management in Acute
Ischemic Stroke
Parisa P. Javedani, B. Zane Horowitz, Wayne M. Clark and
Helmi L. Lutsep; Portland, OR
Around 25% of strokes occur during sleep, excluding them
from intravenous tPA. While perfusion imaging has helped
identify patients with salvageable tissue for endovascular
therapy in patients with unwitnessed onset, it is unclear
how the outcomes compare with those with known time of
stroke onset.
Patients admitted to a large volume stroke center from
January 2009-December 2011 were reviewed. Patients who
had a CT perfusion demonstrating penumbra and treatment
by endovascular methods were selected. Outcomes were
compared between those with witnessed and unwitnessed
stroke onset.
39 patients (median age 62, males 51%, median NIHSS
13) were reviewed. At discharge, 46% showed NIHSS
improvement by 4 (witnessed onset: 13/28-46%, unwitnessed onset: 5/11-45%; p ¼ 0.95). Six of seven deaths in
the study, and two cases of symptomatic intracerebral hemorrhages were in the witnessed onset group. Similar rates of
patients in both groups were discharged home or to rehabilitation centers (p ¼ 0.30).
Endovascular intervention can achieve comparable outcomes in patients with witnessed and unwitnessed stroke
onset by using perfusion imaging. Contemporary therapies
in acute stroke may see a paradigm shift from time-based
treatments to tissue physiology based options.
Study supported by: None.
Background: The use of long-term oral anticoagulation is
indicated for prevention of cardiac thromboembolism in
patients with non-valvular atrial fibrillation. With the emergence of dabigatran, physicians must become familiar with
the management of such patients.
Case Report: A 54-year-old man on with dabigatran presented 69 minutes after an ischemic stroke. A National
Institutes of Health Stroke Scale (NIHSS) was 9. Recombinant tissue plasminogen activator (rtPA) administration was
not recommended secondary to dabigatran therapy. Angiography demonstrated occlusion of the left middle cerebral
artery (L MCA), and suction thrombectomy achieved flow
through the inferior division of the L MCA. CT showed
possible intracranial hemorrhage (ICH), and dabigatran
reversal was attempted with prothrombin complex concentrate (PCC) and recombinant factor VIIa (rFVIIa). He was
discharged to rehabilitation with an NIHSS score of 8.
Conclusion: The thrombin time, Hemoclot thrombin
inhibitor assay, and ecarin clotting time are sensitive assays,
but PTT is insensitive. Although PCC and rFVIIa can
reverse the anticoagulant effect, a true antidote is not available. Conservative recommendations suggest waiting 48
hours since the last dabigatran dose before administering
rtPA.
Study supported by: Unfunded
S127. High Resolution Magnetic Resonance Imaging
(HRMRI) in Intracranial Atherosclerosis
Tanya N. Turan, Truman R. Brown, Zoran Rumboldt and
Robert J. Adams; Charleston, SC
S129. A Retrospective Study of Complications and
Discharge Dispositions after Treatment for Acute
Ischemic Stroke Based on the Nationwide Inpatient
Sample from 2006-2009
Tobias B. Kulik, Kate C. Young, Ann M. Leonhardt,
Babak S. Jahromi and Curtis G. Benesch; Rochester, NY
Introduction: HRMRI can identify prognostically important plaque features (intraplaque hemorrhage (IPH), fibrous
cap, and lipid core) in extracranial carotid disease, but plaque features in intracranial atherosclerosis (ICAS), a more
common cause of stroke worldwide, have not been systematically examined. This study aimed to refine a HRMRI
protocol that will consistently visualize the arterial lumen,
vessel wall, and atherosclerotic plaque components in
patients with ICAS.
Methods: 36 patients with 50-99% ICAS underwent a
brain MRI using a 3Tesla Siemens scanner with a 32 channel head coil. Stepwise adjustments to the imaging protocol
were made to refine the image quality. Images were assessed
We sought to establish national estimates for the frequency
of complications, the need for additional procedures, and
discharge disposition for patients with acute ischemic stroke
treated with either intravenous tPa (IVtPa), intra-arterial
therapy (IAT) or without interventional treatment. In addition, we analyzed the discharge disposition by region
(Northeast, Midwest, South, West) and teaching hospital
status.
Discharge records from the Nationwide Inpatient sample
between the years of 2006-2009 were obtained and
admissions for acute ischemic stroke identified utilizing the
ICD-9 discharge diagnosis code. Data were analyzed with
Microsoft Excel and SPSS.
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In patients who had undergone IAT the rate of ICH and
the need for a craniotomy, mechanical ventilation and tracheostomy placement, were significantly higher compared to
patients treated with IVtPa (p0.05). However, the rates of
PEG tube placement, aspiration pneumonia and DVT did
not differ significantly between both treatment groups. The
rate of routine discharges after IVtpA were significantly
higher compared to IAT, while the rates of discharge to
short-term care, SNF rehab and hospice were comparable.
The rate of fatal demise was significantly higher with IAT.
Study supported by: N/A
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Parental hypertension was associated with SVD events (OR
¼ 1.8, 95%CI 1.2-2.7) and with higher DBP: mean DBP
¼ 82.1/7.6 vs.80.8/7.7, p ¼ 0.04; most recent DBP ¼
80.7/10.4 vs. 77.8/10.6, p<0.0001.
Conclusion: Increased DBP but not SBP is associated
with lacunar events and with parental history of hypertension. DBP might play a particular role in the heritability of
SVD.
Study supported by: CSC
S132. Is the Susceptibility to Carotid Atherosclerosis
Reduced in Small Vessel Disease? Evidence from a
Population-Based Study
Linxin Li, Ziyah Mehta, Ursula Schulz and Peter M.
Rothwell; Oxford, United Kingdom
S130. No Significant Association of Aspirin Use with
Cerebral Microbleeds in the Asymptomatic Elderly
Chi Kyung Kim, Hyuk Tae Kwon, Jong-Ho Park and
Hyung-Min Kwon; Seoul, Korea and Koyang, Korea
Background: The distribution of atherosclerosis between intracranial vessels and carotid bifurcation differs between ethnic groups. Such difference in site-specific susceptibility may
also exist within ethnic groups. We hypothesised that
patients with small vessel ischaemic events may be less susceptible to atherosclerosis at the carotid bifurcation.
Methods: In a population-based study of Caucasian
stroke/TIA patients, we compared the frequency of atherosclerotic risk factors and the site-specific prevalence of atherosclerosis related disease (coronary disease; PVD; carotid stenosis) in patients with lacunar (LACI) versus non-LACI
events.
Results: Of 1659 stroke/TIA patients, the prevalence of
coronary disease (19.7% vs.19.3%) and PVD (6.7%
vs.7.1%) was similar in both groups. However, despite similar age and sex-adjusted prevalences of hypertension (OR ¼
1.1, 95%CI 0.8-1.5), diabetes (1.2, 0.8-1.8), hyperlipidemia
(0.9, 0.7-1.2), and smoking (1.3, 1.0-1.8), patients with
LACI events had lower prevalence of 70% carotid stenosis
(5.1% vs.9.5%, p ¼ 0.03).
Conclusion: Within a Caucasian population, patients
with lacunar events have a similar risk factor profile to those
with non-lacunar events and a similar frequency of PVD
and coronary disease, but less severe carotid stenosis, possibly due to reduced susceptibility to atherosclerosis at the
carotid bifurcation.
Study supported by: CSC
Background and purpose: Cerebral microbleeds (CMBs)
may predict future risk for intracerebral hemorrhage (ICH).
We sought to investigate whether aspirin use is associated
with CMBs in subjects without previous history of stroke.
Methods: Asymptomatic elderly subjects (n ¼ 1,452)
were included. The subjects were categorized into two
groups depending on CMB location: strictly lobar and deep
or infratentorial microbleeds. Information about aspirin use
was obtained using a structured questionnaire.
Results: A total of 138 subjects (9.5%) were found to
have CMBs. In the group of aspirin use, 43 subjects
(11.2%) had CMBs. Compared with the non-use group,
the risk for CMBs did not increase in the group of aspirin
use (OR, 1.10; 95% CI, 0.73-1.66) and the risk for strictly
lobar microbleeds and deep or infratentorial microbleeds
also did not increase. For the group of aspirin use above 5
years, the proportion of CMBs did not increase compared
with the group of short-term use and non-use group.
Conclusions: The prevalence of CMBs did not increase
in the group of aspirin use, and the presence of CMBs was
not associated with the duration of aspirin use in asymptomatic elderly subjects.
Study supported by: This work was supported by a grant
from the Boramae Medical Center (03-2011-9). The funding organization had no role in the design, conduct, or analysis conducted during this study or in the preparation of
this report.
S133. The Secondary Degeneration in Red Nuclei
Following Striatum Infarction Revealed by Diffusion
Tensor Imaging
Zijun Wang, Chao Qin, Zhijian Liang, Xuean Mo, Daobin
Cheng, Yajuan Chen, Wei Ye and Yi Dai; Nanning,
Guangxi, China
S131. A Population-Based Study of Pre-Morbid Blood
Pressure in Patients with Small Vessel TIA and Stroke
Linxin Li, Nicola L.M. Paul, Linda Bull, Ziyah Mehta and
Peter M. Rothwell; Oxford, United Kingdom
Background: There is some evidence that hypertension is a
particularly important risk factor for small vessel (SVD)
stroke. However, the relative importance of systolic (SBP)
versus diastolic (DBP) blood pressure is uncertain. We studied pre-morbid DBP and SBP in patients with SVD events
versus other subtypes and in relation to parental family history of hypertension.
Methods: In a population-based study with stroke/TIA,
we studied all pre-morbid BP measurements over the 10
years preceding the event. Aetiological subtype was categorised using the TOAST classification.
Results: In 1659 patients with over 20,000 pre-morbid
BP measurements, mean (SD) pre-morbid SBP (mmHg)
was similar in patients with SVD versus others (145.7/14.7
vs.145.2/15.8), but DBP was higher in those with SVD:
mean DBP ¼ 83.0/7.1 vs. 80.6/7.6, most recent DBP ¼
80.7/9.6 vs. 77.7/10.9, both p<0.0001. Results were similar
in the subset of 1238 patients with family history data.
Objects: To investigate the secondary degeneration in red
nuclei after striatum infarction with diffusion tensor imaging (DTI) and its significance.
Methods: Thirty two patients with striatum infarction
underwent a DTI scan and a clinical evaluation with modified Rankin Scale (mRS) and Barthol Index, and the five
patients with symptoms like Parkinson disease underwent an
additional evaluation with the third subscale of unified Parkinson’s disease rating scale (UPDRS III) in the twelve
weeks from symptom onset. Thirty two healthy volunteers
underwent a DTI scan as controlled.
Results: Compared with the control group, the MD of
ipsilateral side red nuclei in patients increased 27.72 percent
(P<0.01), and the FA value of ipsilateral side red nuclei
decreased 31.36 percent (P<0.01). Compared with the
other patients, the MD of ipsilateral side red nuclei in the
five patients with some symptoms like Parkinson disease
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trol). Exclusions: TIA without infarct (n ¼ 9), cerebral venous
thrombosis (n ¼ 1), dissection (n ¼ 7), laboratory evidence of
liver disease/disseminated intravascular coagulation (n ¼ 4),
or inherited/acquired factor deficiency (n ¼ 17). Mean
factor activities of cases and controls were compared using
Student’s t-test.
Results: We enrolled 105 cases (47% female, mean age
67) and 99 controls (57% female, mean age 57). Mean
activities: Factor IX cases 137% (SD 26.1), controls 137%
(SD 28.9), p NS; Factor XI cases 113% (SD 24.2), controls
111% (SD 24.2), p NS. Results were unchanged after
excluding control patients with history of stroke/TIA.
Conclusions: Our study did not demonstrate higher
mean factor IX or XI activities in subjects with ischemic
stroke as compared to those with stroke mimics.
Study supported by: no sponsor
increased 5.87 percent(P <0.05). Moreover, he MD of ipsilateral side red nuclei in the five patients correlated with
their UPDRS III positively(P<0.05).
Conclusions: The secondary degeneration in red nuclei
may be partly responsible for the symptoms like Parkinson
disease in striatum infarction patients.
Study supported by: national natural science foundation
of china
S134. Early Plasma Biomarkers of Ischemic Penumbra
in Acute Stroke
Svetlana Lorenzano, Natalia S. Rost, Hens B. Brouwers,
Alfredo J. Caceres, Matthew S. Siket, Octavio M. Pontes Neto,
Hua Li, Rebecca E. Green, Tijy Thankachan, Allison J.
Dipietro, Brenda J. Thornell, Ona Wu, Ken Arai, Sophia
Hartdegen, Angel T. Som, Loc-Duyen D. Pham, Peter J. Kelly,
Gordon J. Harris, Eng H. Lo, Steven K. Feske and Karen L.
Furie; Boston, MA and Dublin, Ireland
S136. Partial to Complete Recanalization in Middle
Cerebral Artery Occlusion Following Intra-Arterial
tPA and Transcranial Doppler Monitoring
Amer M. Malik, Krislynn Barnhart and Yince Loh; Seattle, WA
Introduction: Advanced neuroimaging techniques may provide fundamental data with regard to brain tissue viability
in acute ischemic stroke (AIS). We sought to assess whether
plasma biomarkers of oxidative stress predict diffusion-perfusion mismatch in AIS patients.
Methods: We measured plasma levels of high sensitivityCRP (hs-CRP), matrix metalloproteinase (MMP)-2 and
MMP-9, F2-isoprostane(F2isoP), 8-hydroxydeoxyguanosine
(8OHdG), and the Oxygen Radical Absorbance Capacity
Assay (ORAC) in consecutive AIS patients presenting within
9 hours from symptom onset. Diffusion-(DWI) and perfusion-weighted(PWI) MRI sequences were analyzed using
semi-automated volumetric method. Mismatch was defined
as baseline mean transit time (MTT) volume on PWI
minus DWI volume. A percent mismatch cut-off of 20%
was considered clinically significant.
Results: Mismatch was present in 154/228 (67.5%)
patients (69.4614.4 years; 41.2% women). Compared to
those without MRI evidence of mismatch, patients with
mismatch were more likely to have higher ORAC-PCA (p
¼ 0.03)and F2isoP (p ¼ 0.07). After adjustment for confounders, multivariate logistic regression demonstrated that
plasma F2isoP (OR1.74, 95%CI 1.06-2.9; p ¼ 0.04) and
ORAC-PCA (OR3.66, 95%CI 1.27-11.012; p ¼ 0.02)
were independent predictors of PWI-DWI mismatch.
Conclusions: Elevated hyperacute plasma levels of F2isoP
and ORAC-PCA are associated with radiographic evidence
of mismatch in AIS subjects. If validated, these findings
may provide further understanding of the role of oxidative
stress in cerebral tissue fate during acute ischemia.
Study supported by: SPOTRIAS - Specialized Program of
Translational Research in Acute Stroke, NIH/NINDS Grant
P50-NS051343
Background: As new primary and adjunct applications are
pursued for sonothrombolysis, it is becoming increasingly
accepted as a therapeutic strategy because it achieves the
desired dual outcomes of increasing the rate of arterial
recanalization while keeping hemorrhagic complications at a
minimum.
Methods: We report a case utilizing the minimally invasive combination of sonothrombolysis sequentially after
intra-arterial tPA without direct clot manipulation in order
to facilitate recanalization.
Results: Following 5 mg of IA tPA without direct manipulation of clot, a remaining subocclusive MCA thrombus
was treated with targeted TCD to facilitate complete
recanalization.
Conclusions: This case demonstrates the utility of TCD
to monitor initial findings and subsequent recanalization.
When necessary, direct insonation with TCD to achieve full
recanalization immediately following IA tPA delivery without
requiring direct manipulation of a thrombus may offer an
alternative, safer approach to treating patients with intracranial occlusions. Additionally, this case suggests that there may
be a basis for taking a subset of acute ischemic stroke patients
to the angiography suite despite a low NIHSS score, or when
outside the window of systemic thrombolysis.
Study supported by: Amer M. Malik reports no
disclosures.
Krislynn Barnhart reports no disclosures.
Yince Loh reports no disclosures.
S137. Clinical and Radiologic Significance of Dilated
Perivascular Spaces in Patients with Cognitive
Impairment
Sergi Martinez-Ramirez, Amy Halpin, Megan Quimby,
Andrew P. Dumas, Mahmut Edip Gurol, Eithan Auriel,
Steven M. Greenberg and Anand Viswanathan; Boston, MA
S135. Elevated Factor IX and XI Activities May Not Be
a Risk Factor for Ischemic Stroke
Jennifer J. Majersik, George M. Rodgers, Kevin D. Call, Jana
J. Wold, Ronda A. Crist, Anna M. Sherr, Elaine J. Skalabrin
and Kristi J. Smock; Salt Lake City, UT; Provo, UT and
Springfield, OR
Objectives: To investigate the role of dilated perivascular
spaces(DPVS), along with other markers of small-vessel disease, in patients with cognitive impairment.
Methods: Review of prospective data from patients
admitted to our memory clinic having high-resolution neuroimaging (structural 3T MRI) and a neuropsychological
assessment performed within 2 years of scan. DPVS were
rated in basal ganglia (BG-DPVS) and white matter (WMDPVS) on T1 sequences, using an established 4-point semiquantitative score. Additionally, microbleeds, white matter
Background: Elevated factor IX and XI activities contribute
to venous thromboembolism risk. Restrospective data suggests elevations may be associated with arterial thrombosis.
Methods: We conducted a prospsective case-control study
of Factor IX and XI activities to determine if they are elevated
in patients with ischemic stroke. Subjects were eligible if they
presented to the ED with suspected acute stroke. Stroke neurologists adjudicated ischemic stroke (case) vs. stroke mimic (con-
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hyperintensities (WMH), lacunar infarcts and brain parenchymal fraction were quantified. DPVS degree was classified
as high(score >2) or low (score 2). We compared characteristics between DPVS subgroups.
Results: Ninety-three patients were included (mean age
72.7 6 9.99 years, 57% female). Fifty-five (59.1%) patients
had CDR ¼ 0.5 and 38 (40.9%) had CDR 1. High BGDPVS degree was associated with increasing age (80.462.9 vs
71.7 6 1 years, p ¼ 0.005), hypertension (90.91% vs
45.12%, p ¼ 0.007), higher WMH volumes (36.1065.77 vs
15.2662.11 ml,p ¼ 0.001) and higher global CDR scores(p
¼ 0.03). No significant associations were found for high
WM-DPVS degree. In multivariate analysis, age and hypertension were independent predictors of high BG-DPVS degree.
Interpretation: In individuals with cognitive impairment,
BG-DPVS are associated with vascular risk factors. WMDPVS may arise from distinct mechanisms, requiring further investigation.
Study supported by: NIA grant 5P50AG005134-28
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patients who were on heparin in the presence of intraluminal thrombi. Prior studies imply recanalization can be
achieved with heparin;however heparin should only prevent
thrombus propagation theoretically.
Methods: We compared patients with complete/partial
recanalization or improved flow versus those that did not on
CTA and angiograms;with both groups on a standard heparin infusion protocol. Recanalization was noted in
30patients and failure to recanalize in 12patients. Demographics, average PTT during heparin infusion, time
between CTAs, time from stroke onset to receiving heparin,
and vessel occluded were compared between groups.
Results: Using t-test, the average PTT between the recanalization group(60.43833) and non-recanalization(67.91833)
was not significantly different (p>0.05). The average time
between CTAs was not either(78.03 vs.70.33hrs). Durational stratification did not yield significance using the
Fischer exact test(p>0.05).
Discussion: Other studies, clinical implications, and
future directions are discussed.
Conclusion: This is the first study to compare patient
characteristics associated with recanalization of intraluminal
thrombi in acute stroke patients who received heparin infusion. Recanalization of intraluminal thrombi were not associated with average PTT or duration on heparin.
Study supported by: The authors have no disclosures
relating to the abstract.
S138. Protective Association between ACE Inhibitors
and Lobar Intracerebral Hemorrhage
Sharyl R. Martini, Matthew L. Flaherty, William M. Brown,
Charles J. Moomaw, Mary E. Comeau, Mary Haverbusch,
Dawn O. Kleindorfer, Brett M. Kissela, Joseph P. Broderick,
Carl D. Langefeld and Daniel Woo; Cincinnati, OH and
Winston-Salem, NC
Background: Treating hypertension reduces the risk of
spontaneous intracerebral hemorrhage (ICH). The PROGRESS study found fewer lobar ICHs in subjects randomized to ACE inhibitor (ACEI) þdiuretic versus placebo, but
few outcome events were ICHs.
Methods: This prospective case-control study identified
primary ICHs by hot-pursuit at Cincinnati area hospitals.
Controls were matched to each case by age, race, and gender. Each consenting subject underwent structured interview,
including self-reported medications and hypertension status.
Hemorrhage location was classified as lobar or non-lobar. A
multiple logistic regression model was computed to test for
association between ACEI use and lobar/non-lobar location;
covariates were hypertension, warfarin use, first-degree relative with ICH, education level, prior ischemic stroke, and
Apolipoprotein E genotype.
Results: 597 of 2,850 ICH cases consented and were matched
to controls (n ¼ 1548). In logistic regression, treatment with
ACEI was negatively associated with lobar ICH in hypertensive
subjects (P ¼ 0.001; OR ¼ 0.39, 95% CI ¼ 0.21–0.76), compared with non-hypertensive subjects. This association was not
significant for subjects on other antihypertensive class regimens
(P ¼ 0.141; OR ¼ 0.69; 95% CI ¼ 0.42–1.15).
Conclusion: Treated hypertension is associated with
reduced risk for lobar ICH, and this protective association
may be greatest with ACEI.
Study supported by: NIH
Salaries for several authors are/ have been paid from the
NIH grant supporting this study, or from the stroke T32
training grant at University of Cincinnati. Other co-authors
are contracted researchers paid from the NIH grant supporting the study.
S140. Cerebral Vasospasm and Anterior Circulation
Stroke Secondary to an Exacerbation of Hereditary
Corproporphyria – First Reported Case
Stephen Mullin, Andrew Platts and Kashmir Randhawa;
London, United Kingdom
Neurological sequalae are a well documented complication
of acute porphyria. Vasospam has been described in exacerbations of acute intermittent porphyria (AIP), but has not
been previously been reported in an acute attack in hereditary coproporphyria (HCP). We describe the first reported
case of porphyric crisis (triggered by rifampicin) leading to
vasospasm and stroke in a previously undiagnosed case of
HCP.
Study supported by: no support to declare
S141. Physiologic Device-Based Diagnosis of Stroke in
Acute Vertigo: Proof-of-Concept
Ali S. Saber Tehrani, Georgios Mantokoudis, John H. Pula,
Cindy Guede, Kevin A. Kerber, Richard Rothman, Daniel F.
Hanley, David S. Zee, Jorge C. Kattah and David E.
Newman-Toker; Baltimore, MD; Peoria, IL and Ann Arbor,
MI
Objective: Experts distinguish central from peripheral causes
of acute vestibular syndrome (AVS) using oculomotor findings (‘‘HINTS’’–Head Impulse test, Nystagmus, Test of
Skew). We sought to generalize this approach by using a
quantitative, portable video-oculography device to diagnose
posterior circulation stroke.
Methods: Prospective observational study at two academic medical centers (08/2011-03/2012). Convenience
sample of adult emergency department (ED) patients with
AVS defined as >24hrs of acute dizziness/vertigo, nausea/
vomiting, head motion intolerance, gait unsteadiness, and
nystagmus. We measured tolerability, usability, and diagnostic oculomotor findings according to a standard protocol
(‘‘HINTS’’). Funding limitations precluded uniform gold
standard neuroimaging (MRI DWI >48hrs after onset) in
all patients, but was available clinically in most.
S139. Heparin May Not Improve Recanalization of
Intraluminal Thrombi in Acute Stroke Patients
Haris Kamal, Ping Li, Mohammed Shafie, Max Mokin and
Bijal K. Mehta; Buffalo, NY and Torrance, CA
Background: Intravenous heparin is usually contraindicated
in acute stroke patients. We present a study of acute stroke
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tein(LDL)] measured at the Offspring 4th examination to 10year risk of incident ischemic stroke and MI.
During a mean follow-up of 9 years, 296 participants
experienced incident ischemic stroke. In multivariateadjusted analyses HDL 40 was associated with increased
risk of ischemic stroke (HR [95%CI]:1.58[1.23-2.0],
p<0.001). We did not observe any association with TC,TG
or LDL and incident ischemic stroke. In MI-free sample (N
¼ 5795, 389 events), we observed strong associations
between TC, HDL, TG and LDL and MI risk.
Conclusion: In our stroke-free sample, we observed that
low HDL, but no other lipid biomarkers were associated
with risk of incident ischemic stroke. We also observed the
usual associations between lipid biomarkers and risk of MI.
Study supported by: This work was supported by
National Institutes of Health/National Heart, Lung, and
Blood Institute Contract and the National Institute of Neurological Disorders and Stroke R01 NS17950.
Results: 88 screened; 14 eligible; 13 AVS patients
enrolled (mean age 61 years, 46% female). All patients completed testing; none vomited. Mean patient-reported comfort was 8.9/10. Mean research assistant-reported usability
was 8.4/10. In the 11 patients with definitive neuroimaging,
accuracy of stroke (n ¼ 6) versus peripheral vestibular (n ¼
5) diagnosis by video-oculography-based ‘‘HINTS’’ exam
was 100%.
Conclusion: It is feasible to perform the HINTS battery
in the ED using a video-oculography device. Preliminary
results show promising diagnostic accuracy, and further
study is warranted.
Study supported by: No funding supported this project.
The video oculography goggles were provided free of charge
by GN Otometrics, Sydney, Australia.
S142. Ischemic Burden in Relation to Apolipoprotein
B/AI Ratio in Intracranial Atherosclerotic Stenosis
Jong-Ho Park; Goyang, Republic of Korea and Seoul, Republic
of Korea
S144. Transient Aura Attacks in Cerebral Amyloid
Angiopathy Respond to Migraine Prophylactics
Patrick Pullicino, Ross W. Paterson and Ken Uchino;
Canterbury, Kent, United Kingdom and Cleveland, OH
Background: Preexisiting brain infarct (PBI), usually silent
is frequently seen on MR imaging in stroke patients. High
levels of apolipoprotein B (apoB)/apoAI ratio are a risk predictor of ischemic stroke and associated with intracranial
atherosclerotic stenosis (ICAS). Little is known about association of apoB/apoAI ratio with PBI in stroke patients with
ICAS.
Methods: A total of 522 statin/fibrate naı̈ve patients with
acute ischemic stroke were categorized into ICAS (n ¼
254), extracranial (ECAS, n ¼ 51), and no cerebral atherosclerotic stenosis (NCAS, n ¼ 217). The apoB/apoAI ratio
and demographics were compared between those with and
without PBI. PBIs were divided into deep subcortical (dsPBI) and hemispheric (h-PBI) by location.
Results: Patients with PBI showed a higher apoB/apoAI
ratio than those without (0.8160.28 versus 0.7260.23,
P<0.001). Patients with higher quartiles of the apoB/apoAI
ratio had a higher number of ds-PBI (P ¼ 0.025) in the
ICAS group. With multivariable analyses, the highest apoB/
apoAI ratio quartile was associated with ds-PBI (OR ¼
2.48; 95% CI, 1.33–4.62) and advanced (3) ds-PBIs
(2.68, 1.27–5.63) in the ICAS group. ApoB/apoAI ratio
conferred no increased risk for h-PBI.
Interpretation: A higher apoB/apoAI ratio might constitute deep subcortical ischemic burden in Asian patients with
ICAS.
Study supported by: This study was supported by a clinical research grant from Kwandong University Myongji
Hospital.
We report three patients with cerebral amyloid angiopathy
(CAA) with recurrent stereotyped migraine aura-like episodes with response to migraine prophylactics. Three
women (74, 71, 81yrs) had MRI typical of CAA. None had
prior history of migraine. Patient 1 had left sided numbness
migrating from the face to leg over minutes seven times a
day over three years. They resolved on topirimate 50mg bd.
Patient 2 had bilateral visual bright lights and pinwheels
lasting half an hour five times a day over three months
resolving with verapamil 120mg bd. Patient 3 had ten episodes of arm numbness, weakness and mumbling speech
lasting five minutes. The duration of attacks and response
to migraine prophylactics supports a ‘‘spreading depression’’
pathogenesis. The clinical distinction of these attacks from
TIAs is important as antiplatelet agents could increase the
risk of hemorrhage. Gradient echo MRI should be performed in all elderly patients with recurrent migraine like
auras. Topiramate or verapamil should be tried as treatment.
Study supported by: none
S145. Superposition of Stents in the Management of
Intracranial Aneurysms in Arterial Bifurcations
Ricardo A. Rangel-Guerra and Alberto Garcia-de la Fuente;
Monterrey, NL, Mexico and Monterrrey, NL, Mexico
Introduction: The management of aneurisms in the intracranial artery bifurcation with wide neck, was conservative
in nature and with surgical complicated techniques.
Objective: Experience with 8 cases of this type of lesions.
Material and Methods: Year 2010-2011, we collected 8
cases with intracranial aneurysms both incidental and symptomatic. Age of the patients ranged from 35-74. 7 women
and 1 man.
In all patients STENTS ENTRPRICE were used, placing
the first STENT in the most angulated artey, leaving the
micro catheter within the aneurysm for positioning the coils
inside the aneurysm for its final occlusion. All patients
received platelad antiaggregation with 600 mg of clopidogrel, 100 mg of aspirin and they were heparinized.
Results: From the 8 patients, one did not received the
coils. In all cases there was proof of complete occlusion of
the aneurysm. In 4 patients digital Pan angiography was
performed 6 months later, and it was confirmed that was no
S143. Lipid Measurements and Risk of Ischemic
Vascular Events: Framingham Study
Aleksandra Pikula, Alexa S. Beiser, Jayandra J. Himali,
Margaret Kelly-Hayes, Carlos S. Kase, Sudha Seshadri and
Philip A. Wolf; Boston, MA and Framingham, MA
Background: Lipid biomarkers are used to assess the risk of
ischemic heart disease, but their value in stroke risk assessment remains controversial. We explored the relationship
between plasma lipid measurements and incident ischemic
vascular events in our middle-aged community cohort.
Methods/Results: In 6187 stroke-free Framingham participants (64610yrs,56%F), we related plasma lipid levels [total
cholesterol (TC) and high density lipoprotein (HDL)], measured at the Original cohort 15th and 20th examination, and
[TC, HDL, triglycerides (TG) and low-density lipopro-
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recanalization or growing of the aneurysm or intra Stent
stenosis.
Conclusion: The use of DUAL ‘‘Y’’ STENTS is useul
for the management of aneurysms when located in arterial
bifurcations, avoiding the recanalization of the aneurysms.
Study supported by: I
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can precede the onset of hematologic abnormalities in TTP.
TTP should be part of the differential diagnosis of cryptogenic stroke despite absence of hematologic abnormalities.
Study supported by: UTSW Medical Center
S148. Genetic Variants Associated with Severity of
Leukoaraiosis Predict Ischemic Stroke Risk
Natalia S. Rost, William J. Devan, Jing Wang, Guido
Falcone, Poneh Adib-Samii, Matthew Traylor, Alesandro Biffi,
Kaitlin M. Fitzpatrick, Valerie Valant, Alexa Beiser, Steven
Bevan, Bradford B. Worrall, Christopher Levi, Cathie Sudlow,
Peter Rothwell, Giorgio Boncoraglio, Martin Dichgans, James
Meschia, Philip A. Wolf, Hugh Markus, Karen L. Furie,
Qiong Yang, Sudha Seshadri and Jonathan Rosand; Boston;
London, United Kingdom; Charlottsville; Newcastle, Australia;
Edinburgh, United Kingdom; Oxford, United Kingdom;
Milan, Italy; Munich, Germany and Jacksonville
S146. A Recombinant Human Neuron-Binding IgM
Protects the Brain Against Experimental Stroke by
Improving Motor Function, Reducing Infarct Volume
and Preserving Tissue Integrity
Bharath Wootla, Aleksandar Denic, Makoto Eriguchi, Istvan
Pirko and Moses Rodriguez; Rochester, MN
Cerebral ischemia induces an inflammatory pervasive environment that results in neuronal damage. We demonstrated that
the recombinant form of a natural human IgM antibody,
rHIgM12, binds to neurons in vitro and promotes neurite
outgrowth. Here we show that administration of rHIgM12
protects mice from ischemia-induced damage and improves
neurologic deficits in the photo-thrombotic model of experimental ischemic stroke. Animals administered with a single
low dose of 200 lg rHIgM12 30 minutes after stroke induction demonstrated improved locomotor function beginning 3
days after treatment, persisting until experiment termination at
30 days. Conversely, the saline control group deteriorated in
function below the baseline and did not recover (p<0.05).
The functional improvement mirrored a reduction of infarct
volume and a concomitant increase of the magnetization transfer ratio (rHIgM12 [46.060.9] vs saline [41.9þ08], P ¼
0.01) in the ischemic region (control region [59.960.9]),
which suggests preservation or partial normalization of tissue
integrity. This is the first demonstration that a fully recombinant natural human monoclonal IgM antibody directed against
neurons is efficacious in improving behavioral and MRI outcomes in animals after experimental cerebral ischemia.
Study supported by: This work was supported by grants
from Minnesota Partnership for Biotechnology and Medical
Genomics.
Background: MRI-detectable white matter hyperintensity
(WMH), or leukoaraiosis is a common and heritable stroke
risk factor. We hypothesized that the common genetic variants which contribute to WMH severity also affect individual ischemic stroke (IS) risk.
Methods: We identified single nucleotide polymorphisms
(SNPs) associated with WMH volume in a genome-wide
data meta-analysis of 2,504 IS cases enrolled through the
International Stroke Genetic and Wellcome Trust Case Control Consortia. A genetic risk score (GRS) derived as a sum
of the risk alleles across 961 loci of interest associated
with WMH at p-value<10e-4 and applied to 4,176
healthy Framingham Heart Study participants, of whom
168 developed IS.
Results: Entered as an independent variable into the multivariable Cox proportional hazards model with incident IS
as outcome, the GRS was associated with incident IS risk
(OR ¼ 1.16, p ¼ 0.03), corresponding to 16% risk increase
per each GRS unit.
Conclusions: The GRS comprised of SNPs related to
WMH burden in a large, genome-wide IS study is associated with incident IS risk among healthy adults. Shared
genetic variation may contribute to severity of leukoaraiosis
and individual stroke risk.
Study supported by: The American Heart Association
Bugher Foundation; the Massachusetts General Hospital
Deane Institute for Integrative Research in Atrial Fibrillation
and Stroke; the National Institutes of Health: NINDS
K23NS064052, R01NS059727, P50NS051343, R01
NS42733; NHLBI N01-HC-25195, and N02-HL-6-4278,
and NIH AG033193, HL093029 and NS17950; the Robert
Dawson Evans Endowment of the Department of Medicine
at Boston University School of Medicine and Boston Medical Center; the Australian Stroke Genetics Consortium; and
the Wellcome Trust (085475/B/08/Z, 085475/Z/08/Z,
WT084724MA).
S147. Acute Ischemic Stroke Caused by Thrombotic
Thrombocytopenic Purpura without Significant
Hematologic Abnormalities
Julio C. Rojas, Fazeel Siddiqui, Bardia Nourbakhsh,
Chirantan Banerjee and Craig Powell; Dallas, TX
Background: Thrombotic thrombocytopenic purpura
(TTP) is a hematologic condition that can present with
transient ischemic attack (TIA) or stroke. Neurological manifestations of TTP are typically associated with profound
thrombocytopenia, and the diagnosis is rarely suspected in
the setting of normal or near-normal platelet counts. Case
summary: We present the case of a 29 year-old Hispanic
woman who presented with an acute right middle cerebral
artery (MCA) territory stroke and mild thrombocytopenia.
Her vascular imaging, transesophageal echocardiogram,
hypercoagulable and autoimmunity markers, were unremarkable. Her stroke was considered cryptogenic in the setting of oral contraceptive use. She presented two months
later with a left MCA territory TIA and profound thrombocytopenia. She had evidence of microangiopathic hemolytic
anemia and the diagnosis of TTP was confirmed by severe
ADAMTS13 deficiency and increased ADAMTS13 inhibitory antibodies. She was treated with plasmapheresis and
steroids, with rapid improvement of thrombocytopenia and
anemia and no further neurovascular events.
Conclusion: This case highlights the major therapeutic
implications of recognizing that neurological manifestations
S149. Body Mass Index and Mortality in Acute
Ischemic Stroke
Lesli E. Skolarus, Brisa N. Sanchez, Deborah A. Levine, Kevin
A. Kerber, Lewis B. Morgenstern, Melinda A. Smith and
Lynda D. Lisabeth; Ann Arbor
Background and Purpose: Guidelines for patients with
acute ischemic stroke (AIS) recommend a goal BMI of 18.5
to 24.9 kg/m2 and are largely extrapolated from primary
cardiovascular disease prevention studies. We examined the
relationship between BMI and all-cause mortality in AIS
patients.
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Methods: AIS patients (n ¼ 1,791) were identified from
the population-based Brain Attack Surveillance in Corpus
Christi (BASIC) study from June 1, 2005 to December 31,
2010. Median follow-up was 660 days (range 0-2038 days).
All AIS patients had in-hospital self-reported BMI recorded.
The association between BMI and mortality was estimated
using Cox regression models.
Results: Median BMI was 27.1 kg/m2. After adjusting
for demographics, stroke severity, stroke and mortality risk
factors, the relationship between BMI and mortality was
U-shaped. As BMI increased from 17 to 30 kg/m2, mortality decreased. As BMI increased above 31 kg/m2 mortality
increased becoming significantly harmful when BMI reached
38 kg/m2.
Conclusion: BMI has a heterogeneous effect on mortality
in AIS patients with a protective effect for mild obesity and
a detrimental effect for severe obesity. More research is
needed on individual and incremental benefits and harms of
weight management post-stroke.
Study supported by: NIH/NINDS R01NS038916
Dr. Skolarus was supported by an American Academy of
Neurology Foundation Clinical Research Training Fellowship and is supported by NIH grant K23NS073685.
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Methods: The mononuclear cells (MNCs) were extracted
from carotid endarterectomy (CEA) samples by enzymatic
digestion and magnetic cell sorting. Gene expression of proinflammatory/pro-thrombotic (P38, ERK-1, JNKb1, EGR1, PAI-1, TLR-2 TLR-4, MMP-9, TNF-a, MCP-1, TF,
mTOR) and anti-inflammatory (PPAR-c and TGF-b) mediators were compared with the Ficoll-derived peripheral
MNCs.
Results: The expression levels of both pro-inflammatory/
pro-thrombotic and ant-inflammatory mdiators were higher
in the the CEA MNCs as compared to the peripheral
MNCs. An inverse relationship was observed between the
expression levels of inflammatory mediators in the CEA
MNCs and the peripheral MNCs of CDPS.
The p38 and PPAR-c expression levels were lower in the
CEA MNCs of symptomatic as compared to asymptomatic
patients. TLR-2, TLR-4 and PPAR-c expression levels were
higher in the peripheral MNCs of diabetic patients as compared to non diabetic patients.
Higher expression levels of MMP-9 and PPAR-c, and
lower expression levels of MCP-1 in CDPs as compared to
HCs were observed.
Conclusion: Pro-inflammatory and anti-inflammatory
mediators are upregulated in the immune cells of the
plaque.
Study supported by: Jug for the Jake
S150. Comparative Gene Expression Profiling of
Simvastatin Single and Vytorin Combination Therapy
in Hypercholesterolemic Subjects
Zohara Sternberg, Trevor Chichelli, David Hojnacki, Alison
Drake and Frederick Munschauer; Buffalo
S152. A Comparative Study of Immune Cells, and Their
Activation State, in the Carotid Plaque and in the
Peripheral Circulation
Zohara Sternberg, Kristen Glotti, Joseph Tario, Richard Curl,
Sonya Noor, Paul Wallace, Frederick Munschauer and Paresh
Dandona; Buffalo, NY
Objectives: To test the hypothesis that treatment with Ezetimibe/Simvastatin (Vytorin), a combination of lipid-lowering
agent which inhibits both intestinal cholesterol absorption
and cholesterol synthesis, leads to broader changes in immunomodulatory genes, independent from their lipid lowering
effects, when compared to Simvastatin monotherapy.
Methods: Illumina’s GenomeStudio gene expression module was used to compare both the global and the immunomodulatory gene profiles of Vytorin and Simvastatin in 20
hypercholesterolemic subjects in a randomized crossover
design.
Results: We observed alterations in gene expression postVytorin and post-Simvastatin therapy. However, broader
changes in both global gene expression and immunomodulatory gene expression were observed by Vytorin combination therapy compared to Simvastatin monotherapy.
In addition, the characteristics of the immunomodulatory
genes altered by Vytorin were different from those altered
by Simvastatin: Vytorin mostly altered the expression levels
of genes related to inflammation/oxidative stress and cellular
adhesion/migration/coagulation, while Simvastatin mostly
altered the expression levels of genes related to cellular apoptosis/cell proliferation.
Furthermore, Vytorin combination therapy reduced various components of lipid profiles more effectively than Simvastatin monotherapy.
Conclusion: The nature of the pleiotropic effects may
play a role in Vytorin’s and Simvastatin’s clinical efficacy.
Study supported by: Merck
Objective: This study aimed to characterize, quantify and
compare mononuclear cells’(MNCs) subpopulations
between carotid endarterectomy (CEA) samples and those
cells in the peripheral circulation.
Methods: MNCs were extracted from 16 CEA samples
by enzymatic digestion. Peripheral MNCs of the carotid
patients (CPs) and 12 age- and gender-matched healthy
controls (HCs) were separated by Ficoll. Resting (R) and
activated (A) MNCs were compared between carotid CEA
and peripheral circulation.
Results: The percentage of R-MNCs was lower, and that
of A-MNCs was higher in the CEA samples as compared to
the peripheral circulation. The percentage of the peripheral
A-T cells and A-B cells were higher in CPs as compared to
HCs, Symptomatic patients showed a trend toward a higher
percentage of peripheral A-MNCs, and a lower percentage
of the CEA A-MNCs as compared to asymptomatic
patients. Patients stratification based on the use of anti-diabetic medications showed a trend toward a higher percentage of A-MNCs in both the peripheral circulation and in
the CEA samples of those patients on anti-diabetic drugs.
Conclusion: The immune inflammatory status is upregulated in the environment of the carotid plaque.
Study supported by: Jug for the Jake
S153. Dissection in the Veterans’ Administration
(DIVA): Re-Examining Spinal Manipulation and
Cervical Artery Dissection
David E. Thaler, Xuemei Cai, Ali Razmara, Karen
Switkowski, Sergey D. Goryachev, Leonard D’Avolio, Pari J.
Fariborz and Edward Feldmann; Boston, MA
S151. Immune Inflammatory Cross-Talk between
Carotid Plaque and Peripheral Circulation
Zohara Sternberg, Husam Ghanim, Elad Levy, Adnan
Siddiqui and Paresh Dandona; Buffalo, NY
Objectives: To characterize, quantify and compare the contribution of immune cells to the inflammatory status in the
carotid plaque and in the peripheral circulation.
Background: Cervical artery dissection (CAD) has been
associated with spinal manipulative therapy (SMT) in case
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series and case-control studies. Cassidy et al also associated
case status with primary care physicians (PCP) visits, so
questioning the causal effect attributed to SMT. We
hypothesized that Cassidy’s case definition included subjects
with strokes unrelated to dissection which would confound
their conclusion.
Methods: We searched the national VA electronic medical
record (EMR) for ICD9 codes that defined cases for Cassidy
(433.0x, 433.2x). EMR text from these records was searched
for the word ‘‘dissection.’’ Records were manually reviewed
by vascular neurologists to diagnose atraumatic CAD.
Results: The EMR contained 11,372 unique subjects
with the specified ICD9 codes. Of those, ‘‘dissection’’ was
found in EMR text documents in 19%. Manual review of
50 randomly selected records found 2 (4%) atraumatic dissections and 1 (2%) involving the vertebral artery.
Conclusions: Our data suggest that ICD-9 codes have
low specificity for dissection and misclassify cases. Assuming
that misclassification does not differ by exposure to SMT,
Cassidy likely underestimated the association of SMT and
dissection. Uncontrolled confounding likely explains the
relationship between cases and PCPs.
Study supported by: CTSI Pilot Grant
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posterolateral thalamic nucleus (VPL). Lesioned mice develop robust and long-lasting mechanical allodynia and cold
hypersensitivity in the contralateral hind paw. We tested two
prevailing hypothesis concerning CPSP pathogenesis,
namely (1) that disinhibition of the medial pain system after
VPL lesion contributes to CPSP and (2) that the thalamic
lesion itself induces lateral thalamic hyperexcitability.
Our results show that inhibiting the medial pain system
by blocking TRPV1 positive nerve endings peripherally or
ablation of a major afferent projection (spinal cord lamina
I) did not reduce pain behavior in the CPSP model. In contrast, microinjecting lidocaine into VPL of CPSP mice to
reduce hyperexcitability completely reversed tactile and cold
hypersensitivity. In conclusion, we have generated the first
mouse model of CPSP and provided evidence that CPSP
results from increased lateral thalamic excitability rather
than a disinhibited medial pain system. In addition to providing pathophysiologic insights, this model might prove
useful for testing new therapies.
Study supported by: Post-doc fellowship of the Medical
Faculty of the University of Heidelberg
S156. The Third International Stroke Trial (IST-3) of
Intravenous rt-PA: Effect of Age and Time among 3035
Patients Randomised
Graham Venables, Richard Lindley, Peter Sandercock, Joanna
Wardlow and Geoff Cohen; Sheffield, United Kingdom;
Sydney, Australia and Edinburgh, United Kingdom
S154. Lobar Microbleeds without Intracerebral
Hemorrhage: A Clinical, Genetic and Neuroimaging
Analysis
Ellis S. van Etten, Eitan Auriel, Alison M. Ayers, Anastasia
Vashkevich, Kristin M. Schwab, Jonathan Rosand, Anand
Viswanathan, Steven M. Greenberg and M. Edip Gurol;
Boston, MA
Background and aims: IST-3 seeks to improve the external
validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic
stroke, and to determine whether a wider range of patients
might benefit.
Methods: International, multi-centre, prospective,
randomized, open, blinded endpoint (PROBE) trial of
intravenous rtPA 0.9 mg/kg in acute ischaemic stroke.
Patients had to be assessed and able to start treatment
within 6 hours of developing symptoms, and brain imaging
must have excluded intracranial haemorrhage and stroke
mimics; detailed protocol at www.ist3.com.
Results: We will report effects of time to randomisation
and age on response to treatment among the 3035 patients
recruited.
Conclusion: The data from the trial will provide new
evidence on the effect of age and time on the benefit from
intravenous rtPA in a wider range of patients, especially
among patients over 80 years, a group which has largely
been excluded from previous randomised acute stroke
thrombolysis trials.
Study supported by: Australian Heart Foundation, Australian NHMRC, Dalhousie University Internal Medicine
Research Fund. Norwegian Research Council. Government
of Poland. AFA Insurances, the Swedish Heart Lung Fund,
Karolinska Institutet, Stockholm County Council, ALF-project grants. Swiss National Science Foundation, Swiss Heart
Foundation. Medical Research Council UK, The Health
Foundation, The Stroke Association, DeSACC, The University of Edinburgh. Drug and placebo for the 300 patients in
the double-blind component of the start-up phase were supplied by Boehringer-Ingelheim UK.
Background/Objective: The classical presentation of cerebral amyloid angiopathy (CAA) is lobar intracerebral hemorrhage (ICH), but lobar microbleeds (MB) are frequently
detected on MRI in the absence of ICH. We compared the
risk factors, genetic and radiologic features of these patients
to CAA patients with lobar ICH.
Methods: Data on vascular risk factors and apolipoprotein E (APOE) genotype were compared between 511 CAA
patients presenting with ICH and 79 without ICH. Microbleed counts and Pittsburgh Compound B (PiB) retention
on PET were also compared.
Results: Patients presenting without ICH were younger
(70610 vs 7469.9,p ¼ 0.002), more likely to have ApoE4
allele (54% vs 37%,p ¼ 0.009) and hypercholesterolemia
(47% vs 32%,p ¼ 0.011) after adjustment for other risk factors and statin use. Patients without ICH had more lobar
MBs(p<0.001). Global and regional values of amyloid deposition on PiB-PET were similar between the groups, including
high occipital/frontal ratios characteristic of CAA pathology.
Conclusion: Patients who present with lobar MBs on
MRI without ICH have a clinical, genetic, and neuroimaging profile suggestive of severe CAA pathology. These data
raise the possibility that particular clinical or genetic factors
may influence whether advanced CAA proceeds to trigger
lobar ICH.
Study supported by: S155. A New Mouse Model for Central Post-Stroke Pain
Simon Gritsch, Rohini Kuner and Daniel Vardeh; Heidelberg,
Germany and Boston
S157. Should We Thrombolyse the Oldest Old?
Julio R. Vieira, Shankar Awasthi and Barbara Koppel;
New York, NY
Approximately 8% of stroke victims suffer from chronic
post stroke pain (CPSP), but the underlying pathophysiology and anatomical substrate remain poorly understood.
We generated a mouse model of CPSP, produced by
either a hemorrhagic or excitotoxic lesion of the ventral
Objective: Determine if patients age >80 or with recent
Coumadin use can safely receive thrombolysis.
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Background: Although age >80 is a relative tPA exclusion, this includes many stroke patients. We sought predictors of poor outcome in this group.
Design/Methods: Analysis of all stroke codes, 20072011, for outcome in elderly and those recently using
coumadin.
Results: A 90 year-old woman on Coumadin (INR ¼
1.1) for atrial fibrillation presenting with aphasia and hemiparesis suffered terminal multifocal hemorrhages three hours
after thrombolysis. During this period, tPA was given to five
patients with history of Coumadin use and INR<1.6, with
one other death due to GI bleeding. Hemorrhagic transformation occurred in a 63 year-old man. A 94 year-old
woman did not improve with tPA. Overall, 19% of 214
stroke-codes were for patients >80 years.
Conclusions: Clinicians will increasingly have to decide
on tPA use in the elderly. Without recent Coumadin use,
(mortality rate 40%), its use appears safe. Coumadin,
advanced age, and possible amyloid angiopathy contributed
to ICH in our patient. In our center, tPA is now avoided in
anyone who has used Coumadin in the previous week, or
dementia, but clinical judgement is needed in the
oldest old.
Study supported by: No financial support
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abnormal findings such as cerebral venous sinus thrombosis(CVST). She had high fever, tachycardia, bloody stool
and diarrhea. Blood examination showed anemia and elevated erythrocyte sedimentation rate(ESR), suggesting her
UC was uncontrolled. We started intravenous(iv) glycerol,
antibiotics and mesalazine for UC. Neurological deficit
improved quickly but on the fifth day of hospitalization,
brain CT showed another intracerebral hemorrhage at the
right occipital lobe, and the initial edema increased. We
considered her condition as brain hemorrhage caused by cerebral vasculitis due to UC and added iv steroids followed by
oral prednisolone. After steroid therapy, edema on brain
MRI improved in a short time and the patient discharged
with no sequela. UC is a rare cause of stroke. Although
most of them are CVST, there are few reports of cerebral
vasculitis with brain hemorrhage.
Study supported by: none
S160. Genetic Variants on 9p21.3 Are Associated with
Brain Arteriovenous Malformations with Associated
Flow-Related Arterial Aneurysms
Helen Kim, Nasrine Bendjilali, Jeffrey Nelson, Shantel M.
Weinsheimer, Mark Segal, Charles E. McCulloch, Ludmila
Pawlikowska and William L. Young; San Francisco, CA
Background: The 9p21.3 locus is associated with risk of
coronary artery disease and intracranial and abdominal aortic aneurysms (rs10757278). We investigated whether previously reported 9p21.3 SNPs are associated with risk of brain
arteriovenous malformations (BAVM), which often have
accompanying flow-related arterial aneurysms.
Methods: Genotypes for 6 SNPs, including rs10757278,
were imputed using 1000 Genomes Phase 1 CEU data
(R2>0.9). We tested for association using logistic regression
of imputed dosages adjusting for age, sex and top 3 components of ancestry in: (a) 338 BAVM cases vs. 504 controls,
(b) 75 BAVMþ(with) aneurysm cases vs. 504 controls, and
(c) 150 BAVM-(without) aneurysm cases vs. 504 controls.
Results: rs10757278-G was marginally associated with
BAVM (OR ¼ 1.23, 95% CI ¼ 0.99-1.53, P ¼ 0.064).
Compared to controls, the association was stronger in
BAVMþaneurysm (OR ¼ 1.50, 95% CI ¼ 1.03-1.89, P ¼
0.035) than in BAVM-aneurysm cases (OR ¼ 1.03, 95%
CI ¼ 0.77-1.33, P ¼ 0.832). Similar effects were observed
for other SNPs in linkage disequilibrium (r2>0.8) with
rs10757278.
Conclusion: Common 9p21.3 variants showed similar
effect sizes as previously reported for aneurysmal disease.
The SNP association with BAVM appears to be explained
by known association with aneurysms, suggesting that
BAVM associated aneurysms share similar vascular pathology mechanisms.
Study supported by: K23 NS058357 (HK), R01
NS034949 (WLY), and P01 NS044155 (WLY)
S158. Early Arrival to Stroke Centers Should Be Most
Emphasized in Public Education Concerning Strokes
Kuniyasu Wada, Tadashi Terasaki, Yasuhiro Ogata and Yukio
Ando; Kumamoto, Japan
Objective: To clarify effective methods for public stroke
education, we investigated the chronological change of
stroke awareness after the approval (2005) of the intravenous alteplase treatment in Japan.
Methods: Every December from 2006 to 2009 a questionnaire was conducted for subjects subscribed to the complete health screening checkup program of our hospital.
Results: The questionnaire response rate was 77.1%
(7,814/10,130 subjects). While the respondents who knew
the name or method of alteplase treatment had increased
between first and second year (30.5% vs. 38.6%;
p<0.0001), no change was seen between second, third or
fourth years (38.6% vs. 39.6% vs. 38.0%). During the survey period, public knowledge of stroke risk factors and
symptoms remained unchanged. However, there was a continuous increase in the number of respondents from first to
forth year, who would decide on consultation ‘‘immediately’’
or ‘‘several minutes -1 hour’’ after the onset of symptoms
(33% vs. 40%; p<0.0001).
Conclusion: Since knowledge of the necessity of haste is
easier to improve and maintain than that of stroke risk factors, symptoms or specific treatment, early arrival to stroke
centers should be most emphasized in public education.
Study supported by: N/A
S161. Impact of Acute Ischemic Stroke Treatment in
Patients over Age 80: The SPOTRIAS Consortium
Experience
Joshua Z. Willey, Santiago Ortega-Gutierrez, Nils Petersen,
Pooja Khatri, Andria L. Ford, Natalia S. Rost, Latisha K. Ali,
Nichole R. Gonzales, Jose G. Merino, Brett C. Meyer and
Randolph S. Marshall; New York, NY; Cincinnati, OH;
St. Louis, MO; Boston, MA; Los Angeles, CA; Houston,
TX; Bethesda, MD and San Diego, CA
S159. Recurrent Brain Hemorrhage Caused by Cerebral
Vasculitis Due to Ulcerative Colitis: A Case Report and
Review
Heisuke Mizukami, Toshiyuki Yanagisawa, Hisanao Akiyama,
Yuta Hagiwara, Takahiro Shimizu, Makoto Shiraishi and
Yasuhiro Hasegawa; Kawasaki, Kanagawa, Japan
53 year-old right-handed female, with a 23-year history of
ulcerative colitis(UC), presented with sudden onset of disorientation and sensory aphasia. Brain CT showed intracerebral hemorrhage at the left temporal lobe and low density
area surrounding the hemorrhage which was considered as
edema. Angiography and CT Angiography showed no
Background: Few acute stroke studies have included
patients 80 years. We outline in-hospital outcomes in (1)
patients 80 years versus <80, and (2) those 80 receiving
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intra-arterial therapy (IAT) compared to those treated with
intravenous recombinant tissue plasminogen activator
(IVrtPA).
Methods: SPOTRIAS (Specialized Program of Translational Research in Acute Stroke) centers prospectively collected data on all patients treated with IVrtPA or IAT from
1/1/2005 to 12/31/2010. IAT was categorized as bridging
therapy (BT: IAT after IVrtPA), and endovascular therapy
alone (ETA). In-hospital mortality was compared in (1)
patients age 80 versus <80, and (2) IAT/BT/ETA versus
IVrtPA only among those age 80 using multivariable logistic regression.
Results: 3378 were treated with IVrtPA, 808 with IAT
(383 with ETA and 425 with BT). Patients 80 (n ¼
1182) had a higher risk of in-hospital mortality compared
to younger counterparts. Among those age 80, IAT (OR
0.95, 95%CI 0.60-1.49), BT (OR 0.82, 95%CI 0.47-1.45),
and ETA (OR 1.15, 95%CI 0.64-2.08) versus IVrtPA were
not associated with increased in-hospital mortality.
Conclusions: IAT does not appear to increase the risk of
in-hospital mortality among those over age 80 compared to
intravenous thrombolysis alone
Study supported by: SPOTRIAS is funded by the
National Institutes of Neurological Diseases and Stroke
(NINDS P50 NS049060). JZW was funded by NINDS
1K23 NS 073104-01A1 and the NIH Loan Repayment
Program (AG 31009).
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Conclusion: The NGT method succeeded in streamlining
the process of identifying competencies, learner levels, and
prerequisites used to develop competency-based curricula for
training clinicians in appropriate use of neuromodulation
device therapies.
Study supported by: Medtronic, Inc
Some authors are employees or consultants for Medtronic
S202. Improved Timeliness of Neurology Consults
in the Emergency Department
Marius Birlea*, Charles Braun, Drew Kern, William Jones,
Steven P. Ringel and Kenneth L. Tyler; Aurora, CO
Efficient neurological consultation in the Emergency
Department (ED) is desirable because of a high volume of
ED patients, ED congestion and delays in care. Neurology
residents at the University of Colorado, who are responsible
for both ED consults and inpatients, documented 136 randomly selected consults they performed in the ED over 4
months. A structured questionnaire was used to analyze
components of the consult response process for 60 consults
evaluated during an initial 2 months phase, and then following an intervention, response times for 76 consults during the subsequent 2 months were evaluated. The intervention was to ‘‘prioritize’’ consults in the ED over other
inpatient activities: time limits were set for the Neurology
residents to start examination (‘‘time to start’’) and complete
the consult (‘‘time to peak’’). Consequently, the median
‘‘time to start’’ and ‘‘time to peak’’ were reduced by 21
minutes and 30 minutes respectively. Also, the median
length of stay in ED for all patients receiving Neurology
consults decreased by 37 minutes, and by 83 minutes for
those directly discharged from the ED. There were no
adverse outcomes in inpatient care or education using this
new strategy.
Study supported by: N/A. None
Education
S201. Competency-Based Curricula in Neuromodulation
Device Therapies
Bruce Bellande, Zev Winicur, John Huffman, Maged Hamza,
David Caraway, Michael Saulino, Michael Turner, David
Charles, Bruno Gallo, Kevin Benson, Steven Siegel, Mary
Elizabeth Nelson, Susan Bennett, Susan Heath, Gail
McGlothlen, Myra Joseph-Gonzales, Glenn Sulley, Cynthia
Reese, Suzanne Dawidowicz, Kathleen Cox, Jamie Boche,
Andrea Larson and Peter Scott; Carmel, IN; Silver Spring,
MD; Richmond, VA; Huntington, WV; Philadelphia, PA;
Indianapolis, IN; Nashville, TN; Miami, FL; Sioux Falls, SD;
Woodbury, MN; Milwaukee, WI; Buffalo, NY; San Francisco,
CA; Napa, CA; San Antonio, TX; Oklahoma City, OK and
Minneapolis, MN
S203. What? No Ascending Paralysis?
Joseph Khalil and Frank Hrisomalos; Indianapolis, IN
Guillain-Barre syndrome should be categorized as a group
of syndromes with several distinct subtypes. The common
presentation of ascending paralysis is not essential for
diagnosis.
A 53 yo Male presented with a constellation of neurologic symptoms following a giardial diarrhea treated with
flagyl. Recent history included extensive camping in Colorado and Kentucky, spring water ingestion, and multiple
mosquito bites. Notable findings included generalized weakness, hyporeflexia, severe lower back pain, bilateral posterior
leg and hand pains and paresthesias, perioral numbness, and
dysautonomia including constipation, urinary retention,
hot/cold reversal, and hypertension. Differential diagnosis
was wide given this unique history and nonspecific pattern
of findings. Among the many conditions considered were an
acute neurological process, acute infectious process, flagyl
toxicity, vitamin deficiency, and rare toxic exposure.
CSF, EMG, MRI strongly revealed classic findings for
GBS. Viral serologies and serum assays were negative. We
concluded that the patient displayed an atypical presentation
of GBS. Notably, his autonomic instability and extremity
pains/paresthesias, classify his disease as a mixture of pure
sensory and dysautonomic subtypes. Symptoms improved
with 5 days of IVIG.
Our patients atypical presentation provides insight into
the heterogeneity of this disease and resulting diagnostic
challenges that may arise.
Study supported by: self
Introduction: Education in neuromodulation devices has
generally lacked a systematic curriculum, using instead a
loosely related series of didactic and hands-on activities heavily dependent on individual faculty input. To improve neuromodulation device education, systematic development of
competency-based curricula in four therapeutic areas was proposed, and a short-term, modified Nominal Group Technique (NGT) was tested to more efficiently validate and
stratify competencies identified by educational planners from
existing course content in deep brain stimulation for Parkinson’s disease, tremor, and dystonia; sacral nerve stimulation
for bladder and bowel control; neurostimulation for pain
control; and intrathecal drug delivery for pain and spasticity.
Methods: In three NGT rounds, therapy-specific physician and midlevel provider panels reviewed the identified
competencies to validate relevance; assess learner level; and
specify sequencing.
Results: In 10 weeks, panelists validated 109 neurostimulation competencies for physicians/fellows and 44 for midlevels; 108/93 in sacral nerve stimulation; 121/98 in deep
brain stimulation; 234/277 for intrathecal baclofen for spasticity; and 117/97 for intrathecal drug delivery for pain.
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S204. A Survey To Identify Neurology Education in
Africa
Heather Koons and Gretchen Birbeck; Nashville, TN and East
Lansing, MI
S207. The Neurology Boot Camp: Tackling the ‘‘July
Phenomenon’’
Wazim Mohamed, Maysa M. Basha and Benjamin E.
Atkinson; Detroit, MI
Objective: We sought to develop an overview of neurology
educational opportunities in Africa.
Methods: The survey was constructed for general physicians or non-physician healthcare workers involved in neurologic care. Email addresses were identified through the
World Federation of Neurology. The survey was distributed
electronically but recipients were offered the option of feedback by post, fax, or return call.
For non-responding countries, inactive email addresses, or
where no respondent was identified, we conducted a Pub
Med and Google Scholar search with criteria using country
names.
Results: 26 respondents from 15 countries provided information for 28% of African countries. Respondents were
neurologists (34.6%) and non-neurologist physicians
(65.4%). All reported that non-physician healthcare workers
provide neurologic care in their country. There were no
neurologists or neurosurgeons practicing within country for
20 and 12% respectively. Where specialist care was available,
33% were trained in country, 29% partly in other countries,
and 38% entirely in other countries. Neuro-educational
opportunities identified included pharmaceitical seminars
and local medical society meetings.
Conclusions: This 2011 survey yielded response rates
and data similar to the WHO Neurology Atlas (20052006), suggesting little has changed in terms of neurologic
resources in Africa of the past 5 years.
Study supported by: No one.
Introduction: The ‘‘July Phenomenon’’ is the propensity of
newly appointed residents to make medical errors. Our residency program requires the incoming residents to manage
neurological emergencies they face in the intense care unit.
We hypothesize that a ‘‘boot camp’’ would help the residents make this transition.
Methods: A 4 day camp was held in July for incoming residents. The camp dealt with neurological emergencies including training in acute stroke management.
Residents took a pre-test, post-test and an 8 month
post-test. Residents were also asked to complete an
anonymous survey.
Results: The median pre-test,post-test and 8 month
post-test scores were 98(35-149),158(150-166) and
142(124-164) respectively. There were significant differences between the pre-test and post-test(p < 0.001); the pretest and 8 month post-test(p < 0.001); the post-test and
8 month post-test (p ¼ 0.006). 82% of residents agreed
that the camp helped them prepare for emergency
situations.
Discussion: Admissions at the beginning of July are associated with increased number of preventable errors. Training
in competency based education can prepare residents for
these challenges. A neurosurgical bootcamp conducted in
2010 concluded that it provides a model for enhanced
learning and safety. The median score after our camp
increased significantly and helped the residents deal with
emergent neurological situations as reflected by 82% in the
survey.
Study supported by: None
S205. Withdrawn
S206. Neurological Diagnoses among the Uninsured
Farrah J. Mateen; Baltimore, MD
S208. Who Needs Us Most? – Seeking out Those
Needing Rapid Neurological Assessment
Catriona L. Gribbin, Edward J. Newman, Paul Gallagher
and John Paul Leach; Glasgow, United Kingdom
Background: An estimated 48.2 million people, or 18% of
the U.S. population, <65 years old, lack health insurance.
Methods: A search was performed of all billing records at
the Johns Hopkins Medical Institutions in Maryland including 2 large urban referral hospitals and 3 outpatient centers
(July 2000-Feb 2012) for all inpatient and outpatient international classification of disease-9 diagnoses made within
the Department of Neurology for Medicaid, pending Medicaid, charity care, and non-voluntary self-pay visits. Comparison was made to all visits insured by Blue Cross/Blue
Shield CareFirst.
Results: There were 913 separate diagnoses for 43,268 visits among the uninsured including self-pay (54%), Medicaid
(39%), pending Medicaid (7%), and Charity Care (<1%).
The leading diagnoses were other convulsions(8%), transient
alteration of awareness(6%), cerebrovascular disease(4%), scoliosis and kyphoscoliosis unspecified(3%), intractable partial
epilepsy(3%), cerebral artery occlusion with cerebral infarction(3%), and unspecified neuropathy(3%). There were
40,644 diagnoses among those covered by CareFirst with the
most frequent being unspecified neuropathy(6%), intractable
partial epilepsy(6%), transient alteration of awareness(5%),
multiple sclerosis(4%), and dizziness(3%).
Conclusions: The uninsured and insured have similar
common chronic neurological diagnoses but the uninsured
bear a heavier burden of acute, life-threatening neurological
diagnoses upon presentation compared to an insured group.
Study supported by: Dr. Mateen is supported by the
American Academy of Neurology Practice Research Fellowship Grant.
Introduction: Up to 30% of neurology out-patient referrals
result from functional symptoms, many of which are purely
sensory. We need to provide faster access to those most in
need of our expertise.
Methods: General referrals to a neurology service were
vetted by a single neurologist (JPL) over a 3-month period
(June- August 2011). Communications reporting isolated
sensory symptoms were recorded. Histories suggesting
peripheral neuropathy or mononeuropathy were excluded.
We recorded additional history, examination findings, results
of investigations and final diagnosis.
Results: 69 patients (68% female, median 43 years) were
included. Eleven (15.9%) patients failed to attend. The final
diagnosis was as follows: medically unexplained symptoms
(MUS) (56.9%); degenerative spinal disease (12.1%);
mononeuropathy (12.1%); migraine with aura (6.9%); and
multiple sclerosis (5.2%). In 5.2%, the diagnosis remained
elusive. The strongest predictors of organic disease were
abnormal clinical examination, odds ratio 5.1 (95% CI 1.7
– 16.0), and additional history of non-sensory symptoms,
odds ratio 2.5 (0.8-7.5).
Conclusion: The most common underlying diagnosis
was functional disorders. The proportion of functional disorders was higher than in previous studies, but only 13.0%
had significant neurological conditions unheralded by the
referral letter.
Study supported by: No funding required for study
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S209. Churg–Strauss Syndrome in a Patient Previously
Diagnosed with Multiple Sclerosis: A Case Report
Pamela Sarkar, Richard T. Ibitoye and Douglas A. Promnitz;
London, United Kingdom; Preston, United Kingdom and
Ipswich, United Kingdom
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S302. Emerging Therapeutic Targets in Merlin-Deficient
Tumors
Clemens O. Hanemann, Sylwia Ammoun and Lu Zhou;
Plymouth, United Kingdom
Deficiency of the tumor suppressor protein merlin leads to
the development of benign tumors of the nervous system
such as schwannomas, ependymomas and meningiomas.
These tumors can occur spontaneously or as part of a tumor
predisposition syndrome called neurofibromatosis type 2
(NF2), which involves multiple tumors. Schwannomas are
the hallmark tumors of NF2 and are the most frequent and
well-characterized of the merlin-deficient tumors. Surgery or
radiotherapy are used to treat single tumors and can leave
the patient with substantial morbidity. Limitations of other
treatment options for merlin-deficient tumors, such as the
lack of effectiveness of chemotherapy, have led to an urgent
requirement for new pharmaceutical therapies. Merlin-deficient tumors are genetically well-defined, which allows
rational testing of new molecular therapies that have been
developed and successfully used to treat various cancers in
the past few years. We will prsent data on receptor tyrosine
kinases—the ErbB family, platelet-derived growth factor
receptor b, insulin-like growth factor 1 receptor, and vascular endothelial growth factor receptors —focusing on their
role in schwannoma pathobiology and the therapeutic
potential of targeting these receptors and their downstream
signaling pathways. Initial results of early clinical trial results
will also be presented.
Study supported by: none
Objective: We present how a systemic vasculitis such as
Churg–Strauss Syndrome (CSS) can clinically be missed, by
discussing a case with Multiple Sclerosis (MS), the diagnosis
of which we questioned.
Case Report: We discuss a case of a woman in her 70s,
admitted with cough and breathlessness.
MS was diagnosed in her 50s with a 5-year history of
right leg weakness. Positive findings included oligoclonal
immunoglobulin G bands in CSF unmatched with
serum, and bilateral delay on visual evoked responses.
Myelography was normal. In her 60s, asthma was diagnosed, with symptoms refractory to corticosteroids, and
features suggestive of rhinosinusitis. Transient eosinophilia
was noted.
During this admission, she developed left-sided weakness.
Eosinophils were increased and p-ANCA was positive. MRI
head showed multiple areas of increased signal intensity on
the diffusion weighted, T2 and fluid-attenuated inversion
recovery sequences, consistent with vasculitis. NCS confirmed extensive axonopathy, again consistent with
vasculitis.
CSS was thus identified as the unifying diagnosis for the
chronic and acute illness.
Conclusions: CSS is often diagnosed late due to insidious onset, vague symptoms, and masking of disease by
steroid treatment. Neurological sequelae of CSS may be
misdiagnosed as MS.
Study supported by: No conflict of interests
S303. Ataxia, Ophthalmoplegia and Areflexia: What
Would You Think?
Nazia Karsan, Phillip Fletcher, Istvan Bodi and Bridget K.
Macdonald; London, United Kingdom
A fit and well 44 year old man presented with a short history of fever, abdominal pain, headache and vomiting. The
case posed diagnostic difficulty as in quick succession he
developed multiple problems including an antibody-negative
Miller Fisher Syndrome (MFS). A post-mortem showed carcinomatous meningitis secondary to signet cell adenocarcinoma. We present this case of carcinomatous meningitis
presenting as MFS, alongside a literature review of previously reported cases. There are four further cases described
in the literature with evidence of tumour invasion within
the central nervous system shown either on cerebrospinal
fluid examination or histology. There are a further five cases
described in which an association between cancer and a
Miller Fisher phenotype has been shown. Some of these
have identified anti-ganglioside antibodies in the serum and
one case also showed antibodies deposited within the primary tumour itself. We hypothesise whether there could be
a paraneoplastic form to MFS. It would be informative
when further cases present in this way to histologically
examine for malignant CNS invasion, and the presence of
anti-ganglioside antibodies in both the malignant primary
and in areas of nervous system thought to be affected in
MFS.
Study supported by: No financial support required
Neuro-oncology
S301. Cerebrospinal Fluid and MRI Analysis in
Leptomeningeal Carcinomatosis
Ameya Save, Nicholas Blondin and Joachim Baehring; New
Haven, CT
Given the importance of prompt diagnosis of neoplastic
meningitis (NM), measurement of the sensitivity of diagnostic methods (CSF cytopathology (CYT), MRI) and evaluation of the impact of diagnostic delay on patient survival is
critical.
We performed a retrospective analysis of patients with
NM referred to a single investigator between 2002 and
2010. We calculated the sensitivity of CYT and MRI. Diagnostic delay was calculated as the time from symptom onset
to objective diagnosis of NM.
83 patients were identified (primary CNS tumors 24,
Non-Hodgkin lymphoma (NHL) 19, breast cancer 15).
The overall sensitivity of CYT and MRI for all tumors
was 0.49 and 0.79, respectively. Sensitivity was 0.22
(CSF)/0.91 (MRI) in patients with primary CNS tumors,
0.29/0.50 in NHL, and 0.60/0.77 in breast cancer.
Patients with melanoma had the largest mean diagnostic
delay (56 days) followed by those with primary lung cancer (39 days).
This study represents one of the largest series of patients
with NM evaluated at a single institution. In our experience,
MRI provides a higher sensitivity than CYT analysis, however, the sensitivity of both diagnostic methods depends
largely on the type of primary cancer.
Study supported by: not applicable
S304. Use of Rituximab in a Case of Paraneoplastic
Sensorimotor Neuropathy with Positive ANNA-1
Antibodies
Inhyup Kim, Shyla Kodi and Etta Eskridge; Valhalla, NY
A 62 year old Caucasian woman smoker, presented with
gait dysfunction, lower extremity numbness and pain. Both
sensory and motor deficits lead to a diagnosis of
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inflammatory demyelinating sensorimotor polyneuropathy.
She was treated with IVIG with marked improvement and
discharged home. One week later, she was readmitted with
seizures and found to have a frontal lobe lesion which upon
biopsy showed perivascular cuffing and gliosis. Subsequently
she developed respiratory failure and worsening motor
strength, leading to a diagnosis of paraneoplastic syndrome
with elevated anti-Hu autoantibodies. She again received
IVIG, plasmapheresis and oral prednisone with some
improvement in upper extremity strength but remained ventilator dependent. A course of rituximab was initiated, after
which a lung biopsy finally revealed Small Cell Lung Carcinoma (SCLC) after seven bronchoscopies. She elected to
undergo chemotherapy but remains ventilator dependent
with no use of her upper extremities. Our case shows that
multiple immunomodulator treatments may have limited
effect in paraneoplastic sensorimotor neuropathy but the
role of rituximab remains unclear and may have the effect
of unmasking the underlying neoplasm. The Hu antibody
titer increased following rituximab treatment and remains
elevated.
Study supported by: none
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MRI of the brain demonstrated multiple cystic and nodular enhancing intraparenchymal lesions, some containing
blood products. Biopsy of a right frontal lesion confirmed
metastatic prostate adenocarcinoma. No meningeal, calvarial, or spinal metastases were detected.
Intraparenchymal brain metastasis from prostate cancer is
rare, and multiple infratentorial and supratentorial metastases are exceedingly uncommon. In the largest case series to
date, of 16,280 patients with prostate carcinoma, 103
(0.63%) had parenchymal metastases. In most cases, metastases were singular and supratentorial. Only three of the
103 (3%; 0.0189% overall) patients had both infratentorial
and supratentorial metastases.
In general, the distribution of metastases in the central
nervous system is thought to depend on hemodynamics (the
mechanical hypothesis) as well as genetic changes in some
cancer cells that allow them to find the biochemical environment of the brain a favorable place in which to grow
(the seed and soil hypothesis).
Study supported by: N/A
S307. Evaluating Corneal Innervation as a Surrogate for
Skin-Biopsy Diagnosis of Small-Fiber Polyneuropathy
Giulio Ferrari, Nambi Nallassamy, Heather Downs, Reza
Dana and Anne Louise Oaklander; Boston, MA
S305. Use of Body-CT and PET-CT in the Investigation
of Paraneoplastic Neurological Syndromes: Retrospective
Audit of Practice in a UK Neuro-Science Unit
Deacon Z.J. Lee, Ammar Kheder, Mhairi Forbes, Ian Craven
and Marios Hadjivassiliou; Sheffield, South Yorkshire, United
Kingdom
Peripheral neuropathy (PN) can cause disabling widespread
pain, sensory loss, weakness, and dysautonomia. Cancer
chemotherapy drugs are common causes, and onset of PN
sometimes forces withdrawal or retrenchment of effective
chemotherapy treatments, hence careful monitoring for PN is
essential. Electrodiagnostic study effectively detects and quantifies PN affecting myelinated fibers but is insensitive to the
small-fiber PN that causes neuropathic pain, often the most
disabling symptom. Objective testing for small-fiber PN currently involves quantitating epidermal innervation in distalleg skin biopsies, however chemotherapy magnifies the small
risk of infection. In vivo corneal confocal microscopy now
enables noninvasive imaging of sensory nerve endings, so its
diagnostic utility for PN is worth investigating. We compared
small-fiber innervation of plantar-hindpaw skin and cornea in
mice intoxicated by a common chemotherapy neurotoxin.
Paclitaxel (0, 5, 10, or 20mg/kg) was administered to C57/
Bl6 mice; at sacrifice, biopsies of cornea and hindpaw skin
were immunolabeled against beta-3 tubulin and PGP9.5
respectively to quantitate innervation. Both tissues demonstrated dose-dependent axonal losses that correlated moderately (r ¼ 0.66). Corneal-innervation measurements might
thus provide non-invasive surrogate markers for monitoring
painful small-fiber PN in chemotherapy patients.
Study supported by: Supported in part by a grant from
the Public Health Service (K24NS059892) and the Bietti
Eye Foundation.
Background: Positron emission tomography (PET) has
emerged as a more sensitive tool for diagnosis of paraneoplastic neurological syndromes (PNS) compared to conventional imaging modalities such as body-CT.
Aims: To analyse use of whole-body CT and PET-CT in
the investigation of PNS.
Methods: Retrospective review of 42 patients with suspected PNS referred for imaging between April 2007-March
2008 was conducted, followed by recommendations that
PET-CT is considered in cases where body-CT is negative.
We re-audited 45 patients referred between July 2008-June
2009 and identified each patient’s final diagnosis along with
any additional investigations undertaken.
Results: In the first cycle, 42 patients underwent wholebody CT for investigation of PNS. 4 scans were positive for
malignancy; 38 were negative, of which only one was followed up with PET-CT. In the second cycle, whole-body
CT was performed in 45 patients, 11 of which proceeded to
PET-CT. 4/45 patients had a final diagnosis of PNS, of
which only 3 had undergone PET-CT.
Conclusion: Early PET scanning in clinically suspected
PNS may prevent expensive and often unnecessary investigations. Trust guidelines now advise use of PET-CT rather
than conventional body-CT in clinically suspected PNS.
Study supported by: None
S308. Neurophysiologic Tests Do Not Correlate Well
with Pain Measures and Quality of Life in Taxane
Neuropathy
Harry Openshaw, Karen Knight, Wei Ye, Gloria Juarez,
Paul Frankel and George Somlo; Duarte, CA
S306. Widespread Intracerebral Metastases from
Prostate Adenocarcinoma
Devin D. Mackay, Eli L. Diamond and Joshua P. Klein;
Boston, MA and New York, NY
To determine if neurophysiologic measures correlate with
pain and quality of life (QOL) in taxane neuropathy, 70
women with stage II/III breast cancer on docetaxel 75mg/
m2 or nab-paclitaxel 100mg/m2 protocols were assessed prospectively by neurophysiologic tests, neuropathy composite
score, Neuropathic Pain Symptom Inventory (NPSI), and
QOL questionnaires. At completion of chemotherapy, 8 of
11 QOL measures had a worsening mean score (p<0.05) as
A 62 year-old man with prostate cancer and only pulmonary metastases presented with a partial seizure involving
forced leftward head deviation and tonic limb posturing. He
complained of diplopia without other symptoms. Physical
examination revealed mild bilateral papilledema, limited
ocular abduction bilaterally, left-sided ataxia, and bilateral
extensor plantar responses.
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did all neurophysiologic measurements. The change was
greater for sensory than motor conductions and greater for
vibration than cold detection. At 12 months after chemotherapy, all neurophysiologic measures except cold detection
and 5 of 11 QOL measures were still significantly worse
than baseline; only QOL emotional well-being was significantly improved (P<0.001). At completion of chemotherapy, there were correlations between NPSI and 8 QOL
measures (r from -0.26 to 0.63, p<0.05). Neither NPSI nor
QOL correlated strongly with neurophysiologic measures. In
conclusion, there is correlation between QOL and NPSI,
but neurophysiologic measures do not correlate well with
each other or with NPSI or QOL. It is important to include
pain and QOL measures in investigative studies of neuroprotective agents.
Study supported by: NCI Grant CA 33572, NIH
M01RR00043, and American Bioscience/Celgene
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factors are peripheral neuropathies/radiculopathies or central
causes with antagonistic rather than co-contraction. Exact
etiology remains unclear. Polysomnographic (PSG)/polymyographic (PMG) findings in PPLMTS have not been
studied.
Seven PPMTS patients (five women, two men; two with
painful symptoms and four without; two had Parkinson’s
disease) underwent overnight PSG with specialized foot
montage (extra muscle channels involving bilateral abductor
digiti minimi, flexor hallucis brevis and extensor digitorum
brevis). In five patients, toe movements were bilateral and
frequent in wakefulness, stage N1 and sleep-wake transitions, rarely persisting into REM sleep in three of these
patients and very frequent in REM sleep in another. They
were associated with cortical arousals in both REM and
NREM sleep in one patient. Movements were a combination of synchronous and asynchronous, myoclonic (>200
msecs) and dystonic (<200 msecs) bursts; in two patients
bursts were purely dystonic. In two patients, one with Parkinson’s disease, movements disappeared in sleep.
PPLMTS is clinically and neurophysiologically heterogeneous. The mixture of myoclonic, dystonic, synchronous
and asynchronous patterns suggests a complex pathophysiology determined by both peripheral afferent/efferent and
supraspinal efferent control.
Study supported by: n/a
S309. Leveraging Expression of the GABA-A Receptor,
alpha 5 in Medulloblastoma as a Novel Therapeutic
Target
Soma Sengupta, Shyamal D. Weeraratne, Hongyu Sun, Bela
Kosaras, Jillian Phallen, Natalia Teider, Sundari Rallapalli,
Mirna Lechpammer, Dimitrios Mathios, Vlad Amani, Jessica
Pierre-Francois, Tenley Archer, James Cook, Frances Jensen,
Michael Lim, Scott Pomeroy and Yoon-Jae Cho; Boston;
Baltimore; Milwaukee and Stanford
S402. Complex Sleep Behavior with Multiple Etiologies:
A Diagnostic Challenge
Rony Dekermenjian, Nancy Gadallah, Sushanth Bhat,
Sumaiya Salim, Luidmila Lysenko, Disha Patel and Sudhansu
Chokroverty; Edison, NJ
Neural tumors display molecular markers suggestive of their
developmental lineage, including the expression of neurotransmitter receptors. Although neurotransmitter receptors
have been well-characterized in normal neurophysiological,
developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors,
and importantly, the effect of their targeting in brain cancers
remains obscure. We previously demonstrated high levels of
GABRA5 expression in a particularly aggressive molecular
subtype of medulloblastoma, and we hypothesized that
modulation of its activity would alter medulloblastoma cell
survival. We treated GABRA5 expressing medulloblastoma
cells with a series of GABA-A receptor agonists and antagonists and then assayed for proliferation, cell cycle distribution, apoptosis, and changes in electrophysiological properties, in vitro and in/ex vivo. While GABA-A receptor
antagonists, had limited effects on cell survival, QHii066, a
highly specific A5/GABA-A receptor agonist, significantly
decreased medulloblastoma cell survival through the induction of apoptosis. Furthermore, QHii066 markedly sensitized GABRA5 positive medulloblastoma cells to radiation
and chemotherapy, in vitro and in vivo. Thus, these results
provide a novel strategy for the treatment and management
of a highly lethal subtype of medulloblastoma.
Study supported by: My salary is supported by an NIH
research grant (R25NS070682). Otherwise, I have no other
conflicts of interest.
We report a case of complex sleep behavior with multiple
etiologies in a patient with medical comorbidities.
A 49 year-old diabetic woman, noncompliant with continous positive airway pressure (CPAP) use for obstructive
sleep apnea, had an episode of sleep violence. Dreaming of
trying to escape from a barrel as the world was ending, she
got out of bed confused with her eyes open, damaged property, threw stones at neighbor’s’ windows, and awoke without recollection of the event. During polysomnography
(PSG), she displayed complex movements at apnea termination (limb/trunk abduction-adduction, flexion-extension and
ballistic posturing, fiddling with wires and clothing, tapping
her abdomen, scratching limbs). On her second PSG study,
CPAP eliminated these movements, but she later became
confused, pulled off her CPAP mask, had dystonic-ballistic
movements, and became diaphoretic and tachycardic. EEG
showed theta-delta slowing. She was severely hypoglycemic,
responding to intravenous dextrose, with no recall of these
events. She later admitted to frequent nocturnal hypoglycemia, caused by taking higher doses of insulin in the evenings when she forgot afternoon doses.
Complex sleep behavior has multiple etiologies, causing
acute and urgent events during PSG studies that necessitate
immediate interventions.
Study supported by: N/A
Sleep Disorders and Circadian Rhythm
S403. Sleep and Circadian Rhythm Disruption in
Incident Parkinson’s Disease – A Multimodal Analysis
David P. Breen, Romina Vuono, Kate Fisher, Shani
Nawarahtna, John M. Shneerson, Akhilesh B. Reddy and
Roger A. Barker; Cambridge, United Kingdom
S401. Polysomnographic and Polymyographic
Characteristics of Painful/Painless Limbs Moving Toes
Syndrome (PPLMTS) Syndrome
Rony Dekermenjian, Nancy Gadallah, Sushanth Bhat, Phillip
Hanna, Fouzia Siddiqui and Sudhansu Chokroverty; Edison
and Harrisonburg, VA
Sleep disturbances are present from the earliest stages of Parkinsons disease (PD), often getting worse as the condition
progresses, but their neural basis is poorly understood. We
PPLMTS consists of continuous/semicontinuous involuntary
foot muscle movement, with or without pain. Predisposing
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probed the nature and extent of these sleep disturbances in
an incident PD cohort.
We studied 30 early PD patients and 15 matched elderly
controls. Alongside clinical assessments, participants underwent actigraphy assessment, polysomnography and 24-hour
circadian rhythm analysis (melatonin, cortisol and peripheral
clock gene expression).
PD patients had significantly higher Parkinsons Disease
Sleep Scale (PDSS) score compared to controls. Five PD
patients had Rapid Eye Movement (REM) sleep behaviour
disorder but no group differences were seen in periodic
limb movements, Apnoea-Hypopnoea Index or Desaturation
Index. PD patients had reduced sleep efficiency and
increased nocturnal awakenings. They also spent significantly less time in slow wave and REM sleep. There was a
significant correlation between sleep efficiency and several
measures of cognitive performance. We will present the
extent to which these sleep disturbances are driven by circadian pathology.
As well as detecting specific sleep diagnoses, we have
found reduced sleep efficiency and altered sleep architecture
in early PD patients compared to matched controls.
Study supported by: Parkinson’s UK/Big Lottery Fund;
Cure PD Trust; NIHR Biomedical Award to Addenbrooke’s
Hospital/University of Cambridge; and Raymond and Beverly Sackler Studentship
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S405. A Longitudinal Study of 322 Individuals with
Narcolepsy
Maurice M. Ohayon; Palo Alto, CA
Objectives: Many progresses have been done in understanding the genetic basis of Narcolepsy. However, little is known
about the evolution of narcoleptic individuals in terms of
mortality and comorbidity.
Methods: A total of 322 narcoleptic individuals interviewed at first time between 2005 and 2007 were contacted again between October 2011 and January 2012.
The success rate in contacting the initial sample was
95.65%. As with the initial interview, during the followup, the interview covered sleep, mental and organic diseases. Initial and follow-up interviews were performed
using the Sleep-EVAL system.
Results: Of the 308 narcoleptic individuals located, 4
refused to participate, 1 was unavailable for other reasons, 5
were too ill and 7 were deceased. At follow-up, subjects
were aged between 21 and 84 years. The most frequently
reported new disease was hypertension (3.1%) followed by
diabetes (2.6%) and cancer (2.2%). Overall death rate was
comparable between narcoleptic sample and the U.S. general
population for the same time period. However, suicide rate
was seven times higher in the narcoleptic sample (RR:7.35
[1.84-29.41]).
Conclusion: Narcolepsy is accompanied by various medical conditions but also mental disorders, which place narcoleptic individuals at greater risk for suicide.
Study supported by: NIH (R01NS044199) and unrestricted educational grant from Jazz Pharmaceuticals
S404. The Tuberous Sclerosis Complex-Mammlian
Target of Rapamycin (mTOR) Pathway Regulates
Mammalian Circadian Rhythms
Jonathan Lipton, Elizabeth Yuan, Ashwin Nathan, Jarrett
Leech, Juliette Han, Fred Davis and Sahin Mustafa;
Boston, MA
S406. Medical Conditions and Psychiatric Disorders
Associated with Narcolepsy
Maurice M. Ohayon; Palo Alto, CA
Disruption of sleep and circadian rhythms is common in
patients with Tuberous Sclerosis Complex (TSC). TSC
manifests with epilepsy, intellectual disability, tumor formation, and sleep disruption. The Tsc1/Tsc2 gene products
collaborate to suppress the activity of the mammalian target
of rapamycin (mTOR), a major integration point for anabolic signaling and protein synthesis initiation. We have
studied the circadian timekeeping system in mouse models
of TSC to target mechanisms of circadian dysfunction and
identify molecular relationships between the clock and anabolic signaling. Mice deficient in Tsc1 or Tsc2 gene function – in which mTOR activity is constitutively increased –
demonstrate aberrant circadian physiology, behavior, and
gene expression. Similarly, genetic or pharmacologic modification of mTOR signaling results in altered circadian timing
in peripheral cells. We have identified a specific biochemical
mechanism by which mTOR signaling modulates the function of the core clock protein BMAL1, contributing to its
subcellular localization and degradation. Our results provide
a mechanistic link between the TSC/mTOR signaling pathway and the circadian clock and add to our understanding
of how anabolic information is directly relayed to circadian
oscillators in health and disease.
Study supported by: American Academy of Neurology
Clinical Research Training Program, Tuberous Sclerosis Alliance Post-doctoral grant, the William Randolph Hearst
Foundation of Harvard Medical School, and an American
Sleep Medicine Foundation Physician Scientist Training
Award, and the NIH/NICHD (K08HD071026-01) (J.L);.
NIH R01 NS058956, Tuberous Sclerosis Alliance, Autism
Speaks, John Merck Fund, Nancy Lurie Marks Family
Foundation, and the Children’s Hospital Boston Translational Research Program (M.S.).
Objectives: Individuals affected by Narcolepsy represent a
vulnerable segment of the population. We have, however,
only a partial understanding of this vulnerability. This study
aims to examine psychiatric disorders and medical conditions associated with Narcolepsy.
Methods: A total of 320 narcoleptic individuals were
interviewed sleeping habits; health; medication consumption, medical conditions (ICD-10), sleep disorders (ICSD)
and mental disorders (DSM-IV-TR) using the SleepEVAL. system A general population comparison group (N
¼ 1,464), matched for age, sex and BMI and interviewed
with the same instrument, was used to estimate odds
ratios.
Results: Five diseases were more frequently observed
among narcoleptic individuals: Hypercholesterolaemia
(OR: 1.51); Diseases of the digestive system (OR: 3.27);
Heart diseases (OR: 2.07); Upper respiratory tract diseases (OR: 2.52) and Hypertension (OR: 1.32). Most frequent psychiatric disorders among the narcolepsy group
were Major Depressive Disorder (OR: 2.67) and Social
Anxiety Disorder (OR: 2.43) both affecting nearly 20%
of narcoleptic individuals. However, most mood and anxiety disorders were more prevalent among narcoleptic
group. Alcohol Abuse/Dependence was comparable
between groups.
Conclusions: Narcolepsy is associated with a high comorbidity of both medical conditions and psychiatric disorders
that need to be addressed when developing a treatment
plan.
Study supported by: NIH (R01NS044199) and unrestricted educational grant from Jazz Pharmaceuticals
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S407. Bmal1 Provides a Molecular Link between
Circadian Clock Function, Brain Metabolism, and
Neurodegeneration
Erik S. Musiek, Miranda M. Lim, Adam Q. Bauer, Guangrui
Yang, Jee Hoon Roh, Benoit I. Giasson, David M. Holtzman
and Garret A. FitzGerald; St. Louis, MO; Philadelphia, PA
and Gainesville, FL
Stage:
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topia, 1/24 focal cortical dysplasia, 1/24 optic chiasma hypoplasia, 2/24 brainstem hypoplasia, 4/24 microcephaly, 2/
24 hemimegalencephaly. 10/50 (20%) had PMG as part of
a syndrome. One karyotype showed a reciprocal translocation 46,XY t(8;22)(p23.1;p11.2). Of 27 CGH microarray
results, 23 (85%) were normal. The detected CGH anomalies included a 22q11del, a 1p36del, a 2p21del of unknown
significance, and a 2p13.3-p16.3duplication. We fine
mapped a subgroup of bilateral perisylvian polymicrogyria
(BPP) patients to 2p16.1-p16.3.
Conclusions: Our data support previous suggestions of
PMG loci on chromosomes 22q11 and 1p36, and narrow a
locus for BPP to 2p13.1-p16.3. These data can help to
identify the causative genes located in these regions.
Study supported by: N/A
Circadian clock proteins regulate many aspects of cellular
function, and circadian oscillation declines with aging and
in neurodegenerative diseases. Deletion of the master clock
gene Bmal1 in mice causes loss of circadian rhythms, systemic oxidative injury, peripheral metabolic dysfunction,
and accelerated aging. We hypothesized that the circadian
clock might regulate bioenergetics and redox homeostasis in
the brain, and examined the impact of Bmal1 deletion on
brain pathology. Deletion of Bmal1 in mice caused severe
age-dependent astrogliosis and microglial activation in cerebral cortex and hippocampus, and was accompanied by neuronal lipid peroxidation and impaired expression of the redox defense protein mitochondrial aldehyde dehydrogenase
(ALDH2). Bmal1 deletion triggered ATP depletion and
activation of the metabolic sensor AMPK, consistent with
cerebral metabolic stress, and optical imaging of resting state
functional connectivity demonstrated neural network dysfunction. Similar neuropathology and biochemical changes
were observed in mice with brain-specific Bmal1 deletion
(Nestin-Cre::Bmal1flox), which have intact sleep/wake cycles,
suggesting that neuropathology was not due to sleep deprivation or peripheral circadian dysregulation. Our findings
implicate Bmal1 as a novel regulator of cerebral bioenergetics and oxidative stress, and suggest that circadian dysfunction may promote neurodegeneration.
Study supported by: NIH grants K08NS079405 (ESM),
HL097800 (GAF), P01NS074969 (DMH), P30NS057105
(DMH), an Ellison Medical Foundation Senior Scholar
Award (DMH), and the Cure Alzheimer’s Fund (DMH).
Dr. FitzGerald is the McNeill Professor of Translational
Medicine and Therapeutics.
S502. The Phenotypic Spectrum of Subcortical Band
Heterotopia in Patients Negative for DCX/LIS1 Gene
Mutations
Eva Andermann, Dina Amrom, François Dubeau, Maria D.
D’Agostino, William B. Dobyns and Frederick Andermann;
Montreal, QC, Canada and Seattle, WA
Objective: To delineate the phenotypic spectrum and elucidate the genetic cause(s) of subcortical band heterotopia
(SBH) in patients negative for DCX and LIS1 gene
mutations.
Method: Chart review, karyotype and/or array CGH in
patients with SBH negative for both DCX and LIS1
mutations.
Results: Fifteen sporadic patients presenting with various
degrees of epilepsy, with or without associated cognitive
delay, had SBH for which no DCX or LIS1 mutation was
found. They were evaluated with a karyotype and DCX
and/or LIS1 mutation analysis, depending on the pattern of
distribution of their SBH. A few patients had both sequencing and deletion/duplication analysis of one or both genes.
In one woman, the karyotype showed a de novo paracentric
inversion of the q13->q22.3 region of one chromosome 9.
CGH microarray (with 135,000 oligonucleotides) did not
reveal any deletion/duplication. Higher resolution CGH
microarray is ongoing in order to detect a possible microdeletion/duplication.
Conclusion: Genetic evaluation of SBH deserves DCX
and/or LIS1 sequencing and deletion/duplication analysis,
but this does not always reveal the genetic cause of this
brain malformation, especially in sporadic cases. Karyotype
and/or CGH array analysis is indicated in these unsolved
cases.
Study supported by: N/A
Neurogenetics
S501. Nonsyndromic and Syndromic Polymicrogyria:
Illustration of Clinical, Radiological and Genetic
Heterogeneity in a Cohort of 50 Patients
Dina R. Amrom, Jacques Michaud, Grant Mitchell,
Emmanuelle Lemyre, Annapurna Poduri, Jennifer Partlow,
Vijay Ganesh, Bernard Dan, Giorgi Kuchukhidze, Ingrid
Unterberger, Eugen Trinka, Nicolas Deconinck, Catherine
Christophe, Benoıˆt Pichon, François Dubeau, Donatella
Tampieri, Jean-Claude De´carie, William B. Dobyns, Frederick
Andermann, Christopher A. Walsh and Eva Andermann;
Montreal, QC, Canada; Boston, MA; Brussels, Belgium;
Innsbruck, Austria; Salzburg, Austria; Seattle, WA and
Montreal, QC
S503. Subarachnoid Hemorrhage and Acute
Hydrocephalus in a Patient with Familial Transthyretin
Type Amyloidosis
Matthew B. Bevers, Nivedita U. Jerath and Patricia L.
Musolino; Boston, MA
We present the case of a 47 year old Nepalese woman with
a history of developmental delay who presented with headache and vomiting, found to have hydrocephalus, subarachnoid hemorrhage and mineralization within the Sylvian
fissure. Neither CT nor conventional angiogram demonstrated evidence of aneurysm or vascular malformation. CSF
was notable for elevated RBCs and xanthochromia, but no
inflammatory pleocytosis. MRI showed diffuse leptomeningeal enhancement as well as mineralization of the meninges
in the Sylvian fissure. Such findings have been reported in
transthyretin type meningocerebrovascular amyloidosis, a
Objective: To llustrate the heterogeneity of nonsyndromic
and syndromic polymicrogyria (PMG).
Methods: Patients with any type of PMG, excluding schizencephaly and confirmed congenital CMV/toxoplasmosis.
This includes review of medical records; karyotype and/or
CGH and/or genomic SNP microarray; and specific gene
analysis when indicated.
Results: We studied 46 sporadic patients and two families
with two siblings each. Their PMG pattern was variable.
24/50 (48%) had associated brain malformation(s), including 2/24 corpus callosum dysgenesis, 5/24 nodular hetero-
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rare genetic condition that causes amyloid deposition in leptomeninges and subarachnoid vessels that can be a cause of
subarachnoid hemorrhage. The patient had a duodenal biopsy, which confirmed the presence of amyloid deposition
in vessel walls. Genetic testing showed an A to G substitution at position 113 of exon 2 of the TTR gene. This
finding has previously been reported in individuals with
leptomeningeal amyloidosis. Therapy is supportive, and
genetic counseling is being offered to the patient’s children.
Mutations in the transthyretin gene represent a rare cause of
regional amyloid deposition and subarachnoid hemorrhage.
Study supported by: Residency Program
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subjects. In our eGWAS, we tested the PSP risk loci for
association with expression levels of transcripts within
6100kb. Using semi-quantitative neuropathology scores on
458 autopsied PSP subjects and latent modeling, we
obtained quantitative neuropathology endophenotypes to
test for associations. Brain expression levels of SLCO1A2,
MAPT and MOBP were associated with PSP risk variants.
MAPT and MOBP loci showed biologically consistent associations with neuropathology endophenotypes. We conclude
that regulatory variants may explain part of the PSP genetic
risk. Some of these regulatory variants may influence neuropathology, which has implications for search of functional
variants at these loci.
Study supported by: R01 AG032990, P50 AG016574,
KL2 RR024151, CurePSP
S504. Exome Sequencing Identifies Two Separate
Mutations in a Novel Gene as Cause of Autosomal
Dominant Cervical Dystonia in Two Families
Gavin Charlesworth, Jose M. Bras, Rita Guerreiro, Una M.
Sheerin, Kailash Bhatia and Nicholas W. Wood; London,
United Kingdom
S507. Hexanucleotide Repeat Expansion in c9orf72 Is
Associated with Increased Risk of Bulbar Amyotrophic
Lateral Sclerosis (ALS)
Paloma Gonzalez-Perez, Peter Sapp, Zack C. Kennedy, Diane
McKenna-Yasek, Ru-Ju Chian, Andrew Fox and Robert H.
Brown; Worcester, MA
Cervical dystonia is the most common focal dystonia. We
identified a moderately-sized kindred from the UK with
autosomal dominant inheritance of cervical dystonia and
jerky dystonic tremor of the upper limbs, with negative
mutational screening for the known dystonia genes (THAP1
& TOR1A). We performed whole-exome sequencing on
two individuals from this kindred, combined with linkage
analysis, in order to identify novel candidate causal variants.
Subsequent screening of one of these variants by Sanger
sequencing of the exon in which it was located in a further
250 cases of cervical dystonia revealed a second, novel, missense mutation 4 amino acids downstream, predicted to be
pathogenic and affecting a highly conserved base, which segregated with disease in a second, separate autosomal dominant family. The gene in which the two mutations were
found is an ion channel thought to modulate neuronal
excitability that is highly expressed in the striatum and is
thus biologically plausible as a cause of dystonia. Sequencing
of the remaining exons of this large gene to look for further
mutations will soon be completed.
Study supported by: MRC/Wellcome Trust Research
Grant
An expansion of a hexanucleotide repeat in c9orf72
(c9orfþ ) has been recently identified as the genetic cause of
9p-linked ALS associated with frontotemporal lobar dementia (Dejesus-Hernandez et al, Renton et al 2011).
Objectives: Determine the frequency of c9orfþ in a large
set of ALS patients and controls; and investigate the impact
of c9orfþ on phenotype in sporadic and familial ALS.
Methods: A short-tandem-repeat assay was performed on
224 FALS, 900 SALS and 900 controls DNA samples.
Repeat-PCR was carried out on samples with potential
c9orf72 expansions using an ABI3730 DNA Analyser.
Southern blots determined the sizes of the hexanucleotide
expansions.
Results: Expansions were identified in approximately
25% of FALS, 5% of SALS and 0.6% of control cases. Our
data document a significant association between the presence of the hexanucleotide expansions and bulbar onset ALS
but not age of onset or duration of disease.
Conclusions: c9orfþ frequency in our ALS DNA set is
comparable to that previously reported. C9orfþ significantly
predisposes to bulbar onset. Studies are in progress to define
the minimum expansion size threshold for ALS
susceptibility.
Study supported by: This study was supported by the
National Institute for Neurological Disease and Stroke
(5R01-NS050557-05), the Angel Fund, the ALS Association, P2ALS, Pierre L. de Bourgknecht ALS Research Foundation and the ALS Therapy Alliance.
S505. Withdrawn.
S506. Progressive Supranuclear Palsy Genetic Risk
Variants Associate with Brain Gene Expression and
Neuropathology Endophenotypes
Nilufer Ertekin-Taner, Mariet Allen, Melissa Murray, Julia
Crook, Daniel Serie, Fanggeng Zou, High Seng Chai, Curtis
Younkin, Shane Pankratz, Minerva Carrasquillo, Christopher
Rowley, Asha Nair, Sumit Middha, Sooraj Maharjan, Thuy
Nguyen, Li Ma, Kimberly Malphrus, Ryan Palusak, Sarah
Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri,
Christopher Kolbert, Jin Jen, Gerard Schellenberg, Ronald
Petersen, Neill Graff-Radford, Steven Younkin and Dennis
Dickson; Jacksonville; Rochester and Philadelphia
S508. Infrequent NaV1.7 Mutation in Insensitivity to
Pain, Erythromelalgia and Small Fiber Neuropathy
Christopher J. Klein, Dean H. Kilfoyle, Yanhong Wu, Paola
Sandroni, Phillip A. Low, Mark D. Davis and Peter J. Dyck;
Rochester, MN and Epsom, Aucklund, New Zealand
Seven genetic risk loci for progressive supranuclear palsy
(PSP) were identified in a genome-wide association study
(GWAS). We postulate that some of these loci influence
PSP by modifying brain gene expression, given the importance of regulatory variants in human traits. We tested the
association of the PSP GWAS variants with brain gene
expression and neuropathology endophenotypes. We completed an expression GWAS (eGWAS) of brain transcript
levels measured in 800 samples from the cerebellum and
temporal cortex of autopsied subjects with Alzheimer’s disease (AD) and other neuropathologies including 100 PSP
Mutations in Nav1.7 (SCN9A) cause congenital insensitivity
to pain (CIP), erythromelalgia and small fiber sensory neuropathy. SCN9A was sequenced in 19 patients, 6 ¼ CIP,
9 ¼ erythromelalgia, 4 ¼ small fiber neuropathy. In one
erythromelalgia patient, a novel Q10K mutation was identified. In one CIP patient, a novel (IVS8-2), de novo splicing
mutation was identified, this mutation compounded with
nonsense mutation (R523>X) and reduced SCN9A expression to 5% compared to unaffected family members. In
another CIP patient, we identified P610T previously
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considered causal for erythromelalgia, P610T has 2% MAF
in 1000-Genome and is unlikely causal. A splicing junction
deletion mutation (IVS24-7) previously linked to CIP was
found in all indexed patients (het-del in 3 CIP, homdel in 3
CIP and 13 erythomelalgia), suggesting this deletion has
limited effect in pain related phenotypes. Also, a variant
(rs6746030) previously linked to the increased pain perception was found among three CIP indexed patients. Our
results support genetic heterogeneity for CIP, erythomelalgia,
small fiber neuropathy by rare occurrence of SCN9A mutations. The extent polymorphisms in our cohort emphasizes
other factors likley contribute to pain related disorders, and
some variants considered causal in previous studies need further investigation.
Study supported by: Mayo Foundation Clinical Research
Grant, National Institutes of Health (NIH) Grant (K08
NS065007-01A1)(NS36797).
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Results: Truncating mutation in two familial cases and a
novel point mutation in one sporadic case were identified.
Conclusion: PRRT2 gene mutations are also confirmed
in Japanese PKC cases including sporadic case.
Study supported by: None
S511. C9ORF72 Hexanucleotide Repeat Expansion
Analysis in Multiple System Atrophy and Progressive
Supranuclear Palsy
Karen E. Morrison, Rachel V. Denyer, Gilbert Bensimon,
Albert Ludolph, Yves Agid, P. Nigel Leigh, Ammar Al-Chalabi
and on Behalf of NNIPPS Consortium; Birmingham, United
Kingdom; Paris, France; Ulm, Germany; Falmer, Brighton,
United Kingdom and London, United Kingdom
Expanded C9ORF72 hexanucleotide repeats have recently
been described in conjunction with both amyotrophic lateral
sclerosis (ALS) and frontotemporal dementia (Renton, Neuron, 2011). C9ORF72 expansions are associated with distinct neuropathological findings (Snowden, Brain, 2012)
and, in those with ALS, more frequent cognitive and behavioural disturbance (Byrne, Lancet Neurology, 2012). Only
one previous study examined whether C9ORF72 expansion
plays a role in other neurodegenerative disorders, demonstrating presence of the expansion in <1% of patients with
Alzheimer’s disease (Majounie, NEJM, 2012).
Using a repeat primed PCR assay and DNA extracted
from peripheral blood lymphocytes we screened 136 UK
patients enrolled in the NNIPPS trial (Bensimon, Brain,
2009) with either multisystem atrophy (MSA) or progressive
supranuclear palsy (PSP) for C9ORF72 expansions.
The expansion (>23 repeats) was identified in one 75
year-old male patient with MSA. Further clinical details
regarding this patient will be presented. There was no evidence of C9ORF72 expansion in any of the PSP patients.
These results suggest that C9ORF72 expansion may rarely
be associated with other neurodegenerative disorders. Further investigation into the effects of C9ORF72 expansions
may offer broader insights into the pathophysiology of neurodegenerative disorders.
Study supported by: Research supported by grant from
University Hospital Birmingham Charities and Midlands
Neuroscience Teaching and Research Fund.
S509. Improvement of Learning and Memory in Ts65Dn
Mouse Model of Down Syndrome (DS) by GABAB
Receptor Antagonists: DS-Specific and Non-Specific
Mechanisms
Francisco Madamba, Yasaman Pirahanchi, Brett Rasmussen
and Alexander Kleschevnikov; La Jolla, CA
Down syndrome is characterized by deficient learning and
memory. Ts65Dn mice, a genetic DS model, exhibit
reduced synaptic plasticity and deficient learning. It was
shown that efficiency of the GABAergic neurotransmission
is increased in the dentate gyrus (DG) of Ts65Dn mice,
and that GABAB antagonists can improve learning. Interestingly, the improvement was observed only in Ts65Dn, but
not in WT controls, suggesting that some mechanisms are
DS - specific. To examine potential mechanisms, we measured hippocampal levels of BDNF after injections of the
GABAB antagonist CGP55845. The BDNF levels were
increased equally in Ts65Dn and WT mice (p ¼ 0.55). In
hippocampal slices, CGP52432 increased paired-pulse inhibition of the population spikes suggesting an increase of
feedback inhibition. Again, the effects were equal in
Ts65Dn and WT (p ¼ 0.6). Finally, application of
CGP55845 significantly increased NMDA receptor-mediated EPSPs. This change was greater in Ts65Dn mice (p <
0.03). Consequently, long-term potentiation (LTP) was
restored in Ts65Dn to the WT level. Thus, GABAB antagonists improve memory in Ts65Dn mice by a number of
DS-specific and non-specific mechanisms.
Study supported by: The Larry L. Hillblom Foundation;
The Down Syndrome Research and Treatment Foundation
S512. No Association of CETP Genotypes with
Evolution of Dementia Due to Alzheimer’s Disease
Fabricio F. Oliveira, Paulo H. Bertolucci, Marilia A. Smith
and Elizabeth S. Chen; Sa˜o Paulo, SP, Brazil
Objective: To investigate whether CETP polymorphisms
I422V and TaqIB are associated with cognitive change in
patients with dementia due to Alzheimer’s disease (AD).
Methods: Participants with late-onset AD were screened
with MMSE and/or severe MMSE and followed for one
year. Diagnosis of AD was in accordance with NIA-AA criteria, and hypercholesterolemia was treated according to
National Cholesterol Education Program guidelines. GenoR Real-Time PCR
typing was undertaken with TaqManV
technology. Fisher’s exact test was employed, p<0.05.
Results: All 119 patients (67.2% female, mean age of AD
onset 72.2366.42 years-old, mean education 4.4663.82
years) were treated with a cholinesterase inhibitor and/or
Memantine, and 66 (55.5%) were also using statins with or
without Ezetimibe. For I422V (rs5882), minor allele frequency (V422) was 0.34, and 50 patients (42%) were heterozygous. For TaqIB (rs708272), minor allele frequency (A)
was 0.36, and 57 patients (48%) were heterozygous. Age of
AD onset was not susceptible to V422 (p ¼ 0.11) or TaqIB
S510. PRRT2 Mutations in Japanese PKC Cases
Mitsuya Morita and Imaharu Nakano; Shimotsuke, Tochigi,
Japan
Introduction: Paroxysmal kinesigenic choreoathetosis
(PKC) is characterized by brief attacks of involuntary movement triggered by sudden onset of movement. PKC is commonly inherited as an autosomal dominant trait, and
PRRT2 gene was recently identified as the causative gene.
Objectives: To search for mutations in PRRT2 gene in
Japanese cases with PKC.
Patients and Method: Two cases with a family history of
PKC and two sporadic cases were studied. All cases developed symptoms during childhood. Blood samples were collected after obtaining informed consent, and genomic DNA
was extracted using standard procedure. Three exons of the
PRRT2 gene were amplified by PCR, and sequencing was
then carried out using ABI 310 automated sequencer.
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(p ¼ 0.93) genotypes. Evolution of AD was not affected by
these genotypes or by use of statins or Ezetimibe.
Conclusion: No association was found between common
CETP polymorphisms and age of onset or evolution of AD
on this sample.
Study supported by: CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior & FAPESP - The
State of São Paulo Research Foundation
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dation and accumulation of autophagosomes despite mTOR
activation. Similar defects were also observed in vivo in a
neuronal Tsc1 mouse model and in TSC cortical tuber
specimens. These findings reveal that compared to non-neuronal cells, loss of TSC1/2 in neurons results in unexpected
autophagy deficits that may contribute to altered neuronal
homeostasis in TSC.
Study supported by: Intellectual and Developmental Disabilities Research Center (P30HD18655), R01 NS058956
(to MS) and P01 NS024279 (to DJK), the Tuberous Sclerosis Alliance (to ADN), Nancy Lurie Marks Family Foundation and Children’s Hospital Boston Translational Research
Program (to MS)
S513. GLRB Is the 3rd Major Gene-of-Effect in
Hyperekplexia
Charlotte Hunt, Anna Derrick, Thomas Cushion, Sian Wood,
Cheney Drew, Owain W. Howells, Rhys H. Thomas, Seo
Kyung Chung and Mark I. Rees; Swansea, Wales, United
Kingdom and Wales, United Kingdom
S515. Homozygous Nonsense Mutations of C12orf65 in
Patients with Spastic Paraplegia, Optic Atrophy and
Neuropathy
Haruo Shimazaki; Shimotsuke, Tochigi, Japan
Purpose: Glycinergic neurotransmission is a major inhibitory
influence in the central nervous system (CNS) and defects are
associated with paroxysmal neuromotor disorder, hyperekplexia
or startle disease. The alpha1 subunit of the glycine receptor
(GlyR) gene (GLRA1) and its cognate postsynaptic transporter
(SLC6A5) are well-established genes in hyperekplexia, nevertheless, 60% of hyperekplexia cases remain gene-negative. The
beta subunit of the glycine receptor (GLRB), the partner subunit to GLRA1, was selected for further mutation analysis.
Method: 92 gene-negative hyperekplexia patients were
selected for variation screening of the GLRB using multiplex
PCR and direct Sanger sequencing approach. Mutation constructs were prepared for functional characterisation and
Molecular modelling predicts protein-damaging outcomes.
Results: This study identified 9 novel GLRB mutations
within 8 independent hyperekplexia index-cases accounting
for approximately 9% of the gene-negative cohort. This
included 5 recessive, 2 dominant and 1 compound heterozygote inheritance scenarios. The biological consequence of
the nonsense and indel mutations was unambiguous and the
2 missense mutations were further investigated for electrophysiological analysis.
Conclusion: This study describes the largest genetic
screening of GLRB in hyperekplexia and represents a 3rd
major gene for hyperekplexia. It further implicates the glycinergic proteome as the basis for further analysis.
Study supported by: Medical Research Council - UK
Objective: To identify the causative gene responsive to
autosomal recessive spastic paraplegia (AR-HSP) with optic
atrophy and neuropathy.
Methods: This study included two patients in a consanguineous family. Two patients underwent neurological examination and DNA analysis, one underwent skin biopsy. We
performed genomewide linkage analysis with SNP array,
copy-number variation analysis and whole-exome sequencing.
Results: We identified a homozygous nonsense mutation
(c.394C>T, p.R132X) in Chromosome 12 open reading
flame 65 (C12orf65) gene in two patients. C12orf65 gene
mutation was not found in 74 Japanese AR-HSP patients
without known HSP gene substitutions.
Interpretation: The novel nonsense mutation in
C12orf65 could be causative for AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon.
Truncated C12orf65 protein would lead to the mitochondrial protein synthesis defect and respiratory complex
enzyme activity reduction. Mitochondrial translation dysfunction could be one of the pathogenic mechanisms for
the AR-HSP.
Study supported by: This work was supported by a grant
from the Research Committee for Ataxic Diseases (Y.T. and
H.S.) of the Ministry of Health, Labor and Welfare, Japan.
This work was also supported by Grants-in-Aid from the
Research Committee of CNS Degenerative Diseases (I.N.
and Y.T.), and the Ministry of Health, Labor and Welfare of
Japan, and supported by a Grant-in-Aid for Scientific
Research (C) (23591253 to H.S.) from The Ministry of Education, Culture, Sports, Science and Technology in Japan.
This work was supported by a grant from the Research
Committee for Ataxic Diseases (Y.T. and H.S.) of the Ministry of Health, Labor and Welfare, Japan. This work was
also supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases (I.N. and Y.T.), and
the Ministry of Health, Labor and Welfare of Japan, and
supported by a Grant-in-Aid for Scientific Research (C)
(23591253 to H.S.) from The Ministry of Education, Culture, Sports, Science and Technology in Japan
S514. Neuronal Loss of Tuberous Sclerosis Complex
Activity Results in Increased Autophagosome
Accumulation Despite mTOR Activation
Alessia Di Nardo, Mary H. Wertz, Jarrett Leech, Emily
Greene-Colozzi, June Goto, Dennis Wall, David J.
Kwiatkowski and Mustafa Sahin; Boston, MA
Tuberous Sclerosis Complex (TSC) is a genetic disorder
characterized by the development of benign tumors in various organs. The most severe manifestations include epilepsy,
intellectual disability, and autism. A major cellular function
of the TSC1/2 complex is to inhibit the mammalian target
of rapamycin (mTOR), a master regulator of protein synthesis and cell growth. Previous studies performed in nonneuronal cells have reported that mTOR inhibits autophagy,
which is a lysosomal degradation process for the removal of
long-lived proteins and damaged organelles in double membrane organelles called autophagosomes. Therefore, nonneuronal Tsc-deficient cells have reduced autophagosome
number. Here, we investigated autophagy in Tsc-deficient
neurons. We found that, loss of TSC1/2 in neurons results
in increased autophagosome formation via the activation of
mTOR-independent autophagy initiating signals. As a
result, Tsc-deficient neurons have reduced autophagic degra-
S516. Hyperekplexia Phenotypes Associated with GLRB
Mutations
Rhys H. Thomas*, Cheney J. Drew, Owain W. Howell,
Thomas Cushion, Sian E. Wood, Jonathan G. Mullins,
SeoKyung Chung and Mark I. Rees; Swansea, United
Kingdom
Introduction: Classical hyperekplexia is a rare glycnergic
synaptopathy; 40% have mutations in the a1 subunit of the
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glycine receptor (GLRA1) or the presynaptic glycine transporter 2 (SLC6A5). The glycine receptor is a pentameric
ligand-gated Cl- channel with 2a1:3b stoichiometry. We
present the largest cohort with variants in the beta subunit
of the glycine receptor (GLRB).
Methods: Over 200 families with suspected hyperekplexia
have been evaluated on a research basis. Twelve probands
were identified as having variants in GLRB not seen in population studies and deemed likely to be pathogenic following functional modelling analyses. Clinical questionnaires
were scrutinised to identify patient characteristics.
Results: All twelve cases had autosomal recessive inheritance and were unrelated; four were from India and one
from Japan (where GLRA1 variants are less frequently
reported). All had symptoms from birth and startle was
ubiquitous. The presentation includes a neurodevelopmental
spectrum with delayed milestones at one end and severe intellectual disability at the other.
Conclusion: The more severe phenotype associated with
GLRB mutations is similar to that seen with SLC6A5 and
distinct from that associated with GLRA1. Therefore early
identification of the GLRB genotype may enable targeted
genetic counselling and therapeutic studies.
Study supported by: There are no conflicts of interest
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the potassium channel KCNC3. SCA13 is interesting in
that three distinctive allelic forms are known. The first two
described were p.Arg420His and p.Phe448Leu. The phenotypes, though overlapping, are distinct in that p.Arg420His
results in a slowly progressive pure cerebellar adult onset
ataxia. In contrast, p.Phe448Leu appears developmental,
presenting with delayed motor milestones. This phenotypic
bifurcation appears attributable to the biophysical effect of
each mutation on the channel. We provide a detailed phenotypic description of a novel allelic form of SCA13 caused
by a p.Arg423His mutation. Though reported in screening
ataxia DNA repositories, we describe a de novo case presenting at 16 months, and a three-generation family with multiple affecteds. This mutation is unique in its biophysical
properties and phenotypic manifestation. Heralding features
include infantile onset with delayed gross/fine motor milestones, seizures, mental retardation, gait/appendicular ataxia,
dysarthria, nystagmus and hypereflexia. MRI confirms cerebellar atrophy as early as nineteen months of age without
progression. Longitudinal follow-up suggests moderate lifetime improvement in motor and cognitive function.
Study supported by: none
S519. A Meta-Analysis of Genome Wide Association
Studies To Identify Loci Associated with Brain
Atrophy in Multiple Sclerosis
Zongqi Xia*, Nikolaos Patsopoulos, Charles Guttmann, PierreAntoine Gourraud, Sergio Baranzini, Jorge Oksenberg, Jeroen
Geurts, Bernard Uitdehaag, Raija Lindberg, Yvonne Naegelin,
Stephen Hauser, Ludwig Kappos, Chris Polman, Howard
Weiner and Philip De Jager; Boston, MA; Cambridge, MA;
San Francisco, CA; Amsterdam, Netherlands and Basel,
Switzerland
S517. Increased Cancer Incidence in LRRK2-G2019S
Mutation Carriers
Bjørg Johanne Warø, Krisztina K. Johansen and Jan Olav
Aasly; Trondheim, Norway
LRRK2 mutations are the most common genetic cause of
late-onset PD. The pathophysiological mechanism is
unclear, but evidence indicates gain-of-function with
increased LRRK2 kinase activity. Several kinase inhibitors
are FDA-approved as cancer treatments. Kinase inhibitors
may prove valuable in modulating PD. Epidemiological
studies show that PD patients have reduced risk for most
cancers but increased for some. Few studies have examined
cancer risk in LRRK2-G2019S mutation carriers. Our aim
was to study this risk.
Manifesting and non-manifesting carriers of the Trondheim LRRK2 PD cohort and their healthy first-degree relatives were interviewed for cancer history. Medical records of
the individuals confirming cancer were reviewed. Cancer
type was labelled as non-skin cancer or melanoma. Smoking
history was obtained.
142 individuals participated in the study, 71 carriers, 58
non-carriers. 13 were of unknown LRRK2-status. 9/71
mutation carriers had cancer (8 non-skin, 1 melanoma). 6/
13 of unknown LRRK2-status had non-skin cancer. The significantly lowest age-adjusted cancer rate was observed in
the first-degree relatives without the LRRK2 mutation.
LRRK2 mutation carriers seem to have increased cancer
risk compared to their healthy first-degree relatives. This
might be associated with the presumed gain-of-function and
increased LRRK2 kinase activity. More studies are needed.
Study supported by: Liaison Committee between the
Central Norway Regional Health Authority (RHA) and the
Norwegian University of Science and Technology (NTNU).
Multiple Sclerosis (MS) causes progressive neurodegeneration.
Genetic variants associated with MS susceptibility are poorly
correlated with brain atrophy. We performed a meta-analysis
of genome-wide association studies to discover variants influencing brain volume estimated from cross-sectional magnetic
resonance imaging data. The discovery analysis comprises
three strata from GeneMSA that includes subjects from Amsterdam (n ¼ 218), Basel (n ¼ 260) and UCSF (n ¼ 510).
Subjects from the Partners MS center in Boston were used
for replication (n ¼ 690). We additionally performed a joint
meta-analysis using a sample size weighted z-score method.
7.4 million SNPs were imputed with the 1000Genomes reference. A linear regression model was applied with gender,
symptom duration, and principal components as covariates.
While several intriguing candidates emerged, no variant
achieved genome wide significance (P<10-8) in the discovery
or joint analyses, suggesting that the genetic architecture of
brain volume in MS resembles that of most other complex
human traits where common genetic variants have modest
effects Pathway analyses using the top candidate SNPs are
ongoing, as are efforts to enlarge the meta-analysis using
existing collections of MS subjects with volumetric data.
Study supported by: National Multiple Sclerosis Society
S520. Engineering Mouse Chromosomes To Facilitate
Genetic Analysis of Down Syndrome
Xiaoling Jiang, Chunhong Liu, Li Zhang, Pavel V.
Belinchenko, Alexander M. Kleschevnikov, Annie Pao, William
C. Mobley and Y. Eugene Yu; Buffalo, NY and La Jolla, CA
S518. Detailed Phenotype of a Novel Allelic Form of
Spinocerebellar Ataxia Type 13
Michael F. Waters, Kristina Santiago, Alexis K. Harmeling and
Richard P. Morse; Gainesville, FL and Lebanon, NH
Trisomy of human chromosome 21 (Hsa21) is the most frequent live-born human aneuploidy and causes a constellation
of the abnormalities classified as Down syndrome (DS),
which include developmental cognitive disabilities and
The dominant cerebellar ataxias are a heterogeneous group
of neurological diseases anchored by the phenotypic feature
of motor incoordination. SCA13 is caused by mutations in
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including Creutzfeldt-Jakob disease (CJD). Spiroplasma
spp. have been cultured from brains affected with TSE.
Experimental spiroplasmosis in rodents and ruminants is
characterized by neurological deterioration and spongiform
encephalopathy. Here the ability of spiroplasma to bind to
stainless steel was tested as possible route of iatrogenic transmission of CJD. Experimental transmission of TSE occurs
via stainless steel wires exposed to TSE-infected mouse
brains when implanted into normal mouse brains. When
stainless steel wires were incubated with S. mirum cultures
biofilms were detected on the metal surfaces using scanning
electron and confocal laser microscopy. Wires with spiroplasma biofilm dried for three weeks, then explanted onto
SP-4 agar plates grew out spiroplasma colonies after 14 days
incubation at 30 C. Spiroplasma grew from wires exposed
to 5% glutaraldehyde for 5 minutes. Spiroplasma had a propensity to survive other agents used to clean surgical instruments. Recognition of involvement of spiroplasma in transmission of TSEs may lead to new strategies in detection,
treatment and prevention of TSEs, and development of new
methods for cleansing surgical instruments.
Study supported by: This research was supported in part
by NSF#0731908 and USDA-NRT Grant LAB03922, gifts
from families affected with CJD, and the Joseph P. Sardo
family for TSE research.
Alzheimer-type neurodegeneration. The mouse is a premier
model organism for DS because the regions on Hsa21 are
syntenically conserved with three regions in the mouse
genome, which are located on mouse chromosome 10
(Mmu10), Mmu16 and Mmu17. Recently, we have developed a mouse model trisomic for all three Hsa21 orthologous
regions in mice. To further genetic analysis of DS, we are in
the process of generating smaller chromosomal duplications
and deletions in the Hsa21 orthologous regions in mice using
recombinase-mediated long-range chromosome engineering.
The phenotypic analysis of these new mouse mutants may
result in the establishment of minimal critical genomic
regions and eventually new dosage-sensitive genes associated
with the cognitively relevant phenotypes. The success of our
effort should enhance the understanding of the mechanisms
underlying the disease phenotypes and may lead to novel
strategies for developing effective therapeutic interventions.
Study supported by: NIH, Children’s Guild Foundation
S521. Body-Wide Correction of Myotonic Dystrophy
Type 1 (DM1) in Transgenic Mice by RNase H-Active
Antisense Oligonucleotides (ASOs)
Thurman M. Wheeler, Andrew J. Leger, Sanjay K. Pandey, A.
Robert MacLeod, Masayuki Nakamori, Seng H. Cheng, Bruce
M. Wentworth and C. Frank Bennett; Rochester, NY;
Framingham, MA and Carlsbad, CA
S602. Upstate Eastern Equine Encephalitis: A Case
Report
Mirret M. El-Hagrassy and Yaman Eksioglu; Syracuse, NY
Objective: To determine whether systemic delivery of
RNase H-active ASOs can reduce or eliminate RNA toxicity
in a transgenic mouse model of DM1.
Background: DM1 is caused by expression of an
expanded CUG repeat (CUGexp) in the 30 UTR of the
DMPK transcript. Human skeletal actin-long repeat
(HSALR) transgenic mice express CUGexp RNA in the 30
UTR of an hACTA1 transgene. Antisense knockdown of
pathogenic RNA would be expected to mitigate clinical features of DM1.
Design/methods: ASOs were administered by subcutaneous injection. Treatment assignments were randomized and
analysis was blinded. In vivo efficacy was determined by, 1)
transgene mRNA knockdown (qRT-PCR), 2) alternative
splicing (RT-PCR), 3) myotonia, 4) global gene expression
(microarray), and 5) histologic myopathy.
Results: Two ASOs reduced transgene levels by up to
80%, eliminated myotonia, and corrected RNA mis-splicing
in all muscles examined. More than 85% of changes in gene
expression were normalized or improved. Knockdown of
RNA toxicity for 1 year rescued myopathy.
Conclusions/relevance: ASOs that act through the RNase
H pathway may be viable therapeutic agents for DM1.
Study supported by: NIH (K08NS064293, U01NS072323)
Authors SK Pandey, AR MacLeod, and CF Bennett are
employees of Isis Pharmaceuticals, which develops antisense
drugs. Authors AJ Leger, SH Cheng, and BM Wentworth
are employees of Genzyme Corporation, which develops biological therapeutics.
Case: A 4-year-old girl had multiple seizures over several
days with left gaze deviation, unresponsiveness and fever.
She was taken to PICU as seizures and mental status worsened. EEG suggested encephalopathy, probable left hemispheric pathology. LP suggested viral infection. CT and
MRI suggested meningoencephalitis. Therapeutic hypothermia was recommended for high fever. Viral panels confirmed Eastern Equine Encephalitis (EEE) 3 days later. She
deteriorated despite receiving phenytoin, acyclovir and antibiotics. Repeat CT showed bilateral ischemia and left temporal uncal herniation. A ventricular drain improved ICP,
but she did not survive.
Discussion: EEE is a rare neuroinvasive arbovirus borne
disease with 50% US case-fatality in 2010. Culiseta melanura mosquito transmits to birds; bridge mosquito vectors
transmit to humans (dead end hosts). MRI differentiates
from HSV. Nucleic acid amplification assays, reverse transcriptase-PCR and real time RT-PCR are more sensitive and
specific than EEEV antibodies. Treatment is empiric and
symptomatic. Mouse studies suggest hematogenous CNS viral invasion and early amplification in metaphyseal osteoblasts; peripherally inoculated mature animals resist
encephalitis.
Conclusion: EEE is a rare fatal arboviral disease. Hypothermia may reduce metabolic demands and ischemia. Public health measures are crucial; future vaccines and antiviral
agents may be developed.
Study supported by: N/A
Neuroinfectious Disease
S603. HIV-1 Exposure Affects Neural Progenitor Cell
Renewal and Accelerates Astrocyte Differentiation
in Human Brain Slices
Ricardo Martinez, Rebeca Geffin and Micheline McCarthy;
Miami, FL
S601. Spiroplasma Biofilm on Stainless Steel Is a Model
for Iatrogenic Transmission of CJD Via Surgical
Instruments
Frank O. Bastian, Xiaochu Wu and Philip H. Elzer; Baton
Rouge, LA
To study how HIV-1 affects neurogenesis, our ‘‘two-culture’’
assay system exposes human fetal brain slices to H9 T-cells
that chronically produce HIV-1 IIIB (H9/IIIB). Brainstem
Spiroplasma are linked by ultrastructural and molecular
studies to transmissible spongiform encephalopathies (TSE),
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slices exposed to neural progenitor culture medium only for
21 days showed midline and para-midline nestin extensively
co-localized with glial fibrillary acidic acid protein (GFAP).
This suggested renewal of neural progenitor cells. Brainstem
slices exposed to uninfected H9 cells or H9/IIIB cells
showed more dense GFAP, which did not co-localize with
nestin. This suggested preferential differentiation into astrocytes. When analyzed for mRNA expression patterns, brainstem slices exposed to H9/IIIB for 7 days expressed 2-3 fold
higher levels of mRNA for neuronal structural proteins, as
compared to slices cultured in medium alone or slices
exposed to uninfected H9 cells. GFAP mRNA level was
approximately ten-fold higher in H9/IIIB-exposed slices
compared to H9-exposed slices. Thus GFAP mRNA expression at day 7 predicted increased GFAP antigen at day 21.
mRNA for transcripts associated with progenitor cell
renewal (Hes1, Hes5, nestin) were 2-5 fold lower in H9and H9/IIIB-exposed slices. These data suggest that HIV-1
exposure impairs neuroepithelial progenitor maintenance
and accelerates astrocyte differentiation.
Study supported by: Department of Veterans Affairs
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northeast. In addition, cases of recurrent coccidioidal meningitis are not well-described in the literature. A 53-year-old
female with history of hepatitis C, hepatocellular carcinoma,
and coccidioidal meningitis in 2009 presented with gait
instability and confusion. After a normal CT head and CSF
(including negative coccioidal antibody) 4 months prior to
presentation, she had been taken off fluconazole, on which
she had been placed for chronic suppressive therapy after
her episode of coccidioidal meningitis. With her current
presentation, she was found to have hydrocephalus, bilateral
cerebral edema, and extensive meningeal enhancement along
with CSF findings of 273 leukocytes per microliter, high
protein, and low glucose. Coccioidal antibody was eventually found to be positive, and she has thus far responded to
fluconazole. Our patient demonstrates a severe case of
relapsing coccidioidal meningitis complicated by hydrocephalus that to date has responded to fluconazole.
Study supported by: Not applicable.
S606. A Mouse Model of Arachnoid Granulation
Obstruction by Cryptococcus
Jeffrey A. Rumbaugh, Angela Pool, Lindsey Gainey and Yu
Hui Wu; Atlanta, GA
S604. Anti-Ganglioside Antibodies Positive Influenza
Encephalopathy
Hitoshi Mori and Katuro Shindo; Kurashiki, Okayama, Japan
Raised intracranial pressure causes much morbidity and
mortality from HIV-associated cryptococcal meningitis, but
mechanisms leading to increased pressure are not well studied. Blockage of CSF reabsorption at arachnoid villi by
organisms and shed polysaccharide is widely hypothesized.
However, high organism load is necessary but not sufficient,
suggesting other factors must play a role.
We have developed a murine model of cryptococcal infection. We have used a wildtype, normocapsular strain of C.
neoformans, called H99, and a hypervirulent, hypercapsular
strain which is isogenic to H99, called PKR1. We are comparing differences in the ability of these strains to infiltrate
the CNS and obstruct arachnoid villi, using quantitative immunohistochemical techniques. We are also examining in
vivo capsule thickness and its relation to CSF blockage over
time. If these strains obstruct arachnoid granulations similarly, then other factors must account for their difference in
virulence.
With this model, we have easy availability of genetic and
immunologic reagents, and we have chosen intravenous
inoculation because it most closely mimics physiological hematogenously disseminated disease. This mouse model will
be a powerful tool, allowing us to dissect complex fungalhost relationships involved in neuropathogenesis of Cryptococcus in the brain.
Study supported by: Emory Center for AIDS Research
Background: There is no report about relationship between
anti-ganglioside antibodies and influenza encephalopathy.
Some authors say that anti-ganglioside antibodies were not
detected in human subjects infected with 2009 pandemic
influenza A(H1N1) virus. The mechanism of influenza
encephalopathy is incompletely known, we think neuron
specific antibodies will exist in some type of influenza
encephalopathy.
Method: 5 influenza encephalopathy patients were admitted to our hospital from April 2009 to February 2012. We
examined their anti-ganglioside antibodies in serum on
admission.
Results: Anti-ganglioside antibodies were detected in two
of them. A 78-year-old woman with loss of consciousness
and low grade fever was diagnosed as influenza encephalopathy by influenza A (H3N2) virus.GM3, GD3, GQ1b antibodies were detected in her serum. She was successfully
treated by methylprednisolone pulse therapy and peramivir.
A 31-year-old man with delirium and fever was diagnosed
as influenza encephalopathy by 2009 pandemic influenza A
(H1N1) virus.GD1a, GT1b antibodies were detected in his
serum. He recovered by the combination therapy including
methylprednisolone pulse, plasma exchange, intravenous immunoglobulin, oseltamivir.
Conclusion: This is the first report about influenza encephalopathy with positive anti-ganglioside antibodies. This
finding accounts for the usefulness of methylpredonisolone
pulse, plasma exchange, intravenous immunoglobulin in
influenza encephalopathy.
Study supported by: Kurashiki Central Hospital
I’m employed by Kurashiki Central Hospital
S607. Pathways to Neurodegeneration: The Effects of
HIV & Aging on Resting State fcMRI
Jewell B. Thomas, Matthew R. Brier, Florin F. Vaida,
Abraham Z. Snyder and Beau M. Ances; St. Louis, MO and
San Diego, CA
Background: HIVþ patients are living longer due to highly
active antiretroviral therapy (HAART). However, many
HIVþ individuals still have cognitive impairment. Older
HIVþ patients may be at increased risk for developing neurodegenerative disorders.
Methods: This study used resting state functional MRI
(rs-fMRI) to investigate the neurobiology of five functionally-defined brain networks in 52 HIVþ (44% on HAART)
and 52 HIV- controls. Composite scores were computed for
five networks: default-mode (DMN), control (CON), salience (SAL), dorsal attention (DAN) and sensorimotor
S605. A Severe Case of Recurrent Coccidioidal
Meningitis Complicated by Hydrocephalus
Sarah Nelson and Michal Vytopil; Burlington, MA
Coccidioidal meningitis is an unusual manifestation of the
fungal infection coccidioidomycosis and is also the most
fatal. Recommendations are that patients remain on lifelong therapy following treatment of their meningitis because
relapses can occur. Coccidioides fungi are endemic to the
southwestern United States and thus not often seen in the
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(SMN). Independent changes in rs-fMRI due to HIV and
aging were assessed by ANCOVA.
Results: Reduced rs-fMRI correlations were seen within
DMN (p ¼ .003), CON (p ¼ .006), and SAL (p ¼ .03)
while DAN and SMN were spared. Neither markers of HIV
(HIV viral load or CD4þ cell count) nor degree of HIV-associated cognitive impairment correlated with rs-fMRI measures.
Aging led to decreased correlations within the DMN (p ¼
.03) and SAL (p ¼ .006) for both HIVþ and HIV- subjects.
No interaction was seen between HIV and aging.
Conclusions: These results suggest that HIV and aging
cause similar decreases in rs-fMRI. Further longitudinal
studies of older HIVþ patients are needed.
Study supported by: This work was supported by the
National Institutes of Health (NIMH K23MH081786,
NINR R01NR012907, NINR R01NR012657) (BMA) and
(P30 NS048056) (AZS) as well as Dana Foundation
(DF10052) (BMA) Mr. Brier, Mr. Thomas, Dr. Snyder, and
Dr. Raichle report no disclosures. Dr. Ances is on a scientific advisory board for Lily Pharmaceuticals.
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Concordance between clinical history and VER was 66%.
Nerves with a clinical history of ON were more likely to
have the radiological finding of fluid around the nerve (p ¼
0.017). Within patients with prior unilateral clinical ON,
there was an association with reduced minimum cross sectional area (p ¼ 0.03) with a trend towards association with
total optic nerve volume (p ¼ 0.06) in the affected eye. At
the group level however, neither of these atrophy measures
were statistically associated with prior clinical ON or positive VER, with significant inter-subject variability.
This pilot study demonstrated that some radiological features on 3T MRI may be helpful in the assessment of the
optic nerve and workup of possible demyelination, and further study is warranted.
Study supported by: St. James’ Hospital
S703. The Lone Abducting Eye and Laterality of Motor
Control: Congresswoman Giffords’ ‘‘Wrong-Way Eyes’’
Denotes Crossed Right Hemisphere Syndrome in a Right
Hander
Iraj Derakhshan; Veckeley, WV and Cleveland, OH
S608. Clearance of Low Copy JC Virus from CSF of MS
Patients on Natalizumab
Gloria von Geldern, Caroline Ryschkewitsch, Peter Jensen,
Avindra Nath and Eugene O. Major; Bethesda, MD
Backgrounds and Methods: It is commonly believed that
supratentorial lesions affecting the right (minor) hemisphere
is associated with conjugate eye deviation toward that hemisphere (i.e. ‘‘the eyes have it’’). Data indicate that this kind
of eye deviation is often associated with left hemi-sensory
neglect in right handed people. The ‘‘eye-sign’’ is ascribed to
the unopposed action of the left (major) hemisphere in pulling both eyes to the right, with the left eye joked by the
right via the medial longitudinal bundle. Often associated
with left hemiplegia, these cases are not aphasic as the left
hemisphere remains intact. The ‘‘wrong way’’ eye deviation
is often ascribed to hemorrhage in contralateral thalamus,
without further explanation as to its mechanism. The Congresswoman’s photos in the initial stage of her traumatic illness demonstrate that her left eye was deviated to the
extreme left (i.e. towards the damaged hemisphere) as her
right eye stopped at the middle.
Conclusion: Congresswoman Giffords’ is similar to those
of right handers with lesions affecting their left (but minor)
hemispheres; able to communicate fully nervertheless.
Study supported by: entire private
Background: Reactivation of JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), a devastating
demyelinating brain disease. Diagnosis can be challenging
and the significance of low copy numbers of JCV DNA in
cerebrospinal fluid (CSF) needs further investigation.
Methods: CSF of multiple sclerosis (MS) patients on
natalizumab was analyzed by quantitative polymerase chain
reaction (PCR). Forty four patients with <100 copies/mL
were identified. Clinical and magnetic resonance imaging
(MRI) findings were reviewed.
Results: 21/44 had repeat CSF analysis after discontinuation of natalizumab. 8/21 had high copies, 6/21 continued
to have low copies, and 7/21 had undetectable JCV on
repeat. 5/44 patients (all <50 copies/mL) had atypical clinical or MRI findings. 3/5 atypical patients had subsequent
CSF analysis, all had undetactable JCV.
Discussion: Only a third of PML patients with low copy
numbers cleared the virus and this included patients with
atypical clinical or MRI findings. Another third have persistent low virus in CSF and a third have high copy numbers.
While detection of JCV DNA in CSF by itself is not sufficient for diagnosis, attention should be paid even to low
copy numbers.
Study supported by: None
S704. MOG Antibody Positive Optic Neuritis in Adults
Jithin S. George, Joanna Kitley, Mark Woodhall, John Elston,
Maria I. Leite, Angela Vincent and Jacqueline Palace; Oxford,
Oxfordshire, United Kingdom
Objectives: To characterise the clinical features of optic neuritis (ON) in four adults seropositive for myelin oligodendrocyte glycoprotein (MOG) antibodies.
Methods: MOG antibody was tested using cell based
assay. Optical coherence tomography, visual evoked
responses and visual function assessments were performed in
all patients.
Results Conclusions: MOG antibody positive optic neuritis can be unilateral or bilateral and synchronous with longitudinally extensive myelitis. Neuromyelitis optica may be
diagnosed in such cases, however, unlike the aquaporin-4
antibody mediated spectrum of CNS demyelination, MOG
antibody positive cases appear to have better visual function
outcomes.
Study supported by: JG has received support for scientific
meetings from Biogen Idec. JK has received support for scientific meetings from Biogen Idec and is supported by the
NHS National Specialised Commissioning Group for Neuromyelitis Optica. MIL is supported by the NHS National
Neuro-ophthalmology
S701. Withdrawn.
S702. 3-Tesla MRI of the Optic Nerve: A Pilot Study
David Bradley, Iqbal Mudassir, Gerard O’Connor, Lisa
Costelloe, Derbhail O’Driscoll, Andrew Fagan, Jim Meaney
and Janice Redmond; Dublin, Ireland
Optic neuritis (ON) is common in MS. Diagnosis is based
on clinical evaluation and visual evoked responses (VERs).
Standard MR imaging of the optic nerve is uninformative due
to regional structural characteristics. This pilot aimed to examine the ability of 3-tesla (3T) MRI to image the optic nerve.
9 patients (3 female, mean age 43.3yrs) underwent MR
scans at 3T and had VERs recorded, providing data on 18
optic nerves. 5 had prior clinical ON (2 bilateral).
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Specialised Commissioning Group for Neuromyelitis Optica
and AV and MIL are involved in AQP4 and MOG antibody testing, supported by the NHS National Specialised
Commissioning Group for Neuromyelitis Optica and by the
NIHR Oxford Biomedical Research Centre. JE has nothing
to disclose. JP has received unrestricted grants and support
for scientific meetings and scientific advisory honorariums
from Merck Serono, TEVA, Biogen, Bayer Schering and
Novartis, has held MS society grants and is a clinical lead
for the UK Department of Health Risk Sharing Scheme.
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constriction OD, and visual acuity 20/100 and paracentral
scotomas OS were present at the first and second attack,
respectively. MRI revealed widespread enhancement and
thickening in the meninges and ONS, and T2-hyperintense
SON lesion in the right/left episodic side, respectively. Proteinuria and multiple pulmonary CT nodules suggested the
systemic WG. Steroid therapy attenuated visual disturbance
and orbital lesions.
Conclusion: The clinicoradiological courses of our
patients indicated the common mechanism of inflammatory
hypertrophy between pachymeningitis and HPN in WG
patients.
Study supported by: None.
S705. Longitudinally Extensive Optic Neuritis in
Pediatric Patients
Jennifer Graves, Verena Kraus, Bruno Soares, Jonathan Strober
and Emmanuelle Waubant; San Francisco and Munich,
Germany
S707. Is This the Tolosa-Hunt Syndrome?
Ulya S. Malik and Odai Jumma; Birmingham, United
Kingdom
Objective: Optic neuritis (ON) as a first demyelinating
event is common. While extensiveness of spinal cord lesions
predict diagnoses such as neuromyelitis optica, the importance of lesion extent in ON is unknown. We address
whether lesion length of a first ON predicts a non-MS
diagnosis.
Methods: This is a retrospective study of pediatric
patients who presented with a first ON event seen at the pediatric MS clinic at UCSF since inception in 2006. Those
with brain or orbit MRI scans within 3 months of symptom
onset were included. Lesion length, determined by T2
hyperintensity or contrast enhancement, was graded by a
blinded neuro-radiologist as absent, focal or longitudinally
extensive (at least two segments of the optic nerve).
Results: 26 Patients were identified who met criteria and
had interpretable MRI imaging of the optic nerves. Of these
9 (35%) had longitudinally extensive (LE) ON. Almost half
of MS cases had LEON. Extensive lesions were not associated with non-MS vs. MS diagnosis (RR 0.94, 95% CI:
0.21 to 4.2). Younger patients tended to be more likely to
have LEON (p ¼ 0.21).
Conclusions: LEON is common and not necessarily associated with a non-MS diagnosis in pediatric patients.
Study supported by: Dr. Graves is supported by a Sylvia
Lawry Fellowship from the National Multiple Sclerosis Society. Further grants from NMSS and the Nancy Davis Foundation supported this work.
Introduction: Pathology underlying painful ophthalmoplegia is localised to the cavernous sinus/superior orbital fissure
with causes being traumatic, neoplastic, aneurysmal or
inflammatory. Of the latter, a small category develop symptoms secondary to a non-specific mass in the cavernous
sinus and respond to corticosteroid therapy. The disorder is
termed Tolosa-Hunt syndrome.
Case presentation: We present a 27 year old female with
3 weeks history of severe right periorbital pain, progressive
ipsilateral ptosis and numbness affected the first and second
divisions of the trigeminal nerve. A 6mm mass was located
in the right cavernous sinus on MRI exerting mass effect on
the right internal carotid artery. Diagnosis was complicated
by the patient’s depression, manifesting as mixed neurological symptoms including hemiparesis and dysarthria. Symptoms persisted until high dose corticosteroid therapy caused
complete resolution within 24 hours.
Although cessation of headache was expected, resolution
of hemiparesis and dysarthria following corticosteroids
remains unexplained.
Conclusion: Although essentially a diagnosis of exclusion,
the rare Tolosa-Hunt syndrome is an important differential
in patients with painful ophthalmoplegia. While some variation in symptoms among patients is expected, a dramatic
improvement with corticosteroid therapy is almost pathognomonic of the condition.
Study supported by: N/A
S706. Hypertrophic Perioptic Neuritis (HPN) in
Wegener Granulomatosis (WG)
Ken Ikeda, Takanori Takazawa, Tetsuro Nagaoka, Takehisa
Hirayama, Osamu Kano, Kiyokazu Kawabe and Yasuo
Iwasaki; Tokyo, Japan
S708. Ethambutol Induced Optic Chiasmopathy
Subin Mathew, Raghavendra Seetharam, Ravindra Kamble
and Rajani Battu; Bangalore, Karnataka, India
Introduction: Ethambutol (EMB) induced chiasmopathy is
rarely reported.
Results: A 59 year gentleman during evaluation of headache and giddiness was detected to have pituitary mass
lesion (hyperplastic on retrospect) without any effect on the
optic chiasm. His visual fields were normal. He underwent
transnasal endoscopic excision of pituitary lesion. Histopathology showed granulomatous inflammation. Sarcoid
workup was negative. Antitubercular treatment (ATT)was
empirically started. He received EMB, isoniazid, rifampicin,
and pyrazinamide for 9 months. 7 months into therapy he
noticed progressive worsening of vision bilaterally. He continued on ATT for 9 months. His visual acuity by then was
CF at 1 m along with impaired bilateral color vision. Visual
fields revealed centrocecal scotoma. MRI brain showed
empty sella alone. ATT was immediately stopped with a presumptive diagnosis of EMB induced optic neuropathy, a
course of prednisone was administered. Despite EMB
Background: To elucidate a novel pathogenesis of WGassociated HPN.
Methods: We highlighted clinicoradiological hallmarks of
two patients with hypertrophic pachymeningitis and HPN
due to WG.
Results: Patient 1: a 71-year-old man developed bilateral
blurred vision. Visual acuity and field were no light perception and diffuse constriction OD, and 6/12 and nasal constriction OS. MRI disclosed widespread enhancement and
thickening in the mineninges and optic nerve sheets (ONS).
T2-hyperintensity lesions existed along the superficial optic
nerve (SON). Seropositive proteinase-3-antineutrophil
cytoplasmic antibody and multiple pulmonary CT nodules
supported the limited WG. Steroid and cyclophosthamide
treatment improved visual dysfunction and orbital lesions.
Patient 2: a 74-year-old man developed blurred vision
alternatively for one year. No light perception and diffuse
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withdrawal visual fields showed progressive worsening of
bitemporal field defects.
Conclusion: The presence of bitemporal field defects particularly in the setting of pituitary surgery as in this patient,
can lead to potential consideration of compressive optic
chiasmopathy that was negated by repeated MRI studies.
EMB toxicity can worsen despite withdrawal and needs
prompt early recognition of this complication.
Study supported by: All the authors have read and agreed
with the content and its educational motives and have
allowed me to submit the abstract in the conference.
I am currently doing my externship/observership as Resident Doctor in the department of Neuroscience, Vikram
hospital Bangalore. I have done the study myself with the
assistance on my senior faculty members.
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Conclusion: This patient had sequential ON due to
syphilis. Classic dermatologic findings led to a prompt diagnosis. With its increasing incidence and reputation for being
‘‘the great imitator,’’ syphilis should be considered in all
patients with ON. When treated appropriately, syphilitic
ON has a good prognosis.
Study supported by: N/A
S711. Correlation of the Retinal Ganglion Cell Complex
and Contrast Sensitivity in Parkinson Disease
Eric M. Shrier, Christopher R. Adam, Yin Ding, Sophya
Glazman and Ivan Bodis-Wollner; Brooklyn, NY
Purpose: To evaluate functional visual and morphological
correlation of foveal impairment in PD.
Methods: 32 eyes of 16 PD and 34 eyes of 17 matched
controls. Monocular and binocular contrast sensitivity (CS)
was quantified by Pelli-Robson chart. Retinal thickness was
measured using RTVue RT100 EMM5 scans. Thickness
measurements of the retinal ganglion cell complex (GCC)
at 0.25 mm intervals at sequential radial distances from the
foveola in all quadrants were obtained. Raw data files were
imported and analyzed in MATLAB.
Results: Multivariate analysis demonstrated pairwise correlation between monocular CS and age, binocular CS and,
age and IRL thickness at 1.00 mm inferiorly and 1.00 mm
nasally. Age was controlled for in all statistical comparisons.
Mean monocular CS differed between healthy controls and
PD. Bivariate analysis of monocular CS by thickness
revealed a significant difference in the inner retina in a specific perifoveolar annular zone.
Conclusions: Thinning of the GCC in the foveal pit correlates with CS loss in PD. To our knowledge this is the
first time correlation of foveal morphology and visual
impairment is shown in PD.
Study supported by: Michael J Fox Foundation, award#
53947
S709. Optic Disc Edema Does Not Always Correlate
with Retinal Nerve Fiber Layer (RNFL) Thickening
Mark J. Morrow; Torrance, CA
Background: The peripapillary retinal nerve fiber layer
(RNFL) is typically thickened in conditions that cause visible optic disc edema (ODE), including idiopathic intracranial hypertension (IIH). I sought to determine whether this
is always true.
Methods: I quantified optic nerve head (ONH) volume
and compared it with RNFL thickness in patients with
ODE. Spectral-domain optical coherence tomography
(OCT) assessed the RNFL with a standard 3.45mm circle
scan and the ONH with parallel vertical scans. I defined
cylinders of 2mm and 3mm diameter centered on the
ONH and established the volumes of tissue contained
therein, inside the level of Bruch’s membrane.
Results: Using normal subject-derived cutoffs, I identified
70 eyes with enlarged ONHs in 44 subjects. Of these 70
eyes, 28 (16 patients) demonstrated normal or reduced
mean RNFL thickness, only 7 of which showed increased
thickness in any quadrant. Diagnoses in these eyes included
IIH, hydrocephalus and drusen.
Conclusions: Mismatches between optic disc volume and
RNFL thickness may be explained by limited intraocular
extent of axoplasmic engorgement, by mixed populations of
dead and swollen axons, or by intrusions of non-neural material in the ONH with drusen.
Study supported by: Not applicable.
S712. Late Diffusion Changes in Optic Radiations
Predicted by Early Optic Nerve Structure after Optic
Neuritis, Suggesting Trans-Synaptic Effects
Olivia Goodkin, Olga Ciccarelli, Daniel Altmann, Camilla
Fini, Alessia Mirigliani, Thomas M. Jenkins, Alan J.
Thompson and Ahmed T. Toosy; London, United Kingdom
Introduction: We wished to address whether trans-synaptic
changes occur in the optic radiations (ORs) after optic neuritis (ON), by answering: 1) Do longitudinal structural
changes in the ORs occur after ON; 2) Do earlier optic
nerve changes predict later OR changes, suggesting a transsynaptic lag effect.
Methods: Twenty-eight acute ON patients and 8 healthy
controls were recruited. Assessments were at baseline, 3, 6
and 12 months. DTI tractography of the ORs was performed as well as optic nerve MRI.
Results: Lower optic nerve areas in patients at 3 months
were associated with lower fractional anisotropy (FA) (p ¼
0.028) and higher radial diffusivity (RD) (p ¼ 0.038) of
the ORs at 12 months. These associations survived after
adjusting for OR lesion load. ON patients also showed
reductions in OR FA (p ¼ 0.014) and increases in OR RD
(p ¼ 0.003) over the year. Controls were stable.
Conclusions: Following ON, affected optic nerve area at
3 months predicts OR structure at 12 months, suggesting
trans-synaptic effects. The reduction in FA of the ORs can
be explained by an increase in RD presumably reflecting
ongoing axonal loss and/or demyelination.
S710. Syphilitic Optic Neuritis: Possibly Forgotten but
Not Gone
Robert K. Shin, Marc A. Malouf, Shalom E. Kelman, Larysa
D. Kwintkiewicz and Stephen G. Reich; Baltimore, MD
Objective: To report a case of acute syphilitic optic neuritis
(ON), an historically important and common cause of ON
rarely encountered today.
Background: The incidence of syphilis is rising in the
US. Syphilis frequently involves the eye or central nervous
system, though ON is rare.
Case Report: A 46 yo man with hypertension and diabetes awoke with blurred vision OS. Multiple ophthalmologic
evaluations were inconclusive. One week later, he developed
blurred vision OD and was referred to the ED for possible
retinal ischemia. Visual acuity was 20/400 OD and CF OS.
He had a left afferent pupillary defect and mild left optic
disc pallor. An erythematous, scaly rash was present on the
face, palms and soles suggestive of syphilis. Serum RPR was
reactive (1:4) with positive FTA. CSF showed 48 WBCs
and protein 600 mg/dl. He was treated with intravenous
penicillin with improvement in vision.
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Funding Council of England.
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S802. Cognitive Assessment in Rett Syndrome: A Pilot
Study of Eyetracking
Aleksandra Djukic, Maria Valicenti-McDermott, Kathleen
Mavrommatis and Cristina Martins; Bronx, NY
S713. Cerebellar Esotropia Misdiagnosed as VI Nerve
Paresis: A Case Series
Sui H. Wong, Leena Patel and Gordon T. Plant; London,
United Kingdom and London, United Kingdom
Cognitive testing in Rett Syndrome(RTT) have been difficult because most patients are nonverbal,with limited hand
use. Eye tracking may be invaluable in neuropsychological
assessment in RTT.
Objectives: to determine the accuracy of eye gaze for
pointing, to identify clinical characteristics predictive of eye
pointing accuracy; to examine visual preferences in RTT.
Methods: 50 consecutive patients with RTT at Rett Center July-October/2010 were tested using eye-tracker(Tobii
technology). To test eye pointing accuracy 25 stimuli were
displayed, results were associated with clinical characteristics.
To test visual preferences 5 stimuli were displayed(cartoons/
shapes/faces). Number/duration of looks for targets were
determined. Statistics: Chi-square/analysis of variance.
Results: Mean age1067y., 86% had classical RTT, 80%
good eye contact, 26% no hand use; 35 (70%) demonstrated eye pointing accuracy. Girls with eye pointing accuracy were more alert (68%vs.44% p ¼ 0.02), had better eye
contact (91vs.50%p ¼ 0.002), poorer hand use (hand use:
3% vs. 44% p<0.001) and worse language (verbal: 6% vs.
31% p ¼ 0.02). They displayed preferences, looking longer
(2.862’’vs.0.961’’p ¼ 0.024) to cartoons than shapes.
With faces, they focused on eyes(1.76 1’’ (eyes)vs.161’’
(nose)vs.0.860.4’’ (mouth) p ¼ 0.04).
Conclusions: 70% of patients exhibited accurate eye gazepointing. Girls who were more alert, with good eye contact, poorer hand use and worse language skills were more
likely to complete testing. Eye tracking represents a feasible
method to assess cognition in RTT.
Study supported by: This study was funded in part by
the International Rett Syndrome Foundation
Background: Cerebellar dysfunction causing horizontal
diplopia is under-recognised. We report a case series of
patients presenting with horizontal diplopia, misdiagnosed
as VI nerve paresis or with no clear cause identified.
Methods: Prospective observational case series
Results: Seven patients (3 male) with cerebellar degeneration were referred for assessment of binocular horizontal diplopia. One patient had SCA3 cerebellar degeneration, two
(father and daughter) had familial cerebellar ataxia, and four
were idiopathic. The age of presentation of was 31-76 years
(mean 56, median 63). 6/7 had bilateral mild lateral recti
under-action at presentation. All had mild and slowly progressive cerebellar ataxia. All had comitant esotropia to distance vision worse than for near, which was also slowly
progressive.
Conclusion: We present a series of 7 patients with esotropia secondary to cerebellar dysfunction, causing horizontal diplopia to distance vision. The relative preservation of
near fusion suggests that this is due to a divergence paresis,
rather than a supranuclear deficit. The comitant esotropia is
unlikely to be due to bilateral VI nerve paresis in these
patients.
Study supported by: None
S714. Withdrawn.
Pediatric Neurology
S801. Elevated Immune Response to Gliadin in Autism:
Association with Gastrointestinal Symptoms but Not
Celiac Disease
Nga M. Lau, Peter H. Green, Donald D. Kasarda, Luan To,
Abhishek Chandra, Barry E. Kosofsky, Joseph J. Higgins, Anjali
M. Rajadhyaksha and Armin Alaedini; New York, NY and
Albany, CA
S803. Asymptomatic Abnormalities in the White Matter
of Patients with CMT-X
Amy R. Viehoever, Linda Schimmoeller, Tammie Benzinger,
Soe Mar and Amy Viehoever; St. Louis, MO
Background: X-linked Charcot-Marie-Tooth (CMT-X) is
an X-linked dominant hereditary peripheral neuropathy,
Transient and recurrent central nervous system involvement
with white matter changes on magnetic resonance imaging
(MRI) has been reported in this condition, but usually in
the context of abnormal neurologic symptoms. We initiated
a study of CNS involvement in a large family with CMT-X
to understand the relationship between genotype and phenotype of CNS white matter involvement.
Methods: We performed the standard of care clinical
MRI, directional diffusivity DTI sequences, and detailed
neurological evaluation of 9 family members with CMT-X;
All participants had peripheral neuropathy and genetic confirmation of CMT-X. Only one subject had symptoms of
CNS disease.
Results: White matter signal changes were found in all
cases of varying degrees of severity affecting the corpus callosum and periventricular areas with a posterior predominance similar to previous reported cases. In one case, there
were profound multifocal white matter abnormalities.
Conclusions: There can be changes in the white matter
of patients with CMT-X in absence of symptoms of CNS
disease. Further analysis of the changes in the directional
diffusivities could potentially differentiate between the axonal and myelin pathology.
Study supported by: None
Previous studies examining the link between autism and gluten sensitivity have been inconclusive due to methodological
shortcomings. The aim of this study was to measure
markers of gluten sensitivity and celiac disease in children
with autism, diagnosed according to DSM-IV criteria. IgG
and IgA antibodies to gliadin, deamidated gliadin, and
transglutaminase-2 were measured in serum from 37
children with autism, 28 unaffected siblings, and 76 agematched healthy controls. Children with autism had significantly higher levels of IgG antibody to gliadin compared
with unrelated healthy controls (p<0.01). In addition, there
was a significant association between elevated anti-gliadin
antibody and gastrointestinal symptoms in autistic children
(p<0.01). There was no difference in levels of celiac-specific
markers (antibodies to deamidated gliadin and transglutaminase-2) between affected patients and controls. The data
demonstrate an association between autism and elevated
immune response to gliadin, which correlates with increased
gastrointestinal symptoms. However, the majority of patients
with autism and elevated anti-gliadin antibody do not have
celiac disease. Further research is needed to better understand the antigenic specificity and pathogenic relevance of
the immune response to gliadin in autism.
Study supported by: Department of Defense
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S804. Visual Function and Optical Coherence
Tomography in Pediatric Demyelinating Diseases
Amy T. Waldman, Girish Hiremath, Robert A. Avery, Amy
Conger, Michael Loguidice, Lauren S. Talman, Kristin M.
Galetta, Michael J. Shumski, James Wilson, E’tona Ford,
Benjamin M. Greenberg, Jonas Ellenberg, Elliot M. Frohman,
Laura J. Balcer and Peter A. Calabresi; Philadelphia, PA;
Baltimore, MD and Dallas, TX
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that targeting EGFR after injury is clinically feasible for
treatment of white matter injury in premature children.
Study supported by: K08NS073793 (JS); P01NS062686
(VG); Childhood Brain Tumor Foundation (JS)
S806. Drosophila Peroxisomal Biogenesis Defects
Produce Shortened Lifespan and Excess Cystene-String
Protein at the Synapse
Michael F. Wangler, Lucy Liu, Nikolaos Giagtzoglou, Vafa
Bayat, Joseph Faust, James McNew and Hugo J. Bellen;
Houston, TX
Objective: To examine visual function scores and retinal
nerve fiber layer (RNFL) thickness in children with demyelinating diseases and disease-free controls.
Methods: Children (5 to <18 years) with demyelinating
diseases and controls were enrolled across 3 academic centers. Visual function was assessed using high-contrast
(ETDRS) charts and low-contrast Sloan letter charts
(LCSLC, 2.5% and 1.25% contrast). Optical coherence tomography (OCT) was performed using Stratus OCT-3. Linear regression was used to compare visual tests and RNFL
thickness between patients and controls.
Results: 56 subjects were enrolled and compared to 47
controls. Only LCSLC (1.25% contrast) differed between
the groups for both monocular and binocular data
(p<0.001 and 0.012, respectively). Binocular summation
resulted in a 10-letter improvement in the binocular score
compared to the better eye score for patients and controls
(p ¼ 0.4979). RNFL thickness for all disease eyes (110 lm)
was decreased compared to control eyes (100 lm, p ¼
0.001); however, RNFL thickness was preserved among
non-optic neuritis (ON) eyes of children with multiple sclerosis (MS) (109 lm, p ¼ 0.554).
Conclusions: LCSLC captured subtle vision changes in
children. In contrast to adult data, RNFL thickness was preserved in non-ON eyes of children with MS.
Study supported by: National Multiple Sclerosis Society
and American Academy of Neurology Foundation (now the
American Brain Foundation)
Peroxisomal biogenesis is encoded by a group of evolutionarily conserved genes called the pex genes. Peroxisomal
defects produce neurologic problems in patients with Peroxisomal Biogenesis Disorders (PBD). To further understand
the role of peroxisomes within the nervous system, we have
turned to Drosophila melanogaster. We have generated and
characterized loss-of-function alleles of pex16, and of pex2.
As predicted, peroxisomes are grossly abnormal in these
mutants. Interestingly, these mutants are viable, and they
display a crumpled wing phenotype, locomotor defects and
dramatically shortened lifespan. Furthermore, a detailed biochemical analysis reveals a unique lipid metabolism defect.
To better understand the role of peroxisomes in synaptic
biology we performed a detailed characterization of the
Neuromuscular junction (NMJ) for pex2. While vesicle
release is normal in these mutants, FM1-43 dye loading
during stimuation is increased. Additionally, cysteine-string
protein (CSP), a synaptic vesicle protein is dramatically
increased in the synaptic boutons. CSP overexpression has
been reported to result in phenotypes similar to what we
have observed in the pex mutants which suggests the novel
hypothesis that CSP underlies nervous system dysfunction
in peroxisomal biogenesis defects.
Study supported by: K08 NS076547-01
Rehabilitation and Regeneration
S805. Epidermal Growth Factor Treatment Rescues
Neonatal White Matter Injury
Joseph Scafidi, Maria Roncal, Tamas L. Horvath, Robert J.
McCarter and Vittorio Gallo; Washington, DC and New
Haven, CT
S901. Time Limited Functional Properties of
Transplanted Neural Stem Cells
Nina Fainstein, Ofira Einstein, Mikhal Cohen and Tamir
Ben-Hur; Jerusalem, Israel
Neural stem cells (NSC) possess powerful immunomodulatory and neurotrophic properties. NSCs effectively attenuate
neuroinflammation, protect the brain from immune-mediated injury and facilitate its self repair capacity. However,
the therapeutic value of NSC therapy in chronic diseases is
critically dependent on their long term functions. We therefore examined whether transplanted NSCs maintain their
immunomodulatory and trophic properties over time.
Transplanted NSCs could not support their own long
term survival, becoming highly dependent on environmental
cues. Damaging versus induction of a local neurogenic environment significantly compromised or improved graft survival, respectively. In accordance, long term cultured NSC
spheres exhibited dramatic decline in proliferative activity,
increased apoptosis and reduced neurotrophic factor
secretion.
Then, in two experimental paradigms, intracerebroventricular transplanted syngeneic NSCs attenuated an early
relapse of experimental autoimmune encephalomyelitis, but
failed to inhibit delayed relapses, albeit good survival of
transplant. Moreover, following allogeneic transplantation,
NSC grafts failed to inhibit the allogeneic immune reaction
and were rejected from the host brain. In correlation, long
A significant public health concern is the growing numbers
of very preterm infants with neonatal brain injury. Diffuse
white matter injury (DWMI) is a common finding in these
children and correlates with their sustained neurodevelopmental impairments. There are no clinically relevant targeted therapies available that improve function. As shown
recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. It has been demonstrated that
epidermal growth factor receptor (EGFR) plays an important role in oligodendrogenesis. Here, we examine whether
enhanced EGFR signaling stimulates the endogenous
response of EGFR-expressing progenitor cells during a critical period after injury, and promotes cellular, ultrastructural
and behavioral recovery. Using a model of premature brain
injury, we demonstrate that overexpression of EGFR in oligodendrocyte-lineage cells or the administration of intranasal EGF immediately after injury decreases oligodendroglia death, promotes oligodendrogenesis and accelerates
maturation. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioral deficits on
white matter-specific paradigms. We also demonstrate that
EGFR signaling is crucial with loss of function experiments
in vivo. Our multidisciplinary study provides direct evidence
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term cultured NSCs lost their capacity to inhibit immune
cell proliferation in vitro.
In conclusion, long-term functional changes in transplanted NSCs lead to loss of their therapeutic immunomodulatory and neurotrophic properties.
Study supported by: The Taubman Foundation
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Study supported by: the National Research Foundation
(NRF-2010-0020408; NRF-2010-0024334; SC-4160), and
the Chyung Ki Lee Research Fund
S904. OnabotulinumtoxinA Plus Rehabilitation
Improves Functional Outcome in Post-Stroke Upper
Limb Spasticity: A Single-Blind, Randomized Trial
Deidre J. Devier, JoAnn Harnar, Leandro M. Lopez, Allison
Brashear and Glenn D. Graham; New Orleans, LA;
Albuquerque, NM; Albuqueruque, NM; Winston Salem, NC
and Washington, DC
S902. Recovery of Motor Function after Complete
Unilateral Injury of the Corticospinal Tract Using
Electrical Stimulation of Motor Cortex on the
Uninjured Hemisphere in Rats
Jason B. Carmel, Hiroki Kimura, Gabriel Felder, Ashley
Khalili, Melissa Lopresti, Chelsea Jin and John H. Martin;
White Plains, NY and New York, NY
Background and Purpose: This multi-center, prospective
randomized, single-blind, clinical trial explored the potential
benefit of adding weekly occupational therapy to a background of onabotulinumtoxinA (BoNT-A) treatments for
upper limb spasticity, using the upper limb Fugl-Meyer to
assess short-term improvement in patient functional
outcome.
Methods: Thirty-one patients with post-stroke upper
limb spasticity aged 36–75 were enrolled and treated with
BoNT-A. They were randomly assigned to either BoNTAþRehab or BoNT-A no rehab. They were injected up to 2
times and followed for 24 weeks.
Results: Both groups showed significant improvement in
Fugl-Meyer scores. There was also a significant Fugl-Meyer
by Group interaction with the BoNT-AþRehab group
showing significantly more functional improvement. This
improvement was driven primarily by change in the upper
extremity movement and pain subscales. Two self-report
measures, Disability Assessment Scale and Patient Disability
Scale, also showed improvement across study visits, but did
not differ between the two treatment groups.
Conclusions: Rehabilitation therapy following injection
of onabotulinumtoxinA for post-stroke upper limb spasticity
results in improved functional recovery. This effect was
measured over approximately seven months and may continue beyond that time period.
Study supported by: This project was supported by an
unrestricted research grant from Allergan Inc. to the Biomedical Research Institute of New Mexico (BRINM).
Dr. Graham is a consultant for D-Pharm, Ltd. and is a
member of the Global Stroke Community Advisory Panel,
which indirectly receives support from Allergan.
Dr. Brashear performs research and consults with Ipsen,
Allergan and Merz and her conflict of interest is managed
by Wake Forest School of Medicine.
We hypothesized that in mature animals with complete unilateral lesion of the corticospinal tract (CST), electrical stimulation of motor cortex (M1) on the uninjured side would
promote recovery of skilled motor function after chronic
injury. We cut one pyramid and tested motor skill weekly
to show a stable forelimb deficit. We then implanted electrodes over forelimb area of M1 on the intact side. 8 weeks
after CST injury, we used the epidural electrodes to deliver
stimulation 6 hours a day for10 days. At 4 weeks after stimulation, treated rats performed the motor task significantly
better that rats with CST injury alone and similar to uninjured rats. To determine whether the ipsilateral (stimulated)
M1 was responsible for mediating this motor recovery, we
performed pharmacological inactivation of M1. In rats with
stimulation, inactivation of stimulated M1 caused a worsening in the initially impaired forepaw to an error rate similar
to that before stimulation. Thus, in rats with chronic and
complete unilateral CST injury we restored motor control
from M1 on the intact side using electrical stimulation.
Study supported by: N/A
S903. Synergic Effects of Enriched Environment and
Mesenchymal Stem Cells in Hypoxic-Ischemic Brain
Injury through FGF-2 Dependent Mechanism
Jung Hwa Seo, Ji Hea Yu, Yang Hyun Cho and Sung-Rae
Cho; Seoul, Republic of Korea
We investigated environmental enrichment (EE) after transplantation of mesenchymal stem cells (MSCs) could synergistically enhance functional recovery in an animal model of
hypoxic-ischemic brain injury. Brain damage was induced in
CD-1 (ICR) mice (P7). At 6 weeks of age, the mice were
randomly treated with MSCs (1x105 cells) or PBS into the
striatum, assigned to 5 groups: MSC-EE (n ¼ 18), MSCcontrol (n ¼ 19), PBS-EE (n ¼ 12), PBS-control (n ¼ 17),
untreated control (n ¼ 23). As a result, MSC-EE synergistically improved rotarod latency by 8 weeks after treatment
(p<0.05). Cylinder, ladder walking, and grip strength tests
also showed enhanced motor functions in MSC-EE mice.
They also showed a significant increase of Tuj-1þ neurons
of grafted cells prelabeled with BrdU and endogenous striatal neurogenesis (p<0.05). In addition, MSCs and/or EE
exhibited an increment of CD31þ vessel density and
GFAPþ astroglial activation over controls (p<0.05). Furthermore, FGF-2 were significantly overexpressed in MSCEE when evaluated using multiplex ELISA system (Quantibody array) (p<0.05). In conclusion, EE after transplantation of MSCs elicited synergistically beneficial effects for
neurorestoration by promoting endogenous repair process of
neurogenesis coupled with angiogenesis and astroglial activation through FGF-2 dependent mechanism.
S905. Peripheral and Cutaneous Nerve Fiber
Regeneration in the Distal Foot of Macaques after
Spinal Nerve Ligation (SNL)
Gigi J. Ebenezer, Jasenka Borzan, Matthias Ringkamp, Lun
Chen, Justin C. McArthur, Peter Hauer, James N. Campbell,
Richard A. Meyer, John W. Griffin and Michael Polydefkis;
Baltimore
We examined morphological and quantitative changes of
nerve fibers and Schwann cells in the distal nerve and foot
epidermis of Macaque monkeys after SNL to investigate the
mechanisms of neuropathic pain.
Methods: Four months following lesion, peripheral
nerves and skin roll encompassing L5/6 dermatomes were
examined and quantified using electron microscopic and immunohistochemical techniques.
Results: Though injured nerves showed significant loss of
nerves with marked Wallerian degeneration, the size of
remaining unmyelinated axons and Remark Schwann cells
was preserved with evidence of disregulated axonal
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regeneration. There was robust reinnervation of L5/6 dermatome with PGP9.5 þve and CGRP þve dermal nerve
fibers with proliferation of Schwann cells. The epidermal
nerve fiber reinnervation was patchy with increased intraepidermal terminal branching on the plantar side.
Conclusion: SNL resulted in pronounced Wallerian axonal degeneration in peripheral nerves with evidence of irregular axonal regrowth, while there was robust re-innervation
of the skin at the distal foot. The remodeling and collateral
sprouting of uninjured nerve fibers, upregulation of
Schwann cells and release of neuropeptides by regenerating
CGRP fibers at the plantar skin provide a pathological correlate to neuropathic pain.
Study supported by: Blaustein Pain Research fund
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Measurements included: fatigue (Modified Fatigue Impact
Scale); balance (computerized posturography).
Results: The experimental group improved in fatigue (p
< 0.001), improving greater than the exercise control group
(p ¼ 0.024) and the control group (p ¼ 0.005), and in balance (p < 0.001), improving greater than the exercise control group (p ¼ 0.001) and control group (p ¼ 0.003).
Conclusion: A 6-week vestibular rehabilitation program
demonstrated both statistically significant and clinically-relevant changes in fatigue and balance in persons with MS.
Study supported by: This study was partially supported
by the National Multiple Sclerosis Society, Pilot Project no.
PP1501.
This study was published in August of 2011 in the Physical Therapy Journal. Permission to reprint/reproduce for the
purpose of abstract submissions and publications, and conference presentations has been requested and granted. See
mandated requirement for the full citation of this duplicated
material below:
‘‘Reprinted from Hebert JR, Corboy JR, Manago MM,
Schenkman M. Effects of Vestibular Rehabilitation on Multiple Sclerosis-Related Fatigue and Upright Postural Control:
A Randomized Controlled Trial. Physical therapy.
2011;91(8):1166-1182, with permission of the American
Physical Therapy Association. This material is copyrighted,
and any further reproduction or distribution requires written permission from APTA.’’
S906. Vestibular Rehabilitation and Multiple Sclerosis:
Do Patients with Infratentorial Lesions Benefit More?
Jeffrey R. Hebert; Aurora, CO
Background: Multiple sclerosis (MS) frequently affects
infratentorial structures including the brainstem and cerebellum, resulting in impaired balance often leading to
advanced disability. Evidence is evolving that indicates interventions targeting brain lesion involvement may prove more
effective. Yet to be determined is whether vestibular rehabilitation, balance and eye movement training, is most effective
for those with brainstem and/or cerebellar involvement.
Methods: Single-group analysis from a 3-group (N ¼ 38
persons with MS), 14-wk randomized controlled trial, where
the experimental group underwent vestibular rehabilitation.
Experimental group-only (N ¼ 12) analysis of changes in
balance (posturography) was performed based on brainstem
and/or cerebellar lesion involvement: participants with (n ¼
8) and without (n ¼ 4).
Results: Balance improved significantly for participants
with brainstem and/or cerebellar involvement (21.6,
p ¼ 0.002) and insignificantly for those without (10.3,
p ¼ 0.134), with a large between-group standard effect size
(d ¼ 0.99; p ¼ 0.155).
Conclusion: A 6-wk vestibular rehabilitation program
demonstrated statistically significant and clinically relevant
improvements in balance for persons with MS who have
brainstem and/or cerebellar involvement. The small sample
size is a limitation; however, the results warrant larger
investigations.
Study supported by: This study was partially supported
by the National Multiple Sclerosis Society, Pilot Project no.
PP1501.
S908. RTMS in Treatment of Poststroke Aphasia
Wolf-Dieter Heiss, Alexander Hartmann, Josef Kessler, Nora
Weiduschat, Ilona Rubi-Fessen, Carole Anglade and Alexander
Thiel; Cologne, Germany and Montreal, Canada
Non-invasive repetitive transcranial magnetic stimulation
(rTMS) might improve the effect of speech therapy in poststroke aphasia.
A randomized, controlled and blinded study examined the
effect of 1Hz rTMS over the non-dominant Broca’s homologue. Results of 21 subjects with poststroke aphasia in the
subacute stage are reported. According to group allocation
patients received, additionally to conventional speech and language therapy, 10 sessions of rTMS either over the inferior
frontal gyrus of the non-dominant-hemisphere (intervention
group) or over the vertex (control group). The primary outcome measure is the change in the global score of the Aachen
Aphasia Test (AAT) battery, secondary outcome variables are
AAT subtests and the extent of interhemispheric activation
shift as measured with language activation PET.
There was a significant difference in pre- and post treatment global AAT scores between TMS-treated and shamtreated groups with significantly higher mean scores in the
treatment group (TMS-group: 22.8 þ/- 12.36, Sham-group
9.4 þ/- 12.79, p ¼ 0.032). A repeated measures analysis of
variance demonstrated a highly significant treatment effect
across all subtests (P ¼ 0.002). PET revealed a shift of activated language-related cortex towards the left hemisphere in
the intervention group.
Repetitive TMS might be an effective complementary
therapy for poststroke aphasia.
Study supported by: Marga and Walter Boll Foundation
S907. Effects of Vestibular Rehabilitation on Multiple
Sclerosis-Related Fatigue and Upright Postural Control:
A Randomized Controlled Trial
Jeffrey R. Hebert, John R. Corboy, Mark M. Manago and
Margaret Schenkman; Aurora, CO
Background: Fatigue and impaired upright postural control
(balance) are the two most common findings in persons
with multiple sclerosis (MS), with treatment approaches
varying greatly in effectiveness. The objective of the study
was to investigate the benefits of implementing a vestibular
rehabilitation program for the purpose of improving fatigue
and balance in persons with MS.
Methods: The study was a 14-week, single-blinded, stratified blocked, randomized controlled trial. 38 persons with
MS were randomized to: experimental group, exercise control
group or wait-listed control group. The experimental group
underwent vestibular rehabilitation and the exercise control
group underwent bicycle endurance and stretching exercises.
S909. Regulatory Experience with Orphan Disorders of
the Nervous System
Orest Hurko, Andra E. Miller, Ruth Wolff and James G.
Kenimer; Alexandria, VA
Concerns that pharmaceutical companies are dissuaded from
pursuit of therapeutics for neurological disorders with
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limited commercial opportunities prompt interest in the
role of alternate sponsors and FDA’s Orphan Product program. We reviewed the performance of both from the inception of the program in 1983. As of March 14, 2012, there
were 610 FDA designations of Orphan Status for proposed
treatments of disorders affecting the nervous system. In descending order, designations in this category were awarded
to small to medium cap firms (413), large firms (147),
unaffiliated individuals (24), academic institutions (16), disease-related charities (7) and government agencies (3). Neurologic orphans sponsored by large companies achieved an
overall approval of 29.3% vs. 8.72% for those by small-cap
biotechs. The approval advantage of large companies and
governmental agencies over smaller sponsors spanned therapeutic classes: proteins, 40.0% vs. 5.88%; small molecules,
26.7% vs. 11.3%. This disparity accords with our observations of difficulties experienced by emerging sponsors in
demonstrating consistent manufacture and safety, as well
corroboration of findings published by Heemstra: failures
from ‘‘clinical trial design, the level of experience of the
sponsor and the level of interaction with the FDA.’’
Study supported by: Biologics Consulting Group, Inc.
All four authors are full-time employees and part owners
of Biologics Consulting Group, Inc.
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We developed Shefstim, a 64 channels stimulator which
automatically determines the best site of stimulation.
Twenty one participants were recruited. They performed
two walks of 10 m for each of the following conditions: own
setup (PS), clinician setup (CS), automated setup (AS) and
no stimulation (NS). PS and CS used a conventional stimulator. In AS stimulation used Shefstim. Outcome measures
were walking speed andfoot angle at initial contact.
Compared to NS, mean walking speeds improved significantly with all three FES setups. Speed for both AS (0.65
m/s) and CS (0.68 m/s) were comparable. Speed with PS
(0.72 m/s)was significantly better than with AS and CS.
Frontal plane foot orientation at heel-strike was more neutral for AS than others. Dorsiflexion angles for AS were
larger than NS, not different to PS and less than CS. This
study has demonstrated that Shefstim produces results comparable to clinician setup. The technique seems sufficiently
reliable to warrant further studies.
Study supported by: This work was generously funded by
the Sheffield Hospitals Charitable Trust. The Trust had no
involvement in any aspects of the work or publication.
S912. Deconditioning in Patients with Orthostatic
Intolerance
Ajay K. Parsaik, Thomas G. Allison, Wolfgang Singer, David
M. Sletten, Michael J. Joyner, Eduardo E. Benarroch, Phillip
A. Low and Paola Sandroni; Rochester, MN
S910. Examining Driving Ability in Multiple Sclerosis
Maria Schultheis, Chelsea Morse, Josh McKeever, Lisa Zhao
and Thomas Leist; Philadelphia, PA
Objective: To examine the relationship between driving
ability, cognition, and physical impairment in drivers with
Multiple Sclerosis (MS).
Methods: Participants include persons with clinically
defined MS (n ¼ 14). Driving performance was defined
using a virtual reality driving simulator (VRDS). Specifically, speed and lane deviation during basic (highway) and
complex (following a vehicle, dual task) driving were examined. All participants were administered the Multiple Sclerosis Functional Composite (MSFC), visual measures and
neuropsychological measures relevant to driving ability.
Results: Individuals with MS and cognitive impairment
demonstrated greater lane deviation during a truck following
task (t ¼ -2.37, p ¼ .04) and while simultaneously performing an attention demanding behavioral task (t ¼ -2.65,
p ¼ .02). Correlational analysis revealed that the MSFC
(R2 ¼ -.73, p ¼ .04) and contrast sensitivity (R2 ¼ -.71, p
¼ .048) were significantly related to VRDS performance.
Conclusions: The presence of cognitive impairment in
individuals with MS may contribute to greater difficulties in
lane management during complex but not basic driving. Additionally, MS severity and contrast sensitivity may contribute to
driving performance. Together, these preliminary findings
indicate that impairment across various domains (cognitive,
visual, severity) may contribute to changes in driving ability.
Study supported by: National Multiple Sclerosis Society
Background: Recent evidence suggests a central role of
deconditioning in orthostatic intolerance. Frequency and
degree of deconditioning and its relationship with autonomic parameters in these patients have not been studied.
Methods: We retrospectively studied orthostatic intolerance
patients seen at Mayo Clinic between January 2006 and June
2011, who underwent autonomic and exercise testing.
Results: 184 [84 Postural Orthostatic Tachycardia Syndrome (POTS), 100 without orthostatic tachycardia (OI)] fulfilled inclusion criteria. 89 % were females; mean age 27.5
years and symptoms duration 4 years. 93 % patients had
deconditioning (predicted VO2 max % <85%) during exercise. Deconditioning was unrelated to age, gender, and duration of illness and prevalence was similar between POTS
(95%) and OI (91%). Predicted VO2 max % had a weak correlation with a few autonomic and laboratory parameters, but
adequate predictors of deconditioning could not be identified.
Conclusion: Deconditioning is present in almost all
patients with orthostatic intolerance and may play a central
role in pathophysiology. This finding provides a strong rationale for retraining in the treatment of orthostatic intolerance. None of the autonomic indices are reliable predictors
of deconditioning.
Study supported by: This work was supported in part by
National Institutes of Health (NS 32352 Autonomic Disorders Program Project; NS 44233 Pathogenesis and Diagnosis of Multiple System Atrophy, U54 NS065736 Autonomic
Rare Disease Clinical Consortium), Mayo CTSA (UL1
RR24150), and Mayo Funds.
S911. Shefstim: Automated Setup of Functional
Electrical Stimulation for Drop Foot Using a 64
Channel Prototype Stimulator and Electrode Array
Ben W. Heller, Alison J. Clarke, Timothy R. Good, Jamie
Healey, Krishnan P.S. Nair, Emma J. Pratt, Mark L. Reeves,
Jill M. van der Meulen and Anthony T. Barker; Sheffield,
South Yorkshire, United Kingdom
S913. Orthostatic Intolerance with or without Postural
Orthostatic Tachycardia
Ajay K. Parsaik, Thomas G. Allison, Wolfgang Singer, David
M. Sletten, Michael J. Joyner, Eduardo E. Benarroch, Phillip
A. Low and Paola Sandroni; Rochester, MN
Background: We recently reported that deconditioning is
universal in patients with Postural Tachycardia Syndrome
(POTS) and orthostatic intolerance without orthostatic tachycardia (OI-NP). In this study we compared clinical and
Functional electrical stimulation can correct foot drop following upper motor neuron disorders. Some patients have
difficulty identifying sites to place stimulating electrodes.
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autonomic characteristics between: POTS vs OI-NP, Deconditioned vs non-deconditioned.
Methods: We retrospectively studied all patients referred for
orthostatic intolerance at Mayo Clinic between January 2006June 2011, who underwent autonomic and exercise testing.
Results: 84 POTS and 100 OI-NP fulfilled inclusion criteria, 89% were females, mean age 25 and 32 years respectively. Clinical presentation, presence and degree of deconditioning, and autonomic parameters were similar between the
2 groups, Responses to different medications for OI were
poor in both groups. Severely deconditioned patients were
clinically similar to non-deconditioned, except in the following: TST% anhydrosis 1.5% vs 0.5% (clinically insignificant), 24 hour urine volume (ml) 1555 vs 2417, peak heart
rate change during exercise (beats/min) 78 vs 103, peak respiratory rate 33/min vs 37/min, tidal volume (ml) 1656 vs
2054, breathing reserve (ml) 61 vs 48, respectively.
Conclusion: POTS and OI-NP are similar entities. Clinically, deconditioned patients are similar to non-deconditioned but have lower 24 hour urine volume, peak heart
rate and respiratory parameters.
Study supported by: This work was supported in part by
National Institutes of Health (NS 32352 Autonomic Disorders Program Project; NS 44233 Pathogenesis and Diagnosis of Multiple System Atrophy, U54 NS065736 Autonomic
Rare Disease Clinical Consortium), Mayo CTSA (UL1
RR24150), and Mayo Funds.
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function. Similar advances are commencing in spinal-cord
imaging, despite challenges related to the small cross-sectional size of the spinal cord and physiological-related
motions. Emerging techniques including ultra-high-field
MRI, custom coil design, and multi-parametric MRI promise more sensitive and quantitative assessment of spinal-cord
pathology. We report preliminary evidence of new radiologic
capabilities for evaluating myelopathy. One case involved a
young woman left with motor and sensory hemideficits after
inadvertent intramedullary injection into her cervical spinal
cord. Combining high-resolution structural imaging, diffusion tensor imaging and magnetization transfer using 3T
MRI allowed us to detect and serially characterize Wallerian
degeneration of one ascending dorsal column that was
unseen on her clinical MRIs. Another patient had persistent
limb clumsiness, pain, and itch after hemorrhage of a spinal-cord cavernoma. Ultra-high field 7 Tesla MRI and custom-made coils enabled very-high spatial resolution (370
micron). This permitted exquisite localization of specific
symptoms to sub-parts of spinal-cord structures, including
associating neuropathic itch to specific dorsal-horn laminae.
Greater understanding of spinal-cord function and lesions
appears likely to follow.
Study supported by: Public Health Service [NIHK24NS59892], National Center for Research Resources
[P41-RR14075] National MS Society [FG 1892A1/1]
S1002. Neuregulin-1 Effects on Endothelial and BloodBrain Barrier Permeability after Experimental Injury
Josephine Lok, Song Zhao, Wendy Leung, Ji Hae Seo, Deepti
Navaratna, Xiaoying Wang and Lo Eng; Boston, MA and
Jilin, China
S914. Efficacy of Vitamin E Supplementation in
Cisplatin-Induced Neuropathy: A Meta-Analysis of
Randomized Controlled Trials
Rechilda Rhea P. Reyes, Rechilda Rhea Reyes, Rechilda Rhea
Reyes, Rechilda Rhea Reyes and Rechilda Rhea Reyes; Davao
City, Davao, Philippines
Blood-brain-barrier disruption contributes to brain edema,
inflammation, and neuronal cell death after brain injury.
Thus, BBB integrity is an important potential therapeutic
target in the treatment of traumatic brain injury. The effects
of neuregulin-1 (NRG1) on endothelial permeability and
BBB permeability are reported here. Incubation of brain microvascular endothelial cells with IL-1b increased endothelial
permeability, while NRG1 co-incubation ameliorated this
pathological increase. Similarly, incubation with TNFa
decreased the expression of ZO-1 and VE-cadherin. The
decrease was less extensive with NRG1 co-incubation. For
in-vivo studies, C57Bl mice were subjected to controlled
cortical impact (CCI) under anesthesia and BBB permeability was assessed by measuring Evans blue dye extravasation.
NRG1-treated mice exhibited a 35% decrease in BBB permeability compared to vehicle-treated mice. Hemoglobin
ELISA performed at the same time point showed a trend
towards lower levels of hemoglobin extravasation in the
NRG1 group, but the results did not reach statistical significance. MMP-9 activity was not different between groups at
2h. These data suggest that NRG1 decreases the permeability of endothelial cells exposed to inflammatory cytokines
and reduces BBB permeability following experimental brain
trauma.
Study supported by: NINDS
The clinical use of platinum-based antineoplastic agents is
limited by severe peripheral neurotoxicity reported in up to
90% of patients receiving a cumulative dose higher than 300
mg/m2. Recent studies support that cisplatin-induced neuropathy is related to degeneration of large dorsal root ganglion
cell bodies with loss of large myelinated fibers. Evidence suggests that side effects induced by cisplatin treatment are, at
least in part, the result of the formation of free radicals. In
animals, supplementation with antioxidants protects against
renal toxicity and ototoxicity induced by cisplatin; moreover,
human studies indicate that cisplatin treatment induces a
decrease in plasma antioxidant levels due to oxidative stress. It
has been noticed that clinical and neuropathologic features
observed in cisplatin-induced neuropathy are similar to those
observed in vitamin E deficiency neuropathy. The objective of
this paper is to evaluate the efficacy of Vitamin E as prophylaxis against cisplatin-induced peripheral neuropathy. Based on
this meta-analysis, vitamin E supplementation is effective in
the prevention of cisplatin-induced neurotoxicity. It can also
be concluded that Vitamin E may also be effective in the prevention of other polyneuropathy caused by other diseases.
Study supported by: none
Trauma/Injury
S1003. Widely Used Clinical Predictors Do Not Account
for Outcome Variability in Mild Traumatic Brain Injury
Paolo Moretti, Stephen McCauley, Elisabeth Wilde and Harvey
Levin; Houston
S1001. Preliminary Clinical Utility of Advanced SpinalCord MRI
Julien Cohen-Adad, Wei Zhao, Lawrence L. Wald, Bradley
Buchbinder and Anne Louise Oaklander; Charlestown, MA
and Boston, MA
We hypothesized that methods used in the acute evaluation
of mild traumatic brain injury (mTBI) do not allow prospective identification of individuals at risk of unfavorable
outcome. We analyzed data from a prospective study of
Advances in brain imaging have revolutionized neurological
diagnosis and knowledge of normal and pathological brain
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consecutive patients with mTBI. All subjects had negative
acute CT findings and no sources of secondary gain at follow-up. Based on Glasgow Outcome Scale-Extended results
at 3 months post-injury, we compared two groups: Upper
Good Recovery (n ¼ 116; 57.1% of total) and Lower Moderate Disability (n ¼ 21; 10.3% of total). The groups did
not differ on gender, injury severity/mechanism, Glasgow
Coma Scale score, alcohol/toxicology results, or history of
drug/alcohol use. The groups differed on age, education,
and history of psychiatric difficulties (all p<.05). Regression
analysis indicated that although each factor made a significant contribution, the model only accounted for 29% percent of the variance (adjusted r-square ¼ .29). This demonstrates that some of the most widely used predictors of
outcome following mTBI account for only a small fraction
of the outcome variance. Further studies are needed to dissect the factors associated with outcome variability and to
develop more effective prognostic tools in mTBI.
Study supported by: CDC Grant R49/CCR612707
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neurological deficit (ND) or PTSD correlated with episodes
of mTBI with LOC, not with episodes of altered consciousness. 2) Before any interventions, cognitive impairment and
headache frequency correlated with PTSD severity. 3) During
treatment of PTSD, cognitive performance correlated with
headache frequency and intensity, PTSD severity and IS.
Headache frequency correlated with ND severity, IS and
PTSD severity. Pain correlated with PTSD severity and IS.
Thus cognitive impairment and headache severity were most
consistently correlated with PTSD and IS. We felt that NDs
were markers of brain injury. For mTBI, the important role
that brain injury plays is to potentiate the genesis of PTSD
as suggested by the correlation between the prevalence of
PTSD and the number of episodes of mTBI with LOC.
Study supported by: Rehabilitation Research and Development Service of the Office of Research and Development,
Department of Veterans Affairs, United States
S1006. Delayed Imaging Findings in Delayed
Posthypoxic Leukoencephalopathy
Kevin A. Shapiro, Mai Anh Huynh, Riley M. Bove´, Stephanie
L. Cincotta and Jeffrey M. Ellenbogen; Boston, MA
S1004. Systematic Review and Meta-Analysis of Glasgow
Coma Scale and Simplified Motor Scale in Predicting
Traumatic Brain Injury Outcomes
Balwinder Singh, M. Hassan Murad, Larry J. Prokop, Patricia
J. Erwin, Zhen Wang, Shannon K. Mommer, Sonia S.
Mascarenhas and Ajay K. Parsaik; Rochester, MN and
London, United Kingdom
Delayed posthypoxic leukoencephalopathy (DPHL) is a rare
sequela of prolonged cerebral hypoxia, characterized by parkinsonism or akinetic mutism beginning 2-40 days after the
anoxic insult. Brain MRI typically demonstrates diffuse white
matter hyperintensity on T2- and diffusion-weighted sequences, reflecting acute demyelination. However, the temporal
evolution of imaging findings with respect to the appearance
of clinical symptoms is poorly defined. We describe the case
of a 47-year-old woman who presented with rigidity and cognitive decline one month after cardiopulmonary arrest. She
recovered from the arrest within 10 days, and returned home
with only mild memory difficulties. Approximately 10 days
later, she developed worsening short-term memory deficits,
emotional lability, and shuffling gait, which progressed to diffuse rigidity, hyperreflexia, and akinetic mutism. Brain MRI
on day 22 showed patchy T2 hyperintensities in biparietal
white matter, without diffusion changes. Repeat MRI on day
34 showed diffuse white matter hyperintensity on T2weighted images with corresponding diffusion restriction. To
our knowledge, this is the first reported case in which serial
MRI examinations have shown that neuropsychiatric symptoms may precede the development of characteristic imaging
findings, suggesting that white matter injury may be
advanced before it becomes radiographically obvious.
Study supported by: The authors are employed by Massachusetts General Hospital. There are no other relevant
disclosures.
Objective: To compare the Simplified Motor Scale (SMS)
and Glasgow Comma Scale (GCS) in predicting traumatic
brain injury (TBI) outcomes.
Data Sources and study selection: A search of Ovid
EMBASE, Ovid Medline, Ovid PsycInfo, evidence-based
medicine Reviews, Scopus and related conference proceedings was performed through February 28, 2012 for studies
comparing SMS and GCS in predicting TBI outcomes
[emergency tracheal intubation (ETI), clinically significant
brain injuries (CSBI), neurosurgical intervention (NSI) and
mortality].
Data Synthesis: Five retrospective studies including
102132 TBI subjects (63.4% males), with 14670 (14.4%)
ETI, 16201 (15.9%) CSBI, 4730(4.6%) NSI and 6725
(6.6%) mortality, were eligible. Pooled AUC of the GCS vs
SMS was as follows: CSBI 0.79 vs 0.75 (p ¼ 0.16), NSI 0.83
vs 0.81(p ¼ 0.34), ETI 0.85 vs 0.82 (p ¼ 0.31) and mortality 0.90 vs 0.87 (p ¼ 0.01), respectively. Large heterogeneity
between the studies was observed in all analysis (I2 > 50%)
Conclusion: Even though CSBI, NSI and ETI after TBI
can be predicted by SMS with accuracy similar to total
GCS, but mortality is better predicted by GCS. Due to heterogeneity and limited number of studies, further prospective studies are required.
Study supported by: None
S1007. When Mild Traumatic Brain Injury Isn’t so Mild
Latha G. Stead, Aakash N. Bodhit, Keith R. Peters, Lawrence
Lottenberg and Bayard D. Miller, Sr; Gainesville, FL
S1005. Headaches and Cognitive Performance after
Combat Mild Traumatic Brain Injury (mTBI) Correlate
with Episodes of Loss of Consciousness (LOC),
Post-Traumatic Stress Disorder (PTSD) and Impaired
Sleep (IS)
Ronald G. Riechers, Robert L. Ruff, Xiao-Feng Wang, Suzanne
S. Ruff and Traci Piero; Cleveland, OH
Objective: The present study characterizes patients with mild
traumatic brain injury (TBI) findings on neuroimaging.
Methods: We conducted an observational cohort study of
consecutive adults presenting to the Emergency Department
with TBI and Glasgow Coma Score 15 upon arrival.
Results: The cohort (n ¼ 409) was 60% male, median
age 38 yrs (IQR 24-59). Racial composition was 76%
white, 18% black, 4% Hispanic and 2% other. The CT was
abnormal in 25% (103),; 81% with bleed; 36% with fracture; 25% having both.
The mechanism of MVC vs. fall was significantly associated with bleed (p ¼ .0075). This held true even after
adjusting for age, sex, and associated symptoms of injury
We correlated headaches and cognitive performance with episodes of mTBI, PTSD and IS in 126 Middle East combat
veterans. Study group obtained from 2091 veterans sequentially screened for episodes of mTBI with loss of consciousness (LOC). Final steps were neurological and psychological
examinations. Important observations were: 1) Prevalence of
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(p ¼ .0245, R2 ¼ 13.7%). Regression modeling showed
older age and vomiting demonstrating a statistical trend
t(p ¼ 0.0666). For bleeds, vomiting demonstrated a strong
association, p ¼ 0.0076, R2 ¼ 23.6%.
Conclusions: This study underscores: 1) the importance
of neuroimaging in all patients with TBI, including those
with a GCS 15. Fully 8% of our cohort was not imaged.
Extrapolating, these would represent 4.8% bleeds, and 2.9%
fractures. 2) The limitations of GCS in classifying TBI, as
patients with even the mildest of mild TBI have a high frequency of gross CT abnormalities.
Study supported by: n/a
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risk. Resting state functional connectivity (rs-fc) may be an
early biomarker. We studied if a FH of AD disrupts rs-fc in
cognitively normal individuals.
Methods: rs-fc was obtained in participants with at least
one biological parent with AD (FHþ) (n ¼ 196) and those
without parents having AD (n ¼ 152) (FH-).
Results: To obtain optimal seed regions, rs-fc was compared between 8 AD participants and 8 cognitively normal
individuals. Significant decreases in rs-fc were observed
between the posterior cingulate cortex (PCC) and retrosplenial cortex, left and right hippocampi, left and right lateral
parietal lobules, and anterior cingulate. These regions were
subsequently used to assess rs-fc differences between FHþ
and FH- cognitively normal individuals. While rs-fc was
decreased between each seed, only rs-fc between bilateral
hippocampi and the PCC were significantly decreased for
FHþ compared to FH- subjects after controlling for age,
sex, apolipoprotein E genotype.
Conclusion: FHþ of AD decreases rs-fc between the hippocampi and PCC. These changes may be an early biomarker of AD, but larger longitudinal studies are required.
Study supported by: NIH (NINR and NIMH)
Dr. Ances is on the advisory board for Lily and
Medscape.
2012 Annual Meeting Monday,
October 8, 2012
Poster Session Abstracts
Posters will be displayed in Gloucester, located on the
3rd floor in the Back Bay Hall of the Marriott Copley
Place from 11:30 am – 6:30 pm, with authors present
from 5:30 pm – 6:30 pm.
NOTE: An asterisk designates a resident/fellow travel award
winner.
M1103. Interactive Visual Analysis of Diffusion-Tensor
MRI Data Using the Expectation Maximization
Algorithm
Jian Chen, Andrew Maxwell, Haipeng Cai and Alexander P.
Auchus; Hattiesburg and Jackson
Dementia and Aging
M1101. Epigenetics of Induced Neuronal Cells to
Model Neurologic Diseases
Andy J. Liu, Bradley T. Hyman, Asa Abeliovich, Benjamin S.
Bleier and Mark W. Albers; Boston, MA; North Chicago, IL
and New York, NY
Background: Three-dimensional visualization of dense
streamtube from DT-MRI tractography often produces visual clutter and poor legibility. This limits the ability to
reveal valuable clinical information effectively and efficiently
to the end-user.
Methods: We designed an analysis toolkit which makes
use of tube clustering to facilitate visual data mining from
human brain DT-MRI images. An expectation maximization
(EM) algorithm provides the clustering information to represent the likelihood of a line belonging to an anatomical
fiber bundle. We tested the algorithm with several artificial
line sets.
Results: We found that the EM algorithms could provide
a principal way to cluster lines with different lengths and
orientations. The algorithm is also computationally efficient.
We are currently comparing usage of the algorithm on normal and pathological cases for automatic detection of neuropathology. Initial applications include Alzheimer’s disease
and related neurodegenerative disorders.
Conclusion: Our work contributes to the design of an
automatic toolkit for facilitating clinical diagnosis of brain
disorders.
Study supported by: National Science Foundation
Grant recipient
Direct conversion of human fibroblasts into induced neuronal
cells (HiNs) have generated cell-based models for genetic and
sporadic neurologic disease. One concern of this approach is
epigenetic memory, i.e. do HiNs retain genomic features of
fibroblasts that may confound mechanistic investigations,
therapeutic screens, and ultimately, cell replacement therapies.
To address this concern, we have developed a technique
beginning with neural progenitor cells derived from nasal
biopsies to induce HiNs with cortical properties. The Ascl1
gene — essential for conversion — is expressed in immature
olfactory neuronal precursors. Introduction of Brn2 and Zic1,
two transcription factors that enhance conversion, result in
HiNs exclusively derived from neuronal precursor cells. Simultaneous induction of HiNs from fibroblasts of the same
patient will provide the reference cells for epigenetic analysis.
Ongoing functional characterization to validate that the
HiNs fulfill criteria for neurons will be followed with an epigenetic analysis using next generation sequencing and DNA
methylation mapping. These results will illuminate the differences in gene expression patterns and epigenetic changes
underlying conversion from these two donor cell types. This
methodology has potential for broad applicability to derive
neuronal subtypes relevant to many neurologic diseases.
Study supported by: NIH
M1104. The Hypothalamus in Alzheimer’s Disease: A
Golgi and Electron Microscope Study
Stavros J. Baloyannis, Ioannis Mavroudis and Ioannis S.
Baloyannis; Thessaloniki, Greece
M1102. Family History of Alzheimer Disease Disrupts
Functional Connectivity between the Hippocampus and
Posterior Cingulate Cortex
Liang Wang, Abraham Z. Snyder, Matthew Brier, Jewell
Thomas and Beau M. Ances; Saint Louis, MO
Alzheimer’s disease is a neurodegenerative disorder, characterized by progressive decline of mental faculties, affective
and behavioural changes, loss of motor skills, eventual autonomic dysfunction and disruption of circadian rhythms.
We describe the morphological findings of the hypothalamus in twelve early cases of Alzheimer’s disease, focusing
our study on the suprachiasmatic, the supraoptic and the
Objective: Cognitively normal individuals with family history (FH) of Alzheimer disease (AD) are at increased AD
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paraventricular nuclei. Samples, excised immediately after
death,were processed for electron microscopy and silver
impregnation techniques. The hypothalamic nuclei demonstrated a substantial loss of neurons, particularly prominent
in the suprachiasmatic nucleus, abbreviation of dendritic
arborisation and spinal pathology. Supraroptic and paraventricular nuclei demonstrated a substantial number of dystrophic neurites,and synaptic pathology. Deposits of Ab peptide and neurofibrillary degeneration were not found.
Proliferation of astocytes was minimal. Electron microscopy
revealed mitochondrial alteration in the soma and the dendritic branches in a substantial number of neurons. The
morphological alterations of the hypothalamic nuclei in Alzheimers disease may be related with the gradual disruption
of the circadian rhythms, concerning sleep and appetite as
well as with the instability of the autonomic regulation of
the blood pressure and cardiac rhythm.
Study supported by: No disclosure
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signaling proteins, and a decrease in surface binding of
BDNF. Using array tomography, we analyzed sub-cellular
locus of these abnormalities and found a specific increase in
pTrkB colocalization with the signaling-endosome related
proteins Rab5, pERK, and pAKT in synapses in Ts65Dn.
Automated classification of synapse subtypes revealed
increase in the number of GABAergic and a decrease glutamatergic and cholinergic synapses. Proteomic analysis at the
single synapse level of resolution demonstrated that
increased TrkB signaling is specific to both pre- and postsynaptic sites at GABAergic synapses. These findings demonstrate that TrkB mediated signaling is abnormal in the cortex of DS model mice, a phenomenon which may
contribute to the pathogenesis underlying cognitive deficits
in DS and AD.
Study supported by: Grant and a postdoctoral fellowship
from the Larry L. Hillblom Foundation (to RLN), The
Down Syndrome Research and Treatment Foundation, The
Thrasher Foundation and NIH grants NS066072, NS055371
M1105. Mixed-Risk Vascular Cognitive Impairment:
Hypertension Plus Hypoperfusion Decrease Cognition
and Gait and Increase Fiber Tract Pathology and
Inflammation
Frank C. Barone, Jin Zhou, Jie Li, Alison E. Baird, Adamski
G. Mateusz, Diana L. Dow-Edwards, Peter J. Bergold, Samah
G. Abdel Baki, Howard Crystal and Daniel M. Rosenbaum;
Brooklyn, NY
M1107. Degeneration of Brainstem Respiratory Nuclei
in Dementia with Lewy Bodies
Michael F. Presti, Ann M. Schmeichel, Phillip A. Low, Joseph
E. Parisi and Eduardo E. Benarroch; Rochester, MN
Respiratory dysfunction is characteristic of multiple system
atrophy (MSA) and may reflect degeneration of brainstem
respiratory nuclei, including the pre-Bötzinger complex
(pBC), nucleus raphe pallidus (RPa) and nucleus raphe
obscurus (ROb). However, impaired ventilatory responses to
hypercapnia have also been reported in dementia with Lewy
bodies (DLB), suggesting that these nuclei may also be
affected in DLB. We applied stereological methods to analyze sections immunostained for the neurokinin-1 receptor
and tryptophan hydroxylase in neuropathologically confirmed cases of DLB, MSA, and controls. There was reduction of neuronal density in all three nuclei in DLB, as well
as in MSA. The magnitude of neuronal depletion in ROb
was similar in DLB and MSA (49% vs. 56% respectively
compared to controls, p<0.05), but neuronal loss in the
pBC and RPa was less severe in DLB than in MSA (pBC
40% in DLB, p <0.05 and 68% in MSA, p<0.0001, compared to controls; RPa 46% in DLB, p<0.05 and 73% in
MSA, p<0.0001, compared to controls). Thus, medullary
respiratory nuclei are affected in DLB but less severely than
in MSA. This may help explain differences in the respiratory manifestations of these two disorders.
Study supported by: N/A
Hypertension and carotid injury on cognition were assessed
in patients and applied to create a rat translational VCI
model. Common carotid artery stenosis- (reduced forebrain
perfusion) or sham-surgery were performed in hypertensive
rats (SHR). Gait and cognitive (active; AA and passive; PA
avoidance) behaviors were measured. Corpus collosum (CC)
myelin (Luxol Fast Blue) and astro- (GFAP) and micro(Iba1) gliosis and circulating CD34þ progenitor cells were
measured. In patients, carotid lesions (p < 0.01) and hypertension (p< 0.05) predicted cognitive impairment. In SHR,
stenosis decreased forebrain perfusion and impaired AA and
gait (p<0.01). PA was not affected. CC myelin was reduced
(48%; p<0.01) with increased astro- (69%; p<0.05) and
micro- (140%; p<0.01) gliosis. Circulating CD34þ progenitor cells were significantly increased (p< 0.02). Here
cerebrovascular risk factors are important components necessary to model VCI. Forebrain hypoperfusion in hypertensive
rat results in cognitive and gait deficits, like VCI, and are
associated with CC injury and inflammation-gliosis.
Increased progenitor cells suggest restorative therapy potential in VCI. This mixed-risk VCI model provides a tool to
probe VCI white matter injury, mechanisms and
interventions.
Study supported by: SUNY Downstate Medical Center
M1108. Pathological Accumulation of a-Synuclein and
Ab in Dementia Associated with Parkinson Disease
Meghan C. Campbell, Paul T. Kotzbauer, Nigel J. Cairns,
Allison W. Willis, Brad A. Racette, Samer D. Tabbal and Joel
S. Perlmutter; St. Louis, MO
M1106. Excessive Trk-B Signaling in GABAeric Synapses
Revealed by Array Tomography in the Ts65Dn Mouse
Model of Down Syndrome
Rachel L. Nosheny, Pavel V. Belichenko, Brad Busse, Kristina
D. Micheva, Stephen J. Smith and William C. Mobley; La
Jolla, CA and Stanford, CA
Prior studies have identified cortical synucleinopathy (Lewy
bodies/neurites) and changes thought to be consistent with
Alzheimer disease (AD) as the two major causes of dementia
in Parkinson disease (PD). To determine relative contributions of individual molecular pathologies to dementia in
PD, we analyzed thirty-two autopsy cases with neuropathological confirmation of PD and a history of dementia.
Three pathologic subgroups were identified: (1) predominant synucleinopathy (38%), (2) predominant synucleinopathy with b-amyloidosis but minimal or no cortical tau
(59%), and (3) synucleinopathy and b-amyloidosis with at
least moderate tauopathy (3%). Pathologic subgroups were
similar in clinical and demographic characteristics. However,
Down syndrome (DS) is characterized by learning, memory,
language, and motor deficits throughout the lifespan, development of neuropathological and clinical manifestations of
Alzheimer’s disease (AD) late in life, and progressive cognitive decline. Ts65Dn mice, which are trisomic for 140 genes
orthologous to those on human chromosome 21, model
DS. Here we show that in Ts65Dn mice have increased
levels and activation of TrkB and associated downstream
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participants with synucleinopathy plus b-amyloidosis had
significantly shorter survival rates (PD onset until death and
dementia onset until death) than participants with synucleinopathy only. We conclude that dementia in PD has two
major pathologic subgroups: synucleinopathy and synucleinopathy with b-amyloidosis. Furthermore, accumulation of
Ab is associated with lower survival rates in PD patients
with dementia. Additional studies are needed to determine
the relationship between a-synuclein and Ab accumulation,
and the role of Ab in the development and progression of
dementia in PD.
Study supported by: National Institute on Aging of the
National Institutes of Health (P50 AG05681 and P01
AG03991), and the Friedman Award to NJC; NINDS grant
NS075321, NS41509, NS058714, NS48924; NIH NCRR
UL1RR024992; the American Parkinson Disease Association (APDA) Advanced Research Center for Parkinson Disease at Washington University in St. Louis; the Greater St.
Louis Chapter of the APDA; the Barnes Jewish Hospital
Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund).
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M1110. Apples Far from the Tree: Clinical and
Electrophysiologic Variability in a Family
with c9FTD/ALS
Elizabeth A. Coon, Jasper R. Daube, Mariely DeJesusHernandez, Anahita Adeli, Rodolfo Savica, David S.
Knopman, Josephs E. Parisi, Rosa Rademakers and Bradley F.
Boeve; Rochester, MN and Jacksonville, FL
Objective: To describe the clinical and electrophysiologic
motor neuron disease features of frontotemporal dementia
(FTD) and/or amyotrophic lateral sclerosis (ALS) in a kindred with the chromosome 9 open reading frame 72 gene
(C9ORF72) expanded repeat.
Background: A hexanucleotide repeat expansion in
C9ORF72 is a major cause of familial FTD and/or ALS
(c9FTD/ALS). Initial studies describe variability in the presentation of ALS while little is known of the electrophysiologic findings.
Methods: Clinical and electrophysiologic data was analyzed in a c9FTD/ALS kindred of Scandinavian ancestry.
Results: Of 6 affected family members, 3 had only ALS,
3 had FTD and 1 had FTD and ALS. Each ALS patient
presented differently; 1 had only bulbar symptoms, 1 had
bulbar and limb involvement, 1 had limb findings, and 1
had primarily upper motor neuron disease. All ALS patients
eventually had bulbar involvement and died from respiratory causes an average of 3.75 years from onset. Electrophysiologic studies demonstrated progressive lower motor neuron dysfunction except in the patient with upper motor
neuron features.
Interpretation: The ALS presentation within families
harboring the C9ORF72 expansion may vary considerably
and electrophysiologic findings reflect this heterogeneity.
Study supported by: Grants AG016574, AG006786, ALS
Association, and Robert H. and Clarice Smith and Abigail
Van Buren Alzheimers Disease Research Program of the
Mayo Foundation.
M1109. Impaired Default Network Functional
Connectivity in Autosomal Dominant Alzheimer’s
Disease: Findings from the DIAN Study
Jasmeer P. Chhatwal*, Aaron P. Schultz, Keith A. Johnson,
Tammie L.S. Benzinger, Clifford R. Jack, Stephen Salloway,
John M. Ringman, Robert A. Koeppe, David L. Marcus, Paul
M. Thompson, Andrew J. Saykin, Sonia C. Correia, Peter R.
Schofield, Christopher C. Rowe, Nick C. Fox, Adam M.
Brickman, Richard Mayeux, Miroslava Rimajova, Chester A.
Mathis, Eric M. McDade, William E. Klunk, Michael W.
Weiner, Randall J. Bateman, Alison M. Goate, Chengjie
Xiong, Virginia Buckles, Krista L. Moulder, John C. Morris
and Reisa A. Sperling; Boston, MA; St. Louis, MO; Rochester,
MN; Providence, RI; Los Angeles, CA; Ann Arbor, MI; New
York, NY; Indianapolis, IN; Coimbra, Portugal; Randwick,
Australia; Melbourne, Australia; London, United Kingdom;
Perth, Australia; Pittsburgh, PA and San Francisco, CA
M1111. Withdrawn.
M1112. Neural Correlates of Face-Name Encoding
Using Simultaneous Eye-Tracking and ERP
Ali Ezzati, Meghan B. Mitchel, Steven D. Shirk, Donald G.
Mclaren, Brandon A. Ally and Alireza Atri; Boston, MA;
Bedford, MA and Nashville, TN
Design: Decreased functional connectivity of the default
mode network (DMN) has been observed in sporadic, lateonset Alzheimer’s disease (AD), but remains largely
unstudied in familial AD. We examine DMN dysfunction
using functional connectivity MRI (fcMRI) in 83 carriers of
dominantly-inherited AD mutations (PS-1, PS-2, and APP)
and 37 asymptomatic non-carriers from the same families.
Results: Using independent component analysis, we
observed significantly decreased DMN fcMRI in mutation
carriers, with progressive decreases seen with increasing clinical impairment, and with the strongest effect seen in the
Precuneus/Posterior Cingulate (PPC; p<0.001). Post-hoc
comparison of asymptomatic mutation carriers to non-carriers demonstrated significantly decreased fc-MRI in the
PPC, lateral parietal, and medial prefrontal cortices. Mutation carriers showed a negative correlation between DMN
connectivity and increasing proximity to their familial age
of symptom onset (R ¼ -.42; p<0.001).
Conclusions: Impaired connectivity among multiple
nodes of the DMN was observed with advancing clinical
decline in familial AD, similar to reports in sporadic AD.
Additionally, early decreases in DMN fcMRI were observed
in asymptomatic mutation carriers compared to non-carriers, suggesting decreasing DMN fc-MRI may be useful as
a biomarker across a wide spectrum of the disease.
Study supported by: NIA U19 AG032438 (DIAN; JCM
as PI)
We combined neuropsychological assessments, and simultaneous quantitative eye-tracking (ET) and event-related brain
potentials ERP during encoding of novel and repeated facename pairs (FN-pairs) in 16 young healthy adults (18-39y)
to delineate essential spatiotemporal processes underlying
normal memory function and as a necessary first step
toward development of a potential complementary noninvasive biomarker (for trait/state/rate/treatment-effect) of
cognitive aging and dementia.
At study 40 FN-pairs, 20 4x-repeated (4R) and 20 shown
once (1R), were presented. At test, new/old judgment and
high/low confidence ratings were assessed for 80 FN-pairs
(40 old, 40 new [novel ¼ N]).
Response accuracy increased with number of presentations (4R>1R, p<0.001). Classic ERP old/new effects were
seen: 1R>N hits were more positive bifrontally between
300-500ms, reflecting enhanced familiarity; 4R>N hits
were more positive at superior parietal electrodes between
500-800ms, reflecting enhanced recollection; and 4R>1R
hits showed positive parietal 500-800ms effects, reflecting
enhanced recollection for material studied numerous times.
Longer mean fixations and larger pupil sizes were observed
with higher number of stimuli presentations.
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These results support combining neuropsychological/clinical assessments with simultaneous ET-ERP during paired-associate encoding to probe essential brain networks that sustain cognitive processes important in health, aging and
dementia.
Study supported by: K23 AG027171-05 (Atri) and
GRECC
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hypothesized and empirical models of pre-diagnostic
declines in AD.
Study supported by: Eli Lilly and Company
M1115. Hippocampal Volumes Predict Response to
Acetylcholinesterase Inhibitors in Patients with
Dementia with Lewy Bodies
Jonathan Graff-Radford*, Bradley F. Boeve, Otto Pedraza,
Tanis J. Ferman, Scott Przybelsk, Timothy Lesnick, Matthew
Senjem, Glenn E. Smith, David S. Knopman, Clifford R.
Jack, Jr, Ronald C. Petersen and Kejal Kantarci; Rochester and
Jacksonville
M1113. Efficacy of a Brain/Cognitive Training
Therapeutic Program for Diagnosed Dementia
Barbara C. Fisher and Danielle M. Garges; Shelby Township,
MI
Background: Patients with dementia with Lewy bodies
(DLB) may respond more favorably to acetylcholinesterase
inhibitors (AChI) than patients with Alzheimer’s disease (AD).
Hippocampal volumes in pathologically-confirmed DLB with
low likelihood AD are preserved. Few studies have investigated
imaging predictors of treatment response in DLB.
Objective: To determine whether hippocampal volumes
predict response to AChI in DLB patients.
Methods: We performed a retrospective analysis on consecutive treatment-naive DLB patients (n ¼ 54) from the
Mayo Clinic ADRC who subsequently received AChI and
underwent MRI with hippocampal volumetry. Assessments
with the Mattis Dementia Rating Scale (DRS) were performed at baseline and follow-up. Patients were divided into
three groups (reliable improvement, stability, reliable
decline) using DRS reliable change indices determined previously. Associations between hippocampal volumes and
treatment response were tested with ANCOVA adjusting for
age, gender, DRS baseline and interval.
Results: Using a conservative psychometric method of
assessing treatment response, there were 12 patients with reliable decline, 29 stable patients and 13 with reliable improvement. The improvers had larger hippocampi than those that
declined (p ¼ 0.02) and the stable group (p ¼ 0.04).
Conclusion: DLB patients with preserved hippocampal
volumes are more likely to improve on AChEI.
Study supported by: This work was supported by the
National Institutes of Health: P50-AG16574/P1 and
R01AG040042 to K.K., P50-AG16574/P1 VJL, R01AG11378 to CRJ, R01-AG015866 to TJF., P50-AG16574
to RCP.; Mangurian Foundation and the Robert H. and
Clarice Smith and Abigail Van Buren Alzheimer s Disease
Research Program.
Introduction: Examine the efficacy of an individually
designed therapeutic program for the remediation of memory deficits resulting from dementia, diagnosis determined
through treating neurologist/cardiologist and neuropsychological testing. Evaluation completed prior to and following
therapeutic intervention in a clinic population.
Method: Adults referred for assessment of memory difficulties (age 64 to 80 years, n ¼ 10). The Repeatable Battery
for the Assessment of Neuropsychological Status (RBANS)
was utilized to measure memory functioning pre and post
treatment. On average a total of 2 to 4 months elapsed
between pre and post testing.
Results: Immediate memory, visuospatial/visuoconstructive, language, attention, delayed memory, total dementia
score improved following treatment when mean differences
were assessed. Between 7.87 and 12 point differences were
found for immediate memory, language, delayed memory
and total dementia score. Paired samples t-tests revealed significant differences between pre and post treatment scores
for overall memory (p < 0.052).
Conclusions: Findings indicate that all areas assessed
evidenced improvement following as short a duration of
time as 2 months of treatment. The individualized therapeutic program appears to be effective in augmenting overall
functioning in diagnosed dementia population.
Study supported by: nothing to disclose
M1114. Cognitive, Functional, and Neuropsychiatric
Trajectories before and after an Alzheimer’s Disease
Diagnosis
Joseph E. Gaugler, David L. Roth, Robert Kane, Martha
Hovater, Joseph Johnston and Khaled Sarsour; Minneapolis,
MN; Baltimore and Indianapolis
M1116. Sustained Cognitive Improvement with
Extended-Release Memantine (28 mg, Once Daily) in
Moderate to Severe Alzheimer’s Disease
Michael Tocco, Suzanne Hendrix, Michael L. Miller, Vojislav
Pejovic and Stephen M. Graham; Jersey City, NJ; Salt Lake
City, UT and Chicago, IL
The purpose of this study was to examine trajectories of stability or decline in individuals’ cognitive function, functional dependence, and neuropsychiatric dimensions in the
years prior to and following an Alzheimer’s disease (AD) diagnosis. 15,443 visits from the National Alzheimer’s Coordinating Center-Uniform Data Set (N ¼ 3,812 individuals)
were utilized that included individuals who did (n ¼ 444)
or did not (n ¼ 3,368) receive an AD diagnosis. Multi-level
linear change models were used to estimate longitudinal trajectories of change before and after AD diagnosis. When
compared to individuals who did not receive an AD diagnosis, persons with AD experienced significant declines across
a range of clinical dimensions that serve as markers for AD
progression, including cognitive decline (e.g., MMSE: B ¼
-.17 and Logical Memory test B ¼ .18 (p < .001)) and
functional status (e.g., FAQ: B ¼ .22; (p < .001). One
exception was neuropsychiatric disturbances, where no significant difference was found prior to AD diagnosis when
compared to usual controls in the same time period. The
results of this trajectory analysis lend additional support to
In this post hoc analysis, sustained cognitive improvement
was assessed in a 24-week, randomized, placebo-controlled
trial of once-daily, extended-release (ER) memantine (28 mg)
in ChEI-treated patients with moderate to severe AD. Five
positive SIB response levels to double-blind treatment were
selected (improvements of 0, 5, 10, 15, and 20
points), corresponding to 0-2 standard deviations (SDs) of
the observed baseline-to-endpoint score change. Numbers of
patients in each group who attained such responses at weeks
4, 8, 12, or 18 and maintained them through week 24 were
compared using Fisher’s exact test. Significantly more memantine ER-treated than placebo-treated patients maintained
week 8 SIB responses of 5 points (26.1% vs 17.0%; P ¼
0.014) and 10 points (14.6% vs 7.6%; P ¼ 0.012) through
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week 24. Similar results were observed for sustained responses
attained at week 12 (5 points: 28.5% vs 19.9%, P ¼
0.025; 10 points: 16.3% vs 8.2%, P ¼ 0.005; 15 points:
9.5% vs 4.1%, P ¼ 0.015) and week 18 (10 points:
18.8% vs 10.0%, P ¼ 0.004; 15 points: 10.9% vs 4.5%, P
¼ 0.006). In conclusion, memantine ER was associated with
cognitive improvement attained after 8-18 weeks and sustained through week 24.
Study supported by: Forest Laboratories, Inc.
Drs. Stephen Graham and Michael Tocco are employed
by Forest Research Institute.
Drs. Michael L. Miller and Vojislav Pejovi&#263; are
employed by Prescott Medical Communications Group, an
independent contractor to several pharmaceutical companies,
including Forest Laboratories, Inc.
Dr. Suzanne Hendrix is employed by Pentara Corporation, an independent contractor to several pharmaceutical
companies, including Forest Laboratories, Inc.
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FTLD caused by GRN mutations. However, the relationship
between PGRN-deficiency, TDP-43 mislocalization, and
neuronal death remains unclear. Though brains from PGRNdeficient mice display some pathologic features of FTLD,
they do not exhibit a robust neurodegenerative phenotype or
TDP-43 redistribution. Because the retina is easily accessible
for clinical imaging of the CNS and since retinal degeneration has been identified in other neurodegenerative disorders,
we sought to determine if retinal abnormalities occur in
FTLD. We report that retinal imaging of living FTLD
patients via optical coherence tomography reveals significant
retinal nerve fiber layer (RNFL) thinning compared to agematched controls. Substantial death of of retinal ganglion
cells (RGCs), microgliosis, and lipofuscinosis also occur in
Grn KO mouse retinas. Notably, we observe key pathologic
features of TDP-43 mislocalization in Grn KO RGCs,
including intranuclear inclusions, nuclear clearing, and cytoplasmic redistribution of TDP-43, all of which precede significant RGC death. This newly described and clinically-relevant FTLD phenotype in humans and mice may prove useful
in exploring the intricate relationship between PGRN deficiency, TDP-43 mislocalization, and neurodegeneration.
Study supported by: UCSF Research Allocation Program
Chartrand Foundation
The Bluefield Project to Cure Frontotemporal Dementia
M1117. Response across Multiple Outcome Measures in
Patients with Moderate to Severe Alzheimer’s Disease
Taking Extended-Release Memantine (28 mg, Once Daily)
Stephen M. Graham, Suzanne Hendrix, Michael L. Miller,
Vojislav Pejovic and Michael Tocco; Jersey City, NJ; Salt Lake
City, UT and Chicago, IL
This post hoc analysis explored the effects of extended-release
(ER) memantine on combinations of outcome measures from a
24-week, randomized, placebo-controlled trial of memantine
ER (28 mg, once daily) in ChEI-treated patients with moderate
to severe AD. Outcomes included the SIB, ADCS-ADL19, NPI,
and CIBIC-Plus. For each measure, two response levels were
defined: improvement/stabilization (‘‘no decline’’) and clinically
notable response (baseline-to-endpoint improvement of 3
points for the SIB, ADCS-ADL19, and NPI; endpoint score 3
for the CIBIC-Plus). Treatment groups were compared (Wald’s
test) by calculating the proportions of patients who achieved a
response on various combinations of efficacy measures. For both
response levels and all outcome combinations, proportions of
responders in the memantine ER group (n ¼ 266-269) exceeded
those in the placebo group (n ¼ 271-272). For clinically notable
responses, memantine ER was significantly superior to placebo
for the 2-measure combination of ADCS-ADL19/NPI (21.3%
vs 15.8%; P ¼ 0.042, NNT ¼ 18) and the 3-measure combinations of ADCS-ADL19/NPI/SIB (15.4% vs 9.6%; P ¼ 0.027,
NNT ¼ 17) and ADCS-ADL19/SIB/CIBIC-Plus (12.4% vs
7.4%; P ¼ 0.030, NNT ¼ 20). In conclusion, this analysis suggests that memantine ER may provide simultaneous benefits on
multiple clinical domains.
Study supported by: Forest Laboratories, Inc.
Drs. Stephen Graham and Michael Tocco are employed
by Forest Research Institute.
Drs. Michael L. Miller and Vojislav Pejovi&#263; are
employed by Prescott Medical Communications Group, an
independent contractor to several pharmaceutical companies,
including Forest Laboratories, Inc.
Dr. Suzanne Hendrix is employed by Pentara Corporation, an independent contractor to several pharmaceutical
companies, including Forest Laboratories, Inc.
M1119. Cerebral Amyloid Angiopathy Independently
Contributes to Ischemic White Matter Disease: A PET/
MRI Correlative Study
Edip M. Gurol, Christopher Gidicsin, Andrew Dumas, Trey
Hedden, Alison Ayres, Alex Becker, Anastasia Vashkevich, Sergi
R. Martinez, Eitan Auriel, Kristen Schwab, Anand
Viswanathan, Jonathan Rosand, Keith A. Johnson and Steven
M. Greenberg; Boston, MA
Objective: We hypothesized that vascular amyloid contributes
to chronic brain ischemia, therefore amyloid burden measured
by Pittsburgh Compound B retention on PET (PiB-PET)
would correlate with the extent of white matter disease
(WMD) in patients with Cerebral Amyloid Angiopathy (CAA)
but not in healthy elderly (HE) or Alzheimer’s Disease (AD).
Methods: Thirty-five non-demented CAA patients, 50
HE subjects and 20 AD patients had brain MRI and PiBPET analyzed. Multivariate linear regression was used to
assess the association between PiB retention and WMD volume while controlling for age, gender and vascular risk factors within each group.
Results: CAA patients were younger than HE and AD
(67610 vs 7367 and 7569, p<0.01) but CAA cases had
higher amounts of WMD (medians:19ml vs 3.2ml and 6.5ml
respectively, p<0.05 for both comparisons). Global PiB retention and WMD showed a strong correlation (rho ¼ 0.52,
p<0.001) in the CAA cohort but not in HE or AD. These associations did not substantially change in the multivariate model.
Conclusions: Our findings support the view that vascular
amyloid burden directly contributes to chronic cerebral ischemia in the CAA population and highlights the possible
utility of amyloid imaging as a marker of CAA severity.
Study supported by: Supported by NIH (T32NS048005,
5R01NS070834-01/02, R01AG026484).
M1118. Retinal Degeneration in FTLD Patients and
PGRN-Deficient Mice Preceded by TDP-43
Mislocalization
Michael E. Ward*, Alice Taubes, Bruce L. Miller, Jeffrey M.
Gelfand, Li Gan and Ari J. Green; San Francisco, CA
M1120. Gephyrin Plaques Identified in Frontal Cortex
of Alzheimer’s Disease Brains
Chadwick M. Hales, Howard Rees, James J. Lah, Allan I.
Levey and Thomas Wingo; Atlanta, GA
Neurodegeneration and cytoplasmic mislocalization of TDP43 are pathologic hallmarks of sporadic FTLD-U and familial
A hallmark of many neurodegenerative disorders is the
abnormal
accumulation
of
protein
evident
at
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neuropathologic examination. In addition to well known
findings of neurofibrillary tangles and b-amyloid plaques in
Alzheimer’s disease (AD), here we show that abnormal accumulations of gephyrin immunoreactivity are highly correlated with the neuropathologic diagnosis of AD (odds ratio
of 72.7; p ¼ 6.844x10-6, n ¼ 17 AD and n ¼ 14 controls). Gephyrin is an inhibitory receptor anchoring protein
also important for molybdenum cofactor biosynthesis and
synaptic protein translation. Furthermore, the gephyrin
accumulations are specific for AD and not observed in Parkinson’s disease (n ¼ 5), corticobasal degeneration (n ¼ 3),
frontotemporal lobar degeneration (n ¼ 5) and progressive
supranuclear palsy (n ¼ 3). Gephyrin accumulations overlap
with b-amyloid plaques but do not completely co-localize.
Neurofibrillary tangles occasionally contain gephyrin immunoreactivity. The normal gephyrin staining of neuronal
processes is significantly reduced in AD cases as compared
to controls. Biochemical studies suggest alterations in the
gephyrin isoform expression profile. Given the involvement
of gephyrin in synaptic organization and that synaptic dysfunction is an early event in AD, these findings suggest a
possible role for gephyrin in AD pathogenesis.
Study supported by: American Academy of Neurology
Foundation Clinical Research Training Fellowship
no conflict of interest
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HD060406, JB is supported by a grant of the Deutsche
Forschungsgemeinschaft DFG (AOBJ586910) and JBT is
supported by a grant of the Alfonso Martı́n Escudero
Foundation.
David J Irwin reports no disclosures.
Corey T McMillan reports no disclosures.
Johannes Brettschneider reports no disclosures.
David J Libon reports no disclosures.
Ashley Boller reports no disclosures.
John Powers reports no disclosures.
Keerthi Chandrasekaran reports no disclosures.
Elizabeth McCarty Wood reports no disclosures.
Jon B. Toledo reports no disclosures.
Leslie Shaw reports no disclosures.
Katya Rascovsky reports no disclosures.
John Woo reports no disclosures.
Dr. David Wolk has received research support from NIH
(R01 AG037376, R01 MH086492, K23 AG028018, P30
AG010124), GE Healthcare, and Pfizer, Inc. He has served
as a consultant for GE Healthcare and Leclair Ryan. He
received speaking honoraria from the American Academy of
Neurology.
Steven E. Arnold reports board membership for Cowan
Group, Eli Lilly and BMS; Consulting services for Philadelphia district attorney’s office and Bonner Kiernan Trebach
& Cociata LLP; Grants from American College of Radiology Imaging Network, Pfizer, Alzheimer’s Disease Neuroimaging Initiative, Johnson & Johnson, National Institute of
Drug Abuse, Neuronetrix, National Institute of Mental
Health, Eli Lilly; Payments for lectures at Harvard University, Rush University Medical Center, Trinitas Regional
Medical Center, and University of Puerto Rico.
Vivianna Van Deerlin reports no disclosures.
Leo F. McCluskey reports no disclosures.
Lauren Elman reports no disclosures.
Virginia M.-Y. Lee reports singleconsulting services to
Pfizer, J&J, MetLife, and BMS; Royalty payments through
Penn licenses; Research support from AstraZeneca and
BMS.
John Q. Trojanowski reports singleconsulting services to
Pfizer, J&J, MetLife, and BMS; Royalty payments through
Penn licenses; Research support from AstraZeneca and
BMS.
Murray Grossman reports no disclosures.
M1121. Clinical, Imaging and Pathologic Features of
C9ORF72 Hexanucleotide Expansion in ALS and FTLD
David J. Irwin, Corey T. McMillan, Johannes Brettschneider,
David J. Libon, Ashley Boller, John Powers, Keerthi
Chandrasekaran, Elisabeth McCarty Wood, Jon B. Toledo,
Leslie Shaw, Katya Rascovsky, John H. Woo, David A. Wolk,
Steven E. Arnold, Vivianna Van Deerlin, Leo F. McCluskey,
Lauren Elman, Virginia M.Y. Lee, John Q. Trojanowski and
Murray Grossman; Philadelphia, PA
We hypothesized that C9ORF72 expansion-positive (C9P)
cases will have unique clinical characteristics compared with
expansion-negative (C9N) TDP-43 proteinopathies.
Available clinical data including neuropsychological testing, MRI voxel-based morphometry (VBM) and neuropathological assessment were obtained in a cohort of 54 C9P
cases (ALS ¼ 29,FTLD ¼ 17, ALS-FTD ¼ 8) and compared to 78 C9N cases with presumed TDP-43 neuropathology (ALS n ¼ 37,FTLD n ¼ 30,ALS-FTLD n ¼ 11).
C9P cases overall had an earlier age of onset (p ¼
0.040), and death (p ¼ 0.007) than C9N. C9P FTLD
showed greater cognitive decline than C9N FTLD in
MMSE (12.2þ4.5 vs. 2.6þ1.0;p ¼ 0.003) and letter fluency (4.8þ0.3 vs. 0.5þ0.6;p ¼ 0.004) tests. VBM revealed
greater atrophy in right frontal and inferior-parietal cortex
for C9P relative to C9N, and a regression related verbal fluency scores to atrophy in these regions. Neuropathological
analysis revealed a higher burden of frontal (p ¼ 0.007) and
inferior-parietal cortex (p ¼ 0.034) gliosis in C9P relative
to C9N, and severity also correlated with verbal fluency performance (p<0.0001).
C9P cases appear to have a significantly greater rate of
cognitive decline, gray matter disease, and neuropathologic
burden in frontal and parietal regions. C9ORF72 genotyping may provide useful prognostic and diagnostic clinical information for ALS and FTLD patients.
Study supported by: This study was supported by the
NIH P30AG010124-20, P01 AG017586, R01 NS44266,
R01 AG15116, P01 AG32953, P01 NS53488, R21
NS06311-01A1 and the Wyncote Foundation. DJI is supported by the NIH T32-AG000255, CTM is support by
M1122. Inflammatory Cerebral Amyloid Angiopathy: An
Unrecognized Cause of Reversible Dementia
Nivedita Jerath, Aarti Jerath, Keri Oxley, Matt Bevers, Shelley
Waite and Steve Greenberg; Boston, MA
An 87 year old woman with a right cavernous sinus meningioma and atrial fibrillation on warfarin developed episodes
of disorientation, falls, memory loss, and urinary and fecal
incontinence. The symptoms progressed over two months to
aggressiveness, an inability to follow commands, and a refusal of medications. On exam, her eyes were clenched and
she repeated a Hail Mary prayer. An EEG showed no epileptiform activity. An MRI showed non contrast enhancing
lesions consistent with inflammatory cerebral amyloid angiopathy: exclusive lobar-based hemorrhages, and confluent
subcortical FLAIR white matter hyperintensities with no
evidence of vasculitis, tumor, vascular malformation, or coagulopathy. Although neoplastic etiologies were considered,
the progression was too rapid and no hemosiderin deposition was seen in the basal ganglia. An empiric course of 5
days of 1 gram of IV methylprednisolone was started for
inflammatory cerebral amyloid angiopathy. The day after
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starting steroids, she opened her eyes, and briskly followed
commands. She was discharged on a tapering regimen of
high dose oral prednisone as well as aspirin instead of warfarin. She is now back to baseline. Inflammatory cerebral
amyloid angiopathy should be recognized as a cause of reversible dementia.
Study supported by: none
Conclusions: These results demonstrate, for the first
time, that PFA is associated with a phenomenon of
enhanced temporoparietal neurodegeneration, a finding that
improves our understanding of the biological basis of Alzheimer’s disease presenting as PFA.
Study supported by: NIH grants R21 AG038736; R01
AG037491 and P50 AG16574
M1123. Inclusion of Axial Rigidity May Improve
Diagnostic Accuracy for Dementia with Lewy Bodies
Fariha Zaheer, John T. Slevin, Erin L. Abner, Peter T. Nelson
and Gregory A. Jicha; Lexington, KY
M1125. Hippocampal CA1 Apical Neuropil Atrophy
and Memory Performance in Alzheimer Disease
Geoffrey A. Kerchner, Gayle K. Deutsch, Michael Zeineh,
Robert F. Dougherty and Brian K. Rutt; Stanford, CA
Objective: The diagnostic accuracy of dementia with Lewy
bodies (DLB) is poor. This study examined demographic
and clinical features that may improve diagnostic accuracy
for the prediction of underlying Lewy body pathology
(LBP).
Methods: Eighty cases with pathological and/or clinical
diagnoses of DLB were identified in the University of Kentucky Brain Bank (n ¼ 523), including 13 cases positive for
DLB clinically and pathologically, 14 cases with DLB but
no LBP, and 52 cases negative for clinical DLB but positive
for LBP. Demographic and clinical metrics were analyzed
between groups to identify variables that might improve
diagnostic accuracy in DLB.
Results: Only axial (p ¼ 0.017; t-test) and lower extremity rigidity (p ¼ 0.034; t-test) differed between true positive
and false positive cases.
Interpretation: Including assessment of axial or lower
limb rigidity as a component of diagnostic criteria for DLB
would improve the positive predictive value from 48%
currently to 82% without a significant tradeoff in negative
predictive value (10.5% currently to 11%). The diagnostic
criteria for DLB need to be revised to detect underlying
pathology based on this and further findings from similar
studies in large pathologic series.
Study supported by: NIA 1 P30 AG028383
In preclinical Alzheimer disease (AD), episodic memory
deficits emerge as neurofibrillary tangle pathology spreads
from the entorhinal cortex to the hippocampal CA1 apical
neuropil. The CA1 apical neuropil is visible in vivo using
ultra-high field 7-Tesla MRI, and its thickness sensitively
discriminates patients with mild AD from normal controls
(Kerchner et al., 2010, Neurology 75:1381-1387). We
tested whether CA1 apical neuropil thickness scales with the
severity of memory deficits amongst patients with mild AD.
Each subject underwent a comprehensive neuropsychological
assessment that included tests of episodic memory, and a
7-Tesla MRI that yielded cross-sectional images of the hippocampus at an in-plane resolution of 0.22 mm. Delayed
recall performance correlated tightly with CA1 apical neuropil thickness, especially in the left hemisphere. Slightly
weaker associations were apparent for the entorhinal cortex
and the CA1 cell body layer, but not the dentate gyrus or
CA3 subfields. These correlations were specific to delayed
episodic memory: Hippocampal microstructure correlated
neither with working memory nor with psychometric tests
of other cognitive domains. Thus hippocampal microstructure, visualized by 7T MRI, sensitively tracks one of the
core features of AD, possibly representing a novel
biomarker.
Study supported by: Alzheimer’s Association
Stanford Institute for Neuro-Innovation and Translational
Neuroscience
NIH
M1124. Quantitative Neurofibrillary Tangle Density and
Brain Volumetric MRI Analyses in Alzheimer’s Disease
Presenting as Progressive Fluent Aphasia
Keith A. Josephs, Dennis W. Dickson, Melissa E. Murray,
Matthew L. Senjem, Joseph E. Parisi, Ronald C. Petersen,
Clifford R. Jack and Jennifer L. Whitwell; Rochester, MN and
Jacksonville, FL
M1126. Dimensions of Dementia: Item Response
Analysis of the Alzheimer’s Disease Assessment Scale
(ADAS-Cog)
Christian Yavorsky, Anzalee Khan, Mark Opler, Guillermo
DiClemente and Sofija Jovic; New York, NY; Hamilton, NJ
and Orangeburg, NY
Background: Neurofibrillary tangles are one of the key histological lesions that define Alzheimer’s disease, and are
associated with brain atrophy.
Methods: We quantified regional neurofibrillary tangle
density in hippocampus and three neocortical regions in 30
subjects with Alzheimer’s disease, 10 of which presented
with progressive fluent aphasia (PFA) and 20 that presented
as dementia of the Alzheimer’s type (DAT) with loss of episodic memory. Regional grey matter volumes of the hippocampus and the same three neocortical regions were measured on subject’s antemortem volumetric MRIs.
Results: Neurofibrillary tangle density was significantly
higher in the temporoparietal cortices in PFA compared to
DAT, with no differences observed in hippocampus. The
ratio of temporoparietal-to-hippocampal neurofibrillary tangle density was higher in PFA than in DAT. The imaging
findings mirrored the pathological findings, with smaller left
temporoparietal volumes observed in PFA compared to
DAT, in the absence of any differences in hippocampal
volume.
Objective: The aim was to investigate the dimensions of
cognitive impairment, and highlight response patterns and
scale properties of the ADAS-Cog to improve the measure
for screening and evaluating dementia.
Methods: 2618 subjects from 7 randomized, doubleblind, placebo-controlled, trials used Item Response Theory
(IRT). An item analysis by mixed Rasch models explored
cognitive dimensions of the ADAS-Cog, and assessed item
bias.
Results: Results showed that recall, recognition, expressive language/naming, and praxis/construction items demonstrated a good relationship between responses and dementia
severity. Orientation was the most sensitive item to differentiate across levels of cognitive impairment. Language comprehension was problematic with regard to its ability to discriminate over the full range of dementia severity. Mixed
Rasch resulted in two dimensions of cognitive function, agecorrelated (expressive language/naming, praxis/construction)
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and non age-correlated (orientation, recall, language comprehension, recognition).
Conclusions: Some items are better at discriminating
across all severity levels of dementia than others, indicating
that an abbreviated version of the ADAS-Cog may correctly
discriminate dementia across various stages.
Study supported by: Investigator Initiated Study: ProPhase LLC, New York, NY; CROnos CCS, Hamilton, NJ
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these five patients confirmed their increasing spontaneous
speech amounts.
In conclusion, rivastigumine seems to have a trend of efficiency on PPA symptoms. We need more cases as well as a
placebo-controlled, double-blind randomized trial to prove
the efficiency of rivastigmine on PPA.
Study supported by: Nothing
M1129. Rest/Activity Fragmentation and the
Risk of AD in Older Adults
Andrew S. Lim, Matthew Kowgier, Lei Yu, Aron S. Buchman
and David A. Bennett; Toronto, ON, Canada and Chicago,
IL
M1127. Quantifying Differences in the Shape
Complexity of the Cerebral Cortex across the
Adult Lifespan
Richard D. King, Sourav Kole and Nikhil Singh; Salt Lake
City, UT
Background: Sleep disturbance and neurodegeneration may
be linked. We recently demonstrated an association between
objective measures of rest/activity fragmentation and crosssectional cognitive performance in older adults. However, it
is unclear whether rest and activity fragmentation predispose
to subsequent cognitive impairment or vice-versa.
Methods: Up to 10 days of actigraphy were obtained
from 734 older individuals without dementia in the Rush
Memory and Aging Project, a prospective observational
cohort study. Rest and activity fragmentation were quantified using recently developed state transition metrics. Subjects underwent structured annual evaluation with a battery
of 19 neuropsychological tests.
Results: Over a mean follow-up of 3.3 years, 96 individuals developed AD. In Cox proportional hazards models,
both rest and activity fragmentation were associated with an
increased risk of AD (HR ¼ 1.21 95%CI 1.03-1.44 and
HR ¼ 1.26 95%CI 1.10-1.44 for 1 SD increases in rest
and activity fragmentation respectively). In linear mixed
effect analyses, both rest and activity fragmentation were
associated with faster cognitive decline (p ¼ 0.037 and p ¼
0.003 for rest and activity fragmentation respectively).
Interpretation: Rest and activity fragmentation are associated with a higher risk of incident AD and more rapid
cognitive decline in old age.
Study supported by: CIHR Bisby Fellowship
AAN Foundation Clinical Research Training Fellowship
NIH R01AG17917 R01AG24480 P30AG010161
Objective: To develop novel neuroimaging biomarkers of
cortical shape to aid in the clinical diagnosis of age-related
diseases by 1) calculating the complexity of the cerebral
cortical ribbon using fractal dimension and 2) computing
the degree of similarity between images by calculating the
deformation energy required to morph images together.
Design/Methods: Magnetic resonance images (MPRAGE) came from a database of cognitively normal adults
in the Dallas Lifespan Brain study (N ¼ 322; Ages ¼ 2090). 3D cortical surface models were generated using FreeSurfer. Fractal dimension (FD) was computed using a custom software program, the Cortical Complexity Calculator.
Large Deformation Diffeomorphic Metric Mapping
(LDDMM) was used to calculate the energy required to
morph images together. Atlases were created based upon age
or FD.
Results: There is a significant negative correlation
between aging and cortical fractal dimension (r ¼ -0.797,
p< 0.001). Variability in cortical structure is highest in
brains of higher age or lower FD. Atlases based upon FD
capture more of the variance in cortical shape than atlases
based upon age (R2 ¼ 0.6245 and R2 ¼ 0.3274
respectively).
Conclusions: Cortical FD is a novel imaging biomarker
that improves upon ‘‘age-related’’ characterization of brain
shape changes.
Study supported by: This project was supported by the
Center for Alzheimer’s Care, Imaging and Research
(CACIR) and the National Institute of Aging
(K23AG03835)
M1130. Does Sporadic Atonia Occur in Alzheimer
Disease?
Leopold Liss; Columbus, OH
Patients with Alzheimer disease do sometimes fall while
standing and are considered the result of a sporadic atonic
episode.
Material and Methods: Patient population of over 2,000
which were followed in the Cognitive Disorders Clinic
(1978-2010) and in the Columbus Alzheimer Care Center
(1991- 2012). All incidences were witnessed. A few were
observed by reliable family caregivers and the interrogation
used questions which were suggestive of other etiologies
rather than atonia.
The description of the atonic event has been described as
a meltdown. These falls are soft fall, without injury, with
the patient frequently surprised and without any deficits.
The possibility of transient ischemic attack, orthostatic
hypotension, or an ictal episode were all ruled out before
the fall was assigned to a sporadic atonia. The only characteristic feature which was observed in some of the falls was
a rapidly disappearing muscular weakness, but there was no
problem in returning to the upright position.
Study supported by: Supported in part by OSU Development Fund # 30-62-46 Alzheimer Initiative Research
M1128. Treatment of Primary Progressive Aphasia with
Rivastigmine
Hisatomo Kowa, Tsuneyoshi Seki, Mikiko Yamamoto, Fumio
Kanda and Tatsushi Toda; Kobe, Japan
Primary Progressive Aphasia (PPA) is one of the clinical
types of frontotemporal dementia characterized by an isolated language dysfunction with asymmetric atrophy of perisylvian association cortices. There have been no established
treatments for PPA. In this study, we tried rivastigumine for
PPA and saw its efficiency on aphasia.
One patient diagnosed with semantic dementia and five
patients diagnosed with non-fluent progressive aphasia were
treated with rivastigmine patch (starting from 4.5 mg/day
and finally dosing up to 18 mg/day). The patients were
evaluated by WAB, Boston naming test and other batteries.
One patient had a skin rash as a reaction of patch and
needed corticosteroid ointment therapy. The others had no
side effects or no gastrointestinal symptoms. Five of the six
patients exhibited some improvements of language function,
especially in naming and repeating. The family members of
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M1131. Diminished Thalamocortical Feedforward
Inhibition in an Aging Mouse Model of Chronic
Tinnitus: Implications for Deafferentation Syndromes
and Aging
Daniel A. Llano, Jeremy Turner and Don Caspary; Urbana,
IL; Jacksonville, IL and Springfield, IL
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sophisticated biomarkers are more efficient than simple
screening or neuropsychological tests focused on memory.
The goal of this work was to evaluate the predictive value of
the Memory Impairment Screen (MIS), a simple and brief
memory test in elderly subjects with subjective memory loss.
Methods: We recruited a prospective cohort of 105
patients with subjective memory loss and normal global cognitive function. They scored 0.5 in the CDR. The final
point was the conversion to dementia, mainly of Alzheimer
type.
Results: After a mean follow-up of 3 years (range: 2-4
years) 57 patients developed AD, and 48 did not. A baseline
score of 0 or 1 in the MIS test predicted conversion to AD
at 42.9 % sensitivity and 98% specificity with a positive
predictive value of 96%. The area under the curve was 0.76
(95% CI: 0.66-0.86).
Conclusions: In the clinical setting the MIS test in
patients referred by memory complaints is useful to predict
the development of AD but it should be combined with a
higher sensitivity test.
Study supported by: NONE
Mechanisms underlying the generation of spontaneous percepts (e.g. pain, tinnitus, visual hallucinations) in deafferentation syndromes are not known. Here, we use an aging mouse
model of tinnitus after peripheral defferentation to explore
potential thalamocortical mechanisms of these disorders. Flavoprotein autofluorescence imaging was used to examine auditory thalamocortical synaptic responses in aged animals
with evidence of tinnitus. Mice were exposed to noise trauma
at 2 months of age and were assessed at 26 months. Noiseexposed animals showed a marked increase in amplitude of
thalamocortical activation compared to controls and they
showed a diminished sensitivity to GABAergic blockade. The
strength of thalamocortical activation was significantly correlated to the degree of tinnitus behavior. Finally, there was no
relationship between auditory cortical activation and activation of the somatosensory cortex in the same slices, suggesting
that the increases in activation were not due to a generalized
hyperexcitable state in noise-exposed animals. These data suggest that peripheral deafferentation is associated with a maladaptive downregulation of cortical GABAergic synaptic transmission. Potential general implications regarding aging and
deafferentation syndromes are discussed.
Study supported by: NIDCD
M1134. Decreased Life Expectancy When Seizures
Develop in Alzheimer’s
Lauren R. Moo and Steven D. Shirk; Bedford, MA and
Boston, MA
While those with Alzheimer’s Dementia (AD) are at
increased risk for seizures, the underlying relationship
between seizures and AD is not well characterized. We retrospectively examined the clinical history of Veterans who
were resident on the Bedford VA Severe Dementia Care
Unit (SDCU) with pathologically confirmed AD to determine the effect of seizures on mortality in AD. Preliminary
analyses limited to those males with confirmed AD, no evidence of stroke, and no history of epilepsy prior to dementia onset, suggest that those with post-AD onset seizures
(ADþS) have a significantly shorter life expectancy
(p<0.01). This reduction appears to be driven by earlier age
of dementia onset (p<0.01) in the ADþS group as the
ADþS and AD-S groups had comparable times from
SDCU admission to death (p>0.2). Thus, while the development of seizures in the setting of AD is correlated with a
shorter life expectancy, it is not clear that the seizures themselves lead to a younger demise. Instead, those who develop
seizures late in AD appear to be a distinct cohort within the
AD population. Further investigation regarding whether
those with AD who develop seizures represent a pathophysiological sub-phenotype is warranted.
Study supported by: GRECC/VA employment
M1132. Does Education Slow Functional Decline in
Alzheimer’s Disease? Revisiting the Reserve Hypothesis
Meghan B. Mitchell, Steven D. Shirk and Alireza Atri;
Boston, MA and Bedford, MA
Objective: To investigate the role of education, a proxy for
cognitive reserve, on the long-term course of daily function
in Alzheimer’s disease (AD).
Method: 1026 participants with probable AD enrolled in
the MADRC Patient Registry underwent serial evaluations
and dementia treatment as part of routine Memory Disorders
Unit clinical care. Mixed effects modeling examined effects of
education on trajectory of functional decline as measured by
the Weintraub activities of daily living (ADL) scale; models
adjusted for baseline levels of cognitive performance and
ADL function and their interactions with time.
Results: Higher education was associated with slower rate
of decline in individuals with mild functional impairment,
but as baseline functional impairment increased, the association of education and functional decline weakened.
Discussion: There remains considerable debate regarding
the effect of education on rate of decline in aging an AD;
some studies suggest that education is associated with concurrent level of cognitive function but does not affect rate
of decline. These results support the potential protective
effects of education to facilitate a ‘‘functional reserve’’ that is
above and beyond cognitive ability and may be particularly
effective in earlier stages of AD.
Study supported by: NIA grant AG027171 (Alireza Atri,
PI) and the Department of Veterans Affairs
M1135. Comparison of the Impact of Alzheimer’s
Disease on Medicare and Medicaid
Lisa Mucha, Amanda Forys, Huai-Che Shih, Joel Bobula,
Trent McLaughlin, Kara Suter, Machaeon Bonafede and
Robert Fowler; Collegeville, PA; Arlington, VA; Abbott Park,
IL and Cambridge, MA
Objective: The objective of the study was to characterize
the economic impact of Alzheimer’s disease (AD) to Medicare and Medicaid.
Methods: Studies were undertaken using claims from
Medicare 5% sample, and a multistate Medicaid file 20018. AD patients age 50 or older were retrospectively identified via the first instance of ICD-9 code 331.0 using the
Medicare 5% Sample and the MarketScan Medicaid MultiState Database (2001-2008). Total direct costs by type of
M1133. Predictive Value of the Memory-ImpairmentScreen Test in Subjects with Subjective Memory Loss
Pedro J. Modrego, Jose´ Gazulla and Pedro J. Modrego;
Zaragoza, Spain
Objective: The use of biomarkers in early Alzheimer’s disease detection is growing. However it is not clear whether
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service are reported for the subsequent 12 month period,
adjusted to 2008 dollars.
Results: The highest costs were associated with long term
care by Medicaid ($26,793). For inpatient care, average cost
was highest for Medicare ($15,713) relative to Medicaid
($7,605). Outpatient costs were higher for Medicare
($1,102) than Medicaid ($57). Medicare incurred more
costs for outpatient services such as durable medical equipment ($1,404) and home health ($6,819).
Conclusions: The economic burden of AD is substantial
to both Medicare and Medicaid but differs by payer. The
site of care impacted the effect on each payer differently.
Medicaid costs were driven by LTC expenses while Medicare
costs were driven by inpatient expenses.
Study supported by: This study has been supported by
Pfizer Inc., and Janssen Alzheimer Immunotherapy.
Dr. Mucha and Mr. Bobula are employees of Pfizer Inc.
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reconstruct three temporal fasciculi: fornix, parahippocampal
cingulum, and uncinate fasciculus. Tract microstructural
measures were corrected for partial volume errors.
Results: In controls, episodic memory was associated
exclusively with variations in fornix microstructure. In contrast, in MCI, memory was associated with integrity of parahippocampal cingulum and uncinate fasciculus, but not the
fornix. Familiarity-based memory was associated specifically
with parahippocampal cingulum microstructure.
Conclusions: In the healthy brain, the fornix bears most
of the episodic memory load. When this system is compromised, structure of other temporal association tracts become
critical to performance. This patterm may reflect functional
reorganisation or a greater reliance on familiarity-based or
semantic memory, which are not dependent on integrity of
the hippocampus and fornix.
Study supported by: Medical Research Council, UK
through a Clinician Scientist Fellowship to MOS
M1136. Optineurin Immunoreactivity in Neuronal and
Glial Intranuclear Inclusions in Adult-Onset Neuronal
Intranuclear Inclusion Disease
Masataka Nakamura, Melissa E. Murray, Wen-Lang Lin,
Hirofumi Kusaka and Dennis W. Dickson; Jacksonville, FL
and Moriguchi, Osaka, Japan
M1138. Cingulum Bundle Microstructure Predicts
Cognitive Control in Ageing and Mild Cognitive
Impairment
Michael J. O’Sullivan, Claudia Metzler-Baddeley, Derek K.
Jones, Jessica Steventon, Laura Westacott and John P. Aggleton;
London, United Kingdom and Cardiff, United Kingdom
Background: Recently, optineurin (OPTN) immunoreactivity has been reported in neuronal intranuclear inclusions
(NII) of neuronal intranuclear inclusions disease (NIID).
Other studies have shown that the RNA-binding protein,
fused in sarcoma (FUS), is a component of NII in NIID.
Aims: To investigate the relationship between OPTN,
FUS and Ubiquitin (Ub) in intranuclear inclusions of
NIID.
Methods: Sections of hippocampus from 4 NIID and 4
control patients were analyzed immunohistochemically.
Results: In control subjects, OPTN was located in the
cytoplasm of neurons. In NIID patients, NII and glial intranuclear inclusions (GII) were immunopositive for OPTN.
The intensity of OPTN immunostaining of neuronal cytoplasm was reduced compared to that of control subjects.
Double immunofluorescence for OPTN, FUS and Ub
revealed co-localization of these proteins within NII and
GII. All of the Ub positive NII was OPTN positive. The
percentage of co-localization of Ub with FUS in NII was
approximately 50%. Electron microscopic examination
revealed both thin and thick filaments in NII were immunolabeled by Ub and OPTN.
Conclusions: These findings suggest that OPTN plays a
central role in the pathogenesis of NIID and that contribution of FUS is a less consistent.
Study supported by: None
Background: Brain injury and fMRI studies implicate the
prefrontal cortex in cognitive control. The anterior cingulate
cortex is involved in control of goal-directed behaviour,
through top-down control of attention and maintenance of
task set. Increasingly such functions are seen as subserved by
distributed networks. Their efficiency might therefore
depend on the status of prefrontal connections.
Methods: We employed diffusion MRI-based tractography and several executive control tasks in 20 healthy older
adults and 25 individuals with amnestic MCI, matched for
age, education and premorbid intelligence. Anterior, medial,
posterior, and parahippocampal portions of the cingulum
were reconstructed. Tract microstructural measures were corrected for partial-volume errors.
Results: Correlations with cognitive control were specific
to the cingulum compared with control tracts (fornix and
corticospinal tract). Verbal/symbolic tasks showed strong left
laterality (Category Fluency and anterior cingulum, left r ¼
0.71, p<0.001, right r ¼ 0.44, p ¼ 0.06). In MCI, this
pattern was maintained; a more spatial task (Tower of London) also related to right anterior cingulum.
Conclusions: Cognitive control in older adults is exquisitely sensitive to variations in anterior cingulum microstructure. Shifts in pattern of association in MCI illustrated how
alternative networks/processes become differentially involved
with onset of disease.
Study supported by: Medical Research Council, UK
through a Clinician Scientist Fellowship to MOS
(G0701912)
Alzheimer’s Research UK (MOS)
CONNECT (EU) (DKJ)
M1137. Redistribution of Memory Load in Temporal
Association Tracts in Mild Cognitive Impairment
Claudia Metzler-Baddeley, Sarah Hunt, Derek K. Jones, John
P. Aggleton and Michael J. O’Sullivan; Cardiff, United
Kingdom and London, United Kingdom
Background: Episodic memory is supported by networks
that connect medial temporal, frontal and parietal regions.
We have shown that the fornix is critical in age-related
memory decline. We evaluated the relationships between
structure of major temporal tracts and memory in amnestic
MCI, where the hippocampus-fornix system is often
compromised.
Methods: 25 patients with MCI and 20 controls matched
for age, education, and premorbid IQ underwent MRI and
detailed evaluation of memory. Tractography was used to
M1139. Alzheimer’s Disease Progression Rates: New
Estimates
Natalia Olchanski, Pei-Jung Lin, Joshua T. Cohen and
Peter J. Neumann; Boston, MA
Background: Estimates of Alzheimer’s disease (AD) progression based on older data may not reflect current clinical
management. This study estimated transition rates from
mild cognitive impairment (MCI) to more advanced AD
using recent data from a large, longitudinal database.
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Methods: We analyzed data (2005-2011) from the Uniform Data Set maintained by the National Alzheimer’s
Coordinating Center. Analysis included patients aged 50
and older, excluding patients with non-AD dementia at
baseline (n ¼ 19,845 patients, 50,413 patient-visits). Disease severity was defined by the Clinical Dementia Rating:
0.5 (MCI); 1 (mild AD); 2 (moderate AD); and 3 (severe
AD). We applied survival analysis to calculate age- and sexadjusted transition probabilities.
Results: The sample included 40.5% males, mean age
76.3. Annual transition probabilities from MCI to mild AD
were 0.091 in males and 0.085 females age 65, 0.100
(male) and 0.094 (female) age 75, and 0.113 (male) and
0.104 (female) age 85. Transition probabilities from mild to
moderate AD ranged from 0.125 to 0.148, and from moderate to severe AD, 0.065 to 0.087.
Conclusion: Disease progression rates were slightly higher
in males and older patients, overall lower compared with
previous CERAD analysis.
Study supported by: Pfizer;
NACC UDS data are supported by NIA grant number
U01 AG016976
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tial therapeutic effects of b-adrenergic antagonists in AD. In
two transgenic AD mouse-models, chronic oral-administration of carvedilol, a b-adrenergic antagonist FDA-approved
for several cardiac indications, decreased brain monomeric/
oligomeric b-amyloid contents, attenuated cognitive deterioration and improved brain basal neuronal transmission.
Additionally, it may have beneficial effects on AD vascular
risk-factors by stabilizing blood pressure and improving
brain perfusion since it’s approved for treatment of hypertension and congestive heart-failure and is neuroprotective
in brain ischemia models. We’re clinically exploring a targetdose of 25mg/day carvedilol to 50 AD patients in a 6month randomized, placebo-controlled, double-blind, single-site trial; change in episodic recall is the primary outcome and biomarker change and safety/tolerability are secondary measures. If we observe significant improvements in
clinical outcomes, we’ll propose a definitive trial of carvedilol in AD. If we observe changes only in biomarker outcomes, this will inform further studies of similar treatment
mechanisms. Carvedilol has advantages in clinical trials since
it has a well-characterized, well-tolerated safety profile and is
available as a generic drug.
Study supported by: Supported by NIH AG037504 to
Giulio Maria Pasinetti.
M1140. Impact of Cerebrovascular Risk over Age of
Onset of Dementia Due to Alzheimer’s Disease in a
Sample of Patients with Low Schooling from Brazil
Fabricio F. Oliveira, Paulo H. Bertolucci, Marilia A. Smith
and Elizabeth S. Chen; Sa˜o Paulo, SP, Brazil
M1142. Changes in Specific Resting State Brain
Networks Correlate with Clinical Measures in PSP and
CBD
Timothy Rittman, Boyd Ghosh, William R. Shirer, Michael D.
Greicius and James B. Rowe; Cambridge, Cambridgeshire,
United Kingdom and Stanford, CA
Objective: To establish the impact of cerebrovascular (CV)
risk factors and schooling over age of onset of dementia due
to Alzheimer’s disease (AD).
Methods: Patients with late-onset AD were assessed for
gender, schooling, age of dementia onset, and CV risk factors (systemic hypertension, diabetes mellitus, hypercholesterolemia, alcoholism, smoking, family history of cardiovascular diseases, obesity and midlife physical inactivity).
Multiple logistic regression was employed for statistical analysis, significance at p<0.05.
Results: Among all 146 included patients, 97 (66.4%)
were female and 49 (33.6%) were male, 52 (35.6%)
reported physical inactivity, 125 (85.6%) had systemic
hypertension, 38 (26.1%) had diabetes mellitus, and 103
(70.5%) had hypercholesterolemia, all under treatment;
mean waist circumference was 94.7612.1cm, mean body
mass index was 25.8364.45kg/m2, mean schooling was
4.463.6 years (range 0-15), and mean estimated age of dementia onset was 72.566.3 years-old. Smoking (OR ¼
1.159;95%CI 0.967-1.389) and obesity (OR ¼
1.145;95%CI 0.995-1.317) were the strongest risk factors
for AD onset before 70 years-old (p ¼ 0.003). Schooling
and all other CV risk factors were not statistically
significant.
Conclusion: Smoking and obesity seem to impact the
age of AD onset in Brazil.
Study supported by: CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior & FAPESP - The
State of São Paulo Research Foundation
Functional connectivity network measures reliably reflect
disease (Zhou 2010; Greicius 2004). Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) often
exhibit tau pathology, but have distinct phenotypes.
Resting fMRI (3T) scans were acquired (21 controls, 30
PSP, 19 CBD). Individual Independent Component Analysis was performed and components compared to standard
network templates to: 1. derive Goodness of Fit (GOF)
scores, 2. identify a best fitting component for each network
template, 3. correlate GOF with clinical measures.
In the basal ganglia network GOF scores were lower than
controls in PSP (p ¼ 0.0003) and CBD (p ¼ 0.04), and in
PSP correlated with disease duration (r ¼ -0.37, p ¼ 0.04).
In the left executive control network GOF scores differed
between PSP and controls (p ¼ 0.03) and in PSP correlated
with verbal fluency (r ¼ 0.38, p ¼ 0.04). In the high visual
network, GOF scores differed between CBD subjects compared with controls (p ¼ 0.03) and PSP subjects (p ¼
0.02).
These findings support functional connectivity measures
as biomarkers of disease, and a tool to understand selective
vulnerability of brain networks to neurodegeneration.
Study supported by: The funders for this study are:
MRC
Wellcome Trust
Sackler Studentship
M1141. Repurposing Anti-Hypertensive Drugs for
Alzheimer’s Disease
Giulio M. Pasinetti and Paul Rosenberg; New York, NY and
Baltimore, MD
M1143. Patterns of Longitudinal Brain Atrophy in the
Logopenic Variant of Primary Progressive Aphasia
Jonathan D. Rohrer, Francesca Caso, Colin Mahoney, Maya
Henry, Howard Rosen, Martin N. Rossor, Bruce Miller, Jason
D. Warren, Gerard R. Ridgway and Maria Luisa GornoTempini; London, United Kingdom and San Francisco
FDA-approved AD treatments do not significantly modify
disease course. In a population-based sample of incident
AD, we observed that using b-adrenergic antagonists was
associated with slower functional decline, implicating poten-
The logopenic variant of primary progressive aphasia is associated with phonological deficits and impaired word
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retrieval. Little is currently known about what happens with
disease progression. In this study 21 patients with longitudinal T1 MR imaging (mean interval 1.2 years) were studied
using volumetric analysis and voxel-based morphometry
(VBM). Baseline imaging showed asymmetrical (left greater
than right) involvement of the posterior superior temporal
and inferior parietal lobes as well as posterior cingulate and
medial temporal lobes. The whole brain rate of volume loss
was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%) than right hemisphere (1.6%). Longitudinal
VBM analysis showed increasing involvement of other language areas in the left hemisphere and atrophy of areas in the
right hemisphere that had been seen earlier in the disease in
the left hemisphere, particularly posterior cingulate. With disease progression there was worsening of anomia, sentence
repetition and sentence comprehension but also deficits in
single word comprehension, single word repetition and verbal
memory. The logopenic variant appears to remain an asymmetrical disease as it progresses but with increasing involvement of the mirror regions in the right hemisphere.
Study supported by: This work was undertaken at
UCLH/UCL who received a proportion of funding from
the Department of Health’s NIHR Biomedical Research
Centres funding scheme. The Dementia Research Centre is
an Alzheimer’s Research UK Co-ordinating Centre. This
work was also funded by the Medical Research Council
UK. Dr Warren has received research support from the
Wellcome Trust (Intermediate Clinical Fellowship).
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neuronal membrane formation), is designed to support syntaptogenesis in Alzheimer’s disease (AD). The Souvenir I
study demonstrated that Souvenaid improved 12-week
memory performance in drug-naı̈ve mild AD (n ¼ 225;
MMSE 20-26). Two additional RCTs were completed: SConnect: 24-week study investigating cognition in 527
mild-to-moderate AD patients (MMSE14-24) using AD
medication; Souvenir II: 24-week study, investigating effects
on memory in drug-naı̈ve mild AD (n ¼ 259;
MMSE20).
S-Connect did not show an effect on cognition in mildto-moderate AD on AD medications. Souvenir II showed
significant improvement on the primary outcome memory
measure in drug-naı̈ve mild AD. Compliance was high
(>94%) and Souvenaid was well-tolerated in both studies.
The hypothesis that Souvenaid acts via improving synapse
formation and function was supported by significant effects
on electroencephalography measures of functional connectivity. These findings offer hope towards a management strategy directed at one of the major hallmarks of early AD.
Clinical studies on the long-term effects and biomarkers are
ongoing (LipiDiDiet2).
1
Souvenaid is a registered trademark and Fortasyn is a
trademark of N.V. Nutricia
2
Funded by the EU FP7 project LipiDiDiet, Grant
Agreement N 211696
Study supported by: Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition,
Wageningen, The Netherlands.
Salary: R.L. Wieggers and P.J.G.H. Kamphuis are
employees of Nutricia Advanced Medical Nutrition, Danone
Research, Centre for Specialised Nutrition, Wageningen,
The Netherlands.
M1144. Differential Patterns of White Matter
Degeneration as a New Biomarker for Dementia
Seyed Ahmad Sajjadi, Julio Acosta-Cabronero and Peter J.
Nestor; Cambridge, Cambridgeshire, United Kingdom
Prediction of the clinical course and underlying pathology at
early stages of dementia remains an unresolved challenge. In
this work we assessed the utility of diffusion tensor imaging
(DTI) maps acquired at the early stages of the disease in 42
clinically diagnosed cases of typical Alzheimer’s disease (AD),
semantic dementia (SD), corticobasal degeneration (CBD),
and progressive supra-nuclear palsy (PSP). DTI maps were
acquired in 63 non-collinear directions and each patient’s map
was separately compared to 26 age-matched controls using the
non-parametric method implemented in Tract Based Spatial
Statistics and statistical maps were obtained for three DTI
metrics (fractional anisotropy and radial and axial diffusivities). Discrete patterns of tract degeneration were readily identifiable using visual rating scales. Inferior longitudinal and uncinate fasciculi, different components of the limbic system,
and thalamic and midbrain tracts were abnormal in individual
cases of SD, AD, and PSP respectively. Furthermore, diffuse
bilateral white matter involvement in the motor and premotor areas was the salient abnormality in CBD. Our findings imply that the topographically distinct patterns of white
matter degeneration seen in individual patients can be utilised
as a diagnostic biomarker in neurodegenerative syndromes.
Study supported by: Donald Forrester Trust
NIHR Cambridge Biomedical Research Centre
M1146. Relationship between ß-Amyloid Retention and
Ischemia in the Patients with Subcortical Vascular
Cognitive Impairment
Young Noh*, Sang Won Seo, Geon Ha Kim, Seun Jeon, Jong
Min Lee, Seung Jun Oh, Jae Seung Kim, Yearn Seong Choe,
Kyung-Han Lee, Jae-hong Lee and Duk L. Na; Seoul,
Republic of Korea
Objective: Previous clinical studies suggested close relationship between cerebrovascular disease and risk of Alzheimer’s
disease. However, direct correlation between ß-amyloid
retention and ischemia has not been elucidated in human.
Moreover, it is possible that ApoE4 might modify this relationship because ApoE4 contribute to the clearance of amyloid. The purpose of this study was to evaluate this relationship in the patients with both vascular and ß-amyloid
pathology.
Methods: We measured brain amyloid deposition using
11C-Pittsburgh compound B (PiB) PET in 136 patients
with subcortical vascular cognitive impairment (SVCI).
Among them, 52 patients with positive result for cortical
PiB binding were study population (mean age 77.46 5.5).
We divided the patients into two groups, ApoE4 carriers
and noncarriers and then performed multiple linear regression analysis separately.
Results: In the patients without ApoE4 allele, significant
positive correlation was shown between the volume of white
matter hyperintensities (WMH) and global cortical PiB
retention ratio (B ¼ 25311, SE ¼ 11299, p value ¼
0.034), whereas, no significant correlation was found in
ApoE4 allele carriers (B ¼ -14143, SE ¼ 10450, p value ¼
0.193).
M1145. Souvenaid Improves Memory in Mild AD –
Results from the Clinical Study Program
P. Scheltens, R. Shah, D.A. Bennett, R.L. Wieggers, T.
Hartmann, H. Soininen and P.J.G.H. Kamphuis; Amsterdam,
Netherlands; Chicago, IL; Wageningen, Netherlands; Homburg,
Germany and Kuopio, Finland
R , containing the specific nutrient combination
SouvenaidV
FortasynTMConnect1 (including precursors and cofactors for
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Interpretation: This is the first clinical study showing
that cerebrovascular disease and amyloid interactively develop in PiBþ SVCI patients without ApoE4.
Study supported by: This study was supported by a grant
from the Korean Healthcare Technology R&D Project,
Ministry for Health, Welfare & Family Affairs, Republic of
Korea.
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norms calculator provides clinician-researchers with an additional tool for gauging normative test performance in older
adults, and especially guides interpretation of individual performances that appear to fall in borderline realms including
classification of subtle impairments according to the NIAAA criteria.
Study supported by: VA/GRECC
NIA K23AG027171 (Atri)
M1147. Prefrontal Cortex: Unilateral Disruption
Differentially Affects Verbal Working Memory in Young
and Older Adults
Jessica A. Shields, Jeffrey Mock and Anne L. Foundas; New
Orleans, LA
M1149. Integrating Human and Fly Genetics To
Understand Alzheimer’s Disease Susceptibility
Joshua M. Shulman, Selina Imboywa, Allison E. Diamond,
Portia Chipendo, Philip L. De Jager and Mel B. Feany;
Boston, MA
Unilateral repetitive transcranial magnetic stimulation
(rTMS) was used to test the hypothesis that the laterality of
verbal working memory (WM) changes in healthy older
adults [Hemispheric Asymmetry Reduction in Older AdultsHAROLD]. This model stipulates that, under similar taskconditions, prefrontal activity tends to be less lateralized in
older than in younger adults.
Right-handed adults (young, n ¼ 36, 18 female, mean
29.4 years; old n ¼ 34, 18 female, mean 68.4) completed
verbal n-back task. rTMS was then administered (90%
motor threshold, 1Hz, 900 pulses) to: left, right, or sham
dorsolateral prefrontal cortex (DLPFC) followed by repeat
WM testing.
Following right (p ¼ .001) and sham (p ¼ .007) conditions the expected practice effects were found in young
adults; left DLPFC rTMS (p ¼ .2) did not show practice
effects. Older adults showed practice effects following left (p
¼ .009), right (p ¼ .001), and sham (p ¼ .001)
stimulation.
The observed differences in stimulation effects between
groups support the postulate that a more bilateral representation of verbal WM may develop with healthy brain aging
[i.e., HAROLD/compensation model]. It may be that older
adults shift cognitive resources to use a top-down executive
processing strategy with input from left and right prefrontal
networks.
Study supported by: n/a
The critical next step following recent discoveries of Alzheimer’s disease (AD) susceptibility loci is to confirm responsible genes and define mechanisms. We have coupled human
genome-wide association studies with an efficient functional
screen in Drosophila. From published studies, 130 candidate
AD susceptibility genes achieved suggestive associations,
nominating 89 fly orthologs for study. Lines predicted to
activate or disrupt function were screened for modification
of retinal toxicity due to human Tau or Amyloid-Beta (Aß).
Selected genes were also evaluated for impact on age-dependent brain neurodegeneration. 12 genes demonstrated
robust interactions with Tau or Aß neurotoxicity in vivo.
Disruption of the fly integrin receptor scb (orthologous to
human ITGAM and ITGA9) or the integrin modulators,
Fit1/2 (orthologous to the kindlin, FERMT2), enhanced
Tau toxicity. We also find that gain- and loss-of-function in
cindr, a regulator of actin dynamics and the ortholog of
CD2AP, reciprocally suppress and enhance Tau toxicity. Our
cross-species strategy highlights several additional molecular
pathways, including kinases (EPHA1) the microtubule cytoskeleton (MAST4), and RNA-binding proteins (SNRPN).
Based on associations with human disease and functional
interactions in Drosophila, we implicate integrin-mediated
adhesion and several other pathways as important in AD
susceptibility.
Study supported by: Grants from the NIH and the Burroughs Wellcome Fund.
M1148. Normative Scores and Calculator for the NACC
UDS Neuropsychological Test Battery
Steven D. Shirk, Meghan B. Mitchell, Joseph J. Locascio,
Sandra Weintraub and Alireza Atri; Bedford, MA; Boston,
MA and Chicago, IL
M1150. Genetic Susceptibility for Amyloid Pathology in
Alzheimer’s Disease
Joshua M. Shulman, Kewei Chen, Brendan T. Keenan, Lori
B. Chibnik, Pradeep Thiyyagura, Cristin McCabe, Jason J.
Corneveaux, Lei Yu, Matthew J. Huentelman, Denis A. Evans,
Julie A. Schneider, Eric M. Reiman, Philip L. De Jager and
David A. Bennett; Boston, MA; Phoenix, AZ and Chicago, IL
The revised AA-NIA criteria for the Alzheimer’s disease clinical spectrum necessitates tools that provide clinicians/
researchers additional information to aid detection and
tracking of subtle cognitive impairment and decline. Comparing results of neuropsychological testing using different
demographic adjustments, particularly age and pre-morbid
functional ability/attainment, may increase AD-specturm
classification accuracy. Recently, using published regression
coefficients and RMSEs (Weintraub et al., 2009), we developed an estimated normative z-score calculator for the
National Alzheimer’s Coordinating Center Uniform Data
Set neuropsychological test battery that adjusts for sex, education, age, and their combination (Shirk et al., 2011). This
simple method provides researchers an accessible tool to create norms for their own unique data sets. This study provides an updated calculator based on raw test data from an
updated NACC-UDS sample of clinically cognitively normal participants (N ¼ 6836). Using conventional methods
of calculating regression-based scores, we provide updated
norms, and provide validation of our earlier calculator. This
Amyloid pathology is among the earliest brain changes of
Alzheimer’s disease (AD); however, the discovery of susceptibility genes for AD has largely focused on the end-stage of
clinically-diagnosed dementia.We evaluated recently reported
AD susceptibility loci for associations with amyloid neuritic
plaque burden in 725 autopsy cases from prospective, community-based studies. In addition to the previously reported
APOE and CR1 susceptibility loci, we find that the ABCA7
(rs3764650, p ¼ 0.02) and CD2AP (rs9349407, p ¼ 0.03)
loci are associated with neuritic plaque burden. In order to
identify novel susceptibility loci, a genome-wide association
study (GWAS) was performed using the neuritic plaque
trait. Among the top results, we discover a novel variant
near the amyloid precursor protein gene (APP, rs2829887)
that is associated with amyloid neuritic plaques (p ¼
3.3x10-6), and this finding was validated in two independent cohorts of cognitively-normal subjects with positron
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emission tomography imaging of fibrillar amyloid
(p<0.005). Our results enhance understanding of AD risk
factors by relating validated susceptibility alleles to increased
amyloid neuritic pathology and implicating common variation at the APP locus in the earliest, pre-symptomatic stages
of AD, extending the established association of rare APP
mutations with early-onset, familial disease.
Study supported by: Grants from the National Institutes
of Health and the Burroughs Wellcome Fund.
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between nutrition and AD risk. Lower plasma nutrient status
in AD patients compared to controls have been observed.
Supplementation with combinations of DHAþEPA,
UMP, choline, phospholipids, vitamins B, C, E, and selenium showed increased muscarinic receptor density,
enhanced receptor-mediated G-protein activation, increased
synaptic proteins mRNA expression and improved learning
and memory.
Based on these insights the specific nutrient combination
FortasynTMConnect (UMP, DHA, EPA, choline, phospholipids, folate, vitamins B6, B12, C, E, selenium) was designed
to support synapse formation and function in AD patients.
R , conIn two randomised controlled studies SouvenaidV
taining FortasynConnect, improved memory in drug-naı̈ve
mild AD patients.
Souvenaid is a registered trademark and Fortasyn is a
trademark of N.V. Nutricia.
Study supported by: Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition
The authors ar employees of and salaries are payed by
Nutricia Advanced Medical Nutrition, Danone Research,
Centre for Specialised Nutrition
M1151. Impaired Nutritional Status in Patients with
Mild Alzheimer’s Disease Compared to Healthy AgeMatched Controls
J.W. Sijben, M.G.M. Olde Rikkert, P. Scheltens, A.M.J. van
Hees, M. Groenendijk and P.J.G.H. Kamphuis; Wageningen,
Netherlands; Nijmegen, Netherlands and Amsterdam,
Netherlands
Epidemiological studies suggest that low intake of n-3 fatty
acids, B-vitamins, and antioxidants increase risk of Alzheimer’s disease (AD). Other studies suggest that patients with
AD have lower plasma levels of these nutrients compared to
age-matched controls, either due to reduced daily consumption, their increased use, different metabolism, or a combination of these factors. In this study, nutritional status in
AD patients was further explored.
Nutritional status was assessed in a subgroup of 84 Dutch
drug-naı̈ve mild AD patients (MMSE20) participating in
the Souvenir II study and in 98 Dutch healthy control subjects, matched for age and gender. Between-group differences in nutritional blood parameters and anthropometrics
were analysed using ANCOVA.
Plasma selenium (p<0.001), vitamin D (p ¼ 0.084), the
proportion of DHA (p ¼ 0.006) and total long-chain n-3
PUFA (p ¼ 0.024) in erythrocyte membranes and Mini
Nutritional Assessment screening score (p ¼ 0.008) were
lower in AD vs. controls. No statistically significant differences were observed for plasma fatty acids, choline and folate.
The nutritional status of patients with mild AD is
impaired vs. healthy controls, suggesting that these patients
could benefit from nutritional support, designed to meet
specific nutritional requirements in AD.
Study supported by: Nutricia Advanced Medical Nutrition, Danone Research, Centre for Specialised Nutrition,
Wageningen, The Netherlands
Salary: J.W. Sijben, A.M.J. van Hees, M. Groenendijk
and P.J.G.H. Kamphuis are employees of Nutricia Advanced
Medical Nutrition, Danone Research, Centre for Specialised
Nutrition, Wageningen, The Netherlands
M1153. A Return to Clinical Skills in the Early
Diagnosis of Alzheimer’s Disease
Cassandra Szoeke, Kathryn Ellis, Ping Zhang, Christopher
Rowe, Ralph Martin, Colin Masters, David Ames and AIBL
Research Group; Melbourne, VIC, Australia and Melbourne,
Australia
Early detection of the prodromal stages of Dementia is crucial to preventing onset of disease. We have identified a
sub-group within the healthy cognition (HC) category at
increased risk of progression to manifest cognitive impairment (MCI) over 18 to 36 months. The cognitive scores of
704 AIBL HC subjects were modeled at baseline to see if
clear classes were apparent within this group. Two groups
were distinguished within the HC population for cognitive
performance. The performance on a simple word list recall
was able to distinguish between these two groups with high
accuracy. The predictive significance of this classification at
18 and 36 month follow-up was tested. Those in the lower
performing group had significant risk for converting to
MCI or AD over 18months with OR of 7.5 (CI 2.6-27.3).
Being in the lower performing group at 18 months was
higher risk for conversion at 3years with OR 10.2 (CI 3.438.1). All analyses were adjusted for age, education, sex and
APOE4. A simple word recall test was able to identify those
with healthy cognition who have 10 times higher risk of
progression to MCI within 18-36 months.
Study supported by: The AIBL Research Group
M1152. Supporting Synapse Formation and Function in
Alzheimer’s Disease: Mechanism of Action of the Specific
Nutrient Combination FortasynTM Connect
John W. Sijben, Patrick J. Kamphuis, Martijn C. de Wilde,
Robert J. Hageman, Laus M. Broersen and Martine
Groenendijk; Wageningen, Netherlands and Utrecht,
Netherlands
M1154. Gait and Balance Dysfunction in Dementia
Yutaka Tanaka, Masao Miyazaki and Lisa T. Connor; IkomaGun, Nara, Japan; Ise, Mie, Japan and St. Louis, MO
Objective: This study was designed to evaluate cerebral
mechanisms underlying gait and balance disturbances in
demented subjects.
Subjects and Methods: 124 consecutive right –handed
subjects with both gait disturbance and cognitive impairment, and 32 age- and education-matched healthy subjects
were studied. Detailed cognitive exams were administered to
all Ss. EEG recordings for 22 of the demented Ss were
made with special attention to primary motor areas, supplementary motor areas, and premotor areas during motor execution and motor imagery tasks (foot extension and flexion)
for 10 seconds each.
Alzheimer’s disease (AD) is a progressive neurodegenerative
disease, leading to gradual decline in cognitive and behavioral function.It is recognized that synaptic loss is the
strongest structural correlate with memory impairment.
Synapses and neurites consist of neuronal membranes
largely composed of phosphatides. Phosphatide synthesis
depends on the presence of the dietary precursors DHA,
UMP and choline. Co-factors in the synthesis pathway of
neuronal membranes are B-vitamins, phospholipids and antioxidants. Several studies have demonstrated a significant link
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Results: No alpha or beta band blocking was detected in
seven or more recordings in 17 of the 22 demented
subjects.
Significant ‘‘no-blocking’’ was found in the right supplementary motor area and premotor area during motor execution and motor imagery in the dementia group.
No relationship was found between dementia severity and
EEG results.
Conclusion: In a group of demented persons with clinically relevant disturbances of gait and balance, EEG abnormalities during tasks of motor execution and motor imagery
were seen in the premotor and supplementary motor areas,
especially in the right hemisphere.
Study supported by: none
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patients receiving memantine ER performed significantly
better than those receiving placebo on the SIB subscales of
Reading/Writing (OC: P ¼ 0.002; LOCF: P<0.001;
MMRM: P<0.001) and Comprehension/Repetition/Discourse (OC: P ¼ 0.048; LOCF: P ¼ 0.004; MMRM: P ¼
0.006). There was no significant difference between treatment groups on the SIB subscale of Naming (OC: P ¼
0.093; LOCF: P ¼ 0.073; MMRM: P ¼ 0.057) or on the
Functional Communication Score (OC: P ¼ 0.257; LOCF:
P ¼ 0.131; MMRM: P ¼ 0.116). In conclusion, for
patients with moderate to severe AD receiving stable ChEI
treatment, the addition of memantine ER may be associated
with benefits in language abilities.
Study supported by: Forest Laboratories, Inc.
Drs. Stephen Graham and Michael Tocco are employed
by Forest Research Institute.
Drs. Michael L. Miller and Vojislav Pejovi&#263; are
employed by Prescott Medical Communications Group, an
independent contractor to several pharmaceutical companies,
including Forest Laboratories, Inc.
Dr. Suzanne Hendrix is employed by Pentara Corporation, an independent contractor to several pharmaceutical
companies, including Forest Laboratories, Inc.
M1155. Pharmacodynamic and Pharmacokinetic
Properties of Novel gamma-Secretase Modulators in
Multiple Animal Model Systems
Brian S. Bronk, Timonthy D. McKee, Robyn M.B. Louriero,
JoAnn Dumin, Vladislav Zarayskiy, Wesley F. Austin, Nathan
O. Fuller, Jed L. Hubbs, Ruichao Shen, Paul Pearson, Jeffrey
Ives, Jeffrey Jonker and Barbara Tate; Cambridge, MA
Gamma-secretase enzyme modulation is a promising therapeutic approach for the treatment of Alzheimer’s disease.
Satori has identified a novel class of small molecule gamma
secretase modulators (GSMs). The pharmacokinetic/pharmacodynamic relationship of these novel compounds was
investigated in multiple species. Satori compounds display
low clearance and high volumes of distribution, providing
an extended half-life in all species. These compounds were
capable of crossing the blood-brain barrier and displayed
good oral bioavailability and a delayed Tmax. The PK profile
of SPI GSMs provides brain exposures over a 24 hour period sufficient to afford a statistically significant PD
response. Reductions in both Ab42 and Ab38 were robust,
while Ab40 was not lowered in vivo, replicating the pharmacology of these compounds in in vitro systems. This
effect was shown to be dose responsive and long lasting.
Based on the preclinical data, the clinical PK profile of
Satori compounds is predicted to modulate the gamma-secretase enzyme complex for 24 hours with once daily dosing.
These compounds are expected to lower brain Ab42 levels
in patients, leading to an effective treatment of Alzheimer’s
disease.
Study supported by: Satori Pharmaceuticals
All authors are employees or consultants to Satori
Pharmaceuticals
M1157. Ile143Thr Presenilin 1 Mutation in Sporadic
Atypical Early-Onset Alzheimer’s Disease
Maria Travasarou, Stella Marousi, Vasiliki Kyrimi and
Clementine E. Karageorgiou; Athens, Greece
Introduction: Early-onset Alzheimer’s Disease (EOAD)
accounts for about 5% of all AD cases, typically presents
with gradual memory impairment, followed by progressive
global cognitive decline, affecting subjects <65 years-old.
Most commonly, EOAD concerns genetically predisposed
families carrying mutations in the Amyloid-Precursor-Protein, Presenilin (PSEN) 1 and PSEN2 genes.
Methods: We present a case of sporadic EOAD with an
atypical clinical presentation, positive for the ile143thr
PSEN1 mutation.
Results: A 34 year-old previously healthy male with no
family history of dementia, presented with a 12-month history of apathy, withdrawal, concentration disturbance, and
confabulation for which he had been treated with antidepressants and antipsychotics. Ten months later, memory and
visuospatial impairment appeared. Neurological examination
revealed only generalized myoclonic jerks. Neuropsycological
assessment showed significant deficits in memory, visuospatial ability, and executive functions. Extensive laboratory and
neuroimaging investigations were normal. CSF levels of ptau and Ab42-amyloid indicated a neurodegenerative condition, later confirmed by identification of the ile143thr
PSEN1 mutation.
Conclusion: This atypical case of EOAD underlines the
importance of genetic testing even in patients with sporadic,
non-familial EOAD, and suggests that the disease may initially present with refractory neuropsychiatric symptoms and
non-amnestic cognitive decline.
Study supported by: The study has not received any
financial or other support
M1156. Effects of Extended-Release Memantine (28 mg,
Once Daily) on Language and Communication Abilities
in Patients with Moderate to Severe Alzheimer’s Disease
Michael Tocco, Suzanne Hendrix, Michael L. Miller, Vojislav
Pejovic and Stephen M. Graham; Jersey City, NJ; Salt Lake
City, UT and Chicago, IL
In this post hoc analysis, language and communication abilities were assessed in a 24-week, randomized, placebo-controlled trial of once-daily, extended-release (ER) memantine
(28 mg) in ChEI-treated patients with moderate to severe
AD. Language items from the SIB were grouped into subscales of Naming, Reading/Writing, and Comprehension/
Repetition/Discourse, and a Functional Communication
score was constructed using communication-related items
from 2 scales administered to caregivers: the 19-item
ADCS-ADL19 and the Caregiver-Perceived Burden Questionnaire. For each post hoc measure, the change from baseline at week 24 was compared between groups. At week 24,
M1158. Brain Imaging and Cognitive Predictors of
Incident Stroke, Dementia and Alzheimer’s Disease (AD)
Galit Weinstein, Alexa Beiser, Charles DeCarli, Rhoda Au,
Philip A. Wolf and Sudha Seshadri; Boston, MA and
Sacramento, CA
Objectives: To test the hypothesis that specific patterns of
brain Magnetic Resonance Imaging (MRI) and cognitive
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The LipiDiDiet study2 is a 24-month, randomized, controlled, double-blind parallel-group study designed to investigate the effects of Souvenaid in 300 prodromal AD
patients (Dubois 2007). Primary outcome is cognitive functioning (modified version of the Neuropsychological Test
Battery). Secondary outcomes include progression to AD,
cognitive performance (MMSE, ADAS-cog), functional abilities (ADCS-ADL), depression (MADRS), MRI atrophy
rate, dementia biomarkers, safety, tolerance and nutritional
parameters.
The LipiDiDiet study started in 2009. Enrolment for the
study is expected to be completed in 2012 and the first results
of the intervention are expected to be available in 2014.
Baseline data from the total group of prodromal AD
patients will be presented.
1
Souvenaid is a registered trademark of N.V. Nutricia.
Fortasyn is a trademark of N.V. Nutricia.2Funded by the
EU FP7 project LipiDiDiet, Grant Agreement N 211696.
Study supported by: - EU FP7 project LipiDiDiet, Grant
Agreement N 211696.
- Nutricia Advanced Medical Nutrition, Danone
Research, Centre for Specialised Nutrition, Wageningen,
The Netherlands.
Salary: presenting author is an employee of Nutricia
Advanced Medical Nutrition, Danone Research, Centre for
Specialised Nutrition, Wageningen, The Netherlands
measures predict incident strokes, and that these patterns
differ from those associated with AD or dementia.
Methods: A total of 3,135 Framingham participants
(1,679 Offspring, 1,456 Original cohort) underwent cognitive testing (mean ages 65.767.0 and 67.567.3 years,
respectively). About 87% of the Offspring and 15% survivors from the Original cohort (mean age 84.863.3 years)
also underwent MRI. Cox models were used to estimate the
associations of cognitive and brain MRI measures with 10year risk of incident stroke, dementia and AD.
Results: During follow-up, Offspring participants sustained 55 strokes and Original cohort participants with cognitive and MRI data sustained 95 and 29 strokes, respectively. Offspring with impairment in tests of executive
function had a higher risk of future stroke (HR ¼
2.27;95%CI:1.06-4.85), dementia and AD. A low total
brain volume (TBV) and high WMHV predicted stroke in
the Offspring (HR ¼ 1.97;95%CI:1.03-3.77 and HR ¼
2.74;95%CI:1.51-5.00,respectively) and TBV also predicted
dementia in both cohorts.
Conclusions: There is a specific pattern of cognitive and
brain structure measures observed in middle-aged persons
that can predict stroke risk.
Study supported by: National Institute of Neurological
Disorders and Stroke (NS17950), the National Heart, Lung
and Blood Association (HL93029, U01HL 096917) and
the National Institute of Aging (AG08122, AG16495,
AG033193, AG031287, P30AG013846).
M1161. Pellagra: The Forgotten American Neurological
Epidemic
Adrian C. Williams; Birmingham, United Kingdom
M1159. Beyond the Myths: Forgetting the Fictions of
Alzheimer’s and Facing the Facts
Peter J. Whitehouse; Cleveland, OH
Pellagra caused, as documented in the epidemic of the
southern states of the USA a century ago, all forms of
dementia and many neuropsychiatric diseases. Earlier epidemics in Europe described Parkinsons, Multiple sclerosis
and Motor neurone disease mimics. A festinant gait and fasciculation of the tongue was first described in pellagrins.
Curable neurological syndromes should never be forgotten
for reasons that include lessons about their mechanism and
that we should ensure that less obvious cases have been
eliminated. For instance mitochondrial/NADH aberrations
permeate most current diseases: and the neurology of HIV
bears an uncanny resemblance to pellagrins - who were also
prone to many chronic infections such as TB.
There is curent interest in nicotinamide metabolism and
the evolution and ageing of all species both as being integral
to energy paths and NAD-consumer hubs that control
many aspects of behaviour of individuals and cell fates.
Degeneration like cancerous change and chronic infections
changes these dynamics and may be homeostatic responses
to local energy/NAD circumstances. ‘‘Too much of a good
thing’’ by way of nicotinamide dosage is a possibilty in
more affluent economies and might cause a mirror image of
pellagra with an equally broad phenotype.
Study supported by: No financial support
Starting with the historical origins of dementia, this presentation will progressively expose the fundamental myths
about Alzheimers that have led to failed pharmacological
misadventures, the proliferation of limited brain fitness
products, and the spread of damaging imagery, metaphors,
and meanings about brain aging. It will then present new
ideas and stories — grounded in lived experiences — for
how we can act now to truly protect our brains and the
brains of other vulnerable members of society, and how we
might design local communities capable of supporting the
brain health and quality of life of persons of all ages. An
intergenerational health and wellness health practice based
in a school will be used to illustrate what a Healthy Brains
and Healthy Communities public health effort can achieve
at the local level. Nutrition, exercise, cognitive activity, and
social engagement are seen as key factors to maintain and
enhance cognitive function and quality of life.
Study supported by: None
M1160. Baseline Characteristics of Subjects with
Prodromal Alzheimer’s Disease: The LipiDiDiet Study
Y. Freund-Levi, P.J. Visser, M. Kivipelto, R.L. Wieggers, T.
Hartmann and H. Soininen; Huddinge, Sweden; Maastricht,
Netherlands; Amsterdam, Netherlands; Stockholm, Sweden;
Wageningen, Netherlands; Homburg, Germany and Kuopio,
Finland
M1162. Induction of Autophagy Protects Against
TDP43-Mediated Neurodegeneration
Sami Barmada, Aaron Daub, Michael Ando, Andrea Serio,
Andrey Tsvetkov, Arpana Arjun, Siddharthan Chandran and
Steve Finkbeiner; San Francisco, CA and Edinburgh, United
Kingdom
R , containing the specific nutrient combination
SouvenaidV
FortasynTM Connect1, is designed to support synapse formation and function in patients with Alzheimer’s Disease
(AD). Two earlier randomised controlled clinical trials have
shown that Souvenaid improves memory performance in
drug-naı̈ve mild AD patients (Scheltens 2010; Scheltens
2011), indicating that Souvenaid may have a promising
effect in the early phases of AD.
TDP43, a nuclear DNA- and RNA-binding protein, plays a
prominent role in the pathogenesis of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
We demonstrated previously that expression of wild-type and
mutant TDP43 in primary rodent cortical neurons
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recapitulates key features of ALS and FTD, including nuclear
mislocalization, cytoplasmic aggregation, and mutant-specific
neuronal loss. Two important predictors of cell death in this
model were TDP43 levels and cytoplasmic mislocalization.
Because stimulation of autophagy could potentially address
both factors, we investigated a family of small-molecule compounds capable of inducing autophagy for their ability to
prevent TDP43-mediated neurodegeneration. Using a novel
method of measuring protein turnover in living cells, we first
confirmed that the compounds enhance autophagy in neurons. We then demonstrated that the compounds lower
TDP43 half-life, prevent cytoplasmic mislocalization, and
decrease overall levels of TDP43. Not only did the compounds prevent TDP43-mediated cell death in primary neurons, but they were also beneficial in human stem cell-derived
neurons carrying TDP43 mutations. Our data strongly suggest that induction of autophagy through the use of small
molecules may be a promising and effective therapy for many
patients suffering from ALS and FTD.
Study supported by: NIH/NINDS (5-K08-NS072233-02)
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QD) may provide TPM exposure equivalent to immediaterelease topiramate dosed every 12 hr (TPM-IR Q12hr), but
with a lower Cmax, higher Cmin, and reduced fluctuation
index (FI). In this Phase 1, 2-way crossover, steady-state
study, healthy subjects were up-titrated to 200mg of study
drug (USL255 QD or TPM-IR Q12hr) and maintained at
200mg for 14 days. Subjects were immediately crossed over
to the alternate formulation and maintained for another 14
days, followed by down-titration off study drug. Pharmacokinetic parameters for both formulations were assessed at
steady state, and immediately following formulation switch.
At steady state, both formulations provided equivalent
TPM exposure. As compared with TPM-IR Q12hr, USL255
QD displayed a significantly lower Cmax (P<.001), higher
Cmin (P<.001), longer Tmax, and approximately 26% lower
FI. Additionally, no significant differences were observed in
trough concentrations during formulation switch.
As predicted by modeling, these results confirm that
USL255 QD provides an improved PK profile at steady
state. Further, it may be possible to switch patients from
TPM-IR Q12hr to USL255 QD while maintaining steadystate trough plasma concentrations.
Study supported by: Upsher-Smith Laboratories, Inc.
All authors are employees of Upsher-Smith Laboratories,
Inc.
Epilepsy
M1201. Extended-Release Topiramate Exhibits Linear
and Dose-Proportional Pharmacokinetics
Tricia L. Braun, Lawrence J. Lambrecht, Wesley M. Todd,
Mark B. Halvorsen and T.L. Braun; Maple Grove, MN
M1203. Magnetic Resonance Volumetry Reveals Focal
Brain Atrophy in Transient Epileptic Amnesia
Christopher R. Butler, Willemijn van Erp, Amit Bhaduri,
Alexander Hammers, Rolf Heckemann and Adam Z. Zeman;
Oxford, United Kingdom; Nijmegen, Netherlands; London,
United Kingdom; Lyon, France and Exeter, United Kingdom
Once-daily administration of USL255, an extended-release
topiramate (TPM) formulation, provides TPM exposure
equivalent to immediate-release TPM (TMP-IR) dosed
twice daily, but demonstrates an improved PK profile (eg,
lower Cmax, higher Cmin, decreased fluctuation index [FI]).
This randomized, 5-way crossover, single-dose study in
healthy subjects evaluated tolerability and the pharmacokinetics of five USL255 doses (25, 50, 100, 200, 400mg).
Maximum plasma concentration (Cmax) and area under the
plasma concentration-time curve (AUC) were determined
for each dose and assessed for dose proportionality and linearity. Tolerability was assessed by monitoring treatmentemergent adverse events (TEAE).
Total TPM exposure (AUC) was linear and dose proportional from 25mg – 400mg. Maximum TPM concentration
(Cmax) neared dose-proportionality for the 100mg – 400mg
doses. Subsequent analyses of dose-normalized TPM Cmax
values, comparing 400mg to 200mg, and 200mg to 100mg,
demonstrated that Cmax changed proportionally with dose.
All doses of USL255 were generally well tolerated.
USL255 exhibited a linear and dose-proportional TPM
exposure profile from 25mg – 400mg, and maximum
plasma concentration appeared dose proportional over
higher doses. Together these data suggest that USL255, a
once-daily alternative to TPM-IR, provides flexible dosing
options and dose adjustments should result in predictable
TPM plasma concentrations.
Study supported by: Upsher-Smith Laboratories, Inc
All authors are employees of Upsher-Smith Laboratories,
Inc.
Introduction: Transient epileptic amnesia (TEA) is a syndrome of epilepsy in which the principal manifestation of
seizures is recurrent episodes of isolated memory loss. Many
patients with TEA also demonstrate unusual forms of persistent memory impairment including accelerated long-term
forgetting (ALF) and autobiographical amnesia.
Methods: 40 patients with TEA and 20 healthy controls
underwent neuropsychological testing and brain MRI. Two
volumetric methods were used: i) manual segmentation of
the medial temporal lobe and ii) automated, multi-atlasbased segmentation of the whole brain.
Results: ALF and autobiographical amnesia were detected
in the patient group. Both volumetric methods confirmed
the presence of subtle, bilateral hippocampal atrophy in the
patient group. Additional volume loss was revealed in perirhinal and orbitofrontal cortices. The volumes of these
regions correlated with performance on standard memory
tests. No structural correlates were found for ALF or remote
autobiographical amnesia.
Conclusions: The results are consistent with the hypothesis that TEA is a focal medial temporal lobe epilepsy syndrome, but reveal additional pathology in connected brain
regions. The interictal memory deficits of TEA remain
unexplained by structural pathology and may reflect physiological disruption of memory networks by subclinical epileptiform activity.
Study supported by: National Institute for Health
Research
M1202. Pharmacokinetics of Extended- and
Immediate-Release Topiramate at Steady State and
after Formulation Switch
Tricia L. Braun, Lawrence J. Lambrecht, Wesley M. Todd and
Mark B. Halvorsen; Maple Grove, MN
M1204. SOS for Seizures in SESA
Mirret M. El-Hagrassy and Robert Beach; Syracuse, NY
A 49 year old male alcoholic had body stiffening, fall and
head trauma after 2 days’ drinking. Neurology exam, MRI,
urine toxicology and serum alcohol were unremarkable. He
Modeled steady-state PK data suggests a once-daily,
extended-release topiramate (TPM) formulation (USL255
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developed variable episodes of blank staring, facial twitching, head and gaze to the right, with aphasia, paraphasias
and bizarre behavior. Initial EEG showed slowing, but follow-up showed left frontal non-convulsive status epilepticus.
Subsequent EEGs showed PLEDs during treatment with
lorazepam, levetiracetam, and lacosamide; then gradual
improvement. He returned almost to his clinical baseline.
Discussion: Subacute encephalopathy with seizures in
chronic alcoholism (SESA) is rare, distinct from alcohol
withdrawal. It is characterized by transient neurological deficits, seizures, EEG abnormalities such as focal slowing,
spikes, PLEDs. Seizures were originally described as motor,
but complex partial status epilepticus (CPSE) has been
recently reported. Pathophysiology is unclear; a vascular
cause was proposed. One case reported MRI with left frontal, insular cortical hyperintensity, and SPECT showing left
frontal/temporal hyperperfusion with crossed cerebellar
hyperperfusion. Another reported reversible MRI findings.
Conclusions: Confused alcoholics may be thought to be
delirious, but SESA with CPSE should be considered and
treated if identified.
Study supported by: N/A
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decreases synaptic glutamate concentration. It is unknown
whether leucine has anticonvulsant mechanisms similar to
treatments that affect metabolism, including the ketogenic
diet or rapamycin. We investigated the effects of leucine
using acute seizure tests in normal mice.
Methods: Male NIH Swiss mice aged 3 weeks received
leucine in drinking water (1.5% w/v) for 12 days (controls
received water without leucine). Seizures were induced using
6 Hz, pentylenetretrazol, and kainate tests. Blood ketones
were measured prior to seizure testing.
Results: Leucine-treated mice were protected against 6
Hz-induced seizures (P ¼ 0.02). In the pentylenetetrazol
test, mice treated with leucine had a prolonged latency to
first tail twitch (P ¼ 0.04) but did not differ in other parameters. In contrast, leucine had no effect on kainateinduced seizures. Leucine had no effect on blood ketone
levels.
Interpretation: Leucine has an acute seizure test profile
similar to the ketogenic diet. Anticonvulsant effects could
not be attributed to differences in blood ketone levels.
Study supported by: NINDS/NIH
Johns Hopkins University School of Medicine Clinician
Scientist Award
Salary
M1205. Reduced GABAA Receptor Endocytosis in a
Mouse Model of Absence Epilepsy
Chengwen Zhou, Li Ding and Martin J. Gallagher;
Nashville, TN
M1207. Withdrawn.
M1208. Antiphospholipid Syndrome Presenting as
Epilepsia Partialis Continua
Fenella F. Johnstone and Odai Jumma; Birmingham,
United Kingdom
Recently, we reported that heterozygous deletion (Heta1KO)
of the GABAA receptor (GABAAR) a1 subunit, a protein
associated with human generalized epilepsy, causes electrographic and behavioral absence seizures in mice. We showed
that Heta1KO increases a3 subunit expression and shifts intracellular a1 subunit-containing receptors to the cell surface, effects which alter inhibitory postsynaptic currents
(IPSCs). Here, we determined whether these changes in
GABAAR trafficking resulted from GABAAR recruitment
from the endoplasmic reticulum (ER) or from reduced
endocytosis.
We measured the fraction of ER-resident a1 subunits in
wild type (wt) and Heta1KO cortices using an endoglycosidase-H sensitivity assay. Surprisingly, in contrast to recombinant GABAAR expression systems, neither wt nor Heta1KO
cortices possessed any ER-resident a1 subunit. Therefore,
Heta1KO does not recruit ER receptors.
Next, we determined the effects of Heta1KO on endocytosis. The endocytosis inhibitor, dynasore, increased mIPSC
amplitudes in wt neurons by 28%, but had no effect on
Heta1KO neurons, results consistent with Heta1KO reducing GABAAR endocytosis.
Although reducing baseline GABAAR endocytosis partially compensates for Heta1KO, it also removes a major
mechanism by which neurons dynamically increase synaptic
inhibition. This latter effect may contribute to the development of paroxysmal hyperexcitability and seizures.
Study supported by: National Institute of Neurological
Disorders and Stroke
Case presentation: A 64-year-old woman, with a past medical history of hypertension and cerebrovascular disease, presented with twitching attacks involving her face and left
arm. Each attack lasted 3-5 minutes with ten each hour. On
close examination, these were clearly focal motor seizures
presenting as epilepsia partialis continua. Further examination revealed residual left sided weakness and normal cranial
and systemic examinations. Her blood tests showed a persistently raised anticardiolipin antibody. Her CT head showed
an old right parietal lobe infarct with MRI revealing re-infarction. Her electroencephalogram (EEG) revealed focal
motor seizures. Further history confirmed previous miscarriage and deep vein thrombosis (DVT). She has subsequently started antiepileptic treatment and clopidogrel
added to her aspirin therapy with remarkable improvement
of her seizure control. She was eventually diagnosed with
antiphospholipid syndrome (APS) based on the clinical
manifestations of recurrent stroke, epilepsy, DVT, miscarriage and the presence of persistently positive anticardiolipin
antibody.
Conclusion: Although there are published cases describing APS presenting as status epilepticus, there are no documented case reports of APS presenting as epilepsia partialis
continua. This case highlights the importance of recognising
the neurological sequelae of APS and demonstrates a new
presentation of APS.
Study supported by: Nil
M1206. Leucine Has Anticonvulsant Effects in Acute
Seizure Tests
Adam L. Hartman, Polan Santos and J. Marie Hardwick;
Baltimore, MD
M1209. Race and Sex Differences in Characteristics of
Temporal Lobe Epilepsy
Robert Knowlton, Suzanne Miller, Maria Pisu, Lawrence Ver
Hoef, Kristen Riley and Nita Limdi; Houston, TX and
Birmingham, AL
Objective: Leucine is a ketogenic amino acid that protects
against picrotoxin- and pentylenetetrazol-induced seizures,
but not hexafluorodiethyl ether seizures, in rats. Similar to
rapamycin (which suppresses seizures), leucine depletion
suppresses mTOR activity in cell culture. Leucine also
Objective: To determine differences in characteristics of
temporal lobe epilepsy (TLE) with respect to race and sex
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in a large population of patients from Alabama and surrounding states.
Methods: The UAB seizure monitoring unit database was
queried for discharge diagnoses between 2000 and 2010. A
prior study of the entire population (n ¼ 4188) revealed a
significantly greater proportion of blacks compared to
whites (especially females) diagnosed with TLE, while rates
of other epilepsy types and psychogenic seizure diagnoses
were not significantly different between groups. Differences
were analyzed between the four race-sex groups for the cardinal features of TLE--age of onset, duration, and whether
an epileptogenic lesion was identified on MRI.
Results: Black females versus the other groups had significantly greater mean age of onset (31.0 vs 22.8 yrs,
P<0.0001), shorter epilepsy duration (10.8 vs 18.8 yrs,
P<0.0001), and greater proportion with negative MRI
(58.4 vs 38.7%, a ¼ 0.002).
Interpretation: As part of a greater rate specific for TLE,
African American women develop more adult onset, idiopathic TLE than whites or black males. Race and sex differences, amongst other genetic factors, may be critical to
explaining the enigma of late onset idiopathic localizationrelated epilepsy.
Study supported by: The UAB Epilepsy Center
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Yang, J Zhu and A Laurenza are salaried employees of
Eisai Inc.
M1211. Optogenetic Treatment Approaches for Focal
Neocortical Epilepsy
Laura Mantoan, Rob Wykes, Stephanie Schorge, Matthew C.
Walker and Dimitri M. Kullmann; London, United Kingdom
A new generation of optical probes, the light-sensitive ionchannels, channel rhodopsin-2 and halorhodopsin, allow
modulation of electrical signals with high temporal resolution. These characteristics make optical inhibition a potentially advantageous new anti-epileptic treatment strategy that
relies on optical activation of neurons to interrupt seizures.
This approach is especially promising in focal epilepsy,
which is often drug-resistant and characterized by a defined
ictogenic zone.
We show that optical stimulation of halorhodopsin in
excitatory neurons successfully reduced high frequency epileptic activity in the tetanus toxin (TeNT) rat model of
focal epilepsy in animals co-injected with TeNT and lentivirus carrying halorhodopsin. Control animals injected with
halorhodopsin virus alone or TeNT/GFP virus showed no
significant changes in EEG upon laser illumination. Halorhodopsin was reliably expressed and can be stimulated in
vivo in rat motor cortex, without clinical signs of dysfunction in the live animal, nor histological features of
cytotoxicity.
Our results indicate that optical inhibition of epileptic
discharges represents an exciting new strategy to be pursued
in models of epilepsy: optogenetic techniques will not only
help to dissect the neural networks underlying epileptic circuits but may one day translate into a radically new treatment alternative for human disease.
Study supported by: PhD studentship from the Brain
Research Trust and the Guarantors of Brain
M1210. A Higher Hurdle? Baseline Frequency and
Severity of Seizures in Trials of Perampanel, a New AED,
Compared with Previously Approved AEDs
Gregory L. Krauss, Frank Kerling, Vicente Villanueva, David
Squillacote, Haichen Yang, Jin Zhu and Antonio Laurenza;
Baltimore, MD; Ulm, Germany; Valencia, Spain and
Woodcliff Lake, NJ
Background: Successive studies of new adjunctive AEDs
recruit many patients resistant to current therapies. We
describe baseline seizure frequency and severity in registration trials for the new AED perampanel, compared with
five approved newer-generation AEDs and three older
AEDs.
Methods: We evaluated baseline seizures and AED use
in registration trials for perampanel, levetiracetam, zonisamide, lacosamide, eslicarbazepine, and retigabine. We also
evaluated these parameters for lamotrigine, valproate, and
carbamazepine - these will be included in the full
presentation.
Results: Median number of seizures/28 days at baseline
was generally higher for perampanel (9.3-14.3) versus other
AEDs: levetiracetam (6.7-10.5); lacosamide (5.5-15.0); eslicarbazepine (6.7-9.0); retigabine (7.9-12.1) (zonisamide data
not available). More patients had a history of secondary
generalized seizures in perampanel studies (67.9-71.9%) versus levetiracetam (26.0-27.0%); zonisamide (21.0-24.0%);
lacosamide (43.8-78.8%); eslicarbazepine (28.2-47.1%);
retigabine (23.2-33.7%).
A high proportion of patients required three concomitant
AEDs at baseline in perampanel trials (28.9-38.6%) compared with most AEDs: levetiracetam 5.0-5.1%; zonisamide
21.7-28.8%; lacosamide 0.0-36.9%; eslicarbazepine 0.09.9%; retigabine 0.0-33.8%.
Conclusions: Patients entering perampanel registration
trials generally experienced more frequent and severe seizures at baseline compared with other AED trials.
Study supported by: Eisai Inc.
G Krauss is an investigator and consultant for Eisai Inc.
F Kerling has no disclosures to report. V Villanueva has
participated in advisory boards and pharmaceutical industry sponsored symposia for Eisai Inc. D Squillacote, H
M1212. Effect of Ocimum basilicum Extract Against
Pentylenetetrazole-Induced Seizure in Mice
Mehrdad Modaresi and Arezoo Pouriyanzadeh; Isfahan,
Islamic Republic of Iran
Epilepsy always noticed as a most important nerves disease.
In traditional medicine, Ocimum basilicum used to treatment seizure and effects of anticonvulsant of this drug is
reported. To access this anti-seizures drug with low imposition we survey effect of anticonvulsant drug of extract of
Ocimum basilicum in seizure induced with pentylenetetrazole. Hydro-alcohol extract of Ocimum basilicum with physiologic serum and various dozes (50-100–250–300–350 mg/
kg) of extract inject to mices via interperitoneal 65 minutes
before injection of pentylenetetrazole. And survey factors
onset time of showing seizure effects, number of showing
seizure effects The percentage of dead. We select the slot
time (15-30-50-60-65-80-120 minutes) To survey the relevant slot time between relevant injection doze and pentylenetetrazole. Results of using various dozes (50- 100–250–
300–350 mg/kg) shows that onset time of showing seizure
effects, number of showing seizure effects and The percentage of dead at 250 mg/kg doze, 65 minutes before injection
of pentylenetetrazole dependently (P < 0.05) sequencely
increased, decreased and decreased. The results can be
obtained at a dose of hydroalcoholic mg/kg250 effective as
medication in preventing seizures in animal models
introduced.
Study supported by: Department of Physiology, Khorasgan Branch, Islamic Azad University, Isfahan, IRAN
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M1213. MRI Volumetry of the Temporal Lobe in Sudan;
Comparative Study between Epileptics and Matching
Control
Mohamed A. Nurein, Mohamedsalah M. Magzoub,
Tahir O. Ali, Abdullah M. Jabir and Abdulrahman M.
Fadlalmola; Umdurman, Khartoum, Sudan and Khartoum,
Sudan
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M1215. Synaptic Reporter Labeling of Adult-Born
Hippocampal Neurons in Experimental Epilepsy
Alison L. Althaus, Helen Zhang, Hisashi Umemori and Jack
M. Parent; Ann Arbor, MI
Altered hippocampal neurogenesis may play a role in
mesial temporal lobe epilepsy (mTLE) pathogenesis. Dentate granule cells (DGCs) generated after epileptogenic
insults in rodents are especially vulnerable to abnormal
plasticity, including ectopic migration, axonal sprouting,
and persistent basal dendrites. These features promote
potentially epileptogenic recurrent excitation. To investigate aberrant axonal plasticity in birthdated DGCs, we
generated retrovirus (RV) carrying a synaptophysin-yellow
fluorescent protein (YFP) fusion construct that labels presynaptic terminals. RV only integrates into dividing cells,
enabling axon terminal labeling of age-defined DGC
cohorts based on timing of dentate gyrus RV injections.
We modeled mTLE in male Sprague Dawley rats using
pilocarpine-induced status epilepticus (SE) at P56. RV
was injected at P7 (labeling cells mature at onset of SE)
or P60 (labeling cells born after SE). Animals survived
10 weeks after SE and hippocampi were immunostained
for YFP and bassoon (pre-synaptic marker). Confocal
analysis revealed changes in CA3 mossy fiber bouton size
and structure, and increased hilar bouton density in
post-SE generated DGC axons vs. controls. These findings indicate abnormal axonal development of DGCs
generated after an epileptogenic insult. Ongoing work
aims to determine whether these changes are proepileptogenic.
Study supported by: NIH NS058585
Introduction: Hippocampal MRI volumetric changes in
temporal lobe epilepsy are documented. Controversy is displayed in other regions. This study provided preliminary
database in Sudan.
Methodology: This cross sectional analytic study, in
National Ribat University hospital. Epileptics compared to
healthy matching group. 3D structural MRI for temporal
lobe, superior temporal gyrus, entorhinal cortex and hippocampus in 1.5 Siemens scanner. Volume computed in 3D
slicer 2.6. Each region is compared across genders and
between hemispheres.
Results: 69 control (34 males and 35 female) and 63
patients (32 males and 31 females). Controls displayed
larger volumes in males than in females in all ROIs, left lateralization of temporal lobe, superior temporal gyrus and
hippocampal right lateralization in males. No lateralization
in entorhinal cortex. Epileptics displayed loss of lateralization in temporal lobe of males and left lateralization in
superior temporal gyrus of females. Bilateral volume reduction in the hippocampus of both genders, and in males
entorhinal cortices.
Conclusions: Morbid anatomy in temporal lobe epilepsy
differs between genders. Temporal lobe volumetry is altered
in temporal lobe epilepsy.
Study supported by: minstry of higher education sudan
M1214. Epileptic Aphasia as an Initial Manifestation of
Lyme Meningoencephalitis
Dipakkumar P. Pandya, Anery Patel, Jennie Luna, Megan
McGarry and Sourav Sen; Paterson, NJ
M1216. Dravet Syndrome Patient-Derived Cells and
Mouse Model Suggest SUDEP Mechanisms
David Auerbach, Huilin Shi, Yu Liu, Julie M. Jones,
Miriam H. Meisler, Lori L. Isom and Jack M. Parent; Ann
Arbor, MI
Ictal aphasia is a very rare manifestation of status epilepticus
in adults. It is well known as an acquired aphasia with epileptic encephalopathy in children. The sustained reversible
aphasia may be ictal and it is extremely rare. We report a
case of epileptic aphasia as an initial manifestation of lyme
meningo encephalitis. Based on our literature search this is
first case report.
48-year-old woman came to emergency room because
of global aphasia. She had spontaneous repetitions of
words without sense. Her initial chemistry, blood counts,
toxicology, and MRI brain were within normal limit.
Her EEG monitoring showed left hemisphere periodic
lateralizing electrographic discharges. She was started on
antiepileptic medications with significant improvement.
Her CSF serology was consistent with Lyme meningoencephalitis. She had near complete resolution of symptoms and EEG changes after intravenous ceftriaxone
treatment. After 4 weeks of intravenous ceftriaxone in
conjunction with antiepileptic medications, she had
complete recovery that was correlated with neuropsychological evaluations.
Lyme disease is a tick borne illness caused by Borrelia
Burgdorferri. Our patient has complete recovery from
symptoms. Any adult patient with aphasia should
have comprehensive evaluations including electroencephalogram and CSF evaluations when imaging studies are
normal.
Study supported by: None
Dravet Syndrome (DS) is a catastrophic childhood epilepsy largely caused by dominant mutations in the
SCN1A gene encoding the NaV1.1 sodium channel. Sudden unexplained death in epilepsy (SUDEP) is a major
concern in DS. Because NaV1.1 is also expressed in heart,
we hypothesize that altered Na currents in DS cardiac
myocytes (CMs) lead to arrhythmias and SUDEP. To test
this, we generated induced pluripotent stem cells (iPSCs)
and CMs from DS subjects and controls. We examined
CM markers, beating rate and sodium currents in iPSCderived CMs. We also examined sodium currents in CMs
from DS knock-in mice that express a human SCN1A
mutation causing seizures and premature death. CM differentiation of DS and control iPSCs led to beating cells
that expressed CM markers a-actinin and cardiac troponin-T. Preliminary results indicate higher beating rate and
sodium current density in DS CMs vs. controls. Similarly,
ventricular CMs from P17-19 DS mice show increased
sodium current density vs. wild-type. Characteristics of
the current suggests that it results from enhanced NaV1.5
(SCN5A gene) current that overcompensates for 50%
NaV1.1 loss. These findings suggest a potential cardiac
arrhythmogenic SUDEP mechanism in murine and
human DS.
Study supported by: Citizens United for Research in Epilepsy, University of Michigan Center for Organogenesis,
NIH P20NS076916
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M1217. Hypothermia Attenuates Glial Injury and
Prevents EEG Progression during Status
Epilepticus
Sandipan Pati, J.X. Yin, Y. Gan, J. Georges, F.D. Shi, M.
Maalouf and D.M. Treiman; Phoenix, AZ
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M1219. Mutations in the Novel Protein PRRT2 Cause
Infantile Convulsions with Paroxysmal Kinesigenic
Dyskinesia
Hsien-Yang Lee, Yong Huang, Nadine Bruneau, Patrice Roll,
Elisha D.O. Roberson, Mark Hermann, Emily Quinn, James
Maas, Robert Edwards, Tetsuo Ashizawa, Betul Baykan,
Kailash Bhatia, Susan Bressman, Michiko K. Bruno, Ewout R.
Brunt, Roberto Caraballo, Bernard Echenne, Natalio
Fejerman, Steve Fruct, Christina A. Gurnett, Edouard Hirsch,
Henry Houlden, Joseph Jankovic, Wei-Ling Lee, David R.
Lynch, Shehla Mohammed, Ulrich Mu¨ller, Mark P. Nespeca,
David Renner, Jacques Rochette, Gabrielle Rudolf, Shinji
Saiki, Bing-Wen Soong, Kathryn J. Swoboda, Sam Tucker,
Nicholas Wood, Michael Hanna, Anne M. Bowcock, Pierre
Szepetowski, Ying-Hui Fu and Louis J. Ptacek; San Francisco,
CA; Marseille, France; Saint Louis, MO; Gainesville, FL;
Istanbul, Turkey; London, United Kingdom; New York, NY;
Honolulu, HI; Groningen, Netherlands; Buenos Aires,
Argentina; Montpellier, France; Strasbourg, France; Houston,
TX; Novena, Singapore; Philadelphia, PA; Giessen, Germany;
San Diego, CA; Salt Lake City, UT; Amiens, France;
Ishikawa, Japan and Taipei, Taiwan
The aim of this study is to assess the neuroprotective effects
of hypothermia therapy in a validated rodent model of limbic SE. Adult male Sprague-Dawley rats (n ¼ 38) were
induced SE for 4.5 hours using lithium-pilocarpine and
monitored by continuous EEG. Half of the rats were subjected to hypothermia (rectal temperature 31-33C) beginning at the time of SE induction. The outcome was assessed
at 24 hours. 13 out of 16 rats treated with hypothermia
during SE survived in comparison to 5 out of 16 in the
non treatment SE arm (p < 0.05; odds ratio of surviving
9.53 (p <0.05). Quantitative analysis of neuronal damage
(by H & E; cresyl violet) revealed less neuronal damage in
CA1,CA 3 following SE treated with hypothermia (p
<0.05). This neuroprotective effect by hypothermia was
confirmed by western blotting and by immunofluorescent
imaging using markers: NeuN, activated caspase-3 and IbA1
(for microglial), oxidized protein and IL-1B (p<0.05).
Hypothermia prevented EEG progression of SE from Treiman Stage 3 to Stage 5. Hypothermia attenuates neuro-glial
injury and progression of EEG during prolonged status
epilepticus.
Study supported by: None
Paroxysmal kinesigenic dyskinesia with infantile convulsions
(PKD/IC) is an infantile convulsion/episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We
have now identified four truncating mutations involving the
gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations
were also detected in 28 of 78 additional families. PRRT2
encodes a proline-rich transmembrane protein of unknown
function that has been reported to interact with the
t-SNARE, SNAP25. PRRT2 localizes to axons but not to
dendritic processes in primary neuronal culture, and
mutants associated with PKD/IC lead to dramatically
reduced PRRT2 levels, leading ultimately to neuronal
hyperexcitability that manifests in vivo as PKD/IC.
Study supported by: HHMI, DMRF
M1218. Weight Change Associated with Anti-Epileptic
Drugs
W.O. Pickrell, A.S. Lacey, R.H. Thomas, M.I. Rees and
P.E.M. Smith; Swansea, United Kingdom and Cardiff, United
Kingdom
Introduction: Prediction and quantification of potential
side effects from anti-epileptic drugs (AEDs) are important to both patients and clinicians. Weight change is an
important side effect and is known to occur with several
AEDs. However, population and objective data are
lacking.
Aim: To determine weight change after starting AEDs.
Method: We analysed retrospectively anonymised electronic primary care records of approximately 1.3 million
adult patients in Wales. 19 622 (1.5%) patients had a
diagnosis of epilepsy and of these, 1499 (7.6%) had their
body weight measured within 12 months before starting
and between 3 and 12 months after starting one of five
AEDs.
Results: The mean difference between body weight, after
and before starting each AED (together with 95% confidence intervals and p-values for no difference) were:- topiramate -2.1kg (-3.6,-0.6) p ¼ 0.008; carbamazepine 0.5kg
(-0.2,1.2) p ¼ 0.13; lamotrigine -0.02kg (-0.5,0.5) p ¼
0.94; levetiracetam 1.2kg (0.6,1.7) p<0.005 and sodium
valproate 1.1kg (0.3,1.9) p ¼ 0.007.
Conclusions: Lamotrigine and carbamazepine were not
associated with significant weight change, topiramate was
associated with significant weight loss and levetiracetam and
sodium valproate were associated with significant weight
gain. The study does not account for other factors, such as
polytherapy or genetic backgrounds, which may influence
weight change.
Study supported by: National Institute for Social Care
and Health Research
The author receives an unrestricted clinical fellow training
grant from UCB Pharma
M1220. Appropriate Drug Treatment for Status
Epilepticus Does Not Influence Its Prognosis
Andrea O. Rossetti, Vicent Alvarez, Jean-Marie Januel and
Bernard Burnand; Lausanne, Switzerland
Objective: Status epilepticus (SE) prognosis, is mostly
related to non-modifiable factors (especially age, etiology),
but the specific role of treatment appropriateness (TA) has
not been investigated.
Methods: In a prospective cohort with incident SE
(excluding postanoxic), TA was defined, after recent European recommendations, in terms of drug dosage (630%
deviation) and sequence. Outcome at hospital discharge was
categorized into mortality, new handicap, or return to
baseline.
Results: Among 225 adults, treatment was inappropriate
in 37%. In univariate analyses, age, etiology, SE severity and
comorbidity, but not TA, were significantly related to outcome. Etiology (95% CI 4.3-82.8) and SE severity (95%
CI 1.2–2.4) were independent predictors of mortality, and
of lack of return to baseline conditions (etiology: 95% CI
3.9–14.0; SE severity: 95% CI 1.4–2.2). Moreover, TA did
not improve outcome prediction in the corresponding ROC
curves.
Conclusions: This large analysis suggests that TA plays a
negligible prognostic role in SE, probably reflecting the outstanding importance of the biological background. Awaiting
treatment trials in SE, it appears questionable to apply
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further resources in refining treatment protocols involving
existing compounds; rather, new therapeutic approaches
should be identified and tested.
Study supported by: None
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ECT treatment and urgent evaluation and treatment is warranted as it can increase morbidity and mortality.
Study supported by: None
M1223. The Role of RhoA, Filamin and Formin in
Cortical Development
Gewei Lian, Markus Dettenhofer, Russell Ferland and Volney
Sheen; Boston, MA and Albany, NY
M1221. Planes Trains and Automobiles: Neurologic
Disorders and the Workforce. A Systematic Review
Eva Pilcher, Maria Baldwin and Michael J. Schneck;
Maywood, IL and Pittsburgh, PA
Periventricular heterotopia (PH) is a malformation of cortical development characterized by nodules of neurons along
the lateral ventricles of the brain and microcephaly. Human
mutations in the actin-binding protein filamin A (FLNA)
cause PH. Although FLNA interacts with a variety of transmembrane receptors (including integrins) and transmits
extracellular signals to cytoskeleton, the mechanism by
which FLNA gives rise to PH is unclear. Here, we report
that FLNA specifically interacts and binds to RhoA. RhoAdependent activation of integrin receptors is dependent on
FLNA in neural progenitor cells and regulates progenitor
proliferation. Moreover, endogenous levels of activated
RhoA are diminished in the null FlnA mouse. We also find
that both activated RhoA and FLNA bind to formin 2
(FMN2), a protein involved in actin polymerization. Activated RhoA competes with the binding of FMN2 C-terminus to the FMN2 N-terminus thereby activating FMN2 dependent actin nucleation. RhoA activation leads to
internalization of both FlnA, FMN2, and integrin to the
Golgi through a cholera toxin/ caveolin mediated mechanism. Overall, actin dependent mechanisms through RhoA,
FLNA and FMN2 regulate integrin activation and internalization at the cell surfuce and thereby determine brain size.
Study supported by: NYSTEM, State of New York
NIH
Objective: To investigate how neurological disorders impact
upon employment in regulated occupations related to public
safety and welfare.
Methods: A systematic search was conducted of MEDLINE databases from 1995 to May 2011 using terms for
employment, occupation or occupation injury and a broad
range of neurological diseases and impairments with particular emphasis on epilepsy, sleep disorders, cerebrovascular disorders, headache, and dementia or other neurodegenerative
disorders.
Results: We found 36 relevant papers for a literature
review. We reviewed work limiatiosn relevant to firefighters,
police officers, military personnel, commercial drivers, airplane pilots, train conductors, ship operators, and health
care providers. We found that the regulations applying to
different occupations are variable and inconsistent both
within occupations as related to different disorders (ie stroke
versus epilepsy versus sleep disorders) and between occupations (ie firefighters versus police) including highly variable
requirements for length of disease-free interval.
Conclusion: Uniform guidelines should be established
for the determination of work-place restrictions on workers
with neurological disorders employed in occupations that
affect public safety or public welfare as current regulations
are not evidence-based or supported logically by clinical
data.
Study supported by: no support
M1224. Seizure Etiology & Outcome in HIVþ Zambian
Adults
Omar K. Siddiqi, Melissa Elafros, Izukanji Sikazwe, Chris
Bositis, Michael J. Potchen, Igor J. Koralnik, William
Theodore and Gretchen L. Birbeck; Boston, MA; Lusaka,
Zambia; East Lansing, MI; Baltimore, MD; Lawrence, MA
and Bethesda, MD
M1222. Electroconvulsive Therapy Induced Absence
Status Epilepticus
Umang Shah, Evren Burakgazi and Usman Mogul; Camden,
NJ
Objective: Recognize finding of absence status epilepticus
(SE) after electroconvulsive therapy (ECT).
Background: ECT uses an electric current to produce a
seizure as a treatment for refractory depression. Most therapeutic ECT seizures last from 15 to 70 seconds. Prolonged
seizures or SE can be seen as rare complication after ECT
treatment.
Design/Method: Case of absence SE after ECT
treatment.
Result/Case: Forty-four year old female with history of
major depression is brought to the hospital for change in
mental status. She has undergone fourteen ECT treatments
and last was week before her presentation. Her initial electroencephalogram (EEG) was markedly abnormal with frequent generalized ten to thirty seconds of high-voltage
rhythmic two to three Hz spike and wave discharges during
which she was having staring spell with lapses of memory.
She was treated with valproic acid and zonegran with good
response.
Discussion: Absence seizures are non-convulsive seizures.
Increased oscillation between thalamus and cortex is considered as underlying cause in addition to decreased cortical inhibition on thalamic oscillations. Seizure and SE should be
considered in patients with change in mental status after
Background: Epilepsy risk factors in people with HIV/
AIDS in sub-Saharan Africa with new onset seizures are
unknown.
Objective: To characterize seizure etiology and recurrence
risk in HIVþ Zambian adults.
Methods: We enrolled HIVþ adults presenting with new
onset seizure who recovered to a Karnofsky of >50. CD4,
Na, glucose, malaria RDT, RPR, and extensive CSF analyses
were performed. Patients were followed for recurrent
seizures.
Results: Of 89 HIVþ adults with seizure, 21(24%) met
inclusion criteria. Karnofsky < 50 was the commonest reason for exclusion. Patient characteristics were mean age 35.4
years, 11 males (52.4%), mean CD4 167cells/ll, with
7(33.3%) on ARVs. Ten (47.6%) had some focal aspects to
their seizures and/or examination.
Two patients with serum RPRþ had CSF VDRL-. CSF
PCR revealed 5/21(23.8%) EBV DNA and 1/21(4.8%)
each for MTB and JCV DNA. One sample was both EBV
and TBþ and one sample was both EBV and serum RPRþ.
India ink identified one cryptococcal infection. Within 2
months, 4(19.0%) patients suffered recurrent seizures and
another 4(19.0%) died.
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Conclusions: Seizures in HIVþ adults in Zambia are
associated with significant morbidity and mortality. An
infectious etiology can often be identified.
Study supported by: NIH grant R21NS073509
American Academy of Neurology Clinical Research Training Fellowship
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M1227. Intravenous Sodium Valproate for Status
Epilepticus
Yuan Wu, Xiaofei Liu, ZiBin Chen, MeiGang Ma and Li Su;
Nanning, Guangxi, China
To determine whether intravenous sodium valproate was
more effective or safer than other drugs in patients with status epilepticus, we performed a meta-analysis.
A literature search was performed using Medline, Embase,
and the Cochrane Central Register of Controlled Trials
CENTRAL. From 544 articles screened. Main outcomes
were SE controlled, risk of seizure continuation. The metaanalysis was performed with the Random-effect model. The
quality of the included studies was evaluated by Grade
software.
There was no statistically significance in SE controlled
between Intravenous sodium valproate and Phenytoin.
Compared with diazepam, sodium valproate had a statistically significant lower risk of time interval for control of
RSE after giving drugs, however, there was no statistically
significant difference in SE controlled within30 minutes
between the two groups. There was no statistically significant difference in cessation from status between Intravenous
sodium valproate and Levetiracetam.
Intravenous sodium valprate was as effective as intravenous phenytoin for SE controlled and risk of seizure
continuation.
Study supported by: the First Affiliated Hospital,
Guangxi Medical University
M1225. Ketamine in the Treatment of Refractory Status
Epilepticus
Andrea S. Synowiec, Deepinder S. Singh, Vamsi Yenugadhati,
James P. Valeriano, Carol J. Schramke and Kelly M. Kevin;
Pittsburgh, PA and Philadelphia, PA
Refractory status epilepticus (RSE) is a neurological emergency with high morbidity and mortality. Limited data
exist regarding ketamine use in this population. We
describe our experience with ketamine in RSE between
2003 and 2011. Eleven adults who had previously failed
standard treatment protocols were treated with ketamine
via continuous intravenous infusion. Data were collected
on age, gender, history of epilepsy, etiology of RSE, daily
total dosing of ketamine, co-therapeutic agents, treatment
response, and disposition. RSE was successfully terminated
in all 11 patients. Co-infused continuous anesthetic agents
were able to be discontinued in 8/11 (73%) of patients
within 72 hours. Ketamine was the last AED used prior to
resolution of RSE in 7/11 (64%) cases. Administration of
ketamine was uniformly associated with decreased pharmacological vasopressor support, and during ketamine infusion, pressors were discontinued in 6/7 (85%) patients
who required them previously. Favorable outcome as
defined by discharge to home or inpatient rehabilitation
facility was attained in 5/11 (45%) patients. No acute
adverse effects were noted. These findings suggest that ketamine may be a useful adjunctive agent in the treatment
of RSE, especially in patients whose treatment options for
RSE are limited by hypotension.
Study supported by: None
M1228. Protective Effect of Alpha -Asarone in Sombati’s
Cell-Based Model of Epilepsy
Yuan Wu, Xiao-Fei Liu, Yue-Juan Wu, Jie Su and Mei-Gang
Ma; Nanning, Guangxi, China
To explore the effect of alpha-asarone on neuronal apoptosis with mitochondrial damage, and changes in neuron cellular ultrastructure in Sombati’s cell-based model of
epilepsy.
Dissociated hippocampal neurons from rats were cultured
in vitro to induce Sombati’s cell-based model. The apoptotic
ratio of neurons was measured after treatment with alphaasarone. JC-1 staining was used to detect apoptosis with mitochondrial damage, and neuronal ultrastructure was
observed by transmission electron microscopy.
Compared with the model group, the apoptosis of groups
treated with alpha-asarone that had sustained mitochondrial
damage was significantly reduced. JC-1 staining revealed
bright green and red fluorescence of the normal group but
faint red and bright green fluorescence in the model group.
With alpha-asarone treatment, the red fluorescence was
restored, and both the number and area of red fluorescent
faculae increased. Electron microscopy revealed nuclear distortion, chromatin condensation and margination, and mitochondrial swelling in neurons of the model group, and
the mitochondria of 120 lg/ml alpha-asarone group were
slightly swollen.
Neuronal apoptosis was observed in Sombati’s cellbased model, and treatment with a-asarone was able to
alleviate this effect. Alpha-asarone reduced mitochondrial
damage and decreased the apoptosis of neurons in this
model.
Study supported by: This study was supported by grants
from the National Natural Science Foundation of China(No.30960111), the Natural Science Foundation of
Guangxi Province of China(No.2010GXNSFA013168), and
the Major Program of Health Commission of Guangxi
Province, China(No.200916).
M1226. Self Reported Anger and Depression
in Patients on Levetiracetam in Mono and
Polytherapy
Udo C. Wieshmann and Gus Baker; Liverpool, United
Kingdom
Objective:To ascertain the frequency of self-reported anger
and depression in Levetiracetam (LEV).
Methods: We included 158 patients with epilepsy (PWE)
on LEV in monotherapy or as part of polytherapy and 260
patients on Anti Epileptic Drugs (AED) other than LEV
and 41 control subjects. All PWE and controls completed
the Liverpool Adverse Event Profile (LAEP).
Results: Forty nine percent of PWE on LEV and 39%
on AED other than LEV reported anger as sometimes or
always being a problem (p(chi square) ¼ 0.042). Forty eight
percent of PWE on LEV and 45% on AED other than LEV
reported depression as sometimes or always being a problem
(p(chi square) ¼ 0.584). Only 7% of control subjects
reported anger as sometimes being a problem. No control
reported depression.
Conclusion: Anger and depression were more frequently
reported as a problem by PWE than by control subjects.
Our unblinded observational study of self reported symptoms suggested anger being more often a problem in
patients taking LEV than in PWE taking other AED. PWE
should be cautioned about the potential side effects of
AED.
Study supported by: Epilepsy Action
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M1229. The Syndrome of Transient Epileptic Amnesia
(TEA)
Adam Zeman and Christopher R. Butler; Exeter, Devon,
United Kingdom and Oxford, Oxfordshire, United Kingdom
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add valuable perspective on identification of eloquent cortex
by classical fMRI paradigms.
A Study supported by: merican Epilepsy Society (Milken
Family Early Career Award); Center for Clinical and Translational Sciences, University of Texas Health Science Center,
Houston, TX
TEA is a recently described - but controversial and underdiagnosed - syndrome of temporal lobe epilepsy, mainly
affecting people over fifty, characterised by episodes of anterograde and/or retrograde memory impairment (Butler,
Annals of Neurology, 2007; Zeman, Current Opinion in
Neurology, 2010). These episodes often occur on waking
and usually last about thirty minutes. Other less prominent
manifestations of epilepsy, particularly olfactory hallucinations, occur in 2/3 of cases. Attacks generally cease on anticonvulsant treatment. To date, none of the proposed etiologies (cerebrovascular, immune-mediated, neurodegenerative)
accounts for the majority of cases. In addition to the amnestic seizures, persistent, interictal, treatment-resistant, memory problems often develop, in particular accelerated longterm forgetting of recently-formed memories, and impairment of remote autobiographical memory. While these deficits are invisible to standard neuropsychological tests, we
have quantified them using tailor-made instruments (Milton, Brain, 2010; Muhlert, Neuropsychologia, 2010). Similar deficits have recently been described in other forms of
temporal lobe epilepsy. These forms of memory loss are of
clinical relevance to epileptologists and cognitive neurologists, and of theoretical interest to memory science. We will
describe the UK-wide TIME project (The Impairment of
Memory
in
Epilepsy,
http://sites.pcmd.ac.uk/time/
index.php) which is investigating these disorders.
Study supported by: Academy of Medical Sciences
Epilepsy Research UK
ESRC
Great Western Research Initiative
Health Foundation
Microsoft Research
Mrs Dale Medical Neurology Research Fund
Patrick Berthoud Charitable Trust
Wellcome Trust
M1231. Attenuated and Augmented Emotional Face
Processing Networks in Temporal Lobe Epilepsy
Brett W. Fling, Jeff Riley and Jack J. Lin; Irvine, CA
Rationale: Emotional processing deficits are common in
temporal lobe epilepsy (TLE) but the functional underpinnings remain unclear. We hypothesize that functional MRI
signals in emotional face processing regions will be altered,
according to the side of seizure onset in TLE.
Methods: Functional MRI data were obtained using a
dynamic fear-face paradigm in 24 TLE patients (Left ¼ 15;
TLE ¼ 9) and 19 age/gender matched healthy controls
(HC). Face-responsive regions (fusiform, FFA; occipital face
area, OFA; superior temporal sulcus, STS; temporal pole,
TP) were identified in each individual using the peak voxel
of the activation clusters. Analyses were performed according
to the side of seizure onset (ipsilateral vs. contralateral).
Results: TLE patients demonstrated significantly
decreased activation in the ipsilateral OFA (P < 0.02), and
a trend toward decreased activation in the ipsilateral STS (P
¼ 0.06) compared to HC. Conversely, TLE subjects activated the contralateral TP significantly more than HC (P <
0.02).
Conclusions: Emotional face processing regions were
attenuated, ipsilateral and augmented, contralateral to the
side of seizure onset, implying both local network disturbances and compensatory mechanisms in distant regions.
Study supported by: NINDS K23 NS060993
M1232. Microelectrodes Produce Unreliable EEG
Recordings
William Stacey, Spencer Kellis, Christopher Butson, Paras Patil,
Trevor Assaf, Temenuzhka Mihaylova and Simon Glynn; Ann
Arbor, MI; Pasadena, CA and Milwaukee, WI
M1230. Oxygen-Enhanced MRI: A New Imaging Tool
for Localization of Focal Epilepsy and Eloquent Cortex
Giridhar P. Kalamangalam, Timothy M. Ellmore, Nelson T.
Nelson and Narayana A. Ponnada; Houston, TX
Recent work has shown the utility of recording intracranial
EEG (iEEG) with greater spatial resolution. We recently
measured the impedances of several commercial microelectrodes and demonstrated that they will distort EEG signals if
connected to commonly-used EEG amplifiers. In this study
we demonstrate the clinical implications of this effect.
Human iEEG data were digitally filtered to simulate the
signal recorded by 2 macro- and 8 microelectrodes connected to a standard EEG amplifier. The filtered EEG data
were read by three trained epileptologists, and high frequency oscillations (HFOs) detected with a well-known
algorithm. Several electrodes underwent scanning electron
microscopy (SEM).
Macroelectrode recordings were unaltered, but microelectrodes attenuated low frequencies, which disturbed
clinical interpretations of slowing, spikes, seizures, and
HFOs. SEM demonstrated marked variability in exposed
electrode surface area, as well as frequent sharp edges that
could damage tissue. In addition, during experimental
recordings the microelectrodes produced much greater
noise, which led to large baseline fluctuations and false
HFOs. While the attenuation can be mitigated by using
high impedance amplifiers, the increased noise cannot.
Great care must be taken when analyzing iEEG from
microelectrodes.
Study supported by: NIH K08NS069783
The paramagnetic nature of deoxyhemoglobin compared to
oxyhemoglobin generates the differential MRI signal that
forms the basis of classical BOLD fMRI. Artificially increasing arterial oxygen content (e.g. inhalation of 100% O2)
directly boosts BOLD signal, and potentially provides metabolic contrast for diagnosing dysfunctional cortex. The latter
hypothesis was confirmed in eight right-handed adult normal volunteers and ten right-handed patients with temporal
lobe epilepsy who underwent echo-planar MR imaging
under phasic hyperoxia. Hyperoxia-associated BOLD deflections from the temporal lobe revealed a significant group
difference between normals and epilepsy patients, with seven
patients exhibiting large deviations from normalcy that diagnosed and lateralized their disease. Two such patients were
nonlesional on conventional high-field structural MRI. In a
separate set of experiments, eight normal subjects were
scanned while performing a finger-tapping motor task under
hyperoxia and normal conditions. Increased task-related activation was seen in six subjects over the motor areas during
hyperoxia compared to normoxia. Oxygen-enhanced MRI
appears to be a novel and potentially valuable imaging tool
in the diagnosis and localization of focal epilepsy, and may
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M1303. Rapid High Volume CSF Loss – A New Cause
of Coma
Minjee Kim, Rose Du and Sherry H.-Y. Chou; Boston, MA
Neurology Critical Care
M1301. Fatal Hyperammonemic Brain Injury from
Valproic Acid Exposure
Danny Bega, Henrikas Vaitkevicius, Torrey Boland, Rebecca
Folkerth, Michael Murray, Katia Meirelles and Sherry Chou;
Boston, MA
Background: CSF loss can occur with dural tear. We report
a case of coma secondary to rapid high volume CSF loss
following craniotomy.
Case: A 74 year-old man had sudden >200cc of serosanguinous fluid output from subgaleal drain after uncomplicated aneurysm clipping, likely from CSF leak. CT scan
showed bilateral thalami and basal ganglia hypodensity, subarachnoid and intraventricular hemorrhage, and cerebral
edema. He developed obtundation, a generalized seizure and
PEA arrest despite drain removal. He was successfully resuscitated. His ICP was <5 mmH2O. 2 month later, patient is
able to follow simple commands and ambulated with
assistance.
Discussion: We add to a literature linking rapid high volume CSF loss to coma with bilateral thalamic infarction.
Unlike prior reports where the dural tear is below the foramen magnum, our case demonstrates that supratentorial
dural tear may produce the same clinical features. One characteristic feature is the low ICP despite CT findings of cerebral edema. We postulate that the basal ganglia and thalami
may be particularly prone to infarction because sudden large
change in CSF pressure may tether and compress small penetrating arteries that supply these structures.
Study supported by: No disclosures
Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid (VPA) exposure. Prompt reduction of elevated ammonia levels may
prevent permanent neurological injury. We report a case of
fatal hyperammonemic brain injury in a woman exposed
to valproic acid.
Case: A 38 year-old woman with schizoaffective disorder
and recent increase in VPA dosage presented with somnolence and confusion and rapidly progressed to obtundation.
Brain MRI showed diffuse bilateral restricted diffusion in
nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at
288 umol/L. Genetic testing showed no mutation in urea
cycle enzymes. Despite successful elimination of ammonia
with CVVH she developed fatal cerebral edema.
Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia
excretion can be facilitated by initiation of CVVH and
administration of scavenging agents (sodium phenylacetate
and sodium benzoate). Severe hyperammonemia can result
from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to
check serum ammonia in any patient with encephalopathy
who has had recent VPA exposure.
Study supported by: No conflicts of interest or disclosures
to make.
M1304. Serum Sodium Values and Their Association
with Adverse Outcomes in Moderate-Severe Traumatic
Brain Injury (TBI)
Lucia Rivera-Lara, Raphael Carandang, Wiley Hall, Cynthia
Ouillette, Frederick A. Anderson, Robert J. Goldberg and
Susanne Muehlschlegel; Worcester, MA
M1302. A Population-Based Study of Aetiology and
Outcome in Acute Neuromuscular Respiratory Failure
Aisling S. Carr, Anne I. Hoeritzaur, Rachel Kee, Michael
Kinney, Aoibhean Hutchinson and Gavin V. McDonnell;
Belfast, Northern Ireland, United Kingdom
Hypernatremia in neurocritically ill patients has been
associated with worse neurological outcomes. There may,
however, be a treatment effect from osmotherapy combating herniation and hyponatremia, which in turn may
exacerbate brain edema, resulting in iatrogenic sodium
repletion. In moderate-severe TBI, serum sodium (sNa)
disturbances are common, but their impact on patient
outcomes is unknown. In a prospective cohort study of
144 consecutive moderate-severe TBI patients admitted to
a Level I trauma center over the period 11/2009–11/
2011, we examined the association of mean, nadir, and
peak sNa and hospital discharge neurological outcome
(Glasgow Outcome Scale [GOS]). The mean age of this
cohort was 51 years, 70% were men, and the median
GCS and injury severity scores were 5 and 32, respectively. Using ordinal regression analysis, controlling for
admission variables, length of ICU stay, severity of injury,
presence of brain edema on head CT, administered hypertonic saline and mannitol, higher mean (p<0.001), higher
peak (p ¼ 0.01), and higher nadir (p<0.001) sNa values
were significantly associated with worse outcome. Our
findings suggest that higher sNa values are associated with
worse neurological outcome, independent of treatment
effect by osmotherapy.
Study supported by: Muehlschlegel:
American Heart Association AHA 09SDG2030022
Worcester Research Foundation
Faculty Scholar Award, University of Masschusetts Medical School
Goldberg: NIH/NHLBI 5 R01HL077248-05, 5
R01HL070283-07, 2R01HL035434-26, 5 R37 HL6987409
Background: Acute neuromuscular respiratory failure
(NMRF) is a life-threatening feature of various neurological
conditions. Population-based data on the frequency, outcome and aetiological spectrum is lacking.
Methods: Regional ICU databases were searched for
patients admitted with acute NMRF from 1/1/2000-31/12/
2010. Demographics, diagnosis, length of stay, follow up
and outcome (mRS) were recorded. A comparison dataset
of all non-NMRF Neurology patients admitted to ICU was
obtained.
Results: 55 acute NMRF patients were identified; age:
17-88 (median: 63 years), M:F ratio 1:1.5. IR: 2.8 (0.8,
4.8) cases per million person-years; MR: 0.3 (0, 2.2) deaths
per million person-years. Final diagnosis was inflammatory
neuropathy (36 cases), myasthenia gravis (10), rhabdomyolysis (1) and motor neuron disease (5). 3 cases were undiagnosed. Follow up ranged from 0-7 years (median: 500.5
days); long term mRS: 1 (range 0-6). NMRF patients were
older (p<0.0001), had longer ICU stay (p:0.02) but significantly better outcome (p<0.0001) than 93 non-NMRF
neurology patients requiring ICU admission whose RR of
long term dependence: 2.0 (1.5, 2.7) and RR death in hospital: 1.1 (1.0, 1.3) was higher.
Conclusion: This work provides the first populationbased data on acute NMRF and highlights the potential for
favourable outcomes.
Study supported by: Nothing to declare
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M1305. Impact of Medical and Neurological ICU
Complications on Moderate-Severe Traumatic Brain
Injury (TBI)
Susanne Muehlschlegel, Raphael Carandang, Wiley Hall, Fred
A. Anderson and Robert J. Goldberg; Worcester, MA
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American Heart Association AHA 09SDG2030022
Worcester Research Foundation
Faculty Scholar Award, University of Masschusetts Medical School
Goldberg: NIH/NHLBI 5 R01HL077248-05, 5
R01HL070283-07, 2R01HL035434-26, 5 R37 HL6987409
Certain admission characteristics are known predictors of
adverse outcomes in patients with moderate-severe TBI, but
explain only 1/3 of outcome variability. Intensive care unit
(ICU) complications occur frequently in this population,
but their impact on patient outcomes remains poorly
defined. In a prospective cohort study of 170 consecutive
moderate-severe TBI patients admitted to a Level I trauma
center over the period 11/2009–2/2012, we examined the
association of ICU complications and 3-month outcome
(Glasgow Outcome Scale [GOS]). The mean age was 51
years, 72% were men, and the median GCS and injury severity scores were 4 and 29, respectively. Using multiple
logistic regression analysis, hypotension requiring vasopressors (HRV) was the strongest predictor of poor outcome
(GOS 1-3 [OR 2.8; 95% CI 1-7.5]) among medical complications. After combining medical with neurological ICU
complications, brain herniation (OR 5.8; 95% CI 1.1-30.2)
and intracranial rebleeding (OR 2.9; 95% CI 1-8.4) were
the strongest predictors of poor outcome, while HRV
approached significance (OR 2.4; 95% CI 0.9-6.4). We
identified important potentially modifiable predictors of
adverse outcomes after moderate-severe TBI. Confirmation
of our findings in a larger cohort is warranted.
Study supported by: Muehlschlegel:
American Heart Association AHA 09SDG2030022
Worcester Research Foundation
Faculty Scholar Award, University of Masschusetts Medical School
Goldberg: NIH/NHLBI 5 R01HL077248-05, 5
R01HL070283-07, 2R01HL035434-26, 5 R37 HL6987409
Neuromuscular Disease
M1401. Novel Choline Kinase Beta Gene Mutation
Associated with Exercise Induced Myalgia and
Mitochondrial Changes
Hena Ahmad, Aleksander Radunovic, Angharad Davis, Sylvia
Marino, Heinz Jungbluth, Chieko Aoyama, Steve Abbs and
David Moore; London, United Kingdom and Tochigi, Japan
Introduction: Choline kinase is a vital part of the phosphatidylcholine (PC) pathway. Impaired phosphatidylcholine
homeostasis is caused by homozygous and compound heterozygous mutations in genes encoding CHKb which cause
congenital muscular dystrophy and mitochondrial structural
abnormalities. We present a case with a novel mutation in
CHKb gene supporting this link.
Case description: A 16-year old Caucasian male, with
mild ichthyosis presented with a seven year history of exercise induced myalgia. Examination was normal. CK varied
between 202-2070. Muscle biopsy showed prominent subsarcolemmal mitochondrial staining with mildly increased
lipid content. Electron microscopy confirmed peripheral
abundant, large mitochondria. Genetic testing revealed a deletion of the steroid sulphatase gene and a novel apparent
homozygous c.-74_-55del20 variant detected in 50 untranslated region of CHKb gene showing conservation and likely
functionally significant. Phosphorus quantification after thin
layer chromatography showed reduced Phosphatidylcholine/
Phosphoethanolamine ratio: 50.6/28.8.
Discussion: This is the first case demonstrating this novel
mutation in CHKB with functionally decreased PC content,
increased CK, mitochondrial changes and exercise induced
myalgia. Recognition of this association is important in
selecting appropriate tests to reach a diagnosis.
References: Mitsuhashi S American Journal of Human
Genetics 2011
Study supported by: N/A
M1306. Incidence Rates of ICU Complications in
Moderate-Severe Traumatic Brain Injury (TBI)
Susanne Muehlschlegel, Raphael Carandang, Cynthia Ouillette,
Wiley Hall and Robert J. Goldberg; Worcester, MA
Retrospective studies suggest that non-neurologic organ failure may contribute to 2/3 of all deaths after TBI, but the
actual incidence rates of specific intensive care unit (ICU)
complications in moderate-severe TBI are not known. In a
prospective cohort study of consecutive TBI patients from a
single Level I trauma center over the period 11/2009 – 2/
2012, we identified the ten most common medical complications after ICU admission according to strict pre-specified
criteria in 170 moderate-severe TBI patients. The mean age
of the study sample was 51 years, 72% were men, and the
median GCS and injury severity scores were 4 and 29,
respectively. Incidence rates of the ten most common medical complications in the ICU were: hyperglycemia (75%),
fever (62%), systemic inflammatory response syndrome
(38%), cardiac complications (36%), hypotension requiring
vasopressors (35%), pneumonia (any type [34%]); sepsis
(33%), anemia requiring transfusion (31%), other pulmonary complications (ARDS, pulmonary edema [26%]), and
hyponatremia (sodium 134mEq/L; [23%]). Medical complications in moderate-severe TBI are very common, and
their association with important patient outcomes should be
further investigated. Specific medical complications may
pose attractive modifiable treatment targets to improve the
outcome of TBI patients.
Study supported by: Muehlschlegel:
M1402. Might Sodium Phenylbutyrate (PBA) Be a Drug
for Sporadic Inclusion-Body Myositis (s-IBM)?
Anna Nogalska, Carla D’Agostino, W. King Engel and Valerie
Askanas; Los Angeles, CA
s-IBM is a common aging-associated degenerative muscle
disease causing severe disability, and it has no enduring
treatment. Characteristic are vacuolated muscle fibers having
accumulations of multi-protein aggregates containing amyloid-b42 (Ab42) and its cytotoxic oligomers. Demonstrated
defective protein-degradation through impaired proteasomal
and lysosomal pathways contributes importantly to the muscle-fiber degeneration. PBA, an FDA-approved orally-active
chemical chaperone, allegedly mimics the function of intracellular molecular chaperones in preventing protein aggregation and oligomerization.
Our experimental IBM model, based on exposing cultured human muscle fibers to chloroquine, an inhibitor of
lysosomal activity, expresses abnormalities similar to those of
s-IBM muscle viz.: a) prominent vacuolization; b) increased
Ab42 and its oligomers; c) decreased activity of the two
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major lysosomal proteases, cathepsin D and B; d) increased
autophagosomal marker LC3-II; and e) increased NBR1, a
marker of impaired autophagy. Treatment of this model
with PBA: a) virtually eliminated vacuolization; b) increased
activities of both cathepsin D (1.5-fold, p<0.01) and B
(2.3-fold, p<0.001); c) decreased LC3-II (90%, p<0.001);
d) decreased NBR1 (45%, p<0.05); e) substantially
decreased Ab42 (45%, p<0.05), and Ab oligomerization.
Those data provide a rationale for considering therapeutic
trials of s-IBM patients with PBA.
Study supported by: MDA and the Helen Lewis Research
Fund.
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Results: Of the fourteen current ALS genetic syndromes,
nine are consistent with classical adult-onset ALS. A further
two syndromes currently not classified as genetic ALS could
be included in a new system.
Conclusion: The current classification system is derived
from genetic studies which are driven by historically available genetic techniques rather than the clinical syndromes
seen in ALS clinics. A rational redesign would benefit clinicians, patients and researchers.
Study supported by: European Community’s Health Seventh Framework Programme 259867; Motor Neurone Disease Association; the NIHR Specialist Biomedical Research
Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry, King’s College London.
AAC is a consultant for two pharmaceutical companies.
M1403. Chaperone-Mediated Autophagy (CMA) in
Sporadic Inclusion-Body Myositis (s-IBM) Muscle Fibers
Mafalda Cacciottolo, Anna Nogalska, Carla D’Agostino, W.
King Engel and Valerie Askanas; Los Angeles, CA
M1405. Putative Mechanisms Involved in Primary
Hyperoxaluria Type 1 Polyneuropathy
Sarah E. Berini, JaNean K. Engelstad, Jennifer A. Tracy,
Dawn S. Milliner, P. James B. Dyck and Peter J. Dyck;
Rochester, MN
Muscle fibers of s-IBM, a common muscle disease associated
with aging, have ubiquitinated aggregates containing multiple proteins, including amyloid-b, phosphorylated tau and
a-synuclein (a-syn). As we previously demonstrated in sIBM, these protein accumulations were associated with
impairment of both the proteasomal and lysosomal degradation. CMA is a form of lysosomal degradation involving the
lysosome receptor Lamp2a, which selectively targets proteins
containing the KFERQ motif, such as a-syn. Proteins to be
degraded are first recognized by Hsc70, which subsequently
binds to Lamp2a and facilitates protein transfer to the lysosome. CMA has not been previously studied in either normal or disease human muscle. Compared to age-matched
controls (n ¼ 8), in s-IBM (n ¼ 9) muscle fibers Lamp2a
and Hsc70 were: a) by immunoblots, increased (6-fold
p<0.005,and 2-fold p<0.05, respectively); b) by immunocytochemistry, accumulated in the form of aggregates which
co-localized with a-syn; and c) by immunoprecipitation
physically associated with each other and with a-syn.
Lamp2a and Hsc70 mRNAs were increased 4-fold p<0.005
and 1.9-fold p<0.05, respectively).
This first demonstration that CMA components are upregulated in s-IBM further illustrates a perturbation of the
complicated cascade of protein degradation in this complex
disease.
Study supported by: Partially by MDA and the USC
NMC Research Fund.
MC is Ruth Ziegler Research Fellow.
Two cases of primary hyperoxaluria type 1 were investigated
for the underlying cause of their length-dependent sensorimotor polyneuropathy affecting both upper and lower
limbs.
The electrophysiologic features suggested prominent axonal degeneration and segmental demyelination. Diameter
histograms of biopsied sural nerves showed moderate loss of
fibers with a shift of the large diameter peak to smaller sizes.
The index of dispersion showed slight variability in the density of fibers. Minimal inflammation was noted. Under
polarizing light, bright cuboidal, hexagonal and starburst
inclusions typical of calcium oxalate monohydrate crystals
were seen. These inclusions were found in teased fiber preparations, paraffin and epoxy sections. Electron microscopy
along the length of teased fibers is being performed to
determine their ultrastructural location. The following
mechanisms of fiber degeneration are being considered: The
neuropathy is attributable to 1- direct toxic effects of calcium oxalate on nerve, 2- crystalline deposition in nerve
and microvessels, 3- uremia.
In conclusion, the crystals of primary hyperoxaluria type
1 polyneuropathy are distinctive and diagnostic. Their role
in polyneuropathy remains unsettled; they might simply
represent cellular sequestration of toxic material. The disease
provides a biologic model for the study of peripheral
neuropathy.
Study supported by: No funding source
M1404. Is the Familial Amyotrophic Lateral Sclerosis
(ALS) Classification Fit for Purpose?
Rubika Balendra and Ammar Al-Chalabi; London, United
Kingdom
Aim: To review the familial ALS genetic classification.
M1406. Cachexia in Two Adults with Single
Mitochondrial DNA Deletions Is Due to Dysphagia
Sergiu C. Blumen, Ron Dabby, Yaron River, Esther LeshinskySilver and Itzhak Braverman; Hadera, Israel and Holon, Israel
Background: The past twenty years have seen great
advances in identifying familial ALS genes. A numbered
classification system exists incorporating fourteen genes, but
does not accurately reflect the ALS clinical syndrome as
there are several anomalies. For example, genes for very
slowly progressive motor syndromes, for juvenile onset, or
for pure upper motor neuron syndromes are over-represented. On the other hand, genes known to be responsible
for a significant proportion of ALS are listed as ALS-FTD
(Frontotemporal Dementia) genes. We therefore propose an
overhaul of the existing ALS genetic classification system.
Methods: Clinical syndromes of genetic ALS were compared with criteria for classical adult-onset ALS. Genes
known to cause ALS as a phenotype were reviewed for classification as ALS genes.
Cachexia in mitochondrial diseases may be due to dysphagia, recurrent vomiting, intestinal pseudo-obstruction or
combinations of the above. To elucidate its main cause, we
followed, from the ages of 42 and 22, two sporadic cases of
progressive external ophthalmoplegia (PEO) with life threatening weight loss. The symptoms started in the early teens
and progressed insidiously together with dysphagia, dysphonia and proximal weakness. Electrophysiological studies
confirmed severe myopathy and excluded polyneuropathy.
Normal cognition, brain MRI, CSF, cardiologic evaluation
and retinal appearence contributed to excluding the Kearns
Sayre syndrome. Normal thymidine phosphorylase activity
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excluded MNGIE syndrome. Muscle biopsies showed myopathy with many ragged red, COX negative and SDH positive fibers. Southern blot analysis of the mtDNA revealed
single deletions of 3.5Kb and 7Kb respectively. Fiberoptic
endoscopic evaluation of swallowing showed severe salivary
pooling with aspirations and decreased pharyngeal food propulsion. With gastric feeding patients’ weights increased
from 24 to 42 kg. and from 31 to 39 kg in six months.
Conclusions: 1. These patients had PEO due to sporadic,
single, large, mitochondrial DNA deletions. 2. Dysphagia
was the main cause of extreme cachexia and gastric feeding
was life saving.
Study supported by: nobody
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Methods: Labial articulation rates (words/minute/breath)
were compared with swallowing rates (mL/minute/swallow/
breath).
Results: Labial [pre-46.1648.8/post-60.2653.1:paired-ttest-p ¼ 0.0003] articulation rates [normal-198.3655.2
words/min/breath] increased significantly. Swallowing rates
[pre-97.66100.3/post-104.7690.9; paired-t-test-p ¼ 0.02]
increased significantly[normal-220646 mL/minute/swallow/
breath]. Rate improvements did not correlate with changes
in ALSFRS-R, vtial capacity or other clinimetrics.
Conclusion: Bulbar speech-articulation/swallowing rates
improved over 2-9 months in ALS/PBA patients having
abnormal speech-articulation rates [3-132 words/minute/
breath]. Treatment effect size for bulbar speech-articulation/
swallowing rates will permit sample-size determination to
employ these outcomes for future controlled clinical trials of
Nuedexta on bulbar function in ALS patients. Improved
speech/swallowing seen in ALS/PBA patients on Nuedexta
requires evaluation in bulbar ALS patients without PBA.
Further studies are needed to assess the clinical importance
and significance of these observations.
Study supported by: Carolinas ALS Research Fund and
Pinstripes Foundation of Carolinas Healthcare Foundation
and Muscular Dystrophy Association - ALS Division
Richard A Smith MD receives royalty payments from
Avanir Pharmaceuticals and is a recipient of an ALS Association grant to study the effect of Nuedexta on bulbar function in ALS. Benjamin Rix Brooks MD was principal investigator and Elena Bravver MD was investigator on clinical
trials leading to registration of dextromethorphan/quinidine
for treatment of PBA. Other authors have no financial relationship with Avanir Pharmaceuticals.
M1407. Slowly Progressing Familial ALS with Bulbar
Onset Due to a Novel VCP Mutation
Sergiu C. Blumen, Paloma Gonzales-Perez, Vivian E. Drory,
Ron Dabby, Diane McKenna-Yasek and Robert H. Brown, Jr;
Hadera, Israel; Worcester; Tel Aviv, Israel and Holon, Israel
Mutations in the valosin containing protein (VCP) gene
produce familial ALS as well as autosomal dominant inclusion body myopathy, frontotemporal dementia and Paget
disease (IBMFPD). We studied a large Arab Israeli family in
which patients from three generations fulfilled the El Escorial clinical and electrophysiological criteria for definite (N
¼ 4) and probable (N ¼ 3) ALS. All patients recalled nasal
speech many years before formal diagnosis (at 30 to 48
years). At presentation most had hyperlordosis, rigid spine,
proximal weakness with weddling gait and peculiar cervical
and upper thoracic paraspinal muscle atrophy. EMG showed
both neuropathic and myopathic features and CPK was
moderatly elevated. Insidiously, weakness with upper and
lower motor neuron features affected distal limbs too, and
the definite patients became pseudobulbar. One patient died
after 6 years and two required assisted ventilation at 9 years
from presentation. By whole exome sequencing and VCP
screening, a novel, R191G, mutation, co-segregating with
the disease was identified. While myopathy belongs to the
spectrum of IBMFPD, other features in this family are unusual; identification of new R191G carriers may indicate
whether this phenotype is the rule or the exception for this
genotype.
Study supported by: friends
M1409. Assessment of Clinical Disease Trajectory [CDT]
in Amyotrophic Lateral Sclerosis [ALS] Patients by ‘‘ALS
Dashboard’’ Containing Cognitive- Behavior
(Depression-Pseudobulbar Affect (PBA)-BulbarRespiratory-Arm-Leg Domains – Longitudinal Validation
over Time and by El Escorial/Awaji Shima Criteria
[EEC/ASC] Clinically-Definite [EECD/ASCD]
Classification at Diagnosis
Benjamin Rix Brooks, Mohammed S. Sanjak, Elena K.
Bravver, William L. Bockenek, Urvi G. Desai, Scott S.
Lindblom, Thomas J. Paccio, Nicole M. Williams, Mindy S.
Nichols, Amber L. Ward, K. Amy Wright, Velma L. Langford,
Michael P. Fischer, Kristy L. Walgren, Louise H. Frumkin,
Priscilla C. Russo, Anne S. Blythe, Nicole P. Smith, Jessica N.
Scrmina, Scott E. Holsten and Heather L. Oplinger;
Charlotte, NC
M1408. Bulbar Speech-Articulation/Swallowing Rate
Changes Measured in Amyotrophic Lateral Sclerosis
(ALS) Patients Treated with Dextromethorphan/
Quinidine(Nuedexta) for Pseudobulbar Affect (PBA) –
Determination of Treatment Effect Size for Future
Clinical Trials
Benjamin Rix Brooks, Elena Bravver, Urvi G. Desai, K. Amy
Wright, Velma L. Langford, Nicole M. Williams, Mohammed
S. Sanjak and Richard A. Smith; Charlotte, NC and La Jolla,
CA
Background: CDT is currently evaluated per-patient by
ALSFRS-R without attention to cognitive and behavioral
(depression/pseudobulbar-affect-PBA) domains which are
not included in current staging algorithms.
Objective: Assess CDT with ‘‘ALS Dashboard’’ cross-sectionally and longitudinally.
Setting: Multidisciplinary ALS Clinic.
Methods: ALS patients(199/263), categorized as
EECD(90) or ASCD(109) were staged longitudinally
according by ALS Dashboard criteria.
Results: At diagnostic visit in EECD/ASCD ALS stage3 cognitive [8.9%/13.8%] and respiratory dysfunction
[7.8%/4.6%] was similar, but stage-3 PBA [11.1%/2.8%;
p ¼ 0.04], depression [25.6%/10.0%; p ¼ 0.007], bulbardysfunction [45.6%/13.8%; p ¼ 0.0001], arm-dysfunction
[35.6%/8.3%;p ¼ 0.0001], leg-dysfunction [55.6%/33.9%;
p ¼ 0.004] were significantly increased in EECD-ALS. ALS
Background: Dextromethorphan is a sigma-1 receptor-agonist and NMDA receptor-antagonist in the CNS. Sigma-1
receptors are highest in cranial motor nerve nuclei followed
by subcortical and cortical neurons. 57 ALS/PBA patients
treated with Nuedexta showed PBA improvement. One
patient, who had to interrupt treatment reported decreased
swallowing which improved on resumption of Nuedexta.
Objective: Measure treatment effect size of quantitative
bulbar outcome measurements from pre-Nuedexta to 2-9
months post-Nuedexta in 18 ALS/PBA patients.
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Dashboard identifies earlier development of Affect-BulbarArm-Leg, but not Cognitive-Respiratory stage-3 disease in
EECD- than ASCD-ALS patients with subsequent faster
progression in EECD-ALS patients. Riluzole was associated
with lower proportion of developing cognitive stage-3
disease.
Conclusion: ALS Dashboard is a new tool for analyzing
disease severity within a single patient and across different
patients. ALS severity in some, but not all domains, segregates differently with a higher proportion of stage-3 legarm-bulbar disease in EECD than ASCD ALS. ALS Dashboard provides description of ALS changes and CDT associated with specific FVC % predicted cutoffs.
Study supported by: Carolinas ALS Research Fund and
Pinstripes Foundation of Carolinas Healthcare Foundation
and Muscular Dystrophy Association - ALS Division
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neurology providers and the drivers of these costs are
unknown.
Design/Methods: The 1996-2007 Health and Retirement Study (HRS) - Medicare Claims linked database was
used to identify individuals with an incident diagnosis of
neuropathy using ICD-9 codes. We examined test utilization by provider type and expenditures performed 6 months
before and after the incident neuropathy diagnosis.
Results: Neuropathy patients with a neurology provider
are more likely to receive electrodiagnostic testing and/or a
MRIs of the neuroaxis compared to those with other provider types (p<0.001). These tests were also more likely
completed after seeing a neurologist (p<0.001). Significant
expenditures are related to electrodiagnostic testing ($475
per patient receiving test) and MRIs of the neuroaxis ($370
per patient receiving test).
Conclusions: Neuropathy patients with a neurology provider
are more likely to have electrodiagnostic tests and MRIs, most
of which are ordered after a visit with a neurologist. Future
studies are needed to define the role of these tests, and whether
they are cost-effective for the evaluation of neuropathy.
Study supported by: The first author is supported by an
ADA Junior Faculty award
M1410. Peripheral Nerve Function Following Treatment
with Tanezumab
Mark T. Brown, William J. Litchy, David N. Herrmann,
Mark Goldstein, Aimee M. Burr, Michael D. Smith, Christine
R. West, Kenneth M. Verburg and Peter J. Dyck; Groton, CT;
Rochester, MN; Rochester, NY and Atlantis, FL
The novel analgesic mechanism of action of tanezumab, an
NGF inhibitor, and reported cutaneous sensory symptoms
raised safety concerns regarding nerve function. This
randomized, double-blind, placebo-controlled study of 219
neurologically normal patients with knee or hip osteoarthritis investigated whether tanezumab (3 administrations of 5
or 10 mg IVq8w for 24 weeks) caused clinically significant changes from baseline (cfBL) relative to placebo in a
composite measure of nerve function (R5NCþHRdb) or in
intraepidermal nerve fiber density (IENFD). The
R5NCþHRdb score included nerve conduction (NC) tests
of peroneal, tibial and sural nerves; and heart rate deep
breathing (HRdb). Skin biopsy assessed IENFD. Measurements were taken at baseline and Week 24 or Early Termination. Least squares mean (standard error) cfBL in
R5NCþHRdb scores at Week 24 were -0.11 (0.29) for placebo, and 0.17 (0.30) and -0.06 (0.30) for tanezumab 5
and 10 mg, respectively. R5NCþHRdb and IENFD cfBL
were not significantly different for either tanezumab-versusplacebo comparison. The magnitude of cfBL in
R5NCþHRdb and IENF density was small, unrelated to
dose, and treatment differences versus placebo were not statistically significant. Evidence linking tanezumab to detrimental (neurotoxic) effects on the peripheral or autonomic
nervous system was not found.
Study supported by: Pfizer, Inc.
Mark T Brown, Michael D Smith, Christine R West and
Kenneth M Verburg are employees of Pfizer and hold stock
& options in Pfizer. Aimee Burr is a paid contractor to
Pfizer and holds stocks in Pfizer. David N Herrmann provided professional consulting to Inflexion Point LLC within
the past year. Peter J Dyck is an Assoc. ed. of Diabetes. William Litchy and Mark Goldstein have no conflicts to
disclose.
M1412. Clinical, Neurophysiological and Histological
Differentiators of Congenital Myasthenic Syndromes
from the General Neuromuscular Disease Cohort
Aisling S. Carr, Estelle Healy, Brian Herron, Stephen Haffey,
Kiang Pang, Jacqueline Palace, David Beeson and John
McConville; Belfast, Northern Ireland, United Kingdom and
Oxford, United Kingdom
Background: Syndrome-specific case series provide best current information on CMS but do not describe diagnosis
and identification from within the general neuromuscular
population.
Methods: A population-based study of CMS in Northern
Ireland (population 1.7 million) between 1/1/2000-31/12/2010.
Results: IR:0.6 (0.2, 1.0) cases per million personyears;PR: 9.5 (5.1, 13.9) cases per million; MR:0.1 (0.01,
0.71) deaths per million person-years. 17 definite and 2 possible cases were identified, M:F ratio 2.2: 1, onset: 0-63 years.
Dok-7 mutations were most common (7/19), followed by
slow channel (5), AChR deficiency (2), fast channel (2) and
COLQ (2) mutations. Phenotype was variable: myasthenialike (3); PEO-like (2); limb-girdle syndrome (4); congenital
myopathy-like (6); distal upper limb syndrome (4). Lid
twitch in ptosis, micro-saccades in ophthalmoplegia and
Dok-7 waddling gait were useful clinical signs. RNS and
SFEMG abnormalities were seen in 6/10 and 6/6 tested.
Muscle histology showed type II fibre predominance in 8/9
cases. Prevalent patients responded to treatment.
Conclusion: Here we provide estimates for frequency of
CMS in the NI population and highlight useful clinical and
paraclinical clues in the identification of this treatable group
of conditions.
Study supported by: Neuromuscular research fellow Ulster Hospital Dundonal (AS Carr): August 2007-July 2008
Neuromuscular research fellow Royal Victoria Hospital
Belfast (AS Carr): August 2008-Jul 2009
M1411. Evaluation of Neuropathy: Tests and
Expenditures by Provider Type
Brian C. Callaghan, Ann Rodgers, Kevin Kerber, Ken Langa
and Eva L. Feldman; Ann Arbor, MI
M1413. High Fat Diet Induces Impaired Glucose
Tolerance and Painful Peripheral Neuropathy
Hsinlin T. Cheng, Jacqueline R. Dauch, John M. Hayes,
Sangsu Oh and Eva L. Feldman; Ann Arbor, MI
Background: Test utilization and expenditures are significantly higher around the time of diagnosis in those with
neuropathy compared with matched controls. The effect of
Impaired glucose tolerance (IGT) is a common condition
that causes idiopathic neuropathy and pain. Current
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understanding for IGT-induced neuropathic pain is very
limited. In order to study IGT-induced neuropathy, we
treated male C57BL/6 mice with high fat (HF, 45% fat calorie) and control chow (CC, 13% fat calorie) starting at 5
wk of age. IGT was determined by a 2 hour-glucose tolerance test. Mechanical and thermal thresholds, as well as
nerve conduction velocities, were measured periodically. By
36 wk of age, HF mice developed obesity, hyperlipidemia
and hyperinsulinemia. However, the fasting glucose and glycosylated hemoglobin levels remained within control ranges.
We detected IGT in HF mice starting at 11 wk of age. In
parallel, mechanical allodynia and thermal hyperalgesia were
detected at 12 wk in HF mice. Impaired sciatic motor and
sural sensory nerve conduction velocities along with significantly higher levels of oxidative stress in peripheral nerves
were detected in HF mice at 36 wk, indicating the presence
of peripheral neuropathy. Our findings suggested that HF
mice could serve as an animal model for studying painful
neuropathy from IGT.
Study supported by: NIH
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a number of ALS patient derived cell lines, including fibroblasts, induced-pluripotent stem cells (iPS cells), and iPSdifferentiated astrocytes and neurons. We have identified
unique expression and splicing patterns in cells derived from
patients carrying the C9orf72 repeat expansion. We have
further validated these data by comparing autopsy tissue and
CSF from multiple human ALS patients carrying the
C9orf72 expansion and control patients. Therapeutic strategies using antisense oligonucleoties (ASO) and RNA
knockdown (siRNA) are under development for other neuromuscular disorders caused by repeat expansions (e.g.,
DM1/2, FXTAS). Using these techniques, we were able to
knockdown C9orf72 expression in the patient-derived
C9orf72 cells without obvious cytotoxicity. Furthermore,
transcriptome profiling yielded a number of candidate biomarkers, whose aberrant expression in the mutant C9orf72
cells can be rescued with ASO/siRNA treatment.
Study supported by: National Institute of Neurological
Disorders and Stroke (NINDS), The Robert Packard Center
for ALS Research at Johns Hopkins, P2ALS, Johns Hopkins
University
M1414. Iatrogenic Mitochondrial Disease Emerging
Years after Stopping Anti-HIV Treatment: The Tip of the
Iceberg in 2012?
Brendan Payne, David A. Price, David Samuels, Ian Wilson,
Kris Gardner, Michael Trenell, Mauro Santibanez-Koref and
Patrick F. Chinnery**; Newcastle upon Tyne, United Kingdom
and Nashville
M1416. Withdrawn.
M1417. Often-Treatable ‘‘Multi-Microcramps’’ (MMCs)
Are Common and Frequently Overlooked Manifestations
of Peripheral Neuropathy
W. King Engel; Los Angeles, CA
We still see untreated patients with aching, painful muscles,
6 visible writhing of small bundles of muscle fibers. They
are often called ‘‘fibromyalgia’’, etymologically and pathogenically wrong, sometimes ‘‘neuromyotonia’’, confused
mechanistically with myogenic myotonias; or ‘‘restless legs’’,
a non-mechanistic complaint. MMCs are neurogenic, seemingly generated by frequent spontaneous discharges from
any part of numerous lower motor neurons (LMNs). Muscle-biopsy reveals small angular fibers and type-grouping,
proving neuropathic pathogenesis. Hypothetically, activation
limited to only a few of a motor-unit’s total fibers is due to:
a) the actual discharges arising in only a few distal twigs of
the LMNs, and/or b) pathologic relative-inactivability of
other distal twigs. The latter can produce EMG-detected
fractionated motor-units manifested as BSAPs (Brief Small
Abundant Potentials), often deemed a ‘‘myopathic pattern’’,
incorrectly in this case. Increased daytime activity can
increase MMCs that evening and next day Stretching
MMC-muscles gives temporary relief. MMCs can occur in:
a setting of minimal genetic þ/- acquired neuropathy, often
with a sensory component; 6 CSF protein increase - e.g.
diabetoid-2 dysimmune neuropathy treatable with IVIG.
Most gratifying symptomatic treatment is prn clonazepam,
e.g. 0.5-1 mg hs 6 0.5mg 1-2x in daytime.
Study supported by: Neuromuscular Center Research
Fund
There is emerging evidence that patients with treated HIV
infection develop unexplained neuromuscular and neurodegenerative disease, but the reasons for this are not known.
Here we show that HIV patients treated with nucleotide
reverse transcriptase inhibitors (NRTIs) develop an acquired
defect of mitochondrial function in mid-life, detectable ten
years after stopping these drugs. Up to 9.8% of skeletal
muscle fibers had a cytochrome c oxidase defect caused by
high levels of mitochondrial DNA (mtDNA) mutations
resembling those found in healthy ageing and neurodegenerative diseases, but at a much earlier age. Ultra-deep nextgeneration sequencing indicated that the increase in somatic
mutations was not due to increased mutagenesis. In vitro
experiments treating mtDNA deletion cell lines with NRTIs
showed that the drugs lead to the preferential amplification
of pre-existing mtDNA mutations through clonal expansion,
accelerated by the mtDNA depletion during NRTI therapy.
This leads to reduced basal ATP levels in vivo shown by
31P-magnetic resonance spectroscopy. These observations
support the role of somatic mtDNA mutations in the aging
and neurodegeneration, and raise the specter of progressive
iatrogenic mitochondrial neurological disease emerging over
the next decade.
Study supported by: The Wellcome Trust.
The Medical Research Council, UK.
M1418. Q-Fever IgM-Positivity in 3/5 sALS Patients:
Any Pathogenic Significance Regarding the XYZ
Hypothesis?
W. King Engel; Los Angeles, CA
M1415. Development of C9orf72 ALS Biomarkers and
Therapeutics
Christopher J. Donnelly, Lyle W. Ostrow, Ying Li, Svetlana
Vidensky, Pingwu Zhang, Alan E. Renton, Rita G. Sattler,
Bryan J. Traynor and Jeffery D. Rothstein; Baltimore, MD
and Bethesda, MD
Coxiella burnetii infection causes Q-Fever. Neurologic complications are uncommon, e.g. headache, meningoencephalitis during acute infection. We report 3/5 afebrile sALS men,
ages 41,43,54, showing IgM-Phase-II 6 IgM-Phase-I QFever antibodies (IgM antibodies generally indicate current/
recent infection). One was positive 4 times. None had live
ungulate exposure. Two treated for 2 & 6 months with doxycycline 100 mg bid þ rifampin 300 mg/d failed to
A hexanucleotide ‘‘GGGGCC’’ repeat expansion in the noncoding region of the C9orf72 gene has recently been identified in greater than 30% of familial and 4-10% of sporadic
ALS cases. Interestingly, the function of the C9orf72 protein
is unknown. In order to begin investigating the pathogenicity of this repeat expansion, we have generated and profiled
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improve. Controls: 2/64 afebrile CIDP patients were IgMpos, 41 other neuromuscular patients were IgM-neg -- 17/
103 of those patients were Q-fever IgGpos-IgMneg, that
being of uncertain significance. Our previously-reported
XYZ Hypothesis of ALS pathogenesis is: 1- remote Cells-X (?
in gut, liver, elsewhere) are infected with a virus, bacterium,
etc); 2- Cells-X either a) fail (due to induced autoimmunity
or another mechanism) to produce their circulating Beneficial Factor-Yb for Cells-Z (Motor-Neurons, MNs), or b) fail
to prevent a selectively Toxic Factor-Yt from circulating; 3Yb or Yt causes, directly or indirectly, a gradually non-recoverable failure of Cells-Z (MNs). Identifying Cells-X and
modulating Factor-Y might allow rejuvination of non-functioning but still-alive MNs, and some clinical improvement.
A possible role of Q-fever in sALS merits exploration.
Study supported by: Neuromuscular Center Research
Fund
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mitochondrial and nuclear DNA damage; 2) Mitochondrial
and nuclear DNA damages are significantly higher in DM1
skeletal muscles; 3) Mutant CUG-RNA stimulates phosphorylation of Ataxia Telangiectasia-Mutated (ATM) kinase,
AMP-activated kinase (AMPK) and cAMP-regulated transcriptional co-activator TORC2; 4) Phosphorylation of
TORC2 results in its nuclear exclusion, reduced occupancy
of the CREB-TORC2 in the PGC-1a promoter and suppression of PGC-1a transcription. These results suggest that aberrantly activated ATM!AMPK!TORC2 signaling plays an
important role in suppressing PGC-1a expression in DM1.
Study supported by: John Seally Fundation
M1421. A Common Link between Three Sporadic
Amyotrophic Lateral Sclerosis Cases in Annapolis, MD
Nicholas C. Field, Sandra Banack, Tracie A. Caller, James
Metcalf, Paul A. Cox and Elijah W. Stommel; Lebanon, NH
and Jackson, WY
M1419. Disruption of Intracellular Redox Homeostasis
by Mutant CUG-RNA in Myotonic Dystrophy Type 1
(DM1)
Xiang Fang, Rui Gao, Arpita Chatterjee, Tapas K. Hazra,
Robert Glen Smith and Partha S. Sarkar; Galveston, TX
The majority of amyotrophic lateral sclerosis (ALS) cases
occur sporadically, and spatial clustering of ALS has been
described. A number of environmental triggers have been
implicated, including beta-methylamino-L-alanine (BMAA),
a cyanobacteria-produced neurotoxin linked to ALS on
Guam. We report a cohort of three ALS patients diagnosed
within 8 years of each other, who lived for a minimum of
10 years on the same street in a suburb of Annapolis, Maryland, USA. After confirming diagnosis, a questionnaire was
completed by a surviving family member of each patient,
ascertaining lifelong dwelling history, exposure history and
social history. One common link identified was the regular
consumption of fresh Chesapeake Bay blue crabs. Cyanobacteria blooms have been present in the Chesapeake Bay
for decades. Chesapeake Bay crabs from the same fish market where the three patients regularly bought their crabmeat
were collected and tested for BMAA. Two out of the three
crabs tested were positive for BMAA. The regular consumption of blue crab contaminated with BMAA may be a common risk factor for sporadic ALS in all three patients. Other
factors may have also contributed to disease development.
Study supported by: Private donation to the ALS Center
at DHMC
DM1 is an autosomal dominant neuromuscular disease
resulting from the massive expansion of CTG repeats in the
30 untranslated region of DMPK gene. DM1 patients develop a complex array of degenerative phenotypes which
greatly resemble premature aging symptoms. However,
although elevated oxidative stress has been implicated in the
pathogenic mechanism of several degenerative dystrophic
muscle diseases, including DM1, how expanded CTG
repeats stimulate oxidative stress remains unknown. In this
study, we investigated the mechanism by which expanded
CTG repeats interrupt the intracellular redox homeostasis in
DM1 in vitro. We found that myoblasts stably expressing
500 CUG repeats showed 45% higher intracellular reactive oxygen species (ROS) levels than control myoblasts
expressing 25 CUG repeats. Transient expression of CUG
repeats also increased intracellular ROS levels, and these
effects were partially inhibited by DPI, a NADPH oxidase
inhibitor. Western blot analyses revealed that expression of
NADPH oxidase subunit p67phox was markedly increased in
myoblasts expressing 500 CUG repeats, while expression of
NADPH oxidase subunits gp91phox, p47phox, and Rac1
remained unaltered. These results indicate that p67phox
mediated ROS generation may play an important selective
role in DM1 pathogenesis.
Study supported by: John Sealy Fundation
M1422. Infections in Myasthenia Gravis (MG)
Raghav Govindarajan, Dennys Reyes, John Morren, Evelio
Velis and Nestor Galvez; Weston, FL and Miami
Objective: MG patients are on long-term immunosuppressants,increasing their chance to infectious complications/
MG exacerbation.
Method: Data of MG patients with at least 1y follow-up
was collected (2001 - 2011). Infections were divided: general
infectious processes (GIP) (self reported during visits, an
infection for which patients seek medical attention, or infections causing an exacerbation); opportunistic (OI) (infection
attributed to immunosuppressant); catheter borne (CBI) (as
an IVIG/plasmapheresis complication).
Result: There were 82 patients (mean age: 53y (33-73),
57% women). URIs were the most frequently reported GIPs
(37%, p< 0.05) and also the most common infection causing MG exacerbation (17%, p<0.05). Lower respiratory infections such as bronchitis/pneumonia (17%) were the next
most commonly reported GIP and second most common
cause of MG exacerbation(7.3%). The overall GIP incidence
was 65% and that of OI was 17%,with non-healing soft tissue/visceral abscess and Candida esophagitis the most common of OI (3%). There was a significant association between
OI and steroid-only Rx (SORx)(v2 ¼ 5.48, p < 0.05) with
M1420. Expanded CUG-RNA Suppresses PGC-1a
Transcription Via Activating DNA Damage Response
ATM Signaling in Myotonic Dystrophy Type 1 (DM1)
Xiang Fang, Rui Gao, Arpita Chatterjee, Tapas K. Hazra,
Robert Glen Smith and Partha S. Sarkar; Galveston, TX
DM1 is the most common form of adult onset muscular
dystrophy in humans. The mutation in DM1 is the expansion of a CTG tri-nucleotide repeat in the 30 untranslated
region of DMPK gene. Massive expansion of CTG repeats
results in degenerative muscle defects, mitochondrial and
metabolic abnormalities in DM1. Our recent study shows
that PGC-1a, a key regulator of mitochondrial respiration
and cellular energy metabolism, is downregulated in DM1
skeletal muscles. In the present study, we investigated the
mechanism by which expanded CTG repeats suppress
PGC-1a transcription in DM1. We found that 1) Ectopic
expression of expanded CUG repeats in myoblasts increase
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OR:8.6 (p<0.05). 85% of these occurred within the first 5
years of SORx. No CBI was observed in our study.
Conclusion: Respiratory tract infections must be sought
and treated aggressively, particularly URIs, as they are the
most common cause of MG exacerbation. Steroid-only
patients should be monitored for signs of opportunistic
infections especially in the first 5 years of Rx.
Study supported by: none
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M1425. Transgenic Mouse Models of FUS/TLS-Mediated
ALS
Lawrence J. Hayward, Hongru Zhou, Guohong Gao and
Robert H. Brown; Worcester, MA
Mutations in the RNA/DNA binding protein FUS/TLS
cause 5% of familial ALS and are associated with neuronal
and glial cytoplasmic inclusions. Multiple functional roles of
FUS have been proposed in both the nucleus and the cytoplasm. We established transgenic mice that constitutively
express human wildtype or mutant FUS (H517Q, R521G,
or R495X) in the brain and spinal cord. FUS mutations
caused a variable extent of cytoplasmic FUS accumulation
in spinal cord motor neurons and other neurons. A high
burden of cytoplasmic FUS(R495X) was tolerated in neurons for >1 year without causing toxicity. Cytoplasmic FUS
accumulated focally in the perikaryon in a pattern resembling Nissl bodies without the formation of well-defined
inclusions. Transgenic FUS mutant mice exhibited normal
nuclear TDP-43 staining. In a subset of mice, FUS mutant
expression was associated with age-related motor deficits
(decreased mobility, generalized tremor, or circling behaviors), but these abnormalities were not consistently observed.
Ongoing experiments will assess the sensitivity of these mice
to increased mutant gene dosage, decreased expression of
endogenous mouse FUS, and external stresses to determine
whether FUS mutants impair neuronal homeostatic mechanisms that could be relevant to ALS.
Study supported by: NIH-NINDS (RC1-NS068391)
ALS Therapy Alliance
M1423. Anti Acetylcholine Receptor Antibodies in a
Patient with LEMS and Idiopathic Thromobocytopenic
Purpura
Raghav Govindarajan and Virgilio Salanga; Weston, FL
Background: Whether myasthenia garvis and LEMS can
co-exist as two separate entities in the same patient remains
controversial.Previous case reports have found a LEMS like
finding on repetitive nerve stimulation (RNS) with positive
AChR antibodies.We report the case of a 70-year-old with
chronic idiopathic thrombocytopenic purpura (ITP) who
had both anti AChR antibodies and antibodies to pre-synaptic voltage gated calcium channel (VGCCA) with LEMS
like pattern on RNS.
Case Report: A 70-year-old male with a history of chronic
ITP for a year,presented with increasing fatigue,inability to
get up from chair,instability while walking,droopy eyes and
intermittent dysphagia for last 4 months.Reflexes were absent
throughout which did not improve with voluntary contraction for 10 seconds.Ach modulating/blocking and VGCCA
were elevated.Compound muscle action potential (CMAP)
amplitude were low in all the nerves tested on conduction
studies.High frequency RNS and brief exercise resulted in a
200% incremental response in the CMAPs.Periodic cancer
screening(last 5 years)have remained negative.
Conclusion: It remains unknown if the presence of
AChR antibodies is of clinical significance or merely a nonpathogenic epiphenomenon.Is there are a common etiopathogenic antigen triggering antibodies to presynaptic
VGCC and postsynaptic AChR also needs to be explored.
Study supported by: none
M1426. A Novel Mutation in the CACNA1S Gene in a
Japanese Family with Hypokalemic Periodic Paralysis
Makito Hirano, Yosuke Kokunai, Yusaku Nakamura,
Kazumasa Saigoh, Susumu Kusunoki and Masanori P.
Takahashi; Sakai, Osaka, Japan; Suita, Osaka, Japan and
Osakasayama, Osaka, Japan
Hypokalemic periodic paralysis (HypoPP) type 1 is an autosomal dominant disease caused by mutations in the calcium
channel encoded by the CACNA1S gene. In HypoPP type
1, only seven mutations have been found since the discovery
of the causative gene in 1994. However, the prevalence of
HypoPP is not extremely low (1:100,000), suggesting that a
few common mutations affect many families. Here we
report a novel mutation in this gene in a Japanese family
with HypoPP. This novel mutation, p.Arg900Gly, may cause
a gating pore current leak, a common pathomechanism in
HypoPP, since this amino acid change loses positive charge
of arginine at the conserved Arg900 residue located in S4
voltage sensors. We also report a clinically important finding
that one patient had a high serum potassium concentration
after recovery from a recent paralysis, though most patients
had low serum potassium concentrations during their acute
phases. This finding complicated the correct diagnosis.
Study supported by: N/A
M1424. Blockade of Matrix Metalloproteinase-3 after
Traumatic Nerve Injury Preserves the Motor End Plate
Tom Chao, Derek Frump, Vincent J. Caiozzo, Tahseen
Mozaffar and Ranjan Gupta; Orange, CA
Functional recovery after repair of traumatic nerve injuries
is poor due to loss of end targets following repair. It has
been found that matrix metalloproteinase-3 (MMP-3) is
responsible for removing agrin, an essential protein for
maintaining the NMJ. This study explores whether the
NMJ may be preserved after denervation if MMP-3 is inactivated. A murine model for a segmental sciatic nerve injury
was created and plantaris muscles were extracted from wildtype and MMP-3 knockout mice at 1 week, 2 week, 1
month, and 2 months after injury to evaluate NMJ components. Functional evaluation of 1 month denervated muscles
was performed ex vivo. In contrast to wildtype mice, MMP3 knockouts showed that AchRs remained intact up to 2
months. Agrin immunofluorescence was also observed late
after denervation in the knockout but not the wildtype.
MuSK remained significantly phosphorylated 1 month after
denervation in knockouts. Functional assessment of muscles
demonstrated that activation with acetylcholine in MMP-3
knockouts was greater than wildtypes. The data provides
evidence that the motor end plate might be preserved following long-term denervation by inhibition of MMP-3.
Study supported by: Jacqueline Glass foundation
M1427. Pathological Involvement of ubiquilin2 in
Autophagy in Sporadic Amyotrophic Lateral Sclerosis
Makito Hirano, Keiji Shimada, Tatsuki Itoh, Yoshiyuki
Mitsui, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno,
Takao Satou, Noboru Konishi, Yusaku Nakamura and Susumu
Kusunoki; Sakai, Osaka, Japan; Kashihara, Nara, Japan and
Osakasayama, Osaka, Japan
Ubiquilin2, encoded by the UBQLN2 gene, is very recently
identified as a causative protein for familial amyotrophic lateral sclerosis (ALS). Because penetrance is incomplete,
mutations might be found in sporadic patients. We thus
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sequenced the UBQLN2 gene in 38 Japanese patients with
sporadic ALS, but found no mutations. Our pathological
analyses of autopsied spinal cords from 3 Japanese patients
with sporadic ALS revealed that ubiquilin2 aggregated in
ubiquitin-positive inclusions. We found for the first time
that this protein also colocalized with Atg5 and Atg7, proteins associated with autophagy. These results suggest that
ubiquilin2 may be involved in the ubiquitin-proteasome system and autophagy even with its wild-type form. Ubiquilin2 may be a key molecule to connect two major protein
quality control systems in pathomechanisms in ALS.
Study supported by: N/A
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atrophy in the biceps muscle (p<0.01), suppressed loss of
motor neurons (p<0.01) and inhibited astrocyte proliferation in the C5-C6 cord (p<0.01).
Conclusion: The present study indicated neuroprotective
effects of ZNS in wobbler mouse spinal motor neuron
degeneration. This drug may have a therapeutic potential
for motor neuron damage.
Study supported by: None
M1430. Serum Lipid, Creatinine, Urate and Ferritin
Levels at the First Time Diagnosed with Amyotrophic
Lateral Sclerosis (ALS) Contribute to Disease
Progression
Ken Ikeda, Takehisa Hirayama, Kiyokazu Kawabe, Osamu
Kano and Yasuo Iwasaki; Tokyo, Japan
M1428. An Unbiased Phenotypic Screen Identifies
Ethoxyquin as an hsp90 Activity Modulating
Neuroprotective Compound for Peripheral Neuropathies
Jing Zhu, Weiran Chen and Ahmet Hoke; Baltimore, MD
Background: Distinct profiles of serum lipid, urate and ferritin levels were reported in Western ALS patients. We
aimed to analyze the relationship between those levels and
disease progression in Japanese patients.
Methods: ALS functional rating scale (ALS-FRS), forced
vital capacity (FVC) and serological variables were measured in
92 consecutive patients at the first time diagnosed with ALS.
Results: As compared to 92 age/sex/body mass indexmatched controls, urate and creatinine (Cr) levels were
decreased, and ferritin levels were increased significantly in sera
of male and female ALS patients. Serum total cholesterol
(TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were increased in female patients. Annual decline
of ALS-FRS and FVC were correlated inversely with serum
TC, LDL-C, Cr and urate levels, and linked to serum ferritin
levels. Multivariate analysis showed that ALS-FRS decline 1/month and annual FVC decline 30% were associated
with baseline serum TC, LDL-C, Cr, urate and ferritin levels.
Conclusion: Our clinico-serological results were in the
similar patterns to Western patients and highlighted a therapeutic impact on metabolism and nutrition of lipid, urate
and iron in ALS patients.
Study supported by: None
Chemotherapy induced peripheral neuropathy (CIPN) is a
significant dose-limiting complication of many chemotherapeutic drugs. Although CIPN is an ideal target for neuroprotective approaches, there are no effective therapies. We carried
out a phenotypic screen looking for small molecules that prevented paclitaxel-induced axonal degeneration in a dorsal root
ganglion (DRG) sensory neuronal line and identified ethoxyquin as a compound that provided >50% neuroprotection.
Confirmatory studies in primary DRG-Schwann cell co-cultures validated the findings for ethoxyquin with peak efficacy
in the 30-300 nM range. Novel analogues of ethoxyquin provided neuroprotection with similar dose response curves.
Ethoxyquin and one of its analogues prevented distal axonal
degeneration by 70% in an animal model of paclitaxel
CIPN. Ethoxyquin did not have any observable toxicity and
did not block paclitaxel’s ability to kill 4 different human
breast cancer cell lines. Binding studies identified hsp90 as
the primary target and demonstrated that ethoxyquin modulates hsp90 chaperone activity without inhibiting ATPase activity. These studies identifies a novel neuroprotective mechanism involving hsp90 that is different than typical hsp90
inhibition and shows that ethoxyquin can be developed as
neuroprotective therapy for paclitaxel CIPN.
Study supported by: Adelson Medical Research Foundation, Foundation for Peripheral Neuropathy, and JHU Brain
Sciences Institute
M1431. Protective Effect of Erythropoietin on
Glutamate-Mediated and Axotomy Induced Motor
Neuron Death
Yasuo Iwasaki, Ken Ikeda, Kiyokazu Kawabe and Osamu
Kano; Tokyo, Japan
M1429. Zonisamide (ZNS) Treatment Attenuates Motor
Neuron Degeneration and Astrocytosis in the Wobbler
Mouse
Ken Ikeda, Yasuhiro Yoshii, Takehisa Hirayama, Kiyokazu
Kawabe, Osamu Kano and Yasuo Iwasaki; Tokyo, Japan
Several members of hematopoietic factors are known to have
neuroprotective effect against glutamate and axotomized
motor neuron death. We carried out a study to determine
whether eruthropoietin(EPO) rescue spial motor neuron
death due to glutamate- and axotomy-induced motor neuron
death. Of 10 day old rats were used for organotypic spinal
cord cultures and new born rats were used for axotomy
induced motor neuron death. EPO prevented spinal motor
neuron death not only glutamate but axotomy induced neuronal death. In addition ChAT activity were increased in both
EPO-treated group. Amyotrophic lateral sclerosis(ALS) is
characterized by death of motor neurons and our results
show EPO may be candidated in therapeuic strategy in ALS.
Study supported by: none
Background: ZNS had multifunctional effects on several
kinds of neurons. Little is known about ZNS effects on
motor neurons. We aimed to study whether this drug can
prevent spinal motor neuron degeneration in wobbler mice.
Methods: Two doses of ZNS (0.2 mg/kg, 2.0 mg/kg,
i.p.) or vehicle were injected daily to affected mice from
aged 3-4 weeks at disease onset for 4 or 8 weeks. Forelimb
motor function of pull-strength and deformity scale, and
body weight were measured weekly for 8 weeks (n ¼ 10/
group). Neuropathological changes of the biceps muscle and
the cervical cord were evaluated at 4 weeks post-treatment
(n ¼ 10/group).
Results: Progression of forelimb motor dysfunction was
delayed significantly from 3 weeks after ZNS (2.0 mg/kg)
treatment compared to vehicle (p<0.01). Gain of body
weight did not differ statistically between three groups.
Higher doses of ZNS administration decreased denervation
M1432. Denervation Causes Lower Expression of
Insulin-Like Growth Factor (IGF) mRNA in
Regenerating Skeletal Muscle
Takahiro Jimi, Yoshiriro Wakayama and Hiroo Ichikawa;
Yokohama, Japan
To maintain functions of skeletal muscle, neural factors
might be essential. Denervation results in incomplete
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recovered in WT whereas in SOD1G127X it did not recover,
consistent with partial loss of motor axons confirmed by
morphological studies. After 1 day there were deviations in
excitability in WT and SOD1G127X, measured by thresholdtracking, consistent with membrane hyperpolarization:
increased rheobase, increase in threshold during hyperpolarizing electrotonus, reduced resting current-threshold slope and
decreased subexcitability of the recovery cycle. Changes were
larger in WT than in SOD1G127X. After 3 days of recovery,
excitability measures returned to near-normal in WT and
SOD1G127X. Our data suggest that in the SOD1G127X there
is inadequate energy-dependent Naþ pumping, as indicated
by the reduced post-stimulation hyperpolarization, which
may lead to neurotoxic Naþ overload.
Study supported by: Danish Medical Research Council
Lundbeck Foundation
Elsass Foundation
regeneration of skeletal muscle. So we examined mRNA
expression of insulin-like growth factor (IGF) in regenerating rat muscles in innervated and denervated conditions.
We made rat regenerating muscles by injection of bupivacaine hydrochloride in both extensor digitorum longus
(EDL) muscles. At the same time of injection, the unilateral
(right) sciatic nerve was removed. At one week after surgery,
both innervated and denervated EDL muscles were excised
from five rats. We carried out RT-PCR of IGF-1 and IGF-2
for each sample using specific primers. Both IGF-1 and
IGF-2 mRNA were down-regulated in the denervated rat
skeletal muscles as compared with the innervated condition.
According to these results, we speculated that denervation
causes decreased expression of IGF-1 and IGF-2 mRNA in
the regenerating skeletal muscle. The lower expression of
IGF mRNA may be involved in the incomplete regeneration
under denervated conditions.
Study supported by: none
M1435. More MS Patients Remain Free from Disease
Activity with Teriflunomide Versus Placebo in TEMSO,
a Phase III Trial
Marcelo Kremenchutzky, Paul W. O’Connor, Jerry Wolinsky,
Christian Confavreux, Giancarlo Comi, Ludwig Kappos,
Tomas P. Olsson, Philippe Truffinet, Deborah Dukovic and
Aaron Miller; London, ON, Canada; Toronto, Canada;
Houston; Lyon, France; Milan, Italy; Basel, Switzerland;
Stockholm, Sweden; Chilly-Mazarin, France; Bridgewater and
New York
M1433. Quantitative Image Analysis of Brain
Abnormality in Myotonic Dystrophy
Nam-Hee Kim, Dong-Eog Kim, Sang-Wuk Jeong, Ho Jin Kim
and Kyung Seok Park; Goyangsi, Korea and Bundang, Korea
Background: Myotonic dystrophy type 1 (DM1) is a myopathy with myotonia and other multi-system involvement
caused by DMPK gene mutation with CTG repeats. Brain
abnormalities have been reported with neurodegenerative
pathologic finding. The purpose of this study was to characterize brain structural abnormalities by mapping of DM1related brain lesions on MRI onto brain template.
Methods: Sixteen patients (17-68 years old) were
included and evaluated with genetic test, neuropsychologic
test, and brain MRI. Brain lesions were quantified by software package (Image_QNA) which can visualize the cumulative data of brain lesion by overlapping image data on a
standard brain template.
Results: Fifteen patients presented multiple high signal
intensities in frontal and temporal lobe. The cumulative
data revealed that periventricular and subcortical white matter were frequently involved and the most overlapping hot
spot was located in subcortical white matter near anterior
horn. Neuropsychologic test demonstrated that the most frequent deficit was frontal lobe dysfunction, corresponding to
the brain involvement. The lesion load and the number of
CTG repeat or disease duration demonstrated no
correlations.
Conclusions: Anterior subcortical white matter was the
most frequent involved site in DM1 through quantitative
imaging method, which is consistent with neuropsychological impairment.
Study supported by: none
Background: Teriflunomide, an oral disease-modifying therapy with a unique mechanism of action compared to existing disease modifying therapies in development for the
treatment of relapsing forms of MS (RMS), reduced clinical
and MRI disease activity in a large placebo-controlled Phase
III trial (TEMSO: NCT00134563). Here, we report its
effects on a composite endpoint of disease activity in
TEMSO.
Methods: 1088 RMS patients were randomized to placebo, teriflunomide 7mg or 14mg once daily for 108 weeks.
Time to disease activity (either clinical relapse, 12-week sustained disability progression or new unique active lesions)
was assessed by a log-rank test. Hazard ratios (teriflunomide
versus placebo) were estimated using a Cox regression model.
Results: Teriflunomide reduced the risk of disease activity
compared with placebo (p ¼ 0.0002 for 14mg, p ¼ 0.0293
for 7mg). 14.3%, 18.4% and 22.9% of patients receiving
placebo, teriflunomide 7mg and 14mg remained free of disease activity. Hazard ratios were 0.834 and 0.726 for 7mg
and 14mg teriflunomide.
Conclusions: Teriflunomide dose-dependently increased
the number of patients free from disease activity compared
with placebo. These findings support previously reported
positive efficacy findings from the TEMSO study.
Study supported by: Genzyme, a Sanofi Company
Drs. Kremenchutzky, O’Connor, Wolinsky, Confavreux,
Comi, Kappos, Olsson, and Miller are all investigators on
this study and have received financial support for the
TEMSO study. Mr. Truffinet and Ms. Dukovic have
received personal compensation as employees of Genzyme, a
Sanofi Company.
M1434. Prolonged High Frequency Electrical Nerve
Stimulation Precipitates Motor Axon Degeneration in
Presymptomatic SOD1G127X Mutant Mice
Susana Alvarez, Alexandru Calin, Stefan Marklund, Karin
Graffmo, Mihai Moldovan and Christian Krarup;
Copenhagen, Denmark; Bucharest, Rwanda and Umea˚,
Sweden
Strenuous activity may precipitate axonal degeneration in
ALS. We performed prolonged high frequency electrical nerve
stimulation of the right tibial nerve of the SOD1G127X mouse
model at 200 Hz for 3 hours. After 1 hour there was a drop
in CMAPs recorded from plantar muscles and CNAPs from
the exposed sciatic nerve in SOD1G127X and WT as compared to the un-stimulated side. Within 3 days, the drop
M1436. Anxiety in Benign Fasciculation Syndrome
Alexandra LaMela, Stephanie Scala, Ioannis Karakis, James A.
Russell and Doreen T. Ho; Biddeford, ME and Burlington,
MA
Objective: To study anxiety in patients with benign fasciculation syndrome (BFS).
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Background: Despite the favorable prognosis of BFS,
patients frequently become distressed. Awareness of fasciculation significance may increase anxiety and the motivation
to seek care. However, psychological correlates of BFS have
not been systematically studied. We postulate that awareness
of fasciculation significance produces anxiety, thus perpetuating symptoms.
Design/Methods: We enrolled nine patients. Patients
were diagnosed by a neuromuscular physician. Anxiety was
measured using the Zung Anxiety Scale (SAS) at diagnosis,
and months one, three, and six, with plans to continue for
two years.
Results: There were seven men and two women with a
mean age of 46.7 66.4 years. Four patients were in a medical field. All patients fell within the normal range (20-44)
on the SAS with a mean score of 32.4 64.72. In eight
patients, fasciculations persisted at six months.
Conclusions/Relevance: Our tentative conclusions are
descriptive due to small sample size. During a six month
follow-up period, mean SAS scores were lower than published normative data. We plan to enroll further patients
and add controls, but our findings suggest that anxiety may
not be higher than normal in this population, despite the
persistence of fasciculations.
Study supported by: None.
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Methods: The authors conducted a retrospective review
of medical records of psoriasis patients seen at the Mayo
Clinic from January 1, 1996 to May 31, 2011. Patients
who had pathologically-confirmed myopathy or inflammation in muscle were included.
Results: Thirteen patients with pathologically-confirmed
myopathies (4 inclusion body myositis, 3 polymyositis, 3
necrotizing myopathy, 2 dermatomyositis and 1 sporadic
late-onset nemaline myopathy) and 2 patients with focal
inflammation in muscle were recruited. The median age-atonset of myopathy was 57 years. Psoriasis preceded the
onset of weakness in two-thirds of patients (median 14.7
years). Psoriatic arthritis and other autoimmune disorders
were seen in 50% and 60% of patients, respectively. Onefourth of the patients received anti-TNF-a therapy before
the onset of myopathy.
Conclusions: While rare, inflammatory myopathies were
the most common type of psoriatic myopathy. Most patients
who developed myopathies had not been exposed to antiTNF-a therapy. Psoriatic arthritis and concomitant autoimmune disorders may be associated with increased risk of
developing myopathy.
Study supported by: None
M1439. Dynactin Mutations in HMN7B Disrupt
Initiation of Retrograde Transport at NMJ Terminal
Boutons
Thomas E. Lloyd, James Machamer, Sarah H. Collins,
Yunpeng Yang and Alex L. Kolodkin; Baltimore, MD
M1437. Myositis with Autoantibodies to c/d
Sarcoglycan: A New Disease
Russell Lane, Chiara Marini-Bettolo, Peter Charles and
Federico Roncaroli; London, United Kingdom
p150Glued is the major subunit of dynactin, a complex that
functions with dynein in retrograde axonal transport. The
CAP-Gly microtubule-binding domain of Glued is mutated
in Hereditary Motor Neuropathy type VIIB (HMN7B) and
Perry Syndrome; however, the function of this domain in
neurons is unknown. We generated a Drosophila model of
HMN7B that replicates key features of the disease including
aggregate formation, distal-predominant NMJ phenotypes,
and adult-onset locomotor dysfunction. Interestingly, axonal
transport occurs normally in Glued flies, but rather we find
a specific disruption of retrograde vesicle trafficking at terminal boutons (TBs), the distal-most ends of synapses. Loss
of Glued function causes both the dynein retrograde motor
and the kinesin anterograde motor to accumulate on endosomes at TBs, and live imaging data demonstrate that
p150Glued is required for initiating dynein-mediated retrograde transport at TBs. Interestingly, distinct CAP-Gly
mutations that cause Perry Syndrome, characterized by neurodegeneration of dopaminergic neurons, do not cause mislocalization of dynein. Together, these data suggest that the
distal axonopathy that occurs early in motor neuron degenerative disease begins with an inability to initiate retrograde
transport at synaptic termini.
Study supported by: NIH/NINDS
Robert Packard Center for ALS Research
We report two cases of inflammatory myopathy with autoantibodies to c/d sarcoglycan. The presenting features were
generally typical of polymyositis but from the outset, the
pattern of muscle involvement in the upper limbs was reminiscent of IBM but the quadriceps remained clinically unaffected throughout. Muscle biopsies showed IBM-like features but the inflammation included a significant
component of CD4 helper cells and plasma cells, and there
was prominent deposition of C5b-9 on muscle cell membranes. None of the recognised myositis specific autoantibodies were detected in patients’ sera using line-immunoblot
and western blotting techniques against HeLa cell extracts
but a previously unidentified band of 35kB was identified.
Subsequent immunoblotting studies using patients’ sera
against normal human sarcolemma and recombinant sarcoglycans showed that this antibody was reactive with c/d sarcoglycan. Both patients responded to steroids and also
showed objective temporary improvement in strength following plasma exchange. This is the first inflammatory myopathy in which pathogenic antibodies to a muscle-specific
surface membrane antigen have been identified. The existence of this new disease also supports the concept that myositis is a clinical and pathological continuum, in which different entities are determined by their immunopathic
characteristics.
Study supported by: The Myositis Support Group and
the Jani Foundation
M1440. Phenotypic Diversity of Mutations in the
Ryanodine Receptor (RYR1): A Series of Six Cases
Charles Marshall, Hena Ahmad, Nicholas Parkin, Stephen
Abbs, Silvia Marino, Sujit Vaidya, Heinz Jungbluth and
Aleksandar Radunovic; London, United Kingdom
M1438. Psoriatic Myopathies: The Mayo Clinic
Experience
Teerin Liewluck and Jennifer A. Tracy; Rochester, MN
The ryanodine receptor 1 (RyR1) is a calcium channel responsible for excitation-contraction coupling in striated
muscle. Mutations in the RYR1 gene that encodes this
channel have long been known to cause malignant hyperthermia, but the broad spectrum of muscle disease phenotypes is expanding.
Introduction: Psoriasis is a T-cell mediated skin disorder
with uncommon associated extracutaneous autoimmunity
except for seronegative arthritis and inflammatory bowel diseases. Rare patients with psoriatic myopathies with or without exposure to TNF-a antagonists were reported.
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Here, we present a series of six cases with muscle MRI
and muscle biopsy findings, as well as genetic analysis. The
phenotypes include: axial myopathy; exercise-induced rhabdomyolysis; proximal myopathy; proximal myopathy with
ptosis and ophthalmoplegia; myalgia; and mixed proximal
and distal myopathy. All six cases carry one of four heterozygous mutations affecting highly conserved amino acids
within the RYR1 gene.
Study supported by: None
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ing; enhanced carer wellbeing; improved breathing; and
increased speech clarity.
Discussion: A range of obstacles need to be overcome by
patients initiating NIV, however those achieving regular use
perceive a range of gains to their quality of life. Key recommendations are: the need for early accessible in-person
advice; pre-empting potential issues and solutions with
users; early and regular discussion of the potential benefits
of NIV.
Study supported by: National Institute for Health
Research, Research for Patient Benefit Programme.
M1441. Advanced Neuroimaging Study of Molecularly
Defined Hereditary Spastic Paraplegias (HSPs)
Andrea Martinuzzi, Domenico Montanaro, Nicola Martino,
Hana Hlavata, Giuseppe Rossi, Gabriella Paparella, Francesca
Peruch, Maria G. Rossetto, Alessandra T. Baratto and Maria
T. Bassi; Conegliano and Bosisio Parini, Italy; Pisa-Massa,
Italy and Conegliano, Italy
M1443. Steroid Responsive Anti-GAD Antibody Positive
Spino-Cerebellar Ataxia
Shri K. Mishra, Yama Akbari and Parampreet Singh; Los
Angeles, CA; Baltimore, MD and Sylmar, CA
We describe a case of Anti-GAD antibody positive Spinocerebellar ataxia (SCA), responsive to high dose corticosteroids. Anti-GAD antibody targets Glutamic-Acid-Decarboxylase enzyme, which transforms glutamate to GABA. It is
highly specific for autoimmune disorders such as diabetes,
rheumatoid arthritis, and ‘‘stiff-man syndrome’’. Recently,
Anti-GAD has been associated with SCA, presumably an
autoimmune disease; the exact pathogenesis of this disorder
is unknown. We report a 44 year-old female with an 11 yrs
history of chronic-progressive ataxia. There is consanguinity
in her parents, with however, no additional relevant family
history. On exam she demonstrated truncal and appendicular ataxia, ocular dysmetria, pyramidal and dorsal column
signs. Electrodiagnostics exhibited a sensory-predominant
polyneuropathy, and MRI showed cerebellar atrophy. Her
serology, CSF analysis, and an exhaustive paraneoplastic and
ataxia testing including common SCA’s were all normal.
Remarkably, an elevated anti-GAD titer of 2.3 (N<0.5) was
observed. A course of high-dose prednisone(60mg/day)
improved her symptoms. However, low-dose prednisone
(20mg/day), and four-cycles of IVIG were not beneficial.
The clinical gains were transient; however, her overall disease course has not worsened. Anti-GAD positive SCA is an
extremely rare presentation. Furthermore, patient’s responsiveness to high-dose steroids supports a possible autoimmune hypothesis for the syndrome. Details will be
presented.
Study supported by: None
Background: HSPs are clinically defined molecularly heterogeneous conditions for which a definite neuroimaging
(MRI) pattern discriminating HSPs patients from controls is
not described.
Objective: To explore in a large and composite cohort of
HSP patients the presence of objective markers for cortical
or white matter involvement by non conventional MRI
techniques.
Methods: 18 HSP patients (10 SPG4, 4 PG3a, 2 SPG5,
1 SPG10, 1 SPG31) and 22 age matched controls were
studied using a 1.5T device. All but the two SPG5 patients
showed a normal conventional MRI. Rolandic regions were
bilaterally sampled with single voxel H-MRS technique.
Diffusion Fractional Anisotropy (FA) and average apparent
Diffusion Coefficient (avADC) were sampled with ROIs
along the cortico-spinal tract.
Results: FA and avADC were significantly different in
patients compared to controls. No specific pattern could be
identified for H-MRS. There was a trend for correlation
between DTI values and clinical data.
Conclusion: In spite of normal conventional imaging
and the small number of patients DTI can detect objective
quantitative changes in the cortico-spinal tract of HSP
patients. Larger series and longitudinal studies will now be
needed to explore MRI/genetic correlations and indicators
of progression.
Study supported by: Italian Ministry of Health
M1444. Confocal Microscopy Analysis of Altered
TDP-43 Expression in Peripheral Blood Lymphocytes
from ALS Patients
Jean-Luc C. Mougeot, Sriparna Ghosh, Anne C. Lutin,
Andrea E. Price, Richelle A. Hemendinger, Edward J.
Armstrong and Benjamin R. Brooks; Charlotte, NC
M1442. The Use of Non-Invasive Ventilation for Patients
with Motor Neurone Disease: Patient and Carer
Perceptions of Obstacles and Outcomes
Susan K. Baxter, Wendy O. Baird, Sue Thompson, Stephen
Bianchi, Stephen Walters, Sam H. Ahmedzai, Alison Proctor,
Pamela J. Shaw and Christopher J. McDermott; Sheffield,
United Kingdom
Objective: Advances in amyotrophic lateral sclerosis (ALS)
gene expression studies in whole blood, peripheral blood
mononuclear cells (PBMCs) and peripheral blood lymphocytes (PBLs) have been made. Our objective was to investigate changes in non-nuclear and nuclear expression of TAR
DNA-binding Protein 43 (TDP-43) in PBLs from ALS
patients compared to healthy controls (HCs).
Methods: PBMCs were collected from ALS patients and
HCs at an academic medical center-based ALS clinic. AntiTDP-43 antibody was used for immunocytochemistry. A
Zeiss LSM 710 confocal microscope was used to determine
TDP-43 non-nuclear and nuclear staining in PBLs.
Results: Non-nuclear expression of TDP-43 is increased
in PBLs from ALS patients (n ¼ 13) compared to HCs (n
¼ 17). Changes in TDP-43 non-nuclear expression in PBLs
Objectives: The purpose of this study was to examine the
perceptions and experiences of patients with Motor Neurone
Disease and their carers following the recommendation to
use non-invasive ventilation (NIV). It aimed to describe factors impacting on acceptance and patient perceptions
regarding any benefits gained.
Methods: The work used a qualitative design, interviewing patients and carers within one month of NIV being
initiated.
Results: The study identified themes relating to: first
impressions of the technology; issues of sleep disturbance;
adverse sensations of pressure and pulsing; dry mouth;
design of the mask; and fitting the mask. Patients/carers perceived benefits related to: increased energy; improved sleep-
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from ALS patients did not correlate with riluzole (Rilutek)
treatment, disease duration or the ALS functional rating
scale-revised (ALSFRS-R).
Conclusions: Confocal microscopy is a useful tool to
assess TDP-43 expression in PBLs from ALS patients as a
potential biomarker for diagnosis, rate of progression and
response to therapy. Investigation of ALS-specific mechanisms involved and the generation of longitudinal data are
necessary to establish correlations with clinical variables.
Study supported by: Carolinas ALS Research Fund and
the Pinstripes Fund of the Carolinas Healthcare Foundation
at Carolinas Medical Center
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ness, and trabecular microarchitecture did not significantly
differ between subjects and controls. Men with biopsy-proven SFPN thus have apparently healthy skeletal parameters
proximally and distally. This small study cannot exclude
modest influences but substantial or consistent skeletal
effects of adult-acquired SFPN appear unlikely.
Study supported by: Funded in part by the Public Health
Service NIH-K24NS59892.
M1447. Mononeuropathy of the Lateral Cutaneous
Nerve of the Calf (LCNC) in Patients Previously Labeled
with ‘‘Complex Regional Pain Syndrome-I’’
Anne Louise Oaklander and Jose´ Ochoa; Boston, MA and
Portland, OR
M1445. Myasthenia Gravis Associated with Graves’
Disease
Hiroyuki Murai, Natsumi Yamashita and Jun-ichi Kira;
Iizuka, Fukuoka, Japan; Matsuyama, Ehime, Japan and
Fukuoka, Japan
‘‘CRPS’’ is a descriptive label for patients reporting persistent pain plus sensory, motor and microvascular symptoms
after limb trauma. Some have objectively identified nerve
pathology (‘‘CRPS-II’’; formerly causalgia), but most do not
(‘‘CRPS-I’’; formerly reflex sympathetic dystrophy), and
their symptoms remain unexplained. Here we report an
unrecognized cause of symptoms among ‘‘CRPS I’’-labeled
patients; mononeuropathy of the LCNC branch of the common peroneal. Five women presented with post-traumatic
‘‘CRPS-I’’ centered lateral and distal to one knee; all had
remote knee surgery. Mean onset was at age 27; interval to
diagnosis averaged 6 years. All had LCNC-territory hypoesthesia, allodynia, and microvascular abnormalities. 2/2 routine electrodiagnostic studies were normal. When detectable,
LCNC responses were absent unilaterally (1/1). Skin biopsy
revealed profound LCNC-territory denervation in 1/1
patients studied and restudy documented cutaneous reinnervation after the ‘‘CRPS-I’’ resolved. These findings
demonstrate that rigorous neurological and neurophysiological evaluation can detect undiagnosed mononeuropathies
among patients descriptively classified as ‘‘CRPS-I.’’ LCNC
mononeuropathy should be considered among patients with
posterolateral-calf-predominant ‘‘CRPS’’ because identification and localization of nerve injuries enables evidence-based
and disease-modifying treatments, plus facilitating insurance
and disability assessments.
Study supported by: Funded in part by the Public Health
Service NIH-K24NS59892
The aim of the present study was to clarify the characteristics of myasthenia gravis (MG) associated with Graves’ disease. We used the data of the nationwide epidemiological
survey 2006. We studied onset-age, sex, coexistence of thymoma, MG classification, anti-AChR antibodies, history of
crisis and outcome of Graves-associated MG (Group G) and
compared these results with the results from patients who
did not have Graves’ disease (Group N). Among 3,141 MG
patients, 165 (5.3%) had Graves’ disease. Average onset ages
were 34.3 years in Group G and 42.8 years in Group N.
When compared with Group N, Group G showed higher
percentage of early-onset, and lower percentage of elderlyonset cases. Group G showed the characteristics of female
predominancy, a lower percentage of thymoma-coexistence,
and a higher percentage of ocular type. Anti-AChR antibody
positivity was lower in Group G (63.3% vs 74.5%). Frequency of crisis was lower in Group G (7.3% vs 13.6%).
The rate of good outcome (CSR, PR or MM in MGFA
postintervention status) was higher in Group G (63.9% vs
57.1%). Graves-associated MG seems to affect relatively
young females, with a low rate of thymoma, and a reduced
likelihood of falling into crisis.
Study supported by: N/A
M1446. Effects of Small-Fiber Polyneuropathy (SFPN)
on Bone Mineral Density and Skeletal Microarchitecture
Benjamin Z. Leder, Ruchit Khumbani, Erica Siwila-Sackman,
Heather Downs and Anne Louise Oaklander; Boston, MA
M1448. The Incidence and Prevalence of CIDP in
Iceland
Brynhildur Hafsteinsdottir, Elias Olafsson and Sigurjon
Stefansson; Reykjavik, Iceland
There is increasing recognition of neural influences on bone
development and health. Bone innervation is largely by sensory and autonomic small-fibers. Although the effects of
SFPN on skeletal health have not been systematically studied, skeletal malformation, dysmetabolism, and resorption
are well described in genetic (e.g., HSAN, neurofibromatosis-I), infectious (e.g., leprosy) and traumatic (e.g., complex
regional pain syndrome) small-fiber-predominant sensory
neuropathies. We performed high-resolution quantitative
computed tomography of distal tibia, dual energy x-ray
absorptiometry (DXA) of the hip and spine, and measured
bone-related serum markers in 12 men with SFPN (age 3060y) and 12 healthy, age-matched male controls. Exclusions
comprised diabetes, calcium regulatory disorders, hypogonadism, recent fracture, and bone-active medications. SFPN
was quantified using standard PGP9.5-immunolabeled distal-leg skin biopsies. Comparisons between patients and agematched controls were performed by paired t-test. Despite
skin-biopsy confirmation of profound SFPN in subjects; tibial, hip, and spine bone mineral density, cortical-bone thick-
Objective: We determined the incidence and prevalence of
chronic inflammatory demyelinating polyneuropathy
(CIDP) in Iceland, over a 20 year period (1991-2011).
Methods: We did a retrospective population-based study.
Cases were identified from records of the only neurology
department, neurophysiology laboratories and all practicing
neurologists in Iceland. All cases fulfilled the EFNS/PNS
diagnostic criteria for CIDP (Hughes RAC et al., J Peripher
Nerv Syst 2005). Patients were excluded if they had diabetes
mellitus, paraproteinemia, malignancy or history suggestive
of Charcot-Marie-Tooth disease.
Results: We identified 20 individuals, who met the criteria.
The prevalence (31 Dec. 2011) was 4.69/100,000 and the average annual incidence 0.32/100,000. Average age at diagnosis
was 57 years and M:F ratio 4:1. The course was chronic progressive (30%), remitting-relapsing (25%) and monophasic
(45%). The symptoms were symmetrical proximal and distal
weakness with sensory impairment in all extremities (55%),
predominantly distal weakness (30%), predominantly sensory
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symptoms (10%) and one had pure motor affection. Immunomodulating treatment was given to 85%.
Conclusion: Very few studies are available on the frequency of CIDP. We report the incidence and prevalence of
CIDP, in a well defined population, over a 20 year period.
Study supported by: This study had no financial support
M1451. Sub-Regional Dual-Energy X-Ray
Absorptiometry (DEXA) Analysis: A Potential Endpoint
Measure for Therapeutic Trials in Myotonic Dystrophy
Type 1 (DM1)
Araya Puwanant, Noya Rackovsky, Jeffrey M. Statland, Katy J.
Eichinger, Richard T. Moxley, III and Charles A. Thornton;
Rochester, NY
M1449. Abundant FUS-Immunoreactive Pathology in
the Skin in Sporadic Amyotrophic Lateral Sclerosis
Seiitsu Ono, Takahiko Yamano, Hirotsugu Mikami, Takeshi
Watanabe, Tomomi Tsukie, Hiroyuki Fukazawa, Kazuhiro
Higashida, Yoshihiko Oketa, Hiroaki Ishikawa, Kanako Yasui,
Makoto Nomura and Megumi Suzuki; Ichihara, Chiba, Japan
Objective: To determine whether sub-regional DEXA analysis of lower leg lean tissue mass (LTM) correlates with quantitative strength (QMT) of ankle dorsiflexion and six-minute walk distance in DM1.
Background: Distal weakness is common in DM1, but
correlation of lower leg LTM with six-minute walk distance
has not yet been evaluated.
Methods: We performed segmental DEXA analysis of
LTM in both legs dividing each leg into thigh, lower leg,
and foot segments in 48 DM1 patients. LTM was correlated
with right and left foot dorsiflexor QMT and with a 6-minute walk test.
Results: LTM of lower leg segments significantly correlated with the 6-minute walk test (right, r ¼ 0.57; left, r ¼
0.57) and with QMT of ankle dorsiflexion (right, r ¼ 0.53;
left, r ¼ 0.56). The LTM of lower leg segments provided
the strongest correlation with dorsiflexor QMT and 6-minute walk distance compared to segments of thigh and foot
or whole leg.
Conclusion: Sub-regional DEXA analysis is a simple,
cost-effective, and time-efficient method that may be used
as an appropriate endpoint for studies of disease progression
and therapeutic efficacy in DM1.
Study supported by: NINDS U54NS48843
Background: Recently, mutations in a gene coding the
fused in sarcoma (FUS) have been identified in familial
amyotrophic lateral sclerosis (ALS). Also, FUS has been
found in neuronal cytoplasmic inclusions in sporadic ALS,
suggesting that FUS has an important role in the neurodegeneration occurring in ALS, However, there has been no
study of FUS in ALS skin.
Methods: We have performed a quantitative immunoreactive study of FUS in biopsied skins from 22 patients with
sporadic ALS and from 22 controls.
Results: The proportion of FUS-immunoreactive (ir) cells
in the epidermis in ALS patients was significantly higher
(p<0.001) than in controls. There was a significant positive
relationship (r ¼ 0.78, p<0.001) between the proportion
and duration of illness in ALS patients. The optical density
of FUS-ir cells in the epidermis in ALS patients is markedly
stronger (p<0.001) than in controls. There was a significant
positive relation (r ¼ 0.49, p<0.05) between the immunoreactivity and duration of illness in ALS patients.
Conclusions: These data suggest that changes of FUS in
ALS skin are related to the disease process and that metabolic alterations of FUS may take place in the skin of
patients with ALS.
Study supported by: No.
M1452. A Recombinant Human Neuron-Binding IgM
Promotes Survival and Protects Spinal Cord Anterior
Horn Cells in a Transgenic Murine Model of
Amyotrophic Lateral Sclerosis
Aleksandar Denic, Laurie Zoecklein, Bharath Wootla,
Arthur E. Warrington and Moses Rodriguez;
Rochester, MN
M1450. Brown Sequard Syndrome as an Initial
Manifestation of Idiopathic Spinal Cord Herniation
Dipakkumar P. Pandya, Anery Patel, Jennie Luna, Megan
McGarry, Sourav Sen and Gaetan Moise; Paterson, NJ
We demonstrated that a recombinant human antibody,
rHIgM12, binds to neurons in vitro, promotes axonal outgrowth, and improves spontaneous activity function in a
virus-induced murine model of demyelinating disease.
Based on laboratory evidence of the neuroprotective properties of this antibody, we studied rHIgM12 on survival
and spinal cord pathology in animals with the SOD mutation
(FVB-Tg(SOD1*G86R)M1Jwg/J).
Mice
were
randomized for treatment by one investigator and were
observed for neurological deficits by another blinded investigator to determine when the mice became moribund.
Compared to both saline- and control IgM-treated mice,
rHIgM12-treated mice showed an increased survival of
approximately 21 days, which, by Kaplan-Meier curves was
statistically significant (p<0.0001 and p ¼ 0.003 respectively). Moribund mice were sacrificed and spinal cords
collected for histological analysis. We demonstrated that
the number of preserved anterior horn cells was significantly increased in rHIgM12-treated mice as compared to
saline- and control IgM-treated mice (p<0.001 and p ¼
0.02 respectively). To our knowledge, this is the first demonstration that a fully recombinant neuron-binding human
monoclonal antibody increases the survival of animals with
an ALS phenotype.
Study supported by: This work was supported by grants
from the Mayo Clinic Center for Translational Science
Activities (CTSA)
Idiopathic spinal cord herniation is an extremely rare entity
characterized by progressive spastic paraparesis. It occurs in
middle-aged woman. It is manifested with dural defect
sleeve through which spinal cord prolapsed. The most common manifestation is Brown Sequard syndrome. We present
a unique case of progressive myelopathy in a middle age
woman with idiopathic spinal cord herniation.
Forty seven year old woman with bilateral progressive
paraparesis of last 6-8 months. Current symptoms were
associated with severe posterior abdominal pain involving
both sides with extreme heaviness of both lower legs. She
had diminished pain, temperature over right side and
decrease touch and deep pressure sensations over left side.
MRI thoracic spine showed spinal cord herniation at T4-T5
thoracic spine with severe narrowing of the spinal cord at
anterior level. She underwent successful thoracic laminectomy and spinal cord duraplasty. Her postoperative course
was uneventful and she is improving.
Idiopathic spinal cord herniation is a rare medical condition. It should be considered in differential diagnosis in
middle age woman with predominantly brown sequard syndrome, which is usually resultant from tethering of the spinal cord at the side of the herniation.
Study supported by: None
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M1453. A Clinical Study of the Distal Hereditary Motor
Neuropathies
Alexander M. Rossor, Henry Houlden and Mary M. Reilly;
London, United Kingdom
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M1456. SMN Controlled MiR-183 Regulates Neuronal
Morphology Via mTOR and Akt1
Min J. Kye, Mary H. Wertz, Bikem Akten, Pierre Neveu,
Kenneth S. Kosik and Mustafa Sahin**; Boston, MA; Santa
Barbara, CA and Heidelberg, Germany
The distal hereditary motor neuropathies (dHMN) are a genetically heterogeneous group of diseases characterised by
distal lower motor neuron weakness. To date, mutations in
eleven genes have been identified that account for 20% of
cases.
We describe the genotypic and phenotypic spectrum of a
cohort of patients with dHMN attending the hereditary
neuropathy clinic at the National Hospital for Neurology
and Neurosurgery. Sanger sequencing of the known dHMN
genes, was performed to determine the genetic frequency
and phenotypic spectrum of these mutations. Each patient
with an identified pathogenic mutation underwent a clinical
examination and in selected cases a MRI of the leg
musculature.
No pathogenic mutations were identified in ATP7A or
HSJ1. Of 61 patients with dHMN, 5 patients had a mutation in HSPB1, 1 in HSPB8, 1 in GARS, 2 in BSCL2 and
5 in TRPV4. In patients with mutations in HSPB1, ankle
plantar flexion weakness was greater than or equal to ankle
dorsiflexion weakness providing a useful diagnostic clue to
direct genetic testing. Muscle MRI in these patients confirmed the selective and early involvement of the gastrocnemius and soleus muscles.
Study supported by: This study was supported by the
Medical Research Council (MRC), the Muscular Dystrophy
Campaign and the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases
(U54NS065712).
Reduced levels of SMN protein result in deficits in various
aspects of neuronal development, such as axonal growth,
leading to the devastating pediatric motor neuron disease,
spinal muscular atrophy (SMA). However, the molecular
mechanisms by which SMN regulates neuronal development
are not well understood. Here we report that reduction in
SMN protein alters miRNA expression and distribution in
neurons. In particular, the levels of miR-183 are increased
in neurites of SMN deficient neurons. While reducing
SMN protein lowers the expression of genes in the mTOR
pathway, leading to arrest of neurites outgrowth, inhibition
of miR-183 expression rescues phenotype of SMN knockdown neurons by upregulating mTOR activity. This effect
appears to be due to translational regulation of mTOR,
Akt1 and Rictor by direct miR-183 binding to their
3’UTRs. Moreover, elevated level of miR-183 can block
Akt1 and mTOR translation in growing axons. Taken together, these observations suggest that microRNAs can regulate local translation of specific genes directly and control
protein synthesis broadly by modulating the activity of
mTORC1 and mTORC2 and highlight a new molecular
mechanisms contributing to SMA pathology.
Study supported by: Slaney Family Fund, Whitehall
Foundation, Children’s Hospital Boston Translational
Research Program, the Children’s Hospital Boston Intellectual and Developmental Disabilities Research Center (P30
HD18655), Harvard NeuroDiscovery Center and the Hearst
Foundation
M1454. Withdrawn.
M1455. Electrical Impedance Alterations in Muscle
Induced by Hindlimb Unloading
Jia Li, Andrew Spieker, Glenn D. Rosen and Seward B.
Rutkove; Boston, MA
M1457. Clinical, Molecular and Muscle
Histopathological Features in Myotonic Dystrophy Type
1 (DM1) Associated with Variant CCG Expansions
Marcella Masciullo, Massimo Santoro, Giulia Conte, Roberta
Pietrobono, Anna Modoni, Maria Laura E. Bianchi,
Valentina Rizzo, Maria Grazia Pomponi, Enzo Ricci,
Giovanni Neri and Gabriella Silvestri; Rome, Italy
Objective: Improved approaches for quantifying muscle disuse are needed. Here we evaluate the potential role of electrical impedance myography (EIM) to serve in this role.
Methods: 62 male Wistar rats underwent hind limb suspension for two weeks; this was followed by 2 weeks of recovery with full-weight bearing. EIM was performed on the
gastrocnemius-soleus complex weekly using surface electrodes. Ten rats were euthanized weekly and their gastrocnemius muscles extracted and muscle fiber size measured using
stereological probes.
Results: Hindlimb unloading caused significant alterations in tissue impedance with mean EIM phase decreasing
16.0%, from 16.3 6 0.29 to 13.7 6 0.55 degrees (mean 6
SEM, p < 0.001) over the two-week period; the changes
only partially reversed after 2 weeks of recovery, reaching a
final value of 14.0 6 0.58 degrees. A moderate correlation
was present between muscle fiber size and the impedance
values when including the baseline and two-week suspension
data (r ¼ 0.48, df ¼ 20, P < .05).
Conclusions: These data suggest that EIM is capable of
measuring the effects of disuse. EIM may be useful for
measuring muscle loss due to illness, prolonged bed rest,
microgravity, or age-related sarcopenia.
Study supported by: National Institutes of Health
Dr. Rutkove holds equity interest and receives consulting
fees from Convergence Medical Devices, Inc, a company
whose main focus is the development of devices for the
measurement of muscle impedance.
We assessed clinical, molecular and histopathological features in five unrelated Italian DM1 patients carrying ‘‘variant’’ expansions containing CCG interruptions within the
CTG array at the 30 -end of DMPK, detected by bidirectional TP-PCR and sequencing.
In three patients, manifesting a typical Steinert’s disease,
routine long-range PCR testing was negative; two other
cases were identified among 100 DM1 patients re-evaluated
to estimate the prevalence of variant expansions. The overall
prevalence of variant expansions was 4.8%.
Excluding the lack of a significant cognitive involvement,
variant DM1 patients showed no other atypical clinical features vs Steinert’s patients.
Variant expansions included either short as well as large
expanded alleles, and the repeat size was similar both in
muscle and leukocytes.
Also in such cases, muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the
presence of ribonuclear inclusions co-localizing with
MBNL1 and an aberrant splicing pattern known to be
involved in DM1 pathogenesis.
Our data suggest that CCG interruptions at the DM1
locus would modulate the phenotype mostly influencing the
replication dynamics of expanded DNA repeats, rather than
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affecting the RNAs higher structure and/or their interaction
with MBNL1.
Study supported by: Partially funded by grants from the
Italian Ministry for the Scientific Research
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M1460. In Sensory Neuropathy Contact Heat Evoked
Potential Stimulation (CHEPS) Small Fiber Conduction
Velocity (CV) Is Faster in Peripheral Than in Central
Spinothalamic Pathways
Benn E. Smith, Mark A. Ross, Brent P. Goodman, E.P. Bosch
and Lyell K. Jones, Jr; Scottsdale, AZ and Rochester, MN
M1458. Metabolic Syndrome Reduces Cutaneous Nerve
Regenerative Capacity
J. Robinson Singleton, Robin Marcus, Collin J. Arsenault,
Michael Porzio, Justin E. Jackson and A. Gordon Smith; Salt
Lake City, UT
Introduction: Nerve conduction studies (NCS) predominantly assess large diameter myelinated fibers. CHEPS provides an objective measure of A delta fiber pathway CV.
Methods: To assess small (A delta) fiber CV in the periphery vs. in the CNS twenty-one patients with sensory neuropathy were recruited with IRB approval. Evaluations included
CHEPS of limb and spine (L1 and C7) sites. CV values
were calculated between skin stimulation sites and scalp.
Results: CV values from distal limb sites showed means
of 3.6 m/s (foot) and 2.3 m/s (hand) while spine CV values
had mean values of 1.4 m/s (L1) and 0.7 m/s (C7). These
values are similar to those found in controls.
Conclusions: 1) Small (A delta) fiber CV values are
higher from distal limb than from corresponding spinal
sites, and 2) with the vast majority of the pathway between
spine and cerebral cortex being central and the peripheral
extent of this pathway being longer in peripheral than central segments when stimulating distal limb sites, it may be
hypothesized that peripheral small (A delta) fiber CV is
greater than central small (A delta) fiber CV.
Study supported by: Mayo Foundation
Capsaicin application for 48 hours induces cutaneous
fibers to die back into the dermal skin layer. Re-growth
over 90 days can be monitored by serial 3mm punch skin
biopsies to determine intraepidermal nerve fiber density
(IENFD). We used capsaicin axotomy to compare regeneration rate for subjects without neuropathy symptoms, ages
30-65, in three categories: normal controls (N ¼ 7), metabolic syndrome with prediabetes (MSP) (25), or diabetes
(29). Capsaicin axotomy was repeated during the final
half of six months of intensive diet counseling and weekly
observed exercise. Baseline thigh IENFD (but not other
baseline neuropathy measures), and 30 day regeneration
rate were significantly reduced in MSP subjects (0.088
þ/- 0.047 fibers/mm/day) and diabetes (0.092þ/- 0.067)
compared to controls (0.137, p<0.05 for both comparisons). BMI and fasting glucose correlated with baseline 90
day reinnervation rate (p<0.05 for each). Following 3 and
6 months of dietary counseling and exercise, change in
BMI significantly correlated with change in 30 day and
90 day regeneration ratio (Pearson correlate -0.719 (p ¼
0.003) and -0.485 (p ¼ 0.04) respectively, as did change
in triglycerides. MSP is associated with reduced IENFD
and cutaneous regeneration capacity, while improved obesity and hypertriglyceridemia predict increased regeneration capacity.
Study supported by: American Diabetes Association
M1461. Bortezomib Alters Microtubule Localization and
Mitochondrial Dynamics in Rat Dorsal Root Ganglion
Neurons
Nathan P. Staff, Jewel L. Podratz, Lukas Grassner, Miranda
Lange, Justin Paz, Andrew M. Knight, Charles L. Loprinzi,
Eugenia Trushina and Anthony J. Windebank; Rochester, MN
Bortezomib is part of a newer class of chemotherapeutic
agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There
are no established useful preventative agents for bortezomibinduced peripheral neuropathy (BIPN), and the molecular
mechanisms of BIPN are unknown. We have developed an in
vitro model of BIPN using rat dorsal root ganglia neuronal
cultures. At clinically–relevant dosages, bortezomib produces
a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is
associated with alterations in tubulin dynamics and results in
accumulation of somatic tubulin without changes in microtubule ultrastructure or total tubulin levels. Similar findings are
observed with lactacystin, an unrelated proteasome-inhibitor,
which argues for a class effect of proteasome inhibition on
dorsal root ganglion neurons. Finally, there is a change in mitochondrial motility and morphology induced by bortezomib
in a time-dependent fashion. This robust model will be used
in future mechanistic studies of BIPN and its prevention.
Study supported by: This work was supported by NIHNS40471 (AJW) and NIH-CA124477 (CLL).
M1459. Confocal Microscopy Is a Reliable Measure of
Corneal Innervation
A. Gordon Smith, Gene Kim, Michael Porzio, Blaine Allen,
Kathleen Digre, Mark Mifflin and Rob Singleton; Salt Lake
City, UT
There is an urgent need for surrogate small fiber measures.
Corneal confocal microscopy (CCM) directly visualizes
axons in Bowman’s layer. This study aimed to develop a
standard CCM imaging method. 11 Normal subjects
underwent CCM (Heidelberg HRTIII). 5 nerve fiber
layer images were collected in 5 locations (central, inferior/
superior nasal/ temporal) on the left. A blinded observer
measured nerve fiber length (NFL) and tortuosity coefficient (TC) at each site (CCMetrics) and averaged the
results. CCM was repeated 1 week later. 2 technicians analyzed images. Mean NFL was 2001þ/-398 uM and TC
29þ/-4.5. The intraobserver relative intertrial variability
(RIV) was 6.8þ/-4.0% for NFL (ICC 0.89, p<.0001) and
17 þ/-15% for TC (ICC 0.612, p<0.003). Interobserver
RIV was 4.6þ/-2.8% for NFL (ICC 0.98, p<0.001) and
14þ/-8% for TC (ICC 0.94, p<0.003). ANOVA revealed
no differences between location. Gender, age, height and
weight had no effect. CCM was well tolerated. Average
visit time was 15 minutes (5 minutes of image acquisition). CCM is well tolerated and NFL measurement is
highly reproducible.
Study supported by: ADA08-CR52, ADA 7-11AEC23, NIH R01 DK064814, University of Utah VP for
Research
M1462. Facioscapulohumeral Dystrophy (FSHD): D4Z4
Fragment Size in Patients with Coat’s Syndrome
Jeffrey M. Statland and Rabi Tawil; Rochester, NY
Background: Symptomatic exudative retinal vascular disease
(Coat’s syndrome) is a rare but treatable complication of
FSHD. Although a correlation between severe clinical phenotype and large D4Z4 deletions has been reported, the
relationship of deletion size to Coat’s syndrome is unknown.
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Methods: We searched a national FSHD registry,
reviewed the literature, and sent surveys to 12 FSHD referral centers in the United States and overseas to identify genetically confirmed FSHD patients with a diagnosis of
Coat’s syndrome.
Results: Out of 343 genetically confirmed patients in an
FSHD registry (21 with D4Z4 fragments 15 kb) no subjects reported Coat’s syndrome. We identified 8 genetically
confirmed subjects with Coat’s syndrome: 6 from our survey
and 2 from the literature. The age of onset of Coat’s syndrome ranged from 1st year of life to 53 years old. The median D4Z4 fragment size was 12.5 kb (range 10-13 kb). 1
patient was mosaic (55% 11 kb, and 45% 78 kb).
Conclusions: Coat’s syndrome is a very rare extramuscular complication of FSHD associated with large D4Z4 deletions. Closer surveillance for retinal complications is warranted in FSHD patients with D4Z4 fragments 15kb.
Study supported by: none
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Results: Forty infants were enrolled at 8 sites in North
America and Europe over an 18 month period; 2 subjects
immediately withdrew, leaving 38 subjects. Average age was
5.5 months; 11/38 had a feeding tube and 23/38 had respiratory insufficiency at baseline. 261 adverse events occurred,
including 83 SAEs, and13/38 subjects (34.2%) died; death/
ventilator dependence more than 16 hrs/day occurred in
37%. Over the first six months, motor function (TIMPSI
scores) declined by -4.75, mean ulnar CMAP amplitude/
area declined by more than 50%, and caregiver questionnaire scores increased by 11 points, indicating worsening of
overall status.
Conclusions: We demonstrate feasibility for successful
enrollment of SMA type I infants in multicenter clinical trials. The exploratory endpoints used here demonstrate promise for future trials, indicating measurable disease progression over a six-month period. Presymptomatic diagnosis or
a mechanism for early enrollment of infants in trials immediately following initial diagnosis would maximize benefit
and minimize adverse outcomes in this fragile population.
Study supported by: Families of Spinal Muscular Atrophy
M1463. SMN May Have Multiple Functions
Necessitating Widespread Restoration for Maximal
Therapeutic Benefit in SMA
Tara L. Martinez, Lingling Kong, James P. Van Meerbeke,
Rebecca Gibbs, Crystal Davis, Heather L. Plaster, Chien Ping
Ko, James R. Rusche, Cathleen M. Lutz, Mark M. Rich and
Charlotte J. Sumner; Baltimore, MD; Dayton, OH; Bar
Harbor, ME; Waltham, MA and San Diego, CA
M1465. Fetal Stem Cells in Duchenne’s Muscular
Dystrophy (DMD)
Nataliia S. Sych, Mariya O. Klunnyk, Olena V. Ivankova and
Iryna G. Matiyaschuk; Kiev, Ukraine
Though modern methods can prolong life expectancy of
DMD patients, but fetal stem cell therapy (FSCT) can be
more promising.
Goal of research was to study FSC efficacy in integrated
treatment of DMD.
Study included 27 male DMD patients aging 4-27. Diagnosis was confirmed clinically and on the basis of test results
(high CPK and LDH), EMG, genetic testing, muscle biopsy. Functional capacity of patients was assessed on Total
Functional Grade (TFG) scale, quality of life – on SF-36.
Patients were examined before stem cell therapy treatment
and 6 months after it.
All patients underwent transplantation of hematopoietic
and non-hematopoietic mesenchymal and ectodermal FSC
harvested from germ layers of internal organs of 4-8 weeks
old fetuses.
FSCT resulted in improvements on TFG – from
8,5760,66 before the treatment to 7,7560,54 after the
treatment, p<0,05. 0,5-point improvement was reported in
85,19% cases, 1-point – in 11,11%, and 1,5-point in 3,7%.
FSCT also resulted in physical and psychoemotional
improvement, higher self-esteem and spiritual realization.
FSCT improved functional capacity and life quality of
DMD patients, which proves that this method is very
promising and should be researched and advanced.
Study supported by: Our own company, not by any
sponsors
SMA is caused by inadequate expression of the ubiquitous
survival motor neuron (SMN) protein. In SMA mice, disruptions of peripheral and central synaptic function precede synaptic retraction and motor neuron loss. This period of
impaired synaptic connectivity may define a temporal window of disease reversibility. To characterize the cellular determinants of this synaptic vulnerability, we generated conditional SMA mice in which SMN expression was increased
specifically in motor neurons or muscle. We show that synaptic function and maintenance is solely dependent on SMN
expression in motor neurons, but SMN plays an independent
role in myofiber growth. Thus, SMN has distinct functions
in different tissues and widespread restoration of SMN may
be necessary for maximal therapeutic benefit.
The novel SMA drug RG3039 is in phase I clinical trials
and shows excellent biodistribution in multiple tissues. SMA
mice treated with RG3039 show increased survival and
improved synaptic integrity. Conditional SMA mice with
partial restoration of SMN selectively in motor neurons
show enhanced responsiveness to RG3039 suggesting that
RG3039 may work synergistically with therapies that would
increase SMN specifically in the CNS including gene therapy and antisense oligonucleotides.
Study supported by: HHMI, NINDS, Repligen
M1464. A Multicenter Phase II Open-Label Trial of
Valproic Acid and L-Carnitine in Infants with SMA Type I
Kathryn J. Swoboda, Kristin Krosschell, Thomas Crawford,
Charles Scott, John Kissel, Mary K. Schroth, Gyula Acsadi,
Priya Kishnani, Jurgen-Christoph von Kleist-Retzow, Guy
D’Anjou, Edward C. Smith, Bakri Elsheik, Louise R. Simard,
Thomas W. Prior and Sandra P. Reyna; Salt Lake City, UT;
Chicago, IL; Baltimore, MD; Fort Washington, PN;
Columbus, OH; Madison, WI; Detroit, MI; Durham, NC;
Cologne, Germany; Montreal, QC, Canada and Winnepeg,
MB, Canada
M1466. The Survival Motor Neuron (SMN) Gene as a
Therapeutic Target in Amyotrophic Lateral Sclerosis
Kevin Talbot, Neza Alfazema, Kay E. Davies and Bradley J.
Turner; Oxford, United Kingdom and Melbourne, Australia
Reduced levels of the SMN protein are the cause of spinal
muscular atrophy. Genetic studies have implicated SMN as
a risk factor for the development of amyotrophic lateral sclerosis (ALS). Crossing the SOD1 G93A mouse model of
familial ALS with a mouse expressing 50% of normal SMN
levels results in an accelerated ALS phenotype. Here we test
the hypothesis that increased levels of SMN can ameliorate
the ALS phenotype by crossing SOD1G93A strain with
Objectives: To perform an open label multicenter study of
valproic acid (VPA) and L-carnitine in SMA type I infants
to explore feasibility and potential efficacy endpoints.
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mice (PrP-SMN) overexpressing SMN in neurons. Weight,
survival, locomotor activity and motor neuron number were
compared with control SOD1G93A littermates. Two-fold
SMN upregulation significantly delayed weight loss, delayed
disease onset and preserved spinal motor neurons in
SOD1G93A PrP-SMN animals. There was no effect on
overall lifespan, which is most likely to be due to the depletion of SMN at the end stage of disease by misfolded
SOD1 protein. These results suggest that SMN upregulation
protects against early stages of disease and neurodegeneration in this model of ALS and supports the use of drugs
and biological agents which increase SMN levels in clinical
trials in ALS.
Study supported by: Motor Neurone Disease Association,
National Health and Medical Research Council, Australia
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Typically this has used independent component analysis.
However, alternative complex network or system measures,
including machine-learning classification, have the potential
to capture more subtle patterns of activity. They have been
applied to other conditions indicating that diseased brains
exhibit profound deviances from healthy patterns of
synchronicity.
We have applied multiple kernel optimization techniques
to patterns of complexity derived from R-fMRI scans
obtained from a large group of clinically well characterized
ALS patients seen as part of the Oxford Study for Biomarkers in Motor Neuron Disease (BioMOx). Preliminary
results demonstrate separation of patients from age-matched
healthy volunteers, with significant potential for clinical
translation of this novel biomarker approach in ALS.
Study supported by: Medical Research Council & Motor
Neurone Disease Association Lady Edith Wolfson
Fellowship
M1467. Quantitative Analysis of FLAIR Images in ALS
Has Diagnostic Potential
Jez Fabes, Lucy Matthews, Nicola Fillipini, Kevin Talbot,
Mark Jenkinson and Martin R. Turner; Oxford, United
Kingdom
M1469. Congenital Amyelinating Neuropathy:
A Genetically Heterogeneous Syndrome
Jean-Michel Vallat, Pierre-Marie Gonnaud, Philippe Latour,
Federico Garcia Bragado and Benoit Funalot; Limoges, France;
Pierre Benite, France; Lyon, France and Pamplona, Spain
Therapeutic development in amyotrophic lateral sclerosis
(ALS) would benefit from diagnostic biomarkers to permit
earlier administration of candidate drugs, as well as those
that capture phenotype heterogeneity. A biomarker derived
from routine investigations, such as standard clinical MRI
sequences, would have obvious appeal. T2-weighted MRI
corticospinal tract (CST) hyperintensity is frequently
observed in ALS, but regarded as insufficiently sensitive
when reported visually.
Quantitative objective MRI analysis was performed on
T2-weighted fluid-attenuated inversion recovery (FLAIR)
images acquired at 3 Tesla from 49 patients (33 ‘‘classical’’
ALS, 10 ‘‘flail-arm’’ ALS, 6 primary lateral sclerosis (PLS))
and compared with 21 age-matched healthy controls.
FLAIR intensity was significantly greater in the CST (p ¼
0.001) and corpus callosum (p ¼ 0.003) of MND patients.
Of the phenotype subgroups, the highest intensity was
found in PLS and the lowest in flail-arm patients. Classification of MND patients into the appropriate phenotype
improved from 52% accuracy with clinical measures alone,
to 82% with the addition of FLAIR intensities. In a longitudinal analysis, the increase in FLAIR intensity was correlated with the rate of clinical progression.
Quantitative measurement of regional FLAIR intensity
might provide additional diagnostic value in the clinical
setting.
Study supported by: Medical Research Council and
Motor Neurone Disease Association Lady Edith Wolfson
Fellowship
We report on 2 cases of congenital amyelinating neuropathy
(CAN) for which the causal genetic abnormalities have been
identified.
In one case, the disease was caused by a homozygous
10.7 kilobase-long deletion encompassing a myelin-specific
enhancer of EGR2. This patient had a very severe neuropathy and died at 7.5 months of age. Autopsy showed pathological abnormalities recapitulating the peripheral nervous
system phenotype of homozygous Egr2-null mice. No
EGR2 immunoreactivity was observed in Schwann cell
nuclei. The other case was due to the combination of a
17p11.2 deletion inherited from the father and a PMP22
point mutation inherited from the mother. The patient had
a much less severe clinical phenotype but showed a complete absence of peripheral myelin on sural nerve biopsy.
Our findings confirm that CAN can be caused by various
genetic abnormalities. The frequency of this disease is
underestimated and should be systematically discussed when
a ‘‘floppy infant’’ is examined. The complete absence of
myelin sheath can only be demonstrated by an ultrastructural study of nerve biopsy.
Study supported by: No one
M1470. Cerebral Metabolic Features of Clinically
Heterogenous A3243G Mitochondrial DNA Mutation
Carriers: Prognostic Implications
Nora Weiduschat, Petra Kaufmann, Xiangling Mao, Kristin
Engelstad, Vanessa Battista, Mary Sano, Michio Hirano,
Salvatore DiMauro, Darryl C. DeVivo and Dikoma C.
Shungu; New York, NY
M1468. Complexity-Based Classification of Resting-State
fMRI in Amyotrophic Lateral Sclerosis
Tomer Fekete, L. R. Mujica-Parodi and Martin R. Turner;
Stony Brook, NY and Oxford, United Kingdom
Anticipating the long-term outcome in asymptomatic mitochondrial mutation carriers is challenging and appropriate
biomarkers predicting prognosis do not exist. In the present
study we investigated 135 clinically heterogeneous carriers
of the A3243G mutation and 30 healthy controls (HC).
Mutation carriers included 45 fully symptomatic MELAS
patients; 11 asymptomatic individuals who would develop
the MELAS syndrome during the natural history study
(converters); and 79 individuals who would remain asymptomatic (non-converters).
Brain proton magnetic resonance spectroscopic imaging
(1H MRSI) revealed lactate elevations and reduced N-
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative
process involving extra-motor as well as motor cortical
regions. A robust non-invasively acquired cerebral ‘‘signature’’ reflecting disease activity in ALS, ideally also sensitive
to phenotype, would be extremely valuable diagnostically
and in the development of therapeutics.
Capturing the in vivo neurodegenerative process as a
whole is challenging. Resting-state functional MRI (RfMRI) uniquely allows the assessment of patterns of neuronal synchronicity (in space and time). Changes in R-fMRI
functional connectivity have been demonstrated in ALS.
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acetylaspartate (NAA) levels in fully symptomatic MELAS
patients compared to HC, as described previously. Surprisingly, converters not only had significantly higher lactate
values, but also higher NAA, choline and creatine values
than HC and non-converters, presumably reflecting compensatory changes preceding cerebral energy failure. Furthermore, in carriers significant linear correlations were found
between brain NAA and lactate levels, clinical indices and
peripheral mutation levels.
Cerebral metabolite values as determined by 1H MRS
might help to identify individual mutation carriers at
increased risk for developing MELAS. Continued longitudinal studies will be necessary to further clarify the prognostic
value of 1H MRS for individuals harboring the A3243G
mutation.
Study supported by: NICHD grant P01-HD32062;
CTSA 1-UL1-RR024156; an Irving Scholar Award; the
Marriott Mitochondrial Disorder Clinical Research Fund;
and the Colleen Giblin Foundation
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VAPB) were PCR-amplified from these pools and deeply
sequenced. The SPLINTER algorithm performed read
alignments and variant calling. C9ORF72 expansions were
assayed by repeat-primed PCR.
Results: 39% of familial and 6% of sporadic patients had
C9ORF72 expansions. Ten published mutations were found
in 13 individuals. 14 novel and potentially pathogenic variants were identified in 8 genes. 25 rare variants (MAF
0.5%) and many common polymorphisms were also
present.
Conclusion: Pooled-sample sequencing allowed the simultaneous screening of 17 ALS genes in a cohort of familial and sporadic ALS cases. In addition to rapidly and efficiently finding novel mutations for further characterization,
we identified a cohort of patients without mutations for
future gene discovery efforts.
Study supported by: NINDS K08
M1473. Optimizing the Total Neuropathy Score for
HIV-Associated Distal Symmetric Polyneuropathy
Jessica Robinson-Papp, Sandeep Sharma, David M. Simpson
and Susan Morgello; New York, NY
M1471. The Role for Macrophages in Nerve Repair in
an Animal Model of Autoimmune Neuropathy
Gang Zhang, Nataliia Bogdanova, Lixia Gao and Kazim A.
Sheikh; Houston, TX
Objective: The Total Neuropathy Score (TNS) has been
validated in diabetic and chemotherapy-induced neuropathy.
A modified TNS is used in HIV-associated distal symmetric
polyneuropathy (HIV-DSP), but has not been validated. We
sought to determine if this modification is valid and optimal for assessing HIV-DSP.
Methods: Seventy-one HIV-infected individuals underwent neurologic examination, symptom assessment, nerve
conductions, quantitative sensory testing (QST), and autonomic testing (heart rate response to deep breathing
(HRDB) and quantitative sudomotor axon reflex testing
(QSART)). Modifications of the TNS were assessed for internal consistency reliability (ICR), and validity as determined by correlation with the TNS and agreement with
clinical diagnosis.
Results: The modified TNS had acceptable ICR (Cronbach’s a ¼ .7), was highly correlated with the TNS (r ¼
.94; p<.001), and showed excellent agreement with clinical
diagnosis (Cohen’s j ¼ .77). However diagnostic accuracy
was improved by elimination of QST (j ¼ .83), and
improved further by the addition of autonomic measures
(symptoms, QSART, and HRDB; j ¼ .88). INTERPRETATION. HIV-DSP is best diagnosed using a modified
TNS that includes measures of autonomic function and
eliminates QST. However if autonomic tests are unavailable,
an abbreviated TNS is still reliable and valid.
Study supported by: K23NS066789
Autoantibodies against specific gangliosides contribute to
the development of certain forms of Guillain Barré syndrome (GBS), and are associated with slow and poor recovery in some GBS patients. Our previous work indicates
that human and mouse-derived anti-ganglioside antibodies
(Abs) inhibit nerve repair/axon regeneration both in-vivo
and in-vitro by engaging nerve cell membrane gangliosides. Now we have determined that this Ab-mediated inhibition is dependent on expression of activating Fc
gamma receptors. Macrophages play a vital role in cleaning myelin debris during Wallerian degeneration. Successful recruitment of hematogenous macrophages after nerve
injuries has been suggested to help the process of nerve
repair in peripheral nervous system (PNS). In the present
study, we sought to evaluate the contribution of macrophages in the anti-gangliosides Abs mediated-inhibition of
axonal regeneration after PNS injury in osteopetrotic mice
with macrophage deficiency (op/op mice). Our results
show that, after treatment with anti-gangliosides Abs, op/
op mice have significantly more regenerated myelinated
nerve fibers compared to wild type animals, implicating
that the antibody mediated-inhibition is dependent on the
presence of macrophages. Our studies provide an example
of context-dependent negative influence of macrophages
in nerve repair.
Study supported by: Acknowledgements: These studies
were supported by GBS/CIDP Foundation and NIH/
NINDS (NS42888 and NS54962).
M1474. Motor Neuron Disease-Associated Mutations in
p150/Glued Disrupt the Initiation of Retrograde Axonal
Transport at Synaptic Termini
Thomas E. Lloyd, James Machamer, Sarah Collins and Alex L.
Kolodkin; Baltimore, MD
M1472. Comprehensive Genetic Screening of a Large
ALS Cohort Using Pooled-Sample Sequencing
Matthew B. Harms, Janet Cady, Peggy Allred, Taha Bali,
Ryan T. Libby, Alan Pestronk, John Ravits and Robert H.
Baloh; Saint Louis, MO; La Jolla, CA and Los Angeles, CA
Increasing evidence suggests that defects in axonal transport
may be a primary cause of neurodegenerative diseases.
p150/Glued is the major subunit of dynactin, a complex
that functions with dynein in minus-end-directed microtubule transport. Different mutations within the p150 CAPGly microtubule-binding domain cause distinct autosomal
dominant neurodegenerative syndromes, termed Hereditary
Motor Neuropathy 7B (HMN7B) and Perry Syndrome.
HMN7B-associated mutations introduced into Drosophila
Glued using homologous recombination generate a partial
loss-of-function
allele
(Gl[G38S])
with
impaired
Objective: Genetically characterize a cohort of ALS patients
using pooled-sample sequencing to circumvent costly, timeconsuming, and sample-depleting traditional sequencing.
Methods: DNA from 41 familial probands and 373 sporadic ALS patients was pooled in groups of 25-50 individuals. Coding exons of 17 genes (ANG, C9ORF72, DAO,
DCTN1, EWSR1, FIG4, FUS, OPTN, SETX, SIGMAR1,
SOD1, SQSTM1, TAF15, TARDBP, UBQLN2, VCP,
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neurotransmitter release at the neuromuscular junction
(NMJ) and adult-onset locomotor dysfunction. Interestingly,
Gl[G38S] animals accumulate endosomes within swollen
terminal boutons of the NMJ due to a neuron autonomous
loss of Glued function. Live imaging analysis of vesicle
transport along axons and at the NMJ suggests that this
phenotype is not due to a generalized defect in axonal transport, but rather a specific defect of dynactin in coordinating
initiation of retrograde transport at microtubule plus ends
of the distal-most NMJ boutons, called terminal boutons.
Together, these data suggest that the presynaptic retractions
that occur early in motor neuron degenerative diseases begin
with an inability to initiate retrograde axonal transport at
terminal boutons.
Study supported by: NINDS K08 award; Robert Packard
Center for ALS Research
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T1502. Antipsychotic Drug Effects at Nicotinic AChRs
Studied in a Novel Model System
Tai-Xiang Xu, Limin Hao, Bruce M. Cohen and
Edgar A. Buttner; Belmont, MA
We have shown that pharmacogenomic experiments in C.
elegans identify novel and mechanistically important pathways modulated by antipsychotic drugs (APDs). Recently,
we conducted the first genetic screen for APD targets in an
animal, a genome-wide RNA interference (RNAi) screen for
Suppressors of Clozapine-induced Larval Arrest (scla genes).
The screen covered 17,000 C. elegans genes and led to the
identification of 40 suppressors. We have characterized the
suppressor acr-7, which encodes a homolog of the human
a-like nicotinic acetylcholine receptors (nAchRs). Our preliminary results indicate that acr-7 is strongly expressed in
the pharynx and that clozapine activates ACR-7, leading to
a depolarizing neuromuscular blockade of pharyngeal muscle
and subsequent larval arrest. Importantly, the observation
that APDs activate a-like nAchRs is novel and might be relevant to clinical drug effects. Since human orthologs of acr7 may mediate the therapeutic and/or toxic effects of APDs
in clinical use, we are using physiological studies in heterologous systems to identify mammalian orthologs of acr-7.
These orthologs may pose inviting drug targets for the development of compounds that replicate clozapine’s therapeutic effects but that do not share its side effects.
Study supported by: Shervert Frazier Research Institute
2012 Annual Meeting Tuesday,
October 9, 2012
Poster Session Abstracts
Posters will be displayed in Gloucester, located on the
3rd floor in the Back Bay Hall of the Marriott Copley
Place from 11:30 am – 7:00 pm, with authors present
from 5:30 pm – 7:00 pm.
NOTE: An asterisk designates a resident/fellow travel award
winner.
T1503. From Molecule to Mechanism: How Listening to
Synapses Reveals Novel Insights to OCD Pathogenesis
Nicole Calakos, Yehong Wan, Meng Chen, Kristen Ade,
William Wetsel and Guoping Feng; Durham, NC and Boston,
MA
Behavioral Neurology
T1501. Metabolic Abnormalities in the Caudate in
Patients with Mitochondrial Disorders Measured Using
Proton Magnetic Resonance Spectroscopy
Rebecca Anglin, Patricia Rosebush, Michael Noseworthy,
Mark Tarnopolsky and Michael Mazurek; Hamilton,
Canada
Compulsive behaviors are disruptive, maladaptive behavioral
responses that occur in diverse conditions and across our
life span; arising in conditions such as Obsessive Compulsive Disorder (OCD), Tourette’s Syndrome, autism, drug
addiction, medication side effects and neurodegenerative diseases. Knowledge of the molecular pathways, cellular mechanisms, and circuits that drive compulsive motor behaviors
can greatly accelerate development of effective treatments
and is at present greatly lacking. Using a mouse model that
lacks a postsynaptic scaffold protein and exhibits intransigent grooming, anxiety-like behaviors and therapeutic
response to fluoxetine (Welch et al., 2007), we have found a
role for excessive metabotropic glutamate receptor (mGluR)
signaling at cortico-striatal synapses in driving OCD-like
behavior. Defects in synaptic function and plasticity first
implicated an overactive mGluR signaling pathway and can
be used to predict circuit function and behavioral states.
These results implicate a new class of receptors in compulsive behavioral disorders and elucidate synaptic and circuitlevel mechanisms.
Study supported by: NINDS, Klingenstein Foundation,
Tourette Syndrome Association, Duke Institute for Brain
Sciences
Mitochondrial disorders are clinical syndromes associated
with mutations in the mitochondrial or nuclear genome
that result in impaired oxidative phosphorylation and deficient energy production. To date there has not been a systematic investigation of brain metabolites in patients with
mitochondrial disorders compared to matched healthy controls. This study used single voxel proton magnetic resonance spectroscopy (PRESS, TE ¼ 35 ms, TR ¼ 2000 ms,
256 acquisitions) to measure N-acetyl-aspartate (NAA), creatine (Cr), glycerophosphocholine (GPC), GPCþphosphocholine (PCh), myoinositol (mI), and glutamine þ glutamate (Glx) in the caudate, anterior cingulate and
hippocampus in 15 patients with mitochondrial disorders
and 15 age and sex-matched healthy controls. Patients with
mitochondrial disorders had significantly reduced NAA (p
¼ 0.023) in the caudate compared to controls. Cr,
GPCþPCh and Glx were also reduced in the caudate in
patients compared to controls. These results support previous assertions that NAA is a useful marker of mitochondrial
dysfunction and that the striatum is highly susceptible to
mitochondrial oxidative phosphorylation defects. Given the
caudates role in cognitive and executive functions, our findings also suggest that metabolic abnormalities in the caudate
may contribute to neuropsychiatric symptoms in these
patients.
Study supported by: Physicians Services Incorporated
(Grant R06-24)
T1504. Brainstem Lesions and Central Auditory
Processing
Gastone G. Celesia; Chicago, IL
Auditory processing can be disrupted by brainstem lesions.
Lesions below or within the cochlear nuclei result in ipsilateral auditory processing abnormalities detected in routine
testing, disorders rostral to the cochlear nuclei may result in
bilateral abnormalities or may be silent.
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Lesions in the superior olivary complex and trapezoid
body show a mixture of ipsilateral, contralateral and bilateral
abnormalities, whereas lesions of the lateral lemniscus, inferior colliculus and medial geniculate body do not affect peripheral auditory processing and result in predominantly
subtle contralateral abnormalities that may be missed by
routine auditory testing.
In these cases psychophysical methods developed for the
evaluation of central auditory function should be employed
(dichotic listening, inter-aural time perception, sound localization, etc.).The extensive connections of the auditory
brainstem nuclei not only are responsible for binaural interaction but also assure redundancy in the system. This redundancy may explain why small brain stem lesions are
sometimes clinically silent.
Any disorder of the brainstem (neoplasms, vascular disorders, infections, trauma, demyelinating disorders, neurodegenerative diseases, malformations, etc.) that involves the auditory pathways and/or centers may produce hearing
abnormalities.
Study supported by: none
no conflicts of interest
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such as when administered as intermittent theta-burst stimulation (iTBS) to the vermis in schizophrenia (Demirtas-Tatlidede,2010). Although classically mainly associated with
movement control, the functional role of cerebellum has
recently been also linked to emotion and cognitive regulation (Schmahmann,2010). It is suggested that cerebellum
may exert this regulatory control via cerebello-cortical loops
and its connectivity to areas associated with higher order
cognitive processing including the prefrontal cortex (PFC).
However, human cerebellum-PFC connectivity and the neurophysiological effects of cerebellar stimulation remain relatively unexplored. TMS combined with EEG permits measuring PFC and motor cortex dynamics in healthy and
diseased (Farzan,2010). Here, we employ TMS-EEG to
probe cortical processes in the PFC and motor cortex before
and after active and sham vermis and lateral cerebellar
iTBS. Results to date suggest that active cerebellar iTBS
modulates PFC cortical dynamics compared to sham, a
mechanism which may explain the therapeutic efficacy of
cerebellar stimulation. The results and methods presented
here may ultimately help identify patients who would benefit from cerebellar stimulation therapy.
Study supported by: Supported in part by the Sydney R.
Baer Jr, MINDlink, and Birmingham Foundations. FF
received postdoctoral fellowship scholarship from Canadian
Institute of Health Research (CIHR). This work was conducted with support from Harvard Catalyst | The Harvard
Clinical and Translational Science Center (National Center
for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health
Award #UL1RR 025758 and financial contributions from
Harvard University and its affiliated academic health care
centers). The content is solely the responsibility of the
authors and does not necessarily represent the official views
of Harvard Catalyst, Harvard University and its affiliated
academic health care centers, or the National Institutes of
Health.
FF, MAH, APC and JDM have no conflicts of interests.
APL serves on the scientific advisory boards for Nexstim,
Neuronix, Starlab Neuroscience, Allied Mind, Neosync, and
Novavision, and holds intellectual property on the real-time
integration of transcranial magnetic stimulation (TMS) with
electroencephalography (EEG) and magnetic resonance
imaging (MRI).
T1505. Frequency of Elevated ASO Titer in Children
and Adolescents at Onset or Exacerbation of Tic, OCD
or Aggression and Symptomatic Effect of Antibiotic
Treatment
Brittany M. DiVito, Karen D. Ellis and Drake D. Duane;
Scottsdale, AZ and Tempe, AZ
Background: Whether streptococcal infection with immune
response causes or exacerbates tic, obsessive-compulsiveness
(OCD), or aggressive (Agg) in pediatric patients is debated
(Swedo, 1998; Singer, 2005). This study examines the frequency with which in referred behavioral pediatric patients,
with a history of the above symptoms at onset or increment
within six months or less, an elevated anti-streptolysin O
(ASO) titer was obtained and, if antibiotics (ab) treatment,
no adjustment in concomitant Rx, the course of presenting
symptom(s).
Method: Retrospective chart analysis of pediatric behavioral patients in whom ASO titers were drawn, the frequency of elevated titers, the course of presenting symptom(s) if ab therapy was employed.
Results: N-45(34M), mean age 13þ/-4.5 years; Dx Tourette-10; OCD-24; AD(H)D-11
Elevated ASO titer 16(36%)(13M); 10 ab Rx(2-all 3 sx,
3-with 2 sx)
Symptom Improved/Total Tic 7(86%)
OCD 5/7(7%)
Agg3/3(100%)
No ab Rx: unchanged-3, unknown-3
Conclusions: ASO titers are not infrequently elevated in
behavioral pediatric patients (one-third). Ab Rx may be
associated with acute Sx reducton, whether tic, OCD or
Agg; the mechanism remains obscure.
Study supported by: N/A
T1507. Changes in Cortical Functional Connectivity
Introduced with Intermittent Theta Burst TMS to the
Cerebellum Assessed with fMRI
Mark A. Halko, Faranak Farzan, Andrea Pousada-Casal,
Jeremy Schmahmann and Alvaro Pascual-Leone; Boston, MA
Increasing evidence points to the cerebellum as a universal
modulator of cortical activity, via connections with motor
and non-motor cortical areas which are organized topographically throughout the cerebellum (Schmahmann
1991). Understanding how the cerebellum modulates nonmotor cortical networks is central to understanding the
cerebellar role in cognition and neuropsychiatric disorders.
Resting state functional connectivity (rs-fcMRI) has
recently emerged as a tool to investigate network function
and dysfunction, allowing for study of complex network
functions in humans. Transcranial magnetic stimulation
(TMS) combined with rs-fcMRI can be used to characterize dynamics in large-scale brain networks (Eldaief 2011).
Here we apply this technique to evaluate the role of cerebellar modulation on cortical network function. Healthy
subjects received intermittent theta-burst (iTBS) TMS to
T1506. Modulation and Assessment of the CerebelloCortical Connectivity through Transcranial Magnetic
Stimulation (TMS) Combined with
Electroencephalography (EEG)
Faranak Farzan, Mark A. Halko, Andrea Pousada-Casal,
Jeremy D. Schmahmann and Alvaro Pascual-Leone; Boston,
MA
Clinical studies have demonstrated the efficacy of cerebellar
TMS in ameliorating emotional and cognitive impairments,
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vermal or lateral cerebellar targets. Network activity was
assessed before and after stimulation using rs-fcMRI. Preliminary data suggests vermal stimulation differentially
modulates functional connectivity from the medial frontal
cortex, when compared to lateral or sham stimulation.
These results suggest modulation of cerebellar function
with iTBS TMS may have utility to assess and characterize
network-level abnormalities.
Study supported by: Supported in part by the Sydney R.
Baer Jr, MINDlink, and Birmingham Foundations. FF is
supported by Canadian Institutes of Health Research. This
work was conducted with support from Harvard Catalyst |
The Harvard Clinical and Translational Science Center
(National Center for Research Resources and the National
Center for Advancing Translational Sciences, National Institutes of Health Award #UL1RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers)
MAH, FF, APC and JDM have no conflicts of interest.
APL serves on the scientific advisory boards for Nexstim,
Neuronix, Starlab Neuroscience, Allied Mind, Neosync, and
Novavision, and holds intellectual property on the real-time
integration of transcranial magnetic stimulation (TMS) with
electroencephalography (EEG) and magnetic resonance
imaging (MRI).
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T1509. Effects of the Dopamine Agonist Rotigotine on
Hemispatial Neglect Following Stroke
Nikos Gorgoraptis, Yee-Haur Mah, Bjoern Machner, Victoria
Singh-Curry, Paresh Malhotra, Maria Hadji-Michael, David
Cohen, Robert Simister, Ajoy Nair, Elena Kulinskaya, Nick
Ward, Richard Greenwood and Masud Husain; London,
United Kingdom; Lübeck, Germany and Norwich,
United Kingdom
Hemispatial neglect following right-hemisphere stroke is a
common and disabling disorder for which there is currently
no established treatment. Dopamine agonists have been
shown to play a role in selective attention and working
memory, two core cognitive components of the syndrome.
Here, we investigated the effects of the dopamine agonist
rotigotine using a double-blind, randomised placebo-controlled ABA design. Each patient was assessed for 20 testing
sessions, in three phases: pre-treatment, on transdermal rotigotine for 7-11 days, and post-treatment, with the exact duration of each phase randomised within limits.
16 right-hemisphere patients completed the trial. Performance on the Mesulam shape cancellation task improved
significantly while on rotigotine, with the number of targets
found on the left increasing 12.8% (P ¼ 0.012) on treatment and spatial bias reducing by 8.1% (P ¼ 0.016). This
improvement in visual search was associated with an
enhancement in selective attention but not in working
memory or sustained attention measures. Overall, rotigotine
was not associated with any significant improvement in
motor performance. This proof-of-concept study suggests a
beneficial role of dopaminergic modulation on visual search
and selective attention in patients with hemispatial neglect
following stroke.
Study supported by: Medical Research Council (Experimental Medicine grant) and Wellcome Trust Senior
Fellowship
T1508. PRISM Registry: A Novel Tool To Determine the
Prevalence of Pseudobulbar Affect
Daniel Kantor, Jonathan Fellus and Randall E. Kaye; Ponte
Vedra Beach, FL; Secaucus, NJ and Aliso Viejo, CA
Background: Pseudobulbar affect (PBA) is characterized
by uncontrollable, inappropriate laughing and/or crying
outbursts in patients with neurologic insult. While US
prevalence is estimated at 1.5–2 million, clinicians seldom
ask proactively about symptoms. The PBA registry
(PRISM) was initiated to evaluate PBA prevalence
prospectively.
Objective: Identify barriers to registry participation and
implement strategies to facilitate enrollment.
Methods: Sites enroll via a centralized Web portal and
register with a central Institutional Review Board (IRB).
Patient screening begins following IRB approval. In all, 500
sites will enroll 10,000 patients at PBA risk in Alzheimer’s
disease, ALS, MS, Parkinson’s disease, stroke, or brain
injury. Patients complete the Center for Neurologic Study–
Lability Scale (CNS-LS) and a QoL measure. Demographic/
disease characteristics are also collected.
Results: Initial site-recruitment uncovered obstacles
including community-physician unfamiliarity with GoodClinical-Practice processes, need for local IRB use at some
sites, and lack of startup-cost recognition. Counterstrategies
increased patient-enrollment rate fivefold, to 500/
month. Currently, 2,244 patients have enrolled, with PBA
prevalence 43.3% (by CNS-LS score 13).
Conclusions: PRISM is a novel tool to estimate PBA epidemiology across settings. Successful registries require community-physician training/support, plus flexibility to accommodate local IRBs.
Study supported by: Avanir Pharmaceuticals, Inc.
Dr. Kantor received personal compensation for serving as
a speaker and consultant for Avanir Pharmaceuticals, Inc.
Dr. Fellus has served on speakers bureau and has been
paid honoraria and consultancy fees by Avanir Pharmaceuticals, Inc.
Dr. Kaye is an employee of Avanir Pharmaceuticals, Inc.
and received stock options as a term of employment.
T1510. Sudden Visual Spatial Memory Loss as
Presenting Manifestation of CJD
Nivedita Jerath, Aarti Jerath, Shelley Waite, Deborah Forst,
Shivraj Sohur and Jeremy Schmahmann; Boston, MA
A 62 year old previously healthy man awoke from propofol anesthesia for a colonoscopy with visual spatial memory impairment. He was disoriented in the hospital room,
and whereas he drove himself to the procedure, he was
unable to drive home. T1, T2 and DWI-MRI were unremarkable, but there was subtle FLAIR hyperintensity in
right posterior and medial parietal cortices. Over the
ensuing month, symptoms progressed to right-left confusion, and trouble finding rooms in his house, although
he still paid bills and sent emails. Examination findings
were restricted to difficulty producing the floor plan of
his house, and suboptimal visual encoding and visual
memory. Worsening spatial disorientation and forgetfulness
prompted a PET scan showing right parietal and occipital
hypometabolism, EEG with runs of frontal sharp waves
and triphasic morphology, and LP subsequently positive
for 14-3-3 protein. DWI-MRI 2 months into the course
showed restricted diffusion in right frontal, parietal, and
occipital lobes consistent with CJD. Symptoms progressed
to short-term memory loss, increasing confusion, and
myoclonus, and he succumbed 3 months after onset. Sudden onset of spatial predominant features with initially
normal DWI-MRI are distinctive and unusual manifestations of CJD.
Study supported by: Supported in part by the MINDlink
and Birmingham Foundations
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T1511. Inflammation and Cognitive Decline in Normal
Elderly
Joel H. Kramer, Brianne Bettcher, Ralph Green and Josh
Miller; San Francisco, CA and Davis, CA
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ing disability. The transition into adulthood is a critical
phase in the management of these patients, which is further
complicated by the evolution of the psychiatric symptoms.
Objective: To describe the evolution of the psychiatric
co-morbidity in a cohort of patients with neurologic disabling perinatal conditions during the transition phase.
Materials and methods: 200 subjects with perinatal neurologic conditions were retrospectively traced and analysed
for their psychiatric co-morbidity and therapeutic needs.
The same group was re-analysed after transition into
adulthood.
Results: Psychiatric co-morbidity is seen in 26% of
patients under age 18, with behavioural disturbances in intellectual disability (5.5%) followed by obsessive compulsive
disorder and personality disorders (both around 4%) being
the most prevalent diagnosis. 12% of these patients, once
transitioned into adulthood, required psychiatric care, with
a shift towards the diagnosis of psychosis in most, and need
for psychopharmacological treatment in 86%. New psychiatric co-morbidity emerged in 4%.
Conclusion: The transition phase for children with neurological disabling condition is a critical point of change
including psychiatric co-morbidity requiring appropriate
management.
Study supported by: Institutional Funds
Inflammation represents a normal response to injury. Sustained neuroinflammation, however, can affect cognition
and brain structure. The goal of this study was to determine
if plasma levels of C-reactive protein (CRP), a marker of
chronic inflammation, was associated with longitudinal
change in executive functioning in normal elderly.
We studied 44 normals whose informants corroborated
intact daily functioning and on whom we obtained CRP levels at baseline. The sample include 23 subjects with no detectible CRP (mean age ¼ 70), and 21 subjects with detectible
CRP (mean age ¼ 72; CRP ¼ 0.35 mg/dL). Executive functioning was measured using the NINDS EXAMINER battery
at baseline and 20 months later. The primary dependent
measure was the EXAMINER executive score.
Data were analyzed using general linear model controlling
for age and education. The primary analysis, the group by
time interaction, was significant (p<.05). Follow-up analyses
indicated that the two groups performed similarly at baseline. At follow-up, the executive score in the undetectable
CRP group was stable, whereas the score in the detectible
CRP group dropped by almost one standard deviation.
Mechanisms underlying this association between inflammation and rate of cognitive decline are unclear, but potentially include white and grey matter vulnerability.
Study supported by: NIH
T1514. fMRI Study of Yogic Meditation
Shri K. Mishra, Manbir Singh and Parampreet Singh; Los
Angeles, CA and Sylmar, CA
We present the results of a pilot fMRI study involving 4
subjects to observe and understand the selective activations
of certain brain areas during Meditation. The neural substrates of Yogic meditation are not well understood. Meditation is theorized to be a conscious mental process that induces a set of integrated physiological changes within the
cortex, hypothalamus and other parts of the brain termed as
the ‘‘relaxation response.’’ Trained (Patanjali Yoga) practitioners were studied. A 3-part 1-min block design alternating between a relaxation(control), and meditation(test) with
an imaginary visual fixation and an auditory stimulation,
was used to acquire 10 contiguous 8mm thick axial sections
in a 1.5T GE MRI. The data was analyzed using standard
SPM software. Images showed strongly activated right prefrontal regions during the visual and auditory meditation
phases compared to no activations during the relaxation
state. A comparison between the visual and auditory fixations revealed shifts within the prefrontal and temporal
regions. Activations in occipital and temporal regions were
also observed. Specific cortical activations could be modulating the known neurophysiological and biological effects of
meditation. Another larger study utilizing DTI-fMRI to further comprehend these effects is currently underway. Details
will be presented.
Study supported by: None
T1512. Acute Impairments of Empathy
Richard Leigh and Argye E. Hillis; Baltimore, MD
Hypothesis: Impaired perception of another person’s pain,
positive or negative emotions may differentially depend on
cingulate and insula, as indicated by fMRI studies of empathy in healthy participants.
Methods: We identified areas of acute ischemia associated
with errors in identifying discomfort, positive, or negative
emotions from hearing stories and watching videos in 30
patients with acute right hemisphere ischemic stroke symptoms. Ten were excluded for errors on facts about the stories/
videos. We identified DWI abnormality in 12 regions in
frontal, temporal, parietal cortex, cingulate, insula, and thalamus. We identified associations between ischemia in each
region and impairment empathy tests with Fisher’s Exact.
Results: Ischemia in the right cingulate (p ¼ 0.004) and premotor cortex (p ¼ 0.02) was associated with errors in perception of negative emotions. Volume of infarct (ADC <600) was
not significantly different for patients with and without errors
on empathy tasks (mean ¼ 19.7 vs 1.9 cc; t ¼ -1.1; p ¼ .28).
Patients with insular ischemia made empathy errors, but
most were excluded for factual errors and had large lesions
due to MCA occlusion.
Conclusion: Ischemia in right cingulate or premotor cortex or can cause impaired perception of another’s negative
emotions acutely; more power is needed to confirm the role
of the insula.
Study supported by: NINDS R01 NS047691
T1515. Withdrawn.
T1513. Evolution of Psychiatric Co-Morbidity in the
Transition Phase in a Cohort of Patients with
Neurological Perinatal Disability
Sara Piccoli, Gianni De Polo and Andrea Martinuzzi;
Conegliano, Italy
T1516. A Randomised Controlled Trial of Cognitive
Behaviour Intervention for Impulse Control Behaviours
Affecting Parkinson’s Disease Patients and Their
Caregivers
David Okai, Sally Askey-Jones, Michael Samuel, Sean S.
O’Sullivan, Ray Chaudhuri, Anne Martin, Joel Mack, Richard
G. Brown and Anthony David; London, United Kingdom;
Ashford, United Kingdom and Portland, OR
Background: Psychiatric and behavioural disturbances frequently accompany perinatal neurologic conditions worsen-
Background: Impulse control behaviours (ICBs) are a complication of treatment for Parkinson’s disease (PD). They
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comprise failure to resist an impulse harmful to self /others
and include compulsive gambling, shopping, eating and sex.
There is currently no treatment.
Methods: A randomised-controlled trial of a cognitivebehavioural therapy (CBT) for PD patients with clinically
significant ICBs. Aims were to improve symptom severity,
in the patients and carer burden and distress. The intervention comprised 12 sessions of CBT, compared with waiting
list control.
Findings: 27 patients were randomised to the intervention and 17 to the waiting list. There was significant
improvement in symptom severity in the CBT intervention
group vs. controls (v2 (1, N ¼ 40) ¼ 16.46, p < 0.001).
Anxiety and depression also improved as secondary outcomes. No significant changes in carer burden and distress
were shown, but general psychiatric morbidity improved significantly in the carer group.
Interpretation: This CBT intervention is the first to
show efficacy in ICBs related to PD.ICBs in those on the
waiting list show no tendency to remit. The study demonstrates the potential benefit of a psychosocial treatment
approach for ICBs.
Study supported by: The project was funded by Parkinson’s UK with additional support from NIHR Biomedical
Research Centre for Mental Health at the South London
and Maudsley NHS Foundation Trust (SLaM) and Institute
of Psychiatry, King’s College London.
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Felicia Bergstrom, Rachael Mann, Caroline Schaefer, and
Rebecca Baik are employees of Covance Market Access Services Inc., who were paid consultants to Pfizer in the development of this study.
Dr. Srivinas Nalamachu is a paid investigator for this
study.
T1518. Characteristics of Subjects with Painful Diabetic
Neuropathy (PDN) in the US: BEAT Neuropathic Pain
Observational Study
Felicia Bergstrom, Rachael Mann, Alesia Sadosky, Bruce
Parsons, Caroline Schaefer, Rebecca Baik, Gergana Zlateva,
Brett Stacey, Srivinas Nalamachu, Edward Nieshoff and
Michael Tuchman; Gaithersburg, MD; San Diego, CA; New
York, NY; Portland, OR; Leawood, KS; Detroit, MI and Palm
Beach Gardens, FL
Objective: Characterize pain, sleep, function and healthcare
utilization in US subjects with PDN.
Methods: This was observational, cross-sectional study of
112 PDN subjects recruited during routine visits from general practitioner and specialist sites. Subjects completed a
one-time questionnaire; investigators completed a case
report form based on 6-month retrospective chart review to
capture utilization. Subject-reported pain and function were
assessed using the Brief Pain Inventory-Short Form, and
sleep using the MOS Sleep Scale.
Results: Subjects’ mean age: 61 years; 53% were female.
Most common conditions included sleep disturbance/insomnia (44%), depressive symptoms (41%), and anxiety (36%).
Mean pain severity score was 5.2 (0-10 scale), and 29%
reported severe pain. Mean MOS Sleep Disturbance score:
51.1, MOS Sleep Problems Index: 48.5 (0-100 scale). Mean
pain interference with function was 5.0 (0-10 scale). 86%
of subjects were prescribed medications; top 3 classes prescribed: anticonvulsants (54%), opioids (31%), and
NSAIDs: (19%). Subjects averaged 2.8 physician visits over
6 months.
Conclusions: PDN subjects exhibited high pain levels
which were associated with poor sleep and function. Medication and healthcare resource utilization in PDN were
prevalent.
Study supported by: Pfizer Inc.
Alesia Sadosky, Bruce Parsons, and Gergana Zlateva are
employees of Pfizer Inc.
Felicia Bergstrom, Rachael Mann, Caroline Schaefer, and
Rebecca Baik are employees of Covance Market Access Services Inc., who were paid consultants to Pfizer in the development of this study.
Dr. Srivinas Nalamachu is a paid investigator for this
study.
T1517. Characteristics of Subjects with Chronic Low
Back Pain-Related Neuropathic Pain (CLBP-NeP) in the
US: BEAT Neuropathic Pain Observational Study
Alesia Sadosky, Caroline Schaefer, Bruce Parsons, Rebecca Baik,
Rachael Mann, Felicia Bergstrom, Gergana Zlateva, Brett
Stacey, Srivinas Nalamachu, Michael Tuchman and Edward
Nieshoff; New York, NY; Gaithersburg, MD; San Diego, CA;
Portland, OR; Leawood, KS; Palm Beach Gardens, FL and
Detroit, MI
Objective: To characterize health-related quality of life
(HRQoL), pain, function, and impact on productivity in
subjects with CLBP-NeP.
Methods: The BEAT Neuropathic Pain study is a crosssectional observational study of 106 subjects diagnosed with
CLBP-NeP recruited during routine physician office visits
with primary care or specialty physicians. Subjects completed a questionnaire and physicians completed a case
report form based on 6-month retrospective chart review.
Subject-reported pain and function were assessed using the
Brief Pain Inventory-Short Form, HRQoL using the EQ5D, and productivity using the Work Productivity and Activity Impairment scale.
Results: Subjects’ mean age was 54 years, 58% were
female, 24% were employed. 88% had comorbid conditions
(sleep disturbance/insomnia: 59%, depressive symptoms:
52%, headache/migraine: 46%). Mean pain severity score
was 6.0; mean pain interference with function was 6.6 (010 scale), with most affected domains being; normal work,
sleep, enjoyment of life. 41% reported severe pain. Mean
EQ-5D utility was 0.50 (-0.1 to 1.0 scale). Lost productivity was exhibited as 51% overall work and 64% activity
impairment.
Conclusions: CLBP-NeP subjects exhibit high pain levels, poor HRQoL, and diminished function and
productivity.
Study supported by: Pfizer Inc.
Alesia Sadosky, Bruce Parsons, and Gergana Zlateva are
employees of Pfizer Inc.
T1519. Increased Phosphorylation of the MAPK/ERK
Pathway Is Associated with Social Impairment in BTBR
Mice
Alireza Faridar, Dorothy M. Jones-Davis, Mu Yang, Adam M.
Katz, Michael D. Weber, Eric Rider, Saunak Sen, Jacqueline
Crawley and Elliott H. Sherr; San Francisco, CA and
Bethesda, MD
Increased activation of the MAPK/ERK signaling pathway
has been found in the brains of BTBR Tþtf/J mice, a strain
exhibiting behaviors with face validity to autism. In this
study we evaluated whether dysregulation of the pathway
directly correlates with autism-relevant traits in the strain.
Levels of phospho-ERK were significantly increased in the
frontal cortex of BTBR vs. C57BL/6J mice; although no
significant difference in total ERK protein expression was
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observed. Next, we intercrossed BTBR and C57BL/6J mice
and assessed social behaviors in 400 F2 offspring. The
expression levels and state of phosphorylation of ERK and
related signaling kinases were evaluated in the prefrontal
cortex of F2 mice that lie on the two extremes of the social
behavior spectrum. We observed a significant correlation
between juvenile social behavior and phospho-MEK/ERK
(p ¼ 0.008, p ¼ 0.03, respectively); although, we did not
find any significant association between this behavior and
total protein levels of MEK/ERK. Our findings demonstrate
that autism-relevant behaviors may correlate with activity of
the ERK signaling pathway, and suggest that this pathway
may provide novel diagnostic markers and therapeutic targets for autism.
Study supported by: Pfizer
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ever there was a non-significant trend for patients with family history to have longer remissions.
Family history does not seem to predict electroconvulsive
therapy efficacy. A larger sample size is needed to explore
trends fully, which may prove that the time to relapse is significantly affected, possibly because patients with family history have a more ‘‘biological’’ type of depression.
Study supported by: Cardiff University School of
Medicine
T1522. Syphilitic Polyradiculoneuropathy in an
Immunocompetent Patient
Safaa Zahlane, Nissrine Louhab and Najib Kissani;
Marrakesh, Morocco
Introduction: The neurosyphilis is still prevalent. Its most
common clinical presentation includes tabes dorsalis and
general paresis. In contrast, polyradiculoneuritis has rarely
been reported during syphilis.
Case report: 45 years old man without medical past history, reffered to neurology out patient for acute leg weakness
and heaviness. Clinical examination revealed bilateral leg
weakness. Deep tendon reflexes were absent. Cutaneous
hypoesthesia was on the legs. There were no pyramidal
signs, no cranial nerves abnormalities and no incontinence.
Electroneuromyograms showed sensorimotor demyelination
and axonal loss evoking polyradiculoneuretis. Lumbar punctures showed an albumino-cytological dissociation. VDRL
and TPHA were positive in both serum (VDRL: 1/16,
TPHA :1/1280) and CSF (VDRL: 1/6, TPHA1/640). A
serodiagnostic tests (HIV, Borrelia, hepatitis C and B) were
negative.The patient received 30 million units of intravenous penicillin G daily for 10 days, four times with delay of
3 months, Muscular leg weakness disappeared and his clinical condition improved.
Conclusion: Syphilitic polyradiculoneuropathy has rarely
been reported. Infection due to T. pallidum is a curable
cause of polyradiculoneuritis which may occur in HIV-negative patients; appropriate tests in both serum and CSF
should be performed in patients with polyradiculoneuritis.
Study supported by: Department of neurology and laboratory of neuroscience
T1520. Stepwise Onset of Memory Impairment,
Encephalopathy and Hearing Loss Presenting as Susac
Syndrome
Alvin Shrestha, Tatiana Mihalova, Daniel Burns and Mark
Willmot; Birmingham, United Kingdom
A 40 year old lady was seen in the neurology clinic with
migraines on a background of mild memory impairment
and behavioural changes. An initial MRI brain was normal.
Four months later, she was admitted with acute confusion,
fever and drowsiness, requiring ventilation on ITU. She was
treated empirically with Aciclovir and Cefotaxime. Lumbar
puncture was acellular, with a protein of 0.71g/L. An MRI
brain revealed several subcortical white matter lesions. EEG
showed non-specific encephalopathy. Vasculitis screen was
negative. She improved clinically but repeated MRI scans
over the next 2 months showed new white matter lesions,
including pericallosal lesions. She developed gradual sensorineural hearing loss, requiring a hearing aid. She was diagnosed with Susac syndrome, although an ophthalmology
review failed to demonstrate retinal artery occlusions. MRI
brain 8 months following her encephalopathy showed a
reduction in white matter lesions, but did demonstrate classic punched-out pericallosal lesions. Late attempts with steroids treatment led to a minimal improvement of memory,
headache and behavioural problems.
Susac syndrome should be considered when pericallosal
lesions are seen with an atypical history, including new onset
of progressive hearing loss.
Study supported by: Conflict of interest: Nil
Headache and Pain/Neuro-otology
T1521. The Effect of a Family History of Major
Depression on the Outcome of Electroconvulsive
Therapy
Ceri A. Smith; Cardiff, Wales, United Kingdom
T1601. Lidocaine Desensitizes TRPA1 Receptors in
Human Sural Nerves
Anupam Bhattacharjee, Lionel Ginsberg, Richard Orrell,
Saqiba Jadoon and Reginald Docherty; London, United
Kingdom
Electroconvulsive therapy is an effective treatment for major
depression, however few predictors of response have been
established.
The study aims to examine whether a family history of
unipolar or bipolar depression is a predictor of response,
remission and relapse rates after electroconvulsive therapy in
patients with unipolar or bipolar depression.
Data on 121 patients treated at Whitchurch hospital,
Cardiff was analysed. It was established whether patients
had a family history of unipolar or bipolar depression.
Patients were then administered electroconvulsive therapy
and outcome measures were compared using independent ttests, regression analysis and Kaplan-Meier survival curves.
A high proportion of patients had family history, and
these patients had a significantly earlier age of onset of
depression. Family history does not predict outcomes, how-
TRPA1 and TRPV1 are ion channels of the TRP family
that are expressed in a subset of sensory neurones in human
sensory nerves. They are molecular sensors of environmental
stimuli. In primary sensory neurons their activity is thought
to mediate sensory symptoms of peripheral neuropathy such
as pain and paraesthesia. We conducted in vitro recordings
from human sural and rat saphenous nerves to study the
effects of capsaicin and mustard oil which are selective activators of TRPV1 and TRPA1 respectively. Both human and
rat nerves were depolarized by capsaicin. However, we failed
to demonstrate any depolarizing response to mustard oil in
any human sural nerves tested whereas all rat nerves showed
robust depolarizing responses. When rat nerves were pretreated with 30mM lidocaine to mimic the exposure of
human sural nerve biopsies to the local anaesthetic during
surgery, effects on action potential conduction reversed
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completely but there was a selective abolishment of the
response to mustard oil but not of that to capsaicin. This
study demonstrates that local anaesthetics selectively desensitize TRPA1 ion channels and indicates that they may have
additional mechanisms for treating neuropathic pain that
endure beyond simple sodium channel blockade.
Study supported by: none
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CM(9.1365.81lV) was insignificantly higher compared to
EM(7.9363.14lV) and MOH(7.8664.29lV). In controls,
significant habituation of N19 amplitude in block
2(7.2562.80lV) and block 3(7.0162.96lV) compared to
block 1(7.9162.91lV) was observed. In migraine patients,
there was no habituation in block 2(8.2564.02lV) compared to block 1(8.1764.15lV). Reduction of N19 amplitudes in block 2(P<0.001) and block 3(P<0.001) compared to block 1(P<0.001) were also significantly higher in
controls compared to migraine patients. The lack of habituation significantly correlated with allodynia(P ¼ 0.03).
Conclusion: Lack of habituation of SEP may be a biological marker of migraine.
Study supported by: Nil
T1602. Analysis of the Development of Allodynia:
Correlation between Migraine Duration and Severity
Biao Lu, Xiaodong Li, Songyang Zhao, Emilee Connors and
Shashidhar Kori; Mountain View, CA
Background: Allodynia is the perception of pain from nonnociceptive stimuli. Common during migraine, allodynia is
a manifestation of central sensitization. Mediating factors
for allodynia are not well understood but may include severity and duration of migraine. We evaluated allodynia and
migraine severity and duration to identify mechanisms of
migraine-induced central sensitization.
Methods: In this retrospective analysis, 794 patients from
the double-blind period of a phase 3, placebo-controlled,
randomized trial of an investigational acute treatment for
R ) recorded pain levels in
migraine (MAP0004/LEVADEXV
an electronic diary and provided allodynia status via standard questionnaire. Fisher’s exact test and chi-square test were
used to correlate percentage of patients with allodynia with
migraine severity and duration.
Results: At baseline, 53% of patients experienced allodynia. Migraine duration did not influence development of
allodynia (chi-square P ¼ 0.2182), regardless of pain severity (moderate baseline pain, chi-square P ¼ 0.1807; severe
baseline pain, chi-square P ¼ 0.5830). Significantly more
patients reporting severe pain had allodynia (58.4%) compared with patients reporting moderate pain (48.2%; Fisher’s exact P ¼ 0.0053).
Conclusions: Development of allodynia was associated
with severity but not duration of migraine, suggesting that
severity is a significant predictor of central sensitization.
Study supported by: MAP Pharmaceuticals, Inc.
Biao Lu is a full-time employee of MAP Pharmaceuticals
Xiaodong Li was a consultant to MAP Pharmaceuticals
from 2010 - 2011. From 2011 - present he is a full-time
employee and stockholder of MAP Pharmaceuticals.
Emilee Connors is a full-time employee and stockholder
of MAP Pharmaceuticals.
Shashidhar Kori is a full-time employee, stockholder and
has equity interests of MAP Pharmaceuticals.
T1604. Dextromethorphan Plus Quinidine for Headache
Prophylaxis: The First Case Report
Daniel Kantor; Ponte Vedra, FL
Objective: To report the use of fixed combination dextrometherophan/quinidine (DM/Q) in chronic daily headache
(CDH) prophylaxis.
R is a non-competitive N-MethylBackground: NuedextaV
D-aspartic acid (NMDA) receptor antagonist and sigma-1
agonist combination of DM/Q 20/10mg approved for pseudoublbar affect. DM/Q is being studied in diabetic and
multiple sclerosis pain. Other NMDA receptor antagonists
are sometimes used for headaches.
Methods: Case report.
Results: A 54-year-old woman with a >20 year history
of refractory CDH (intensity 2–7/10) is started on DM/Q
due its role in down-regulating glutamate. Within the first
month of treatment, her headache intensity dropped to 1/
10 (infrequently 2/10) and headache frequency dropped
from daily to several times a week. Her infrequent migraines
became even less frequent and severe. Excedrin use dropped
from four times a day to twice in the first month and she
discontinued percocet. This dramatic result has been sustained for over a year.
Conclusions: Mechanistically, DM/Q may be expected to
be helpful in the treatment of headache/pain. Although it is
possible that our patient demonstrated a placebo response,
the failure of multiple other medications suggests that this
may represent a true therapeutic response. Further research
is warranted.
Study supported by: N/A
T1603. Is Lack of Habituation of Somatosensory Evoked
Potential (SEP) a Biological Marker of Migraine?
Jayantee Kalita, Sanjeev K. Bhoi and Usha K. Misra;
Lucknow, UP, India
T1605. Sustained Pain Relief with Dihydroergotamine in
Migraine Is Potentially Due to Persistent Binding to 5HT1B/5-HT1D Receptors
Shashidhar Kori, Jian Zhang, Donald Kellerman, Thomas
Armer and Peter J. Goadsby; Mountain View, CA and San
Francisco, CA
Aims: To evaluate the sensitization and habituation of median SEP (MSEP) in migraine patients and correlate with
allodynia.
Methods: 74 migraine patients, aged 16-65 years and 63
females were included. Their demographic and clinical characteristics were noted. The patients were categorized into
episodic migraine (EM), chronic migraine (CM) and medication overuse headache (MOH). MNSEP was recorded in
3 consecutive blocks of 100 epochs each and the N19
amplitudes of each block were measured. MSEP was also
done in 28 matched controls.
Results: The baseline N19 amplitude did not differ
between migraine patients (8.1764.15lV) and controls(7.9162.91lV,P ¼ 0.73). The N19 amplitude in
Background: Dihydroergotamine (DHE) produces up to
48 hours’ migraine pain relief despite a 10-13 hour serum
half-life. This sustained action was attributed to 80 -OHDHE metabolite half-life, but this is not supported in
recent studies. We investigated sustained pain relief by
DHE and sumatriptan by comparing duration of binding to
serotonin receptors 5-HT1B/5-HT1D.
Methods: We determined the 50% inhibitory concentration (IC50) of test compound (50lL; 0.01-10,000 nM) by
incubating with 25lL [3H]5-HT (0.6nM [5-HT1B], 0.5nM
[5-HT1D]) and 25lL of membrane extracts (recombinant
CHO-K1-5-HT1B [7lg], CHO-K1-5-HT1D [10lg] membrane/well) for 60 minutes. The mixture was filtered,
washed, and mixed and incubated with MicroScintTM-20
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(50lL). Ionizing radiation was measured with TopCountTM
scintillation counter (1 min/well). Test compound dissociation constant (koff ) was measured at 20 timepoints (0-120
min [5-HT1B], 0-150 min [5-HT1D]) at three concentrations (0.3, 1.0, 3.0 x IC50), and dissociation half-life was
calculated. DHE and sumatriptan were tested with human
5-HT1B/5-HT1D receptors.
Results: Dissociation half-life of DHE vs. sumatriptan: 5HT1B: 1.38 vs. 0.17 h; 5-HT1D: 1.28 vs. 0.09 h.
Conclusions: DHE binds 5-HT1B/5-HT1D receptors 814 times longer than sumatriptan, potentially explaining
DHE’s sustained pain relief in migraine.
Study supported by: MAP Pharmaceuticals, Inc.
Shashidhar Kori is a full-time employee, stockholder and
has equity interests of MAP Pharmaceuticals.
Jian Zhang is a full-time employee, stockholder and has
equity interests of MAP Pharmaceuticals.
Donald Kellerman is a full-time employee, stockholder
and has equity interests of MAP Pharmaceuticals.
Thomas Armer is a full-time employee of MAP
Pharmaceuticals.
Peter J Goadsby has had research support or consulted,
or both for MAP, as well as GSK, Amgen, Allergan, MSD,
eNeura, Neuraxon, Autonomic Technologies, Colucid, EliLilly, Metronic, Linde, BristolMyersSquibb, Boston Scientific, and Pfizer.
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parison meta-analysis (MTC) allows for comparative effectiveness when direct evidence is unavailable. Using an
MTC, we aimed to determine the relative efficacy of triptans for abortive treatment of migraine.
Methods: We included all randomized clinical trials
(RCTs) evaluating triptans versus placebo or another triptan
with outcomes of headache-free and headache relief at 2
and 24 hours post-migraine treatment. We used Bayesian
random-effects MTC adjusting for dosage using metaregression. Results are reported as odds ratios (OR) with
95% Credible Intervals.
Results: We included 97 RCTs. For the outcome of
headache free and headache relief at 2-hour, there were no
significant differences between triptans. At 24 hours, elitriptan had the highest probability of treatment success for
headache-free (77%) and headache-relief (95%). For headache-relief, elitriptan was significantly more effective than
other triptans: sumatriptan (OR 1.69, 1.21-2.40), almotriptan (OR 2.31, 1.12-4.72), naratriptan (OR 2.05, 1.074.16), zolmatriptan (OR 1.09-2.44), and rizatriptan (OR
1.81, 1.08-3.06).
Conclusion: Triptans appear to offer differing treatment
effects. Eliptriptan offered the largest treatment effects at 24
hours.
Study supported by: Pfizer Ltd
T1608. Repetitive Transcranial Magnetic Stimulation
(rTMS) Results in Elevation of b Endorphin Level and
Relief of Migraine Headache
Usha K. Misra, Jayantee Kalita, Gyanesh M. Tripathi and
Sanjeev K. Bhoi; Lucknow, UP, India
T1606. Valsalva Test Responses in Cough Headache
Patients
Russell J.M. Lane and Paul T.G. Davies; London, United
Kingdom and Oxford, United Kingdom
Cough headache is defined as ‘‘headache of sudden onset lasting from one second to 30 minutes, brought on by coughing,
straining and/or Valsalva manoeuvre’’ [1]. The implication is
that cough headache results from transient increase in intracranial pressure. 13 consecutive cough headache patients with
normal neurological examinations were asked to exhale into a
sphygmomanometer tube to 60 mm Hg for 10 seconds and
to report the resulting symptoms. A ‘‘positive’’ test was
recorded if the test reproduced the headache exactly.
8 had positive tests. All had intracranial pathology in the
posterior fossa on MRI (‘‘secondary’’ cough headache: 7 Chiari
1 malformations and one asymptomatic posterior fossa meningioma). Four patients had negative Valsalva tests, and one
experienced minimal headache, not characteristic of the spontaneous symptom. These 5 patients had normal MRI scans
(‘‘primary’’ cough headache). Secondary cough headache was
relieved following surgical treatment in all cases.
We conclude that while secondary cough headache is provoked by Valsalva manoeuvre and presumably results from
transient increase in intracranial pressure, the mechanism of
primary cough headache must be different. This should be
recognised in the forthcoming International Headache Classification definition.
1. IHC2 2nd Edition. Cephalalgia 2003;24, Supplement
1:63.
Study supported by: Not supported
Aim: To evaluate b endorphin (BE) level in migraine
patients before and after rTMS to explain the mechanism of
pain relief.
Methods: 25 migraine patients, aged 20-65years having
>4 attacks/mo were included. Their demographic and clinical details were recorded. Plasma BE level was estimated
before and after rTMS in patients and 25 matched controls
using ELISA. rTMS was applied in left hand motor area
and 600 pulses in 412.4 seconds at 70% of motor threshold
were delivered in 3 sessions on alternate days. The headache
outcome parameters were assessed before rTMS and weekly
for 4 weeks. The project was approved by Ethics Committee
and patients consented.
Results: Baseline plasma BE levels was lower in migraine(4.3562.29ng/ml) compared to controls(6.6862.93ng/
ml,P ¼ 0.005). BE levels were lower in chronic migraine
(3.7462.20ng/ml)
compared
to
episodic
migraine(5.6562.02ng/ml,P ¼ 0.04). Following rTMS migraine
frequency, duration, severity, functional disability, and analgesic use significantly reduced on seventh day compared to
baseline. Following rTMS BE levels significantly increased(6.5863.33ng/ml) compared to baseline(4.3562.29ng/
ml P ¼ 0.001) and the change in BE correlated with clinical improvement.
Conclusion: Pain relief in migraine following rTMS may
be due to increase in BE level.
Study supported by: None
T1607. Comparative Efficacy of Triptans for the
Abortive Treatment of Migraine: A Multiple Treatment
Comparison Meta-Analysis (MTC)
Edward J. Mills, Kristian Thorlund, Ping Wu and Anjan
Chatterjee; Ottawa, ON, Canada; Hamilton, ON, Canada
and New York, NY
T1609. Alice in Wonderland Syndrome: Epilepsy,
Migraine or Both?
W.O. Pickrell, R.H. Thomas, J.A. Johnston, C.P. White and
M.I. Rees; Swansea, United Kingdom and Cardiff, United
Kingdom
Background: Little is known about the comparative efficacy
of triptans for migraine treatment. Multiple treatment com-
We present a family where 10 members of the pedigree suffer distinct, stereotyped episodes of hyper and
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hyposchematia, metamorphopsia including teleopsia and
pelopsia and altered time awareness consistent with the Alice
in Wonderland Syndrome (AIWS). Amongst the 10 affected
family members, 4 also have epilepsy, 1 also has migraine
and 3 people only have AIWS.
Since the first published description of AIWS in 1955,
there have been several reports describing associations with
migraine, epilepsy, viral Illnesses and also drugs. The fact
that AIWS can occur with or without migraine or typical
epileptic seizures raises the question as to its exact nature –
is it a form of migraine, epilepsy, both (migralepsy) or
neither?
There is phenotypic overlap between migraine, epilepsy
and AIWS. Mutations in genes encoding ion channels have
been associated with both migraine and epilepsy. The abnormally high incidence of AIWS, migraine and epilepsy in
this family means there is a underlying genetic cause which
we are currently investigating. A biological model for the
pathogenesis of AIWS could help further our understanding
of both migraine and epilepsy - the two most common paroxysmal brain disorders.
Study supported by: National Institue for Social Care and
Health Research; Welsh Government
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ing neurons (nociceptors) derived from patient fibroblasts.
Marius Wernig showed that it is possible to convert fibroblasts into generic neurons using just three transcription factors. We hypothesized that by expressing additional transcription factors known to be important in nociceptor
development, we could directly reprogram patient fibroblasts into functional nociceptors. We have created mice
that express a fluorescent reporter specifically in nociceptors
by using a nociceptor-specific NaV1.8 Cre driver. Starting
with mouse embryonic fibroblasts from the NaV1.8::reporter mice, we transduce the fibroblasts with combinations
of transcription factors and demonstrate that we can obtain
activation of the nociceptor-specific reporter. We use wholecell patch clamp to confirm that the neurons are physiologically functional. We are currently performing additional
characterization using immunohistochemistry, expression
profiling, calcium imaging, and patch clamp.
Study supported by: GlaxoSmithKline
T1612. The Prevalance of Anxiety and Depression in
Migraine Patients
Hakan Balibey, Halit Yasar, Nalan Bayar and Hakan Tekeli;
Ankara, Turkey and Istanbul, Turkey
Introduction: Migraine is one of the most common primary headaches which worldwide affects more than 10% of
people. Anxiety disorder and depression often accompany
this disease and increase the number and severity of migraine attacks. The purpose of this study is to determine the
prevalence of anxiety and depression disorders in patients
with migraine.
Methods: Two groups are formed with migraine patients
and healthy volunteers. So far 51 patients are included to
migraine group by the neurologist according to ICHD, 2nd
edition. There are 60 subjects in the healthy control group.
After being examined by the psychiatrist both of the groups
meet the psychologist and have the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI).
Results: Until now, in the migraine group BAI is high
with 15 patients (29%) and BDI is high with 19 patients
(37%) whereas in the control group BAI is high with 6 subjects (10%) and BDI is high with 10 subjects (16%). Both
tests have significantly higher scores than the control group
(p < 0.001).
Discussion: The prevalence of anxiety and depression in
patients with migraine is higher than the normal
population.
Study supported by: -None
-There is no conflict of interest
T1610. Analysis of EEG and MRI for Localization of
Structures Affected in Temporal Lobe Epilepsy
Ildefonso Rodrı´guez-Leyva, Ana A. Renterı´a Palomo, Luis
Concha-Loyola and Adriana Martı´nez-Mayorga; San Luis
Potosi, Mexico
Objective: To determinate the relationship between both
hippocampal atrophy and severity of epilepsy in patients
with temporal lobe epilepsy (TLE).
Methods: Volumetric MRI of the hippocampus was performed in 50 consecutive patients (25 men; mean age 40)
with TLE. TLE diagnosis, lateralization and severity (mild,
moderate, severe) of the seizure were based on a comprehensive evaluation including neurologic examination and EEG
in all patients. Patient with evidence of a lesion were not
included in the study. We compare the relation between the
volumetric measurements from both hippocampal using the
C (development at Mayo Clinic) and
Software Analyze 10.0V
the relation with the severity of the epilepsy based in the
EEG.
Results: We found a statistically significant difference (p
< 0.001) in volume, according to the affected side based in
the EEG; and a correlation between the severity of epilepsy
and hippocampal atrophy.
Conclusion: Our results confirm that volume loss to the
hippocampus in patients with TLE correlate with the severity of the epilepsy based in the EEG. The detection of these
differences may help to make early surgery for refractory
temporal lobe epilepsy.
Study supported by: COPOCYT
T1613. Endogenous l-Opioid System as a Research and
Therapeutic Target in Migraine
Alexandre F. DaSilva, Thiago D. Nascimento, Tiffany Love,
Marcos F. DosSantos, Ilkka K. Martikainen, Misty DeBoer,
Chelsea M. Cummiford, Felipe Fregni, Yolanda R. Smith, Eric
Maslowski and Jon-Kar Zubieta; Ann Arbor, MI and Boston,
MA
T1611. Direct Conversion of Fibroblasts into Functional
Nociceptors
Brian J. Wainger, Amy J. Wang, Lee Barrett, Justin Ichida,
Qiufu Ma, Lee L. Rubin, Kevin Eggan and Clifford J. Woolf;
Boston, MA and Cambridge, MA
We investigated how the endogenous opioid system is
affected in migraine, and how it can be safely modulated
for research and therapeutic purposes. First, we examined
changes in the l-opioid system during spontaneous migraine attacks using positron emission tomography (PET)
with [11C] carfentanil, which measures l-opioid receptor
(lOR) availability [Non-Displaceable Binding Potential
(BPND)]. We noticed substantial reductions in lORBPND
(increase in l-opioid release) during the headache phase in
multiple pain-modulatory regions, including PAG. Second,
Multiple difficulties confound the study of pain in humans.
Pain is subjective and discordance often exists between the
severity of pain and the severity of pathology. Animal models and heterologous expression studies also have marked
limitations, and a large number of drugs have appeared
promising in animal models but then failed in clinical trials.
We planned to generate and phenotype primary pain-sens-
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we investigated the analgesic effect of ten active/sham sessions of motor cortex (M1) modulation in chronic migraine
patients using transcranial direct current stimulation
(tDCS). There was a significant decrease in pain intensity of
migraine episodes in the follow-up period in the active
group. In addition, using a high-resolution computational
model, we found that M1-tDCS generated significant electric fields in the pain-matrix. Third, M1-tDCS was performed during the PET session, without posing risks to the
patient. We noticed that there is an immediate reduction in
lORBPND in the pain-matrix. The studies above represent
a change of paradigm, as we directly investigate and modulate our own endogenous opioid mechanism by applying
novel neuroimaging and neuromodulatory tools.
Study supported by: No conflict of interest. The study
was supported by non-profitable organizations: NIHNINDS:K23 NS062946, DANA Foundation’s Brain and
Immuno-imaging award, Migraine Research Foundation
Award
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This dysfunction might result from underlying synucleinopathy, tauopathy, amyloidopathy, or a combination of each.
To explore this hypothesis, we assessed amyloid pathology
using neuroimaging and molecular cerebrospinal fluid
(CSF) analysis in these patients.
Methods: In a cross-sectional design, subjects underwent
Dementia Rating Scale (DRS-2) assessment, lumbar puncture, and quantitative amyloid imaging using AV-45, an
18F-based PET ligand.
Results: 40 subjects, 32 men and 8 women, were
recruited. Average age was 70.3567 years and disease duration was 9.9765.6 years. Mean total DRS-2 score was lower
in PDD (106.3618, p<0.005) and DLB (119.3610) as
compared with PD (133.1616). Higher cortical
amyloid burden correlated with lower total DRS-2 score
(R ¼ -0.39, p<0.05), lower attention subscore (R ¼ -0.57,
p<0.005), and CSF amyloid-b (R ¼ 0.41). Memory
subscore and CSF tau did not significantly correlate with
cortical amyloid burden.
Conclusions: PD and DLB patients may have underlying
amyloid pathology that differs from patterns seen in other
dementias. Longitudinal examination of these parameters
may elucidate amyloid profiles that identify PD patients at
risk of dementia.
Study supported by: This study was supported by a Morris K. Udall Parkinson’s Disease Research Center of Excellence grant from NINDS (NS-053488) and by Avid
Radiopharmaceuticals.
Dr. Akhtar and Ms. Brennan report no financial disclosures. Dr. Weintraub participated on scientific advisory
boards or received honoraria for speaking from Teva Pharmaceuticals, Eli Lilly and Company, Lundbeck Inc., Biogen,
Pfizer, and Avanir Pharmaceuticals. Dr. Weintraub received
a portion of licensing fees from use of the QUIP instrument, which is copyrighted to the University of Pennsylvania. Dr. Weintraub received research support for an investigator-initiated study from Novartis. Dr. Siderowf has been
supported by SAP4100027296, a health research grant
awarded by the Department of Health of the Commonwealth of Pennsylvania from the Tobacco Master Settlement
Agreement under Act 2001-77. Dr. Siderowf has received
consulting fees or speaking honoraria from Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and
Merck Serono.
Movement Disorder
T1701. PARK2 Mutant hiPSC-Derived Neural
Progenitors Exhibit Altered Sensitivity and
Mitochondrial Dysfunction to Neurotoxic Metal
Exposure
Asad A. Aboud, Andrew M. Tidball, Kevin K. Kumar, M.
Diana Neely, Michael Litt, Peter Hedera, Charles C. Hong,
Kevin C. Ess and Aaron B. Bowman; Nashville, TN
Through toxicological studies in human induced pluripotent
stem cells (hiPSCs), we sought to investigate potential disease-toxicant interactions in familial PD. We generated
hiPSCs from an individual with large exonal deletions in
the familial PD associated gene, PARK2. We then differentiated these cells into early CNS neural progenitors which
were exposed to a number of heavy metals, and the PARK2
mutant hiPSC-derived neural progenitors were selectively
vulnerable to copper and cadmium-induced cell death. This
phenotype could not be replicated using fibroblasts used to
generate the stem cells. The PARK2 mutant neural progenitors also demonstrated increased reactive oxygen species production, mitochondrial fragmentation and depolarization
under copper exposure. We conclude that loss of functional
PARK2 gene product, Parkin, leads to selective susceptibility
to copper-induced mitochondrial dysfunction. Parkin plays
a key role in recycling damaged mitochondria; therefore,
our data recapitulates previous findings. We also demonstrate the utility of hiPSCs to study the patient-specific toxicological differences in a particular cell type of interest. Furthermore, this study opens the door to developing highthroughput screening for specific gene interactions with a
wide array of environmental agents.
Study supported by: Grants descriptions: NIH R01
ES016931; NIH P30 ES000267; NIH/NIGMS P01
GM0895354 - RR166-737/4787736 subcontract; Peterson
Foundation for Parkinson’s; Doris Duke Research
Foundation
T1703. Reversal of Levodopa-Induced Dyskinesia
Mathew Alias and Mohamed Hassan; Farmington, CT
Objective: To evaluate treatment regimens that can reverse
levodopa-induced dyskinesias (LID).
Background: Levodopa treatment for Parkinson’s Disease
(PD) eventually leads to dyskinesia. ‘‘Priming’’ is caused by
the pulsatile stimulation of striatal dopamine receptors and
the supra-physiologic concentrations of synaptic dopamine
resulting from levodopa therapy. Reversal of the neurochemical imbalance associated with LID can be achieved by the
gradual reduction of levodopa along with the addition of
longer-acting medications.
Design/Methods: At the University of Connecticut
Movement Disorders Clinic, a total of 2134 new PD
patients were seen from January 1, 2001 to December 31,
2011. Of these, six representative patients are illustrated
with symptoms of LID up to 10 years.
Results: All six cases showed complete reversal of dyskinesias, as the short acting levodopa/carbidopa tapering and
with the concomitant increase of longer acting dopamine
agonists and/or MAO -B inhibitors. Motor symptoms were
T1702. Amyloid Profiles of Subjects with Lewy Body
Disease
Rizwan S. Akhtar, Laura Brennan, Daniel Weintraub and
Andrew D. Siderowf; Philadelphia, PA
Objective: Cognitive dysfunction is a frequent non-motor
symptom of Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB).
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improved and the time for reversal of LID was related to
the dyskinesia duration.
Conclusions: LID can be reversed/reduced by tapering
levodopa in a very gradual manner. These findings may
help LID patients who do not qualify for DBS and prompt
laboratory scientists to study animal models in further elucidating the pathophysiology of the basal ganglia.
Study supported by: Dr. Hassan has received speaker
honoraria from Teva Pharmaceutical Industries Ltd. and
GlaxoSmithKline.
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T1706. Low Frequency DBS in PD Patients with Gait
and Speech Problems
Diana Apetauerova, Janet W. Zani and Stephanie A. Scala;
Burlington, MA
Objective: To analyze the effect of bilateral low
frequency stimulation (60Hz) in patients with Parkinson’s
disease.
Methods: 10 PD patients post DBS STN surgery with
gait freezing and falls were studied on low frequency stimulation for 1 month with 2 week follow up visits consisting
of UPDRS, gait and speech assessment.
Results: Three patients completed study tolerating low
frequency stimulation throughout study duration; 7 prematurely withdrew due to intolerance of tremor recurrence,
bradykinesia and/or rigidity. Speech improved in 3 patients.
Gait improved transiently, eventually worsening due to
severe immobility. 3 patients tried combination stimulation
with less affected body side on low frequency and more
affected side to high and remained on this setting at study
completion with gait, balance and speech improvement.
Bradykinesia and rigidity did not worsen significantly on
low stimulation side; mild dyskinesia occurred on low frequency side only.
Conclusions: Bilateral low frequency stimulation didn’t
show to be beneficial in our study. Speech was the only
symptom which improved. A combination of high and low
frequency stimulation might be a reasonable option for PD
patients with gait and speech problems. This study remains
ongoing.
Study supported by: Robert E. Wise Foundation Grant
T1704. L-Dopa Induced Dystonia, Dyskinesia in
Juvenile Parkinson’s Disease
Sarah M. Misbah El-Saadig; Khartoum, Sudan
Quest Deep Brain stimulation
This is a follow up study to one of the biggest families of
AREOP (Autosomal Recessive Early onset Parkinson’s) disease in North Africa and the Middle-East apart from Algeria
which has the biggest. This Sudanese family has been diagnosed with Juvenile Parkinson’s disease in 2005. 8 family
members have been affected amongst 2-3 generations. Those
alive, have been affected by the disease and side effects of
the medication. They can’t even withstand the smallest dose
of L-Dopa and sinemet. They become very dystonic and
dyskinetic, which was very evident in the video tape of this
family. I think this family might benefit from a surgical procedure including DBS with a rechargeable memory which
can improve morbidity, mortality, and improve their life
style. Other types of genetically related Dystonias did benefit from this procedure. Thus DBS availability as a way of
treatment is very essential.
This family and its new genetic disorder has been published
in Neurology archives 2006.
Study supported by: No sponsor
T1707. Chronic Parkinsonism Associated with Liver
Cirrhosis
Diana Apetauerova, Peter G. Hildenbrand, Janet W. Zani and
Stephanie A. Scala; Burlington, MA
T1705. Amelioration of Somatic and Autonomic
Neuropathy in Patients with Idiopathic Parkinson’s
Disease Following Cobalamin Therapy
Sabrina Apel and Cory Toth; Calgary, AB, Canada
Objective: To study parkinsonism prevalence in patients
with liver cirrhosis and establish correlations between cirrhosis severity, parkinsonism, neuroradiological and biological
findings.
Methods: A prospective study of patients with cirrhosis
undergoing transplantation at Lahey Clinic. Each patient
underwent Unified Parkinson’s Disease Rating Scale
(UPDRS) testing, standard liver pre-transplant evaluation
and repeat testing post-transplant at 6 weeks, 3 and 12
months. Patients with parkinsonism also underwent brain
MRI. Correlation was measured among MELD, motor and
total UPDRS, copper, ammonia, manganese, iron levels and
signal MRI changes.
Results: 62 of 120 patients exhibited parkinsonism. Of
these, we found no correlation between MELD severity and
motor UPDRS (p ¼ 0.71) nor among laboratory levels. All
parkinsonian patients had abnormal signal in the basal ganglia. Thirteen patients with parkinsonism underwent liver
transplant. Improvement was found in gait (p ¼ 0.001),
bradykinesia (p ¼ .02), motor UPDRS (p ¼ 0.02) and total
UPDRS (p ¼ 0.03) 3 months post transplantation. Additional results will be provided at time of abstract
presentation.
Conclusions: Our study demonstrates high incidence of
parkinsonism in patients with cirrhosis. No correlations
were found between cirrhosis severity, manganese levels and
parkinsonism severity. Improvement was found in UPDRS,
gait and bradykinesia post transplant. Our study remains
ongoing.
Study supported by: Robert E. Wise Foundation Grant
Idiopathic Parkinson’s Disease (IPD) patients have greater
prevalence of peripheral neuropathy (PN) than matched
controls. We examined intervention with long-term
monthly intramuscular cobalmin (Cbl) to prevent progression of PN. We prospectively followed 58 IPD patients
with pre-identified PN for clinical, electrophysiological,
autonomic and laboratory measures of PN and IPD over 4
years. All patients were prescribed open-label Cbl. Complete compliance with Cbl occurred in 32/58 of IPD
patients; the remaining 26/58 received <50% of designated Cbl. Non-paired ANOVA testing was performed to
compare compliant/non-compliant groups. Our primary
outcome measure was change in Utah Early Neuropathy
Scale (UENS) score, with cumulative levodopa dosing,
IPD severity, electrophysiology, R-R interval testing, and
fasting methylmalonic acid (MMA) levels as secondary
measures. Compliant patients had a smaller changes in
UENS, sural sensory amplitude and distal latencies, R-R
interval testing (for resting and deep breathing, but not
Valsalva), and downregulation in serum MMA, with no
differences in IPD scores or levodopa intake. Although
limited as an open-label study, regular use of Cbl may prevent progression of PN in IPD patients using levodopa.
We advocate for randomized controlled trials to further
assess.
Study supported by: Alberta Heritage Foundation for
Medical Research
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T1708. A Genetic Study of Wilson Disease in the UK
Oliver Bandmann, Alison Coffey, Magnus Rattray and Ann
Dalton; Sheffield, United Kingdom and Cambridge, United
Kingdom
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Twelve PD patients (7M/5F; 6168) and 7 healthy
controls (4M/3F; 6069) underwent resting-state fcMRI
scanning. Striatal functional connectivity was calculated
for 6 striatal seeds using voxel-wise cross correlation
analyses.
Significant differences in connectivity were found
between: dorsal putamen and pallidum, inferior parietal
lobe (IPL), amygdala, and cerebellum (Cbl); dorsal caudate
and amygdala; and ventral caudate and precentral gyrus,
supplementary motor area (SMA), middle cingulum
(MCC), and superior medial frontal cortex (MeFC). L-dopa
tended to normalize connectivity throughout the striatum.
Dorsal putamen connectivity to IPL and Cbl correlated
with H&Y stage (r ¼ -0.71, r ¼ 0.59); dorsal and ventral
putamen to Cbl with MDS-UPDRS motor score (r ¼ 0.63,
r ¼ -0.58); dorsal caudate to amygdala with Neuropsychiatric Inventory score (NPI; r ¼ 0.64); and ventral caudate to
SMA and MeFC with MDS-UPDRS motor score (r ¼
0.64, r ¼ 0.58), to MeFC with Beck Depression Inventory
(r ¼ -0.59), and to MeFC and MCC with NPI (r ¼ -0.74,
r ¼ -0.79).
These findings suggest altered functional connectivity
within dorsal and ventral striatal networks may underlie
some of the motor and non-motor symptoms seen in PD.
Study supported by: University of Colorado Department
of Neurology
Objective: To evaluate the prevalence and spectrum of ATP7B
mutations in clinically diagnosed Wilson Disease (WD) and
determine the genetic prevalence of WD in the UK.
Methods: ATP7B sequence analysis was undertaken in
181 WD index cases. The entire ATP7B coding region was
sequenced in 1000 controls.
Results: The overall mutation detection frequency in
WD patients was 98%. We report the first cases of WD
due to segmental uniparental isodisomy, three patients with
three ATP7B mutations and three families with WD in two
consecutive generations. The SNP frequency in the 1000
controls is 0.047 or 0.029 if only those SNPs were included
which had previously been reported in WD patients (WDSNP). This frequency of heterozygote mutation carriers is
considerably higher than the previously reported occurrence
of 1:90 or 0.011 (p < 10-14 if all SNPs included, p ¼
1.31x10-5 for WD-SNPs only).
Conclusion: Our study provides strong evidence for
monogenic inheritance of WD. The marked discrepancy
between the genetic prevalence and the number of clinically
diagnosed cases of WD may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients
with this eminently treatable disorder.
Study supported by: N/A
T1711. Short Hairpin RNA Targeting Endogenous aSynuclein Prevents Degeneration of Dopaminergic
Neurons in the Rat Rotenone Model of Parkinson’s
Disease
Jason R. Cannon, Qing Bai, Maxx Horowitz, Victor Tapias, J.
Timothy Greenamyre and Edward A. Burton; Pittsburgh, PA
and West Lafayette, IN
T1709. Metronidazole-Induced Reversible Ataxia and
Numbness
Chirantan Banerjee, Fazeel Siddiqui and Jessica Lee; Dallas, TX
Background: Metronidazole induced neurotoxicity is rare
but severe. Ataxia, encephalopathy, seizures, visual dysfunction and peripheral neuropathy have been reported. Cerebellar dysfunction is almost always associated with MRI
abnormalities.
Case Summary: We present a 65y/o male with diabetes
mellitus, rheumatoid arthritis, systemic lupus erythematosus,
coronary artery disease, and hyperlipidemia who presented
with 2-3 days of gradual-onset dysarthria, ataxia, and worsening of baseline hand/feet numbness. He was on oral metronidazole 500 mg PO TID for 8 weeks prior to presentation for
recurrent clostridium difficile colitis. Exam revealed scanning
speech, gait and symmetric appendicular ataxia, and decreased
sensation to pinprick and vibration in hands/toes. MRI brain
revealed bilateral symmetric cerebellar dentate flair hyperintensities without enhancement. CSF was unremarkable. His renal
and hepatic functions were normal. Symptoms improved after
metronidazole was discontinued. Patient was changed to oral
vancomycin for continued clostridium difficile treatment.
Conclusion: Clinicians should suspect cerebellar toxicity in
patients with subacute ataxia/dysarthria and history of prolonged
metronidazole therapy, even at normal doses with normal renal
and liver function. MRI must be obtained for diagnosis. Prognosis is favorable once metronidazole is discontinued, although
peripheral nerve deficits sometimes persist.
Study supported by: Case report. No funding source.
Convergent evidence implicates both a-synuclein and mitochondrial dysfunction in the pathogenesis of sporadic
Parkinson’s disease (PD). Rats exposed chronically to rotenone, a pesticide linked epidemiologically to PD, show
systemic mitochondrial defects but develop specific PDlike neuropathology, including degeneration of substantia
nigra dopaminergic neurons and a-synuclein accumulation and aggregation. We specifically inhibited expression
of endogenous a-synuclein unilaterally in the adult rat
substantia nigra by viral delivery of a short haipin RNA
(shRNA) targeting the SNCA transcript. Compared with
contralateral dopamine neurons expressing normal levels
of endogenous a-synuclein, substantia nigra dopamine
neurons lacking a-synuclein were robustly protected
against chronic rotenone. Consequently, unlike wild-type
animals, vector-transduced rats did not develop severe
Parkinsonism. These data show that a-synuclein is a critical factor in the specific vulnerability of dopaminergic
neurons to systemic mitochondrial dysfunction, supporting a model in which genetic modulation of a-synuclein
expression can determine whether environmental exposures trigger PD pathogenesis. Since loss of a-synuclein
did not cause detectable toxicity in the nigrostriatal system, shRNA targeting the SNCA transcript should be further evaluated as a neuroprotective therapy in PD
patients.
Study supported by: VA Merit Review Award:
1I01BX000548
VA Pittsburgh GRECC Pilot Grant
Parkinson’s Chapter of Greater Pittsburgh Pilot Grant
NIEHS: 1K99ES019879, 4R00ES019879
T1710. Striatal Functional Connectivity during Rest in
Parkinson’s Disease
Brian D. Berman, Erika Shelton, Mark Hallett and Tor
Wager; Denver, CO; Bethesda, MD and Boulder, CO
Functional connectivity MRI (fcMRI) may be able to give
insight into basal ganglia circuit disturbances in PD and
how these disturbances relate to specific symptoms.
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T1712. Effect of Deep Brain Stimulation on Autonomic
Function in Early Parkinson’s Disease
Anna L. Molinari, Fenna T. Phibbs, Lily Wang, Yanna Song,
Amanda Currie, Maxim Turchan, Danielle S. Cherdak and
David Charles; Nashville, TN
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trols. MT-based cargo transport kinetics into CSF were different in neurons and astrocytes.
This method appears to identify biomarkers in PD subjects that may reflect abnormalities in axonal transport. Discovery of such biomarkers holds promise to improve diagnosis and to perhaps to monitor disease activity. We also
expect that such biomarkers will speed drug discovery since
they can be measured in animal models of disease.
Study supported by: Michael J Fox Foundation and KineMed, Inc
Background: We conducted a pilot trial assessing the safety
and tolerability of deep brain stimulation (DBS) in early
Parkinson’s disease (PD) (NCT00282152). The FDA
required additional autonomic safety monitoring as a condition of the Investigational Device Exemption (G050016).
Methods: 30 early PD patients were equally randomized
to optimal drug therapy (ODT) or ODT plus DBS. Assessments were conducted during week-long medication (and
DBS, if present) washouts at baseline and biannually for
two years and included daily seated and standing blood
pressure (BP) and heart rate.
Results: Changes in systolic BP (SBP) due to orthostatic
stress ON and OFF medicine (and DBS, if present) were
not significantly different between groups after two years.
The mean rate of deterioration in SBP OFF medicine from
baseline to two years was 5.30 mmHg in the ODT group
and 4.67 mmHg in the DBS group (p ¼ 0.75).
Conclusions: This pilot study suggests that DBS in early
PD is not associated with worsening autonomic function
(AF) when compared to ODT. A future multicenter trial
should utilize interval medication washouts to clarify the
deterioration of AF and the effect of DBS on AF in early
PD.
Study supported by: The clinical trial from which this
study is presented is supported by Vanderbilt CTSA grant 1
UL 1 RR024975 from the National Center for Research
Resources, National Institutes of Health, by a research grant
from Medtronic, Inc., and by gifts from private donors.
Vanderbilt University has received grants in excess of
$10,000 from Allergan, Ipsen, Medtronic, Merz, and Teva
for research or educational programs led by Dr. Charles. Dr.
Charles has received income for education or consulting
services from Medtronic, Allergan, Ipsen, Teva, and Merz.
Dr. Phibbs has served as a consultant for Boston Scientific
and Medtronic. She has also received payment for educational presentations for Teva.
T1714. Predictors of Cognitive Performance Following
Bilateral Subthalamic Nucleus Deep Brain Stimulation
Lidia Yaguez, Angela Costello, John Moriarty, Natasha Hulse,
Richard Selway, Chris Clough, Michael Samuel and
Keyoumars Ashkan; London, United Kingdom and Kent,
United Kingdom
The beneficial effects of deep brain stimulation of the subthalamic nucleus for the treatment of motor symptoms in
advanced Parkinson’s disease are well established. Its effect
on cognitive functions is still controversial. Attempts to
determine which pre-operative cognitive measures may help
to predict post-operative cognitive change warrant further
attention.
30 non-demented PD patients underwent detailed neuropsychological assessment pre and post STN-DBS surgery.
The individual significance of deficits, as well as the group
statistical differences pre and post surgery were analysed.
Stepwise regression analysis was used to identify best cognitive predictors of post-operative changes. Post surgery, immediate story recall showed a significant decline in its group
mean; with a large size effect. The best predictors for this
change were pre-surgical list learning and Full IQ.
These results suggest that non-demented patients with
even mild impairments in general intellectual functions and
list learning memory functions may be at greatest risk of
decline in other aspects of verbal memory after STN-DBS.
These should be taken into account when selecting and consenting patients for surgery. The results also demonstrate for
most PD patients there was no significant decline in cognitive functions following STN-DBS.
Study supported by: No funding obtained
T1713. Identification of Axonal Transport Biomarkers in
Parkinson’s Disease
Christine W. Chadwick, Michael J. Aminoff, Po- Yin A.
Wong, Kristofor H. Husted, Shanshan Liu, Victoria M. Liu,
Lori A. Kohlstaedt, Johan Protasio, Timothy Riff, Drina
Boban, Maudi Killian, Lorrie Epling, Elisabeth Sinclair, Julia
Peterson, Richard Price, Marc K. Hellerstein and Patrizia
Farnara; San Francisco; Emeryville, CA and Berkeley
T1715. What Patient Factors Associate with Inaccuracies
in Reporting of Parkinsonian Signs?
Nabila Dahodwala, Andrew Siderowf and Jason Karlawish;
Philadelphia
Identifying early parkinsonism utilizes patient self-reports,
but patient self-reports are often inaccurate. Little is known
about why patients are inaccurate.
Older adults (mean age 68) seen at primary care clinics
completed a self-report questionnaire for parkinsonian signs.
Parkinsonian signs were defined as at least two of four cardinal signs (bradykinesia, rigidity, tremor, gait dysfunction)
identified by examination. Logistic regression determined
whether demographics, mood, cognition, and aging expectations associated with false positive or false negative cases on
the self-report questionnaire.
Results: 18.5% (N ¼ 128) of 692 participants had parkinsonian signs on exam. A cut-point of 2 on the self-report
questionnaire maximized sensitivity (63.6%) with a moderate specificity (53%) for parkinsonian signs: 43 cases categorized as false negatives and 275 cases were false positives.
Older age was associated with a false negative result
(p<0.001). Lower aging expectations and higher depression
Sensitive biomarkers for neurodegenerative diseases would
facilitate early diagnosis and therapeutic advances. Defects
in microtubule-based neuronal transport may be a common
pathway for neurodegeneration. Microtubule transport
(MT) can be studied using 2H2O pulse labeling in animals
and humans since certain newly synthesized 2H-labeled proteins are transported by this system and can be measured in
cerebrospinal fluid (CSF).
Twelve patients with Parkinson’s disease (PD) and 6 controls underwent pulse administration of 2H2O (for 7 consecutive days) and then had CSF collected 1-43 days later
for gas chromatographic/mass spectrometric analysis. We
found striking neuronal transport deficits of 2H-labeled
chromogranin-B, non-amyloidogenic secreted N-terminalfragment of amyloid-precursor-protein (sAPPa), and a-synuclein but not neuregulin-1 in PD patients compared to con-
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scale scores were associated with a false positive result (p ¼
0.007 and p ¼ 0.001, respectively).
Conclusion: Inaccuracies in self-reported symptoms are
related to older age, lower aging expectations and depression
in this sample. Recognition and adjustment for these factors
may improve screening for parkinsonian signs.
Study supported by: NIA
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Study supported by: NIH/NINDS: K23 NS073626
NIH/NINDS: R01 NS040596
T1718. Clinical Assessment of the Effect of
Tetrabenazine on Motor Function in Moderate
Huntington Disease
Robert Fekete, Anthony Davidson and Joseph Jankovic;
Valhalla, NY and Houston, TX
T1716. Previously Unspecified SETX Mutation
Producing AOA2 in Two Siblings
Neil Datta and Anna Hohler; Boston, MA
Objective: We designed a study to test motor performance
using validated scales of hand function and gait on and off
tetrabenazine in patients with Huntington disease (HD).
Background: Tetrabenazine is a monoamine depleter
with well documented effect against chorea associated with
HD. There is paucity of data about how reduction in chorea relates to better performance in activities of daily
living.
Methods: The following instruments were used to assess
cognitive, behavioral, and motor function in 10 patients
with documented HD: The Montreal Cognitive Assessment,
Beck Depression Inventory II, Dynamic Gait Index, Jebsen
Hand Test, Timed 25 foot walk, Berg Balance Test, QuickDASH, and the Unified Huntington Disease Rating Scale
(UHDRS).
Results: Subjects performed significantly better while on
tetrabenazine as measured by the Berg Balance Test,
Dynamic Gait Index, UHDRS Total Motor and Maximum
Chorea scores, and the Stroop Color-Word tests.
Conclusions: Tetrabenazine treatment is associated with
improvement not only in chorea but also in measures of
motor performance.
Study supported by: Lundbeck, Inc.
Dr. Fekete has served as a consultant for Lunbeck, Inc.
The study documents a unique case wherein a previously
unidentified SETX mutation combined with a previously
recognized recessive SETX mutation produces AOA2.
Myriad mutations in the SETX gene (encoding senataxin)
have been associated with the recessive disorder ataxia with
oculomotor apraxia type 2 (AOA2). AOA2 is characterized
by symptoms such as cerebellar atrophy, ataxia, and oculomotor apraxia. We document a novel SETX mutation combination causing AOA2 in a sibling pair.
A detailed family history, neurological exam, and genetic
analysis were conducted for both patients. AOA2 symptoms
presented 17 y.o., with no previous indications. Symptoms
included hypophonia, trace dysarthria, extraocular muscle
dysfunction, etc. Family history includes neurological difficulties in paternal relatives at advanced ages. AOA2 diagnosis was confirmed by MRI, AFP elevation, and genetic testing. The older brother began physical therapy and 1200 mg
CoQ10 anti-oxidant countering the mutated sentaxin. This
treatment improved strength and other symptoms. The
younger sister’s early diagnosis may allow better control.
This study describes a previously unknown SETX gene
mutation combined with an established SETX mutation
(that itself may cause milder and late-onset symptoms) that
results in the onset of full AOA2 disease at normal onset.
Study supported by: None.
T1719. Identification of Individualized Cortical Targets
for Focal Brain Stimulation Based on Intrinsic
Functional Connectivity
Michael D. Fox, Randy L. Buckner and Alvaro Pascual-Leone;
Boston, MA
T1717. Directional EEG Connectivity Method
Demonstrates Complex, Reciprocal Information Flows
during Praxis Performance
Joshua B. Ewen, Balaji M. Lakshmanan, Stewart H.
Mostofsky, Nathan E. Crone and Anna Korzeniewska;
Baltimore, MD
It is becoming increasingly clear that focal brain stimulation techniques such as transcranial magnetic stimulation
(TMS) and deep brain stimulation (DBS) propagate
beyond the site of stimulation to impact a distributed network of connected brain regions. Recently we have suggested that targets for focal brain stimulation should be
selected at least partially based on their connectivity to
other regions. Specifically, we have shown that intrinsic
functional connectivity with the subgenual cingulate is
correlated with average clinical efficacy of different TMS
targets in the dorsal lateral prefrontal cortex used for
depression. In this article we translate these findings into
a method for individualized connectivity-based targeting
of focal brain stimulation based on resting state functional
connectivity MRI. We show that individuals posses large
differences in their ideal stimulation site and that these
differences are reproducible across repeated sessions.
Application to Depression and Parkinson’s disease are
discussed.
Study supported by: We thank the Brain Genomics
Superstruct Project for contributing data. MDF was supported by NIH Grant R25NS065743. APL serves on the
scientific advisory boards for Nexstim, Neuronix, Starlab
Neuroscience, Allied Mind, Neosync, and Novavision, and
is listed as inventor in issued patents and patent applications
on the real-time integration of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) and magnetic resonance imaging (MRI). Work on this study was
Praxis function is known from lesion studies to depend on
left parietal and premotor regions. While the typical physiological model suggests that praxis ‘‘commands’’ are sent
from the left parietal region to left premotor regions and
then to primary motor cortex, EEG studies of go/no-go
praxis tasks suggest more complex interactions between
bilateral anterior and posterior brain regions. Using a high
density EEG array, we recorded data from a praxis task and
analyzed them with Event Related Causality (ERC;
Granger-Causality-based method which estimates dynamical
changes in brain activity flow). Because the ERC method
has been not previously been applied to scalp EEG, we
investigated optimal analysis parameters. Data from the
mental rehearsal portion of the task demonstrated activity
flows between left and right posterior regions and flows
from both posterior regions toward left frontal regions.
Data from the initiation of the pantomime portion demonstrated reciprocal flows, suggesting feedback from left anterior regions to bilateral posterior regions. These results demonstrated the utility of ERC in analyzing scalp EEG
recordings and suggest generally that systems-level neural
complex motor circuits function with reciprocal information
flows.
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also supported by grants from the National Institutes of
Health and National Center for Research Resources: Harvard Clinical and Translational Science Center (UL1
RR025758) and the Howard Hughes Medical Institute.
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T1722. Progressive Ataxia and Palatal Tremor Syndrome
(PAPTS): Clinical and Radiological Findings
Pablo Garcia-Reitboeck, Marie-Helene Marion and Salah
Omer; London, United Kingdom
PAPTS is a rare syndrome of largely unknown aetiology,
although genetic forms have been described. We present
clinical and radiological findings and videos of three male
patients with PAPTS. Age at presentation ranged from 6269. All patients had cerebellar ataxia and palatal tremor.
Onset in patient 1 was with blurring of vision and difficulty
with balance, while in patient 2 palatal tremor preceded development of balance problems, blurring of vision, speech
and swallowing difficulties. Patient 2 had suffered a REM
sleep behavioural disorder for 4 years prior to the onset of
palatal tremor. Patient 3 presented with progressive unsteadiness and sensorineural hearing loss. Only one patient experienced the characteristic ear clicks associated with palatal
tremor. None had a relevant family history. MRI brain demonstrated the presence of hypertrophic olivary degeneration
in all patients. Video-oculography of patient 2 showed torsional right eye oscillation, synchronous with pupillary oscillations. Testing for mutations in the GFAP gene (Alexander
disease) was negative in patient 2 and pending in patient 3.
No mutations were detected in POLG1 gene in patients 2
and 3. Our 3 cases demonstrate the clinical heterogeneity of
this syndrome.
Study supported by: none
T1720. Does Iron Play Different Roles in Various
Neurodegenerations?
Andrzej Friedman and Jolanta Galazka-Friedman; Warsaw,
Poland
Background: Iron may play deleterious role in neurodegeneration by triggering oxidative stress via Fenton reaction.
Iron was studied in Parkinson’s disease (PD) with controversial results. In other neurodegenerations, e.g. Alzheimer disease (AD) and progressive nuclear palsy (PSP) it still needs
evaluation.
Aim: to assess the concentrations of total and labile iron,
and ferritin in PD, AD and PSP.
Material and Methods: samples of substantia nigra (SN),
globus pallidus (GP) and hippocampal cortex (Hip) from
PD, PSP and AD brains were assessed with ELISA, Mössbauer spectroscopy, and atomic absorption.
Results: No increase in the concentration of iron in PD
vs. control was detected, however there was an increase of
labile iron, which constitutes only 2% of total iron in SN.
A significant decrease of the concentration of L chains in
PD compared to control was found. In AD an increase in
the concentration of ferritin was noticed, without a significant increase in iron concentration. In PSP an increase of
total iron was observed.
Conclusion: Our findings suggest that the mechanisms
leading to nervous cells death in these three diseases may be
different, although all may be related to iron mediated oxidative stress.
Study supported by: No financial support
T1723. Progressive Bilateral Parkinsonism Secondary to
a Unilateral Midbrain Lesion
Maiya R. Geddes, A. Jon Stoessl, Alain Dagher, Jean-Paul
Soucy and Anne-Louise Lafontaine; Montreal, QC, Canada
and Vancouver, BC, Canada
Background: Idiopathic Parkinson’s disease (IPD) is characterized by gradual loss of nigrostriatal dopaminergic neurons. Transient toxic or infectious exposure can produce a
progressive syndrome resembling IPD. Evidence from animal studies extends this finding: Unilateral nigral damage
affects contralateral dopamine turnover.
Methods: An individual presenting with left-sided parkinsonism and resting tremor secondary to a right midbrain aneurysm was assessed for ten years. We measured presynaptic
nigrostriatal integrity with [11C]-dihydrotetrabenazine,
[11C]-d-threo-methylphenidate, and 6-[18F]-fluoro-L-dopa
and postsynaptic dopamine function with [11C]-raclopride
positron emission tomography (PET).
Findings: After seven years, bradykinesia and rigidity
emerged ipsilateral to the lesion. Despite progression of parkinsonism, clinical signs and structural imaging of the aneurysm remained unchanged. The patient never experienced
anosmia or a sleep disorder, making coincidental IPD
unlikely. Striatal PET imaging showed bilateral, asymmetric
reduced presynaptic and increased postsynaptic radiotracer
uptake: A rostral-caudal gradient was observed with relative
preservation of the caudate and preferential involvement of
the posterior putamen, a pattern typical of IPD.
Interpretation: This case provides evidence of a static
unilateral midbrain lesion producing progressive, bilateral
dopaminergic dysfunction. This result shows that discrete
nigrostriatal damage can lead to progressive pathology and
unilateral interruption of dopaminergic pathways influences
contralateral dopamine function.
Study supported by: M.R.G. is supported by a Richard
and Edith Strauss Fellowship. A.J.S. is supported by the
Canadian Institutes for Health Research, The Michael
Smith Foundation for Health Research, the Pacific
T1721. Asymmetric Upper Motor Neuron
Disease (Mills’ Syndrome) Presenting as Corticobasal
Syndrome
Shinsuke Fujioka, Masataka Nakamura, Melissa
E. Murray, Zbigniew K. Wszolek and Dennis W. Dickson;
Jacksonville, FL
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor
neurons bilaterally. A rare hemiplegic form of ALS with
asymmetric upper motor neuron degeneration has been
reported under the rubric of Mills’ syndrome. We present
clinical findings and neuropathology of five patients with
Mills’ syndrome. The cases were referred to the CurePSP
brain bank with final clinical diagnoses of corticobasal
degeneration (CBD). Review of available medical records
revealed a mean age of symptomatic onset of 59 years. All
patients had asymmetric clinical features, with asymmetric
increased muscle tone, lack of lower motor neuron signs
and no evidence of lower motor neuron disease on those
patients who had electrophysiological tests. They all had rigidity and bradykinesia. Pathologically, both upper and
lower motor neurons were involved; however, neuronal loss,
gliosis, and cytoplasmic TDP-43 inclusions were much
more severe in the motor cortex than in the brainstem
motor neurons or the anterior horns of the cervical spinal
cord. The histopathological features of CBD were absent
with tau immunohistochemistry. The results suggest that
asymmetrical upper motor neuron predominant presentations of ALS can clinically masquerade as corticobasal
syndrome.
Study supported by: Nothing to disclose
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Alzheimer Research Foundation, and the Canada Research
Chairs program. A.D. is supported by Fonds de Recherche
en Santé du Québec, Canadian Institutes of Health
Research
T1726. GABA Receptor Changes and Functional
Connectivity Abnormalities in Focal Hand
Dystonia
Cecile Gallea, Priyantha Herath, Valerie Voon, Alicja Lerner
and Mark Hallett; Bethesda, MD
T1724. Rapid Onset Dystonia-Parkinsonism Associated
with the I758S ATP1A3 Mutation: A Neuropathologic
Study of Three Affected Siblings
Bernardino Ghetti, Matthew C. Hagen, Joseph Maldjian,
Christopher T. Whitlow, Laurie J. Ozelius, Kathleen J.
Sweadner and Allison Brashear; Indianapolis, IN; Cincinnati,
OH; Winston-Salem, NC; New York, NY and Boston, MA
Focal hand dystonia is characterized by excessive muscle
co-contraction producing abnormal movements. It is associated with impaired inhibitory mechanisms, but the
pathophysiology of the lack of inhibition and its consequence on sensorimotor network functioning is not clearly
understood. We hypothesized that inhibitory impairment
originates in reduced efficacy of GABA-ergic interneurons
of the primary motor cortex and the putamen. Density of
GABA-A receptors using [11C] Flumazenil was measured
with positron emission tomography. Eighteen patients with
right focal hand dystonia and 18 age and gender matched
healthy volunteers participated. Fourteen of the patients
performed right hand motor tasks during functional MRI
acquisition to measure functional connectivity in the sensorimotor network. Compared to controls, patients had
decreased GABA-A receptor density in primary sensorimotor cortex and in the putamen contralateral to the symptomatic hand, as well as in the sensorimotor cerebellum ipsilateral to the symptomatic hand. Abnormal GABA-A
receptor density in the left hand knob of the motor area
and in the right cerebellum correlated with functional connectivity in the striato-cortical and the cerebello-cortical
loops, respectively. We conclude that the changes in GABA
binding affect sensorimotor network activity indicating
functional relevance in dystonia.
Study supported by: NINDS Intramural Program.
Rapid-Onset Dystonia-Parkinsonism (RDP) is associated
with mutations in the ATP1A3 gene. Clinical features
include dysarthria, dysphagia, limb dystonia, bradykinesia
and postural instability. The symptomatology remains stable for decades. This report is a neuropathologic analysis
of three siblings carrying the I758S ATP1A3 mutation.
Immunohistochemical studies included using antibodies
against GFAP, calbindin, synaptophysin, and neuron-specific enolase. Neuronal rarefaction and a moderate astrocytosis in the globus pallidus, subthalamic nucleus, red nucleus, and inferior olivary nucleus were seen. In the
cerebellar cortex, torpedoes of Purkinje cell axons and a
moderate rarefaction of granule cells were noted, while in
the dentate nucleus (DN) there was a significant neuronal
rarefaction. Synaptophysin immunohistochemistry showed
synaptic losses in areas of the DN where neuronal rarefaction was evident. We postulate that in RDP associated
with I758S ATP1A3 mutation there is a damage of the
connectivity of the globus pallidus, subthalamic nucleus
and red nucleus. In addition, the cerebellum shows a significant abnormality in the density of neurons of the DN
and related presynaptic terminals. It is hypothesized that
the dentatorubral-pallidal, olivocerebellar and dentato-olivary pathways are affected.
Study supported by: R01 NS058949, P30 AG010133
T1727. What Issues Face Parkinson’s Patients at Ten
Years and beyond?
Anhar Hassan, Samuel Wu, Peter Schmidt, Irene A. Malaty,
Yun Feng Dai, Janis Miyasaki and Michael S. Okun;
Gainesville, FL; Miami, FL and Toronto, Canada
T1725. Alcoholic Cerebellar Degeneration: Not All Due
to Alcohol
Marios Hadjivassiliou, Stuart Currie, David Sanders and
Nigel Hoggard; Sheffield, United Kingdom
Background: Parkinson’s disease (PD) leads to cumulative
disease burden. Clinical status and health-related quality of
life (HRQoL) at the 10-year milestone are not welldocumented.
Methods: Cross-sectional study of PD patients 10-year
disease duration (PD-10) (n ¼ 1835) enrolled in the multicenter National Parkinson Foundation Quality Improvement
Initiative (NPF-QII).
Results: PD-10 patients (62.2% male), mean age 67.8
years (69.5), mean age of PD onset 52.7 years (610.6),
and median disease duration 14 years (range 11-18). Many
had minimal disability, (HY 1-2, 44.0%), or postural instability (HY 3, 40.3%). Most (88.2%) stood unaided but
54.8% reported falls. Almost all lived at home (93.1%)
with a caregiver (83.8%). Patients had 1.9 (61.4) of surveyed co-morbidities, with arthritis (48.9%) and cardiac
(31.7%) most common. Majority (86.7%) took 2 medications: levodopa (95.7%), dopamine-agonists (45.6%) or
antidepressants (37.3%). 22.4% had deep-brain-stimulation.
Mean HRQoL and caregiver-burden was impaired in all
domains.
Conclusions: PD-10 patients attending NPF-centers
mostly remain mobile and living at home (93%), compared
to previous studies, which may reflect better care or other
biases. Falls, caregiver-burden, and impaired HRQoL are
common. Policies to improve in-home patient/caregiver support are crucial to maintain patients at home.
Study supported by: No disclosures
Amongst 885 patients with progressive cerebellar ataxia
attending a specialist ataxia clinic at the Royal Hallamshire
Hospital, Sheffield, UK, there were 100 patients whose
ataxia was thought to be secondary to chronic excessive alcohol intake. These patients had hematological markers of
alcohol excess (raised MCV, gamma GT). All patients had
MR imaging, were screened for other causes of ataxia and
had their HLA typed.
Sixty one percent had the DQ2 HLA type compared to
30% in healthy local blood donors. HLA DQ2 is associated
with autoimmune diseases such as celiac disease, hypothyroidism etc. Forty four percent of patients had positive antigliadin antibodies (IgG and/or IgA) compared to 12% in
the healthy local population and 10% in patients with genetically confirmed ataxias. None had celiac disease on duodenal biopsy. Voxel-based morphometric analysis of brain
MR showed a different pattern of cerebellar involvement in
those patients with alcoholic ataxia with and without positive serology for gluten sensitivity to what is seen in gluten
ataxia.
Alcohol excess may cause cerebellar degeneration in genetically susceptible individuals and may induce sensitization to
gluten.
Study supported by: no financial support receieved
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T1728. Dysphagia i Spinocerebellar Ataxia Type 3 and
Type 6
Chiharu Isono, Makito Hirano, Hikaru Sakamoto, Shuichi
Ueno, Susumu Kusunoki and Yusaku Nakamura; Sakai,
Osaka, Japan and Osakasayama, Osaka, Japan
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ticularly in motor compensation and development of levodopa-induced-dyskinesia (LID). The red nucleus (RN)
mediates cerebellar involvement in motor control, and iron
changes in the RN may reflect cerebellum-related compensation and/or mark the intrinsic capacity of PD subjects to
develop LID. This is the first study focused on the RN to
test this hypothesis. Multi-echoes T2*-weighted MRI images
were acquired from 38 PD subjects [12 with (PD/DYSþ)
and 26 without (PD/DYS-) history of dyskinesia] and 23
Controls. Iron content was estimated from transverse relaxation rates (R2*) of RNs and SNs. We found that PD subjects overall displayed higher R2* values in both the SN (p
¼ 0.002) and RN (p ¼ 0.019). RN R2* values were significantly higher in PD/DYSþ (p ¼ 0.002), but not PD/DYS(p ¼ 0.180) when compared to Controls. RN R2* values
also were significantly greater in PD/DYSþ than PD/DYS(p ¼ 0.011). The association of higher RN iron content
with PD-related dyskinesia is consistent with the hypothesis
that increased iron content reflects greater cerebellar compensatory capacity and thus increased likelihood of LID
development.
Study supported by: National Institutes of Health
(NS060722 and ES019672 to XH), the Penn State Clinical
& Translational Science Institute, Pennsylvania State University CTSA (UL-1RR033184), and the Pennsylvania Department of Health Tobacco Settlement Funds (C06 RR016499)
Spinocerebellar ataxia type 3 (SCA3) and type 6 (SCA6) are
the most common forms of autosomal dominant ataxia.
Dysphagia in these diseases is important clinically, since dysphagia-related aspiration commonly causes fatal pneumonia.
In this study we evaluated dysphagia in 7 patients with
SCA3 and 13 patients with SCA6 by videofluoroscopic examination of swallowing (VF). The evaluation was based on
the scale established by Japanese Society of Dysphagia Rehabilitation, which can evaluate oral and pharyngeal phases
separately, and on dysphagia outcome severity score
(DOSS), a scale used world-widely. The result showed that
mild dysphagia was detected in SCA6 and severe one in
SCA3 on the Japanese scale. By contrast, DOSS revealed
the abnormality in SCA3 but not in SCA6. The extent of
swallowing abnormalities in SCA3 or SCA6 did not parallel
that of physical disability or durations of diseases, suggesting
that patients with well-preserved physical functions or in
even early stages of the diseases had risks of aspiration. In
conclusion, SCA6 had mild but significant involvement of
swallowing as compared to SCA3. The evaluation of swallowing ability by VF is essential to prevent potential aspiration in both diseases.
Study supported by: N/A
T1731. Side of Parkinson’s Disease Onset Predicts Gray
Matter Loss and Cognitive Impairments
Suman Sen, Paul J. Eslinger, Daymond Wagner, Michele L.
Shaffer, Mechelle M. Lewis, Guangwei Du and Xuemei
Huang; Hershey, PA
T1729. Multiple System Atrophy with Inappropriate
Secretion of Antidiuretic Hormone
Makoto Samukawa, Makito Hirano, Hikaru Sakamoto, Mari
Kitada, Susumu Kusunoki and Yusaku Nakamura; OsakaSayama, Osaka, Japan and Sakai, Osaka, Japan
Although Parkinson’s disease (PD) frequently presents with
asymmetric onset, cortical and subcortical gray matter (GM)
changes associated with onset-side have not been investigated. Moreover, while the causes of motor symptoms have
been established, the relationships between onset-side, neurocognitive dysfunctions, and its neural underpinnings have
not been clearly characterized. To address these issues, we
obtained brain magnetic resonance imaging and neuropsychological testing data from 23 left-onset and 23 right-onset
PD, and 23 healthy controls. Subjects were all right-handed,
matched in age, gender, and disease severity. Voxel-based
morphometry measured cortical and subcortical GM differences between the groups, while neuropsychological tests
assessed right and left hemisphere dysfunction. Neuropsychological data were also examined for correlation to GM
changes in PD. Results indicated that PD subjects sustained
lateralized GM loss depending on the onset-side, with leftonset PD showing more extensive cortical and subcortical
GM loss in the right hemisphere that correlated with decrements in select executive function, visuospatial learning and
memory, and procedural learning tasks. Findings support an
anatomical basis for early cognitive change in PD and
underscore the importance of classifying PD based on
onset-side for future research and clinical practice.
Study supported by: National Institute of Health
Multiple system atrophy (MSA) is a slowly progressive neurodegenerative disease, characterized by cerebellar, pyramidal, extrapyramidal, and autonomic disturbances. MSA also
affects the hypothalamus and tracts from the medulla to the
hypothalamus. Hypothalamic cells synthesize antidiuretic
hormone (ADH), which increases water reuptake in the kidney. Hypothalamic disturbances can lead to the syndrome of
inappropriate antidiuretic hormone secretion (SIADH) and
resultant hyponatremia. So far six patients with MSA and
SIADH have been reported. We here report a patient who
had MSA with extreme hyponatremia (99 mEq/l) and the
highest reported ADH concentration (25.5 pg/ml). This
patient recovered from coma, but became ventilator dependent. We also measured ADH in 14 severely disabled patients
with MSA without symptomatic SIADH, and found significantly higher ADH levels than disease controls with similar
disabilities. Taken together, these findings suggest that
patients with MSA have a risk of hyponatremia or SIADH.
Clinicians and caregivers should thus be aware that patients
with MSA carry a risk of SIADH and should carefully regulate salt and water intake to avoid further disability and
potentially fatal outcomes.
Study supported by: N/A
T1732. Patient Expectations and Outcome after DBS
Nasrin Esnaashari, Jospehine Hwu, Jennifer S. Hui and
Daniel Togasaki; Los Angeles, CA
T1730. Higher Iron in the Red Nucleus Marks
Parkinson’s Dyskinesia
Mechelle M. Lewis, Guangwei Du, Michal Kidachi,
Nisargkumar Patel, Michele L. Shaffer, Richard B. Mailman
and Xuemei Huang; Hershey, PA
Background: Many publications have examined the
outcome of deep brain simulation (DBS) for Parkinson’s
disease, but none have assessed patient satisfaction and fulfillment of patients’ expectations. This study determined
patients’ expectations preoperatively, evaluated their
Although dopamine cell loss and increased iron in the substantia nigra (SN) are well known in Parkinson’s disease
(PD), cerebellar involvement is increasingly recognized, par-
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(DTBZ) and [11C] 2beta-carbomethoxy-3beta-4-fluorophenyltropane (CFT) with in vitro measures of nigral cell
counts and striatal dopamine in monkeys after intracarotid
MPTP (0-0.31 mg/kg) injection.
Striatal BPND for each radiotracer linearly correlated with
stereologic nigral cell counts only for nigral loss < 50% (r2
0.91, p<0.001). In contrast, striatal BPND correlated with
striatal dopamine over the full range of dopamine depletion
(r2 0.94, p<0.001). Interestingly, BPND for each radiotracer
correlated with the others (r2 ¼ 0.98, p<0.001). Striatal
uptake of each tracer did not consistently reflect nigral neurons. This may explain discordant results between neuroimaging and clinical endpoints in PD trials. Furthermore, strong
correlations among BPND values do not support differential
regulation of decarboxylase activity, vesicular monoamine
transporter type 2, and dopamine transporter.
Study supported by: NIH (NS050425, NS058714,
NS41509, and NS075321); Michael J Fox Foundation;
Murphy Fund; American Parkinson Disease Association
(APDA) Center for Advanced PD Research at Washington
University; Greater St. Louis Chapter of the APDA;
McDonnell Center for Higher Brain Function; Hartke
Fund; Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund for PD Research & the Jack Buck Research Fund).
fulfillment postoperatively (6 months) and correlated this
with their self-rated motor improvement and with clinical
evaluations.
Methods: Patients undergoing surgery completed a questionnaire recording three goals for DBS. At 6, 12, 18, and
24 months after surgery patients completed follow-up surveys. Clinicians assessed each patient before and at 6, 12,
18, and 24 months after DBS placement using the Clinical
Global Impression-Improvement (CGI-I) scale.
Results: Six patients have 6-month data. Their individual
expectations were largely met, with 16 of 18 goals improving. All patients reported improvement in their neurologic
symptoms, but the extent of improvement did not correlate
with CGI-I scores. Self-rated improvement in neurologic
symptoms correlated much better, however, with how well
preoperative expectations were fulfilled.
Conclusions: Patients’ self-rated improvement in neurologic status after DBS for Parkinson’s disease did not correlate with physician-rated improvement (CGI-I), but showed
stronger correlation with the degree of fulfillment of their
initial expectations.
Study supported by: N/A
T1733. Lewy Body Negative Idiopathic Parkinsonism
Fariha Zaheer, John T. Slevin, Erin L. Abner, Peter T. Nelson
and Gregory A. Jicha; Lexington, KY
T1735. Randomized, Double-Blind, Double-Dummy
Study of Levodopa-Carbidopa Intestinal Gel in Patients
with Advanced Parkinson’s Disease: Functional and
Quality-of-Life Outcomes
K. Kieburtz, A. Antonini, C.W. Olanow, H.H. Fernandez,
A.J. Espay, D.G. Standaert, S. Hass, K. L. Widnell, W.Z.
Robieson, Y. Pritchett, K. Chatamra and J. Benesh; Rochester,
NY; Padua, Italy; New York, NY; Cleveland, OH; Cincinnati,
OH; Birmingham, AL and Abbott Park, IL
Objective: Pathologic Lewy body (LB) inclusions in the
substantia nigra (SN) are considered the classic anatomic
substrate for idiopathic Parkinsonism (iPD). The present
study was designed to investigate the pathologic substrate in
LB negative iPD.
Methods: Thirty-eight cases with a clinical diagnosis of
iPD proximal to death were identified in the University of
Kentucky brain bank (n ¼ 523), with Lewy body pathology
(LBPþ, n ¼ 19) and without Lewy body pathology (LBP-,
n ¼ 19). Cases were analyzed for differences in semiquantitative pathological variables including LB, cerebrovascular
disease, cerebral amyloid angiopathy, and quantitative differences in neuronal density and pigmentary incontinence.
Results: Half cases with clinically diagnosed iPD/DLB
did not have evidence for LBPþ. There were no differences
between LBP-and LBPþ cases across demographic variables
(age, gender, education). Vascular pathology did not differ
between groups. Further analysis of SN neuronal loss using
stereologic quantitative techniques failed to reveal differences
between LBPþ and LBP- cases (p ¼ 0.39; t-test).
Interpretation: Pathologically-unexplained, clinicallydiagnosed Parkinsonism is prevalent in this communitybased sample. While idiopathic substantia nigral neuronal
loss may explain Parkinsonian symptoms in this group, the
etiologic cause and pathological substrate for such clinical
and pathological features in LBP-, iPD remains unknown
and warrants further investigation.
Study supported by: NIA 1 P30 AG028383
Fluctuating blood levels of levodopa are associated with
motor complications in Parkinson’s disease (PD). Levodopacarbidopa intestinal gel (LCIG) provides continuous levodopa
infusion via intrajejunal percutaneous gastrostomy tube. A
double-blind, double-dummy trial compared the efficacy,
safety, and tolerability of LCIG to that of optimized oral levodopa-carbidopa immediate-release (IR) therapy in patients
with advanced PD and motor fluctuations. Levodopa-responsive patients received LCIG infusionþplacebo capsules or
encapsulated levodopa-carbidopa IR tabletsþplacebo gel infusion for 12 weeks. Outcome measures included: 39-item PD
Questionnaire (PDQ-39), Clinical Global Impression–
Improvement (CGI-I) score, and Unified PD Rating Scale
(UPDRS) Part II (Activities of Daily Living) score in the
‘‘On’’ state. 71 patients were randomized (n ¼ 37 LCIG; n
¼ 34 IR) and 66 (95% LCIG; 91% IR) completed the trial.
LCIG (n ¼ 36) significantly improved PDQ-39 summary
index (difference in LS Mean change ¼ -7.0, P ¼ 0.015),
CGI-I (difference in LS Mean ¼ -0.7, P ¼ 0.026), and
UPDRS Part II (difference in LS Mean change ¼ -3.0, P ¼
0.009) compared with IR (n ¼ 33). These results demonstrate superior improvements by LCIG compared with optimized oral levodopa-carbidopa therapy in functional and
quality-of-life outcomes in patients with advanced PD.
Study supported by: Abbott
Katherine Widnell, Weining Robieson, Yili Pritchett, Steve
Hass, Krai Chatamra, and Janet Benesh are employees of
Abbott. Karl Kieburtz, C Warren Olanow, and Angelo Antonini have received compensation from Abbott for serving as
consultants and participating in scientific advisory boards.
Alberto J Espay and David G Standaert were study investigators and have received compensation from Abbott for serving
T1734. Comparison of In Vivo PET with In Vitro
Measures of Pre-Synaptic Nigrostriatal Neurons
Morvarid Karimi, LinLin Tian, Christopher A. Brown,
Hubert P. Flores, Susan K. Loftin, Tom O. Videen, Steve M.
Moerlein and Joel S. Permutter; St. Louis, MO
Discrepancies between neuroimaging and clinical endpoints
in Parkinson disease (PD) studies raise questions about relationships between neuroimaging and in vitro measures of nigrostriatal neurons.
We compared striatal binding potential (BPND) of 3 PET
tracers 6-[18F]fluorodopa (FD), [11C] dihydrotetrabenazine
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as consultants, lecturers, and/or participating in scientific advisory boards. Hubert H Fernandez was a study investigator
and has served as a consultant for Abbott through a contract
between Abbott and Cleveland Clinic Foundation; he has not
received any personal compensation from Abbott.
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T1738. An Unexpected Cause of Altered Mental State in
a Presumed Healthy Caucasian Male
Tobias B. Kulik and Irene H. Richard; Rochester, NY
A 55 year-old right handed Caucasian man, former college
graduate, with an unremarkable past medical history presented to the Emergency Department of a local hospital after a witnessed episode of loss of consciousness in a local
grocery store. Assessment of his mental state demonstrated
psycho-motor slowing, difficulty with abstract reasoning,
dyscalculia and concrete thinking. His neurological examination was notable for language dysfluency, mild hypomimia,
diffuse choreo-athetosis and bilateral paratonia. However,
there were no abnormalities on sensory, cerebellar, reflex or
gait testing. His EEG did not exhibit signs of epileptiform
activity and his cardiovascular work-up, including tilt table
testing, was unremarkable. A non-contrasted head CT
showed extensive bilateral, symmetric calcifications of the
cerebellum, the white matter tracts within the cerebral cortices and basal ganglia. After disorders of calcium homeostasis, autoimmune disease and toxin exposure had been ruled
out, a diagnosis of bilateral strio-pallidodentate calcinosis
(BSPDC) was made.
BSPDC in the primary form is a rare disease with only
99 cases described worldwide. New insights into the genetic
basis and underlying pathophysiology, typical radiographic
findings and differentiating characteristics, and a diagnostic
algorithm that we developed will be presented.
Study supported by: N/A
T1736. Videotape Assessments of Psychogenic Movement
Disorders Subjects Following Immediate Versus Delayed
Treatment with Short Term Psychodynamic
Psychotherapy: Randomized Parallel Trial
Katie Kompoliti, Vanessa K. Hinson, Burgess Wilson and Glen
T. Stebbins; Chicago, IL and Charleston, SC
Objective: Videotape assessments in psychogenic movement
disorder patients (PMDs) following psychodynamic psychotherapy and continuing neurological observation using a clinimetrically tested videotape-based PMD scale (Hinson 2005).
Background: We conducted a 6 month parallel design
trial with PMD patients assigned to three months of either
active psychotherapy or neurological observation in randomized order. Movements, depression and anxiety improved in
both arms. In this report we compare the PMD rating scale
from entry to end of the study.
Design: A blinded investigator assessed videotapes using
the PMD scale. Data were analyzed using KolmogorovSmirnov Z test for pre-post treatment video ratings.
Results: Fourteen women and one man, age 42.36 11,
disease duration 63.26 73 months, were randomized to immediate (7) or delayed (8) treatment. There were no significant differences between the treatment groups for either visit
1 vs. visit 2 or visit 2 vs. visit 3 (minimum p ¼ 0.28).
Conclusion: In this group of PMD patients, movements,
depression and anxiety improved, but there was no change
in videotape assessments. Scale limitations in assessing longitudinal changes in paroxysmal PMDs may account for these
results.
Study supported by: Departmental funds
T1739. Withdrawn.
T1740. An Unsupported Exploratory Clinical Trial on
Tremor
Gian L. Lenzi, Laura Troilo and Francesca Puledda; Rome,
Italy
Background: Tremor affects 10% of the general population.
The new Rome Tremor Scale (RTS), was tested against a
scale reference, the CTRS, and utilized in an exploratory
clinical trial.
Materials and Methods: 40 outpatients with tremor
completed both CTRS (92 items; 30-90 minutes) and RTS
(six items, 3 minutes). 32 patients - 13 with Parkinson Disease (PD), 19 with Essential Tremor (ET) - were enrolled in
an open-label unsupported clinical trial with rotigotine, a
dopamine-agonist drug.
Results: Correlation coefficient between CTRS and RTS
shows r ¼ 0.943 (full population), r ¼ 0,971 in PD, and
r ¼ 0,907 in ET. During treatment, the patients showed a
significant reduction of tremor both after six months (T1;
RTS mean score: 0,9660,11; p< 0,0001), and after 12
months (T2; RTS 1,05þ0,18; p< 0,0001) in respect to T0
(RTS: 2,09360,1). The significative reduction was also
present in the two subgroups, PD and ET, or dividing all
population according to age (younger and older) or into
SPECT-CIT positive or negative.
Conclusions: Rotigotine shows a long-lasting effect on
tremor, both in PD or ET, regardless of age and/or basal
ganglia dopaminergic status.
Study supported by: Unsupported research
T1737. Binding of the Alpha-Synuclein Radioligand
SIL-23 Reflects the Level of Aggregated Alpha-Synuclein
in Parkinson’s Disease Brain tissue
Paul T. Kotzbauer, Devika Bagchi, Maria Udan, Lihai Yu,
Robert H. Mach and Zhude Tu; St. Louis, MO
Accumulation of misfolded, fbrillar alpha-synuclein (alphasyn) in Lewy bodies and Lewy neurites is the pathological
hallmark of Parkinson’s Disease (PD). Radiolabeled ligands
with high affinity for alpha-syn fibrils could be utilized as
imaging tracers for PD. We identified a group of phenothiazine derivatives that bind alpha-syn fibrils and synthesized
the 125I-labeled phenothiazine analogue Synuclein Imaging
Ligand 23 (SIL-23) to further characterize its affinity for
the pathological form of alpha-syn. Radioligand binding
studies demonstrated that SIL-23 has moderately high binding affinity (Kd 140 nM) for fibrils prepared from recombinant alpha-syn, and that a similar binding site is also present in the insoluble fraction from PD postmortem brain
tissue. The density of SIL-23 binding sites in PD brain tissue correlates with insoluble alpha-syn levels. These results
define a radioligand binding site on alpha-syn fibrils that is
specifically present in PD brain tissue and that can be feasibly targeted to quantify pathological alpha-syn accumulation
in vivo. Further optimization of the binding affinity and selectivity of SIL-23 analogues could yield a radiotracer for
pathological alpha-syn accumulation in PD.
Study supported by: Washington University Institute of
Clinical and Translational Sciences
Michael J Fox Foundation
T1741. 4-aminopyridine for Gait Dysfunction in
Parkinson’s Disease
Corneliu C. Luca and Carlos Singer; Miami, FL
Objective: To determine the effect of administration of 4aminopyridine (4-AP) in Parkinson’s disease patients with
gait impairment.
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Background: Parkinson’s disease (PD) related gait dysfunction is the result of multiple neurotransmitter deficits
including dopaminergic, noradrenergic and cholinergic. 4AP, a drug used for gait dysfunction in multiple sclerosis,
increases neurotransmitter release at multiple levels involved
in gait control and therefore may have beneficial effects in
PD.
Methods: We are currently conducting a single center,
randomized, crossover, placebo controlled trial to evaluate
the safety and efficacy of 4-AP in Parkinson’s disease. 20
patients with PD stage1-3 and gait dysfunction will receive
10 mg po BID of 4-AP or placebo for four weeks, followed
by 2 weeks washout and then 4 weeks of crossover treatment. The primary outcome measure is the change in gait
velocity and stride length measured by video 3D gait analysis system. Secondary outcomes will be changes in Timed
up and Go Test, Timed 25 Foot Walk Test, Freezing of
Gait Questionnaire, and UPDRS motor score. Safety and
efficacy of medication will be monitored during the trial.
Conclusions: AMPYRA is a medication that may have
beneficial effect in PD related gait disorders.
Study supported by: American Academy of Neurology
Clinical Research Training Fellowship and National Parkinson Foundation (66745H)
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cits metabolically effect via diet restriction that reduced
weight. GTE is known to control weight, improve deficits
and exerting anxiolytic effects. We testified GTE that may
control HAL elicited NAS and EPS. HAL was administered
(1mg/kg) with water/GTE (1gm/ liter) drink. Behavioral
and neurochemical analysis performed following six weeks
of treatments. HAL decreases fluid, food intakes and growth
rate were greater in GTE drinking animals where GTE
shown to induce anxiogenic behavior and precipitated
motor deficits. HAL induced locomotor activity was suppressed, innate aversive and fear like exploratory behaviors
were greater in GTE than water drinking animals. HAL
induced serotonergic metabolism was increased in the caudate and nucleus accumbens and decreased serotonin in rest
of the brain in GTE drinking animals. HAL induced
decreased dopamine turnover ratios were increased in the
nucleus accumbens of GTE than water drinking animals.
We provided first time the potential mechanisms involved
in anorexiogenic effects of GTE and HAL induced NAS,
EPS.
Study supported by: The University of Karachi
Student institution relationship.
Researcher institution relationship as a research officer
T1744. Innovative Web-Based Matching Service, Fox
Trial Finder, as a Mechanism To Improve Clinical Trial
Recruitment
Claire C. Meunier, Sohini Chowdhury, Todd Sherer and
Deborah W. Brooks; New York, NY
T1742. Risk Factors for Cardiac Arrhythmia and
Syncope through QTc Prolongation in Parkinson’s
Disease
Naveed Malek, Katherine A. Grosset, David Stewart, Graeme
J. Macphee and Donald G. Grosset; Glasgow, United Kingdom
Two obstacles prevent timely recruitment into clinical
research: 1) patient access to information about trials and 2)
coordinator connections to networks of motivated volunteers. A 2003 NIH survey found 85% of trials finish late
due to low patient accrual. A 2005 Harris Survey found 9%
of Parkinson’s patients participated in a trial. Fox Trial
Finder (FTF) leverages improvements in Web technology to
address this need by matching volunteers with recruiting
clinical trials.
PD-specific match algorithm identifies trials based on
data provided by PD users, including current and past medication use, location, etc. A PD patient or healthy individual
creates a profile to match to a relevant subset of all recruiting trials. Matching users are identified as potentially qualified candidates for coordinators assigned to trials. FTF enables trial volunteers and coordinators to connect through a
secure messaging interface. User contact information is only
revealed once a user authorizes release of this information.
Over 3,000 volunteers are registered and 185 trials posted
in US, UK, Canada, and Australia. FTF is helping speed
trial recruitment by bridging the gap between motivated
volunteers and promising clinical trials.
Study supported by: The Michael J. Fox Foundation for
Parkinson’s Research
Drugs that may prolong the cardiac QT interval, causing arrhythmia, syncope, or rarely sudden death, relevant in managing Parkinson’s disease (PD) patients have been highlighted recently.
We reviewed comorbidities and medications in a crosssection of PD patients, considering risk factors for prolonged QT described by the UK Medicines Regulatory
Agency (eg. age over 60, concomitant use of more than one
QT-prolonging drug, etc).
In 360 PD patients, median age 66.5 years (interquartile
range 58.5-74.8), 86 (23.9%) were taking two or more
drugs with potential to prolong QT, including antidepressants in 20.0%, domperidone in 14.2%, bronchodilators in
8.9%, bladder medications in 4.2%, antibiotics in 3.1%,
and antipsychotics in 2.5%. Prevalence of cofactors increasing risk was: age over 60 years 71.7%; diuretic use 22.2%;
cardiac disease 19.2%; domperidone daily dose >30mg
17.6%. There was a history of arrhythmia in 9.7% and syncope in 5.8%. There was no evidence of increased prescription of domperidone in patients taking dopamine agonists
(18/136, 13.2%) versus other antiparkinson therapy (37/
224, 16.5%), p ¼ 0.452 Fisher exact test.
Exploration of therapy alternatives for PD patients’ complex needs, to reduce risks from QT prolongation, is
warranted.
Study supported by: Self supported.
T1745. LIVECHART: A System for Recording,
Evaluating and Monitoring Botulinum Toxin Treatments
for Any Condition
Austen P. Moore; Liverpool, Merseyside, United Kingdom
T1743. Effects of Green Tea Extract (GTE) on
Haloperidol (HAL) Induced Neuroleptic Anxiety
Syndrome (NAS) in Rat Model of Extrapyramidal
Syndrome (EPS)
Tafheem Malik and Darakhshan J. Haleem; Karachi, Sind,
Pakistan
Botulinum toxin (Bt) users require systems for recording the
treatments given and their effects. In many settings around
the world documentation is inadequate and clinically suboptimal. The LIVECHART (LIVErpool botulinum toxin
CHART) is a fast, concise, simple, cheap system that can be
used anywhere and does not require electronic recording. It
systematically records the exact treatment given and patientreported effects of treatment, including adverse effects and
HAL elicits NAS along EPS. HAL induces c-Fos expression
distributed anxiety-related neural scheme, selected neuronal
population of nucleus accumbens. HAL elicited mood defi-
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therapeutic response expressed in a weekly visual analogue
score (VAS) and Likert scales.
Advantages include 1) enhances understanding and
involvement by patients, and can be completed with or by
carers if needed, 2) flexible goal setting, individualised monitoring and effects scoring for any condition, 3) minimises
injection errors through pattern recognition, 4) facilitates
decisions about the next treatment cycle and overall management strategy, 5) outcome measures accepted by many
payment bureaux, 6) speeds up clinics, 7) outcomes can be
used in controlled n-of-1 and other crossover trials, 8) provides clear information to other health professionals.
Disadvantages include 1) occasional patients unable to
use LIVECHART, 2) inter-patient VAS comparisons are
inappropriate, 3) harder to interpret if completed by different carer each time.
Study supported by: Ipsen UK
I have received travel grants, research funding, honoraria
for speaking and consultancy fees from Ipsen UK, Allergan,
Merz and Eisai who all market botulinum toxins for clinical
use.
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differences between Parkinson’s Disease (PD) and control
patients. Post-mortem brain samples from PD and controls
cases (substantia nigra, putamen, globus pallidus -internal
and external parts-), and blood samples from recently diagnosed and non-treated PD and controls cases were analyzed.
Gene and protein expression studies of the CB2r were carried out by real time-PCR and western blot, respectively.
Gene expression analyses showed that CB2r is significantly
reduced in putamen (-40%) and globus pallidus internal (47%) and external (-31%) parts, but dramatically increased
in the substantia nigra (388%). Protein expression analyses
showed no differences in the Putamen but a significant
diminishment of CB2r protein (-73 %) in the substantia
nigra of PD patients. On the other hand, in lymphocytes
from non-treated PD patients, CB2r gene expression is significantly down-regulated (-30%). The results obtained in
this study revealed CB2r gene and protein expression differences between PD and controls patients, suggesting that
CB2r could have an important role in the neurodegenerative
process of PD.
Study supported by: This work was supported by ‘‘DISTEC professorship for the study of Parkinson’s Disease’’ to
Jorge Manzanares. Francisco Navarrete is a predoctoral fellow supported by MICINN (Spanish Science and Innovation Ministry). We thank ‘‘Fundación CIEN brain bank’’
(Madrid, Spain) and ‘‘London Neurodegenerative Diseases
brain bank’’ (London, UK) for post-mortem brain tissue
supply.
T1746. C9ORF72 Hexanucleotide Repeat Expansion
Analysis in Patients with Parkinson’s Disease
Joanne D. Stockton, Catriona Moorby, Rachel V. Denyer,
Caroline Rick, Keith Wheatley, Carl E. Clarke and Karen E.
Morrison; Birmingham, United Kingdom
Recent research demonstrates that expanded C9ORF72 hexanucleotide repeats occur frequently in both amyotrophic
lateral sclerosis (ALS) and frontotemporal dementia (FTD)
(Renton, Neuron 2011; DeJesus-Hernandez, Neuron 2011),
accounting for around 8% of sporadic ALS and 50% of
familial ALS. 35% of those with C9ORF72 expansion-associated ALS-FTD or FTD have Parkinsonism on clinical examination, mostly of the akinetic-rigid type, and this
appears to be an early clinical feature (Boeve, Brain 2012).
No published studies to date have examined whether
C9ORF72 expansion is present in Parkinson’s disease.
We have tested over 200 patients diagnosed with Parkinson’s disease (PD) from the UK PDGEN cohort (http://
www.pdgen.bham.ac.uk/) for C9ORF72 repeat expansions,
using a repeat primed PCR method and DNA extracted
from peripheral blood lymphocytes.
Results from 232 patients reveal no C9ORF72 hexanucleotide expansions (24 repeats) in any individual with
PD. We will undertake further analysis examining the relationship between repeat length in those patients with 23
repeats or fewer and phenotypic characteristics, such as the
presence of dementia.
Our data demonstrate that C9ORF72 hexanucleotide
expansion is not associated with idiopathic Parkinson’s disease. The relationship between repeat length and specific
phenotypic features remains to be explored.
Study supported by: University Hospital Birmingham
Charities and Midlands Neuroscience Teaching and
Research Fund.
T1748. Randomized, Double-Blind, Double-Dummy
Study of Levodopa-Carbidopa Intestinal Gel in Patients
with Advanced Parkinson’s Disease: Efficacy and Safety
C.W. Olanow, A. Antonini, K. Kieburtz, H.H. Fernandez,
A.J. Espay, D.G. Standaert, A. Vanagunas, K. L. Widnell, S.
Freeman, W.Z. Robieson, Y. Pritchett, K. Chatamra, J. Benesh
and R.A. Lenz; New York, NY; Padua, Italy; Rochester, NY;
Cleveland, OH; Cincinnati, OH; Birmingham, AL; Chicago,
IL and Abbott Park, IL
Fluctuating blood levels of levodopa may contribute to
motor complications in Parkinson’s disease (PD). Levodopacarbidopa intestinal gel (LCIG) infusion provides more continuous delivery of levodopa than oral levodopa. A doubleblind, double-dummy trial compared the efficacy, safety,
and tolerability of LCIG to oral levodopa-carbidopa immediate-release (IR) therapy in patients with advanced PD and
motor fluctuations. Levodopa-responsive patients received
LCIG infusionþplacebo capsules or encapsulated levodopacarbidopa IR tabletsþplacebo gel infusion for 12 weeks.
The primary endpoint was change from baseline to Week
12 in ‘‘Off ’’ time normalized to 16 waking hours. ‘‘On’’
time without troublesome dyskinesia (TD) was a key secondary outcome. 71 patients were randomized (n ¼ 37
LCIG; n ¼ 34 IR), and 66 (93%) completed the trial.
LCIG produced superior improvements in ‘‘Off ’’ time (LS
mean difference ¼ -1.91 hr; P ¼ 0.0015) and ‘‘On’’ time
without TD (LS mean difference ¼ 1.86 hr, P ¼ 0.0059)
compared with IR. Change in ‘‘On’’ time with TD was not
significant. Adverse events occurred in 35 (95%) and 34
(100%) patients receiving LCIG and IR, respectively; complication of device insertion (51%), abdominal pain (42%),
procedural pain (32%) and nausea (25%) were most
common.
Study supported by: Abbott
Katherine Widnell, Weining Robieson, Yili Pritchett, Krai
Chatamra, Janet Benesh, and Robert Lenz are employees of
Abbott. Stefanie Freeman was an employee of Abbott when
T1747. Cannabinoid CB2 Receptor Gene and Protein
Expression Differences in Parkinson’s Disease PostMortem Brain Samples and Lymphocytes from Recently
Diagnosed and Non-Treated Patients
Francisco Navarrete, Marı´a Salud Garcı´a-Gutie´rrez, Jose´
Antonio Molina, Carlos Leiva and Jorge Manzanares; San
Juan de Alicante, Spain; Madrid, Spain and Alicante, Spain
The aim of this study was to analyze central (brain) and peripheral (lymphocytes) CB2r gene and protein expression
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the studies were conducted. C Warren Olanow, Angelo
Antonini, and Karl Kieburtz have received compensation
from Abbott for serving as consultants and participating in
scientific advisory boards. Alberto J Espay, David G Standaert, and Arvydas Vanagunas were study investigators and
have received compensation from Abbott for serving as consultants, lecturers, and/or participating in scientific advisory
boards. Hubert H Fernandez was a study investigator and
has served as a consultant for Abbott through a contract
between Abbott and Cleveland Clinic Foundation; he has
not received any personal compensation from Abbott.
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a botulinum toxin. The mean baseline JRS total score was
5.0. The CGI-Severity at baseline was 32.8% normal-tomild, 35.5% moderate, 22.4% marked and 9.3% severe.
The SF-12v2 mean scores were 49.1-Mental and 43.1-Physical. At the onset of symptoms, 105 subjects were employed.
Of those employed, 33 felt that their symptoms affected
their productivity (estimated productivity was 82.8% (100%
¼ normal and 0% ¼ no productivity). A total of 17 subjects received or were seeking employee disability benefits
related to symptoms.
Conclusions/Relevance: A significant proportion of blepharospasm patients find that their disorder has negative
consequences on their QoL and employment status.
Study supported by: Merz Pharmaceuticals, LLC
LeDoux, Jankovic, Fernandez: Consulting/Clinical
Research fees
Sethi, Verma, Pappert: Salary (employees of Merz)
T1749. A Prospective, Observational Trial Evaluating
Xeomin (incobotulinumtoxinA) for Cervical Dystonia
(CD) or Blepharospasm in the United States –
Preliminary Baseline Results on the Health Impact of
CD on Patients Using the Cervical Dystonia Impact
Profile (CDIP)
Joseph Jankovic, Madhavi Thomas, Alberto Vasquez, Kapil D.
Sethi, Amit Verma, Eric J. Pappert and Hubert H. Fernandez;
Houston, TX; St. Petersburg, FL; Greensboro, NC and
Cleveland, OH
T1751. A Prospective, Observational Trial Evaluating
Xeomin [IncobotulinumtoxinA] for Cervical Dystonia
(CD) or Blepharospasm in the United States –
Preliminary Baseline Results for Patients with CD
Daniel D. Truong, Fabio O. Danisi, Kapil D. Sethi, Amit
Verma, Eric J. Pappert and Hubert H. Fernandez; Fountain
Valley, CA; Kingston, NY; Greensboro, NC and Cleveland,
OH
Background: XCiDaBLE is an ongoing observational study
to evaluate patient-reported outcomes following incobotulinumtoxinA treatment.
Methods: Subjects are followed for 2 treatment cycles.
Subject-reported scales include the CDIP. There are 58
items in the CDIP grouped into 8 subscales. Each subscale
score was transformed to have a common range of 0 (no
impact) to 100 (most impact).
Results: As of September 1, 2011, 130 CD patients were
enrolled and CDIP data were available for 115 subjects
(mean age 57.7 years, 84.4% female, 93.0% Caucasian).
82.6% were previously treated with a botulinum toxin. At
baseline, the CDIP subscales scores: Head and Neck Symptoms: 60.5; Pain and Discomfort: 58.7; Upper Limb Activities: 41.0; Walking: 35.7; Sleep: 40.4; Annoyance: 44.3;
Mood (7 items): 35.8; Psychosocial Functioning: 40.6. Total
CDIP score at baseline was 43.1.
Conclusions: CD has a clinically meaningful adverse
impact on QoL. The total CDIP and its various subscales
and domains is a useful tool to measure the health impact
of CD.
Study supported by: Merz Pharmaceuticals, LLC
Jankovic, Thomas, Vasquez, Fernandez: Consulting/Clinical Research Fees
Sethi, Verma, Pappert: Salary (employees of Merz)
Background: XCiDaBLE is an ongoing open-label, prospective, observational study intended to evaluate patient-reported
outcomes following incobotulinumtoxinA treatment.
Methods: Subjects are followed for 2 treatments. Investigators rate the Clinical Global Impression (CGI)-Severity at
baseline. Subjects rate the Cervical Dystonia Impact Profile
(CDIP) [CD], Subject Global Impression-Severity and
Improvement, SF-12v2, an employment questionnaire, and
work history.
Results: As of September 1, 2011, 130 CD subjects were
enrolled (80.8% female; mean age 57.6 years; 92.3% Caucasian). 83.1% were previously treated with a botulinum
toxin. CGI-Severity at baseline was: 20.2% normal-to-mild,
48.1% moderate, 20.9% marked, 9.3% severe and 1.6%
extreme. The CDIP score at baseline is 43.1. The SF-12v2
mean scores for CD were 44.0-Mental QoL and 38.1-Physical QoL. At the onset of symptoms, 92 CD subjects were
employed. Of the subjects employed, 31 felt that their
symptoms affected productivity. 25 subjects received or were
seeking employee disability benefits related to symptoms.
Conclusions: CD can have a significant adverse impact
on QoL and employment status.
Study supported by: Merz Pharmaceuticals, LLC
Truong, Danisi, Fernandez: Consulting/Clinical Research
fees
Verma, Pappert, Sethi: Salary (employees of Merz)
T1750. A Prospective, Observational Trial Evaluating
Xeomin [IncobotulinumtoxinA] for Cervical Dystonia or
Blepharospasm in the US – Preliminary Baseline Results
for Patients with Blepharospasm
Mark S. LeDoux, Joseph Jankovic, Kapil D. Sethi, Amit
Verma, Eric J. Pappert and Hubert H. Fernandez; Memphis,
TN; Houston, TX; Greensboro, NC and Cleveland, OH
T1752. Rapid Generation of iPSCs from
Lymphoblastoid Cell Lines Using an Episomal Plasmid
Containing Multi-Reprogramming Factors in a Single
Cassette
Sharan Paul, Warunee Dansithong, Karla Figueroa and Stefan
M. Pulst; Salt Lake City, UT
Background: XCiDaBLE is an ongoing observational study
intended to evaluate patient- reported outcomes following
incobotulinumtoxinA treatment.
Design/Methods: Subjects are followed for 2 treatment
cycles. Investigators rate the Clinical Global Impression
(CGI)-Severity at baseline. Subjects completed the Jankovic
Rating Scale (JRS), an employment questionnaire, work history and the SF-12v2 at baseline.
Results: As of September 1, 2011, 184 blepharospasm
subjects were enrolled (mean age 64.9 years, 72.3% female,
91.8% Caucasian). 97.8% had been previously treated with
Reprogramming of skin fibroblasts is increasingly used for
modeling of human neurological diseases. In contrast to
skin fibroblasts, blood lymphocytes and especially lymphoblastoid (LB) cells are difficult to reprogram and induced
pluripotent stem cell (iPSC) colonies are usually formed after weeks and with very low efficiency. We have developed a
novel technique that requires four days to generate iPSCs
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from patient lymphoblasts (EBV-B) using an episomal plasmid containing multi-reprogramming factors (RFs) (cMYC, KLF4, SOX2, and OCT3/4) in a single cassette. The
four RFs are expressed under individual control of a modified CMV promoter. Plasmids are introduced into LB cells
by electroporation and plated on Geltrax coated plates.
Within 1 day, cells tend to attach and start to form colonies. At day 3, lymphoblasts-derived iPSCs showed ES cell
morphology and expressed pluripotent cell-specific genes.
Furthermore, the iPSCs could be differentiated into cells of
the germ layers in vitro. The ability to reprogram banked
patient EBV-transformed cell lines efficiently will offer an
unprecedented opportunity to rapidly generate genetic disease models and also provide a translational platform for
therapeutic drug development.
Study supported by: Grants RO1NS33123 and
RC4NS073009 from the National Institutes of
Neurological Disorders and Stroke to SMP.
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lated by writing a letter other than that which appeared on
a screen, but not by simple letter copying [2]. The rTMS of
the inferior frontal cortex, but not of the dorsolateral prefrontal cortex, increased the dual-task processing speed [3].
In a three-stimulus paradigm, the distractor stimulus evoked
an early potential (latency 200 ms) not known from scalp
recordings [4].
Conclusion: The modulation of cognitive functions is
selective. The STN might modulate non-motor activities via
contextual modulation of certain cortical areas. Our findings
support the hypothesis of a cortico-STN bypass of the Basal
Ganglia-Thalamocortical circuitry when processing cognitive
functions. There is a spatial overlap of sites regulating various functions in the STN, motor as well non-motor. That
might explain that a beneficial effect of STN DBS may be
accompanied by cognitive impairment.
1.
2.
3.
4.
T1753. Is Psychiatric Disease a Core Phenotype of
Myoclonus Dystonia Syndrome Caused by SGCE
Mutations?
Kathryn J. Peall, Manju A. Kurian, Mark Wardle, Martin
Smith, Hardev Pall, Jean-Pierre Lin, Tammy Hedderly, Alan
Whone, Cathy White, Andrew Lux, Adrian J. Waite, Michael
Samuel, Timothy Lynch, Patrick F. Chinnery, George Kirov,
Mary King, Derek J. Blake, Huw R. Morris, Daniel J. Smith
and Michael J. Owen; Cardiff, United Kingdom; London,
United Kingdom; Birmingham, United Kingdom; Bristol,
United Kingdom; Swansea, United Kingdom; Dublin, Ireland
and Newcastle, United Kingdom
Baláž M. Mov Disord 2008
Rektor I. Parkinsonism Relat Disord 2009
Baláz M. Exp Brain Res 2010
Bocková M. J Neural Transm 2011
Study supported by: CEITEC
T1755. The Addenbrooke’s Cognitive Examination in
Parkinsonian Disorders at Baseline and 18 Months
Timothy Rittman, Boyd C.P. Ghosh, Jonathan R. Evans, Peter
McColgan, David P. Breen, Roger A. Barker and James B.
Rowe; Cambridge, Cambridgeshire, United Kingdom
Differentiating Parkinson’s disease (PD) from atypical parkinsonian syndromes is challenging. We assessed whether the Revised Addenbrooke’s Cognitive Examination (ACE-R) could
separate parkinsonian disorders and track disease progression.
We administered ACE-R at baseline and 18 months in
21 PD, 30 Progressive Supranuclear Palsy (PSP) 21 Corticobasal Degeneration (CBD) subjects.
In distinguishing PD from PSP, the verbal fluency subscore was sensitive (0.9) and specific (0.87), with ACE-R
being sensitive (0.9) but not specific (0.46). Significant
group level differences were found between PD and PSP for
ACE-R and all subscores except language and memory; and
between CBD and PD for ACE-R, MMSE, attention/concentration, visuospatial and fluency subscores.
Significant decline between visits was seen in CBD subjects for ACE-R (p ¼ 0.003), visuospatial subscore (p ¼
0.00001) and MMSE (p ¼ 0.02), and more weakly in PSP
subjects for ACE-R (p ¼ 0.04) and visuospatial subscore (p
¼ 0.02).
This data suggest that the ACE-R score and verbal fluency are effective methods in differentiating PD from PSP,
and a useful measure of disease progression in CBD.
Study supported by: This work has been funded by:
MRC
Wellcome Trust
Sackler studentship
Background: Myoclonus Dystonia Syndrome (MDS) is a
childhood onset, alcohol responsive movement disorder
caused by mutations in the SGCE gene in a proportion of
cases. Single family and case series have suggested co-morbid
psychiatric disease but have not compared cases to a control
group.
Aims: To establish a cohort of MDS patients with SGCE
mutations and a control group of alcohol-responsive tremor
patients, and to systematically assess for psychiatric symptoms using standardised questionnaires.
Methods: We collected 27 patients with SGCE mutations
and 45 tremor control cases. The MINI International Neuropsychiatric Interview, PHQ-9, MADRS, YBOCS and
AUDIT were used to assess psychiatric disease according to
DSM-IV criteria.
Results: There was a higher rate of psychiatric disease in
MDS patients compared to controls (p<0.05), specifically
social phobia (p<0.05) and Obsessive-Compulsive disease
(OCD) (p<0.001). Excess alcohol use was higher amongst
the MDS group once cases <18yrs were excluded.
Conclusions: Overall psychiatric disease is elevated
amongst the MDS cohort compared to a control group
with a chronic, socially stigmatizing disorder. OCD appears
to be the greatest contributor to this effect and may reflect
a pleiotropic function for the SGCE gene.
Study supported by: The IPSEN fund
T1754. Role of the Subthalamic Nucleus in Modulating
Cognitive Functions. A Viewpoint Based on Recordings
from DBS Electrodes
Ivan Rektor, Marek Bala´z, Martina Bockova´ and Irena
Rektorova; Brno, Czech Republic
T1756. Alpha-Synuclein Expression in the Epidermis
and Epithelial Tissue in Parkinsonism
Ildefonso Rodriguez-Leyva, Ana Laura Calderon-Garcidueñas,
Ana Arely Renteria-Palomo, Rodrigo Valdez-Rodriguez, Julio
Sepulveda and Juan Pablo Castanedo-Cazares; San Luis Potosı´,
Mexico; Jalapa, VER, Mexico and Monterrey, NL, Mexico
The STN is implicated in tasks with increased cognitive
loads. A dual task, but not a simple oddball task, evoked
local field P3-like potentials [1]. Oscillations were modu-
The alpha-synuclein has an unknown function is a useful
marker for Parkinsons disease. Although the presence of
alpha-synuclein has been reported in the nerve endings of
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Parkinson patients skin, recent studies have suggested that
sebaceous glands might express some of its base peptides
too. We are trying to prove that it might be possible to find
it in other skin structures as well.
A skin biopsy was taken from 21 patients with Parkinson’s disease (PD), 9 patients with a clinical diagnosis of
atypical parkinsonism (AP) and 10 control subjects (CS). A
total of 80 biopsies were examined using immunohistochemestry, confocal and electronic microscopy with a polyclonal antibody for alpha-synuclein.
We observed an important expression of alpha-synuclein
in patients with PD, compared to patients with AP, whereas
it was not found in the control group. The biggest expression was found in the pilosebaceous units followed by the
spinous cell layer (SCL) and the eccrine glands (EG).
The expression of alpha-synuclein was strongly positive in
PD, moderate in AP and absent in the CS. This findings
ask for further confirmations because they open a window
in the study of neurodegenerative diseases.
Study supported by: COPOCYT
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Background: PTD patients often report delay in receiving correct diagnoses.
Subjects: 623 PTD patients newly diagnosed in 20032007 in Kaiser Permanente Northern California (KPNC),
6230 matched controls.
Design/Methods: Case-control comparison of diagnoses
made prior to PTD in electronic medical record; interview
a subset to determine consequences of mistaken diagnosis;
odds ratios adjusted for age, gender, and duration of
membership.
Results: Diagnoses made prior to the correct PTD diagnosis included acute stress (PTD 23%, controls 15%, OR 1.7,
95% CI 1.39, 2.08, p<0.0001), anxiety (PTD 31%, controls
19%, OR 1.95, 95% CI: 1.62, 2.34, p <0.0001), musculoskeletal strain (cervical dystonia 62%, controls 47%, OR
1.83, 95% CI 1.32,2.53, p<0.001), cervical disc disease (cervical dystonia 45%, controls 18%, OR 3.96, 95% CI 2.89,
5.42, p<0.0001), laryngitis (spasmodic dysphonia 4%, controls 0.2%, OR 18.2, 95% CI 4.26, 77.86, p < 0.0001).
Median time from symptom onset to correct diagnosis was 2
years. 64% reported adverse effects of delayed diagnosis.
Conclusion: Correct diagnosis of PTD is commonly
delayed, with associated harmful effects. Education to minimize delayed diagnosis is needed.
Study supported by: AHRQ RO1 HS018413; NIH
1RO1 NS046340; Dystonia Medical Research Foundation;
James & Sharron Clark
T1757. Paradigm for Neuroprotection in
Presymptomatic Huntington’s Disease
H. Diana Rosas, Gheorghe Doros, Sona Gevorkian, David H.
Salat, Martin Reuter, Bruce Fischl, Keith Malarick, Wayne R.
Matson, Clemens R. Scherzer, Robert J. Ferrante and Steven
M. Hersch; Charlestown, MA; Boston, MA; Bedford, MA;
Cambridge, MA and Pittsburgh, PA
T1760. Analysis of Wave III of Brain Stem Auditory
Evoked Potential during Microvascular Decompression
of Cranial Nerve VII for Hemifacial Spasm
Balaji Krishnaiah, Parthasarathy D. Thirumala, Miguel
Habeych, Donald Crammond and Jeffrey Balzer; Pittsburgh, PA
Huntington’s disease (HD) commences more than 20 years
before clinical symptoms. A major therapeutic goal is to
delay or prevent onset in those who are not yet symptomatic. We report the first therapeutic trial in presymptomatic individuals at risk for HD. We utilized high dose creatine monohydrate, a leading candidate disease modifying
therapy for HD and a novel recruitment strategy that
included premanifest individuals known to have the HD
mutation as well as 50% at risk individuals who did not
wish to know their genetic status. Subjects that did not have
the HD mutation provided a control group for biological
measures while removing the risk of coerced genetic testing.
The trial consisted of a double-blind, placebo-controlled
phase lasting 6 months and an unblinded open label phase
in which all subjects were followed for an additional year.
Clinical, neuroimaging, and blood markers of HD were
assessed longitudinally. We show that it is feasible to conduct therapeutic trials in individuals at-risk for HD, that
clinical and biological markers can measure progression in
these subjects, and that high dose creatine, slowed brain atrophy, beneficially impacted additional markers, and may be
disease modifying in premanifest HD.
Study
supported
by:
NINDS
PO1NS058793,
NS042861, NCCAM AT000613
Introduction: Intraoperative monitoring (IOM) of Brainstem
Auditory evoked potential (BAEP) during microvascular
decompression (MVD) prevents hearing loss (HLS) in patients
with hemifacial spasm. Previous studies have shown changes in
wave III (wIII) is an early sign of auditory nerve injury.
Objective: To evaluate changes in amplitude and latency
of wIII (AwIII, LwIII) of BAEP during MVD and its association with postoperative HLS. HLSwas classified by AAOHNS criteria, based on changes in pure tone audiometry
and speechdiscrimination score.
Methods: Pre and post operative audiograms and BAEPs
in patients who underwent IOMduring MVD were analyzed. The results classified into patients who did and did
not have HLS asgroup I and II respectively.
Results: The AwIII was significantly decreased in the
group with HLS (p< 0.015).
The LwIII was not found to be significantly different
group I and II. Regression analysis did not find any changes
in the amplitude of wIII to increase the odds of HLS.
Conclusion: Changes in wIII did not increase the odds
of HLS in patients who underwent BAEPs during MVD.
This information might be valuable to evaluate the value of
wIII as alarm criteria during MVD to prevent HLS.
Study supported by: None
T1758. Withdrawn.
T1759. Diagnostic Error in Primary Torsion Dystonia
Caroline M. Tanner, Stephen K. Van Den Eeden, Samuel
Goldman, Raymond Y. Lo, Connie Marras, Kathleen B.
Albers, Amethyst D. Leimpeter, Robin Fross, Kathleen Comyns,
Zhuqin Gu, Robin Smit, Annelie de Kleijn, Laurie Ozelius,
Susan Bressman, Rachel Saunders-Pullman, Cynthia Comella,
Lorene M. Nelson and Jeffrey Klingman; Sunnyvale, CA;
Oakland, CA; Taiwan, Taiwan; Toronto, ON, Canada;
BeiJing, China; Nijmegen, Netherlands; New York City, NY;
Chicago, IL and Palo Alto, CA
T1761. Establishing Baseline Values for Brainstem
Auditory Evoked Potentials (BAEP) during
Microvascular-Decompression for Hemifacial Spasm
Santhosh Kumar Mohanraj, Parthasarathy D. Thirumala,
Miguel Habeych, Donald Crammond and Jeffrey Balzer;
Pittsburgh, PA
Introduction: Changes in brainstem auditory evoked potential (BAEP) waveforms are used to alert the surgeon during
Objective: To identify delay in the diagnosis of primary torsion dystonia (PTD).
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recognition items. Data from 96 control (mean age ¼ 59;
mean education ¼ 14.7) and 78 HD (mean age ¼ 53;
mean education ¼ 14.4) participants were analyzed using
Maximum Likelihood models. Significant differences in
recall between control and HD participants existed in freerecall and multiple-choice-recognition (v2 ¼ 105.562, v2 ¼
20.325, respectively, ps < .0001). Odds-ratios showed that
controls performed better in free-recall, cued-recall, and
multiple-choice-recognition conditions (OR ¼ 3.374; OR
¼ 1.067; OR ¼ 2.158, respectively), but that HD nearly
matched control participants in cued-recall. These results
suggest that the MoCA is able to measure memory subtype
differences. Furthermore, they provide insight into the progression of memory deterioration in HD, supporting
research that suggests retrieval is initially most impaired, but
that for those whose deficits are advanced, encoding difficulties also occur.
Study supported by: This research was supported by the
UCSD Huntington’s Disease Society of America Center of
Excellence and UCSD Shiley-Marcos Alzheimer’s Disease
Research Center NIH P50 AG 005131
microvascular-decompression (MVD) for Hemifacial spasm
about impending hearing-loss. These changes are compared
to the baseline values of BAEP set at the beginning of the
procedure.
Objective: Evaluate the appropriate time to set baseline
values for BAEPs during MVD for hemifacial spasm and its
implications on the alarm criteria.
Methods: We retrospectively identified 63 patients who
had intraoperative monitoring with BAEP during MVD
and compared the latency(Lw-V) and amplitude(Aw-V) of
wave-V at baseline (before beginning of the procedure) and
at dura-opening (before major manipulation) to the changes
in Lw-V and Aw-V of BAEPs when the surgeon was alerted.
Results: Higher percentages of alerts were communicated
to the surgeon when baseline values were set before the
beginning of the procedure when compared to baseline
values set before major manipulation.
Conclusions: Baseline values should be set before major
manipulation rather than the beginning of the case. This information will be valuable in reducing false alarms and
unnecessary anxiety during surgery.
Study supported by: None
T1764. Inhibitory Neurons In the Ventral Medial
Medulla Modulate Gait and Tone
Veronique G. VanderHorst, Brian Ellison and Clifford B.
Saper; Boston, MA
T1762. Proteomic Analysis of Serum Microvesicles in
Parkinson’s Disease
Paul R. Tomlinson, Samuel Evetts, Michele Hu, Chris
Gradner, Benedikt Kessler, Kevin Talbot and George K.
Tofaris; Oxford, United Kingdom
Gait abnormalities are an important source of disability, but
brainstem circuitries mediating gait remain unknown. We
developed methods for genetic manipulation of inhibitory
or excitatory neurons in specific brainstem sites, and for
evaluating their role in gait. In this study, we characterize
connections and functions of inhibitory neurons in the ventral medial medulla (VMM), an important relay between
fore- and midbrain motor regions and the spinal cord.
Pathways from inhibitory VMM neurons that express the
vesicular GABA transporter (vgat) were studied by injecting
a conditional, cre-dependent viral vector into the VMM of
vgat-cre mice. The function of these neurons was studied
using conditional, vgat-floxed knockout mice in which
motor performance was assessed using video gait analysis,
kinematics, complex motor tasks, and EMG.
The results show that inhibitory VMM neurons project
to spinal motoneurons, with a preference for selected pools.
Deletion of vgat from the VMM results in a decrease in
stance duration and stride length, accompanied by postural
changes, but does not affect complex motor tasks. Increased
EMG activity is present during rest, gait, and REM sleep,
suggesting an important role of this system in the control of
tone.
Study supported by: Thomas Hartman Foundation
Judy Goldberg Foundation
Although the clinical diagnosis of Parkinson’s disease (PD)
can be made with accuracy, by the time patients present to
the clinic the majority of dopaminergic neurons have degenerated. Biomarkers are needed to identify at risk patients
before clinically significant neuronal death has occurred and
monitor the disease progression. Membrane vesicles termed
exosomes, are 40-100nm particles that are secreted by most
cell types under normal and pathological conditions. We
hypothesized that serum microvesicles include brain-derived
membrane particles and as such may constitute a useful biomarker of degenerating neurons.
Sera were collected from participants recruited into the
Oxford PD longitudinal study for biomarker discovery. Our
study groups consist of age-matched control subjects and
carefully characterized patients within three years of the clinical diagnosis of PD. All recruited subjects were screened for
glucocerebrocidase (GBA) and Leucine-Rich Repeat Kinase 2
(LRRK2) mutations.
To isolate microvesicles, we developed a protocol based
on serial centrifugations and confirmed the purity of our
preparations using gel electrophoresis, electron microscopy
and nanoparticle tracking analysis. We used label-free quantitative nanoflow liquid chromatography mass spectrometry,
MSE to compare microvesicle-associated protein changes
between healthy control subjects and patients with sporadic
and genetic forms of PD.
Study supported by: Parkinson’s UK
T1765. Genetic Association Studies (Single Nucleotide
Polymorphisms) in South Indian Parkinson’s Disease
Patients and Controls
Padmaja M. Vishwanathan, Devaprasad Markandeyan,
Meenakshi Jayaraman, Srikumari C.R. Srisailapathy, Bhanu
K. Murthy, Srinivasan A. Venkatesan and Ramesh Arabandi;
Chennai, Tamilnadu, India and Chennai, Tamil Nadu, India
T1763. Examining Memory Subtypes in Huntington’s
Disease Using the Montreal Cognitive Assessment
Charles P. Van Liew, Shea Gluhm, Daniel Brown, Jody L.
Goldstein and Jody Corey-Bloom; San Diego, CA
Objective: To determine the association status of Single nucleotide polymorphisms (SNPs) of genes, CYP1A1, CYP
2D6*4, CYP2D6*3, DRD2, NAT2, PARK2, NR4A2 and
SNCA in South Indian Parkinson’s disease (PD) patients
and controls.
Methodology: The study consisted of 140 affected
patients (26 familial and 114 sporadics) recruited from
Brief assessments of memory subtypes (e.g., retrieval, recognition) for Huntington’s disease (HD) are lacking. We
sought to determine whether the Montreal Cognitive Assessment (MoCA) could be used to examine memory subtypes
in HD. The MoCA has an optional component that assesses
short-term, verbal memory using free-recall, cued-recall, and
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Movement Disorder Clinic, Madras Medical College, Chennai. Age and ethnically matched 201 unaffected subjects
were also recruited. SNPs were analyzed by PCR –RFLP
method. The gene frequencies were calculated by gene
counting method. Multiple logistic regression analysis and
odds ratio was calculated.
Results and Conclusion: 1) Analysis of DRD2,
CYP2D6, CYP2D6*3 and NAT2 SNPs showed no significant association with PD in our population.
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positive, with titres up to 1:5120. Undiluted CSFs were
positive in 14/15. The IgG1 antibodies bound to anterior
horn cell neurons, and increased internalisation of HEK cell
GlyRs. Some patients had a monophasic disease, but many
slowly progressed or relapsed. Excessive startle, painful
spasms (often touch-sensitive), stiffness, and rigidity were
found in 90%. Brainstem disturbance leading to oculomotor
abnormalities, dysphagia, dysarthria or trismus were also
common (60%). Autonomic or cognitive involvement, seizures or sleep disturbance were less frequent (up to 30%).
MRI and CSF findings were often uninformative but two
had thymomas and one had a lymphoma. All patients
received symptomatic treatments and most improved substantially with steroids and plasma exchange or IvIg, but
relapses have occurred, and delayed diagnosis may have
been responsible for three deaths. The clinical spectrum of
this immunotherapy-responsive condition is wide and not
all the patients can be defined as PERM.
Study supported by: The Oxford NIHR Biomedical
Research Centre; the NIHR National Commissioning Service for Neuromyelitis Optica; Euroimmun AG
We receive small grants from Euroimmun AG, and PW
and MW are supported by the NIHR National Commisioning Service.
2) CYP1A1 - T6235C locus was a significant predisposing factor in late onset sporadic PD patients and it was not
significant predisposing factor for familial and early onset
(age 45) cases.
3) SNCA C-116C!G locus predisposes to the early
onset sporadic PD, while NR4A2 G12803T predisposes to
sporadic PD.
4) PARK2 : While the SNP G601A had no significant
association with PD, the intronic polymorphism T25C
(IVS2) was significantly associated to PD (40%) compared
to the control group (11%).
Study supported by: 1 UGC-SAP-PROGRAMME OF
GENETICS DEPARTMENT
2.UICIC (UNIVERSITY INDUSTRYCOMMUNITY
INTERACTION CENTRE)PROGRAMME FROM UNIVERSITY OF MADRAS
T1768. Short Latency Cortical Activation during
Clinically Effective Ventral Intermediate Nucleus Deep
Brain Stimulation for Essential Tremor
Harrison C. Walker, He Huang, Christopher L. Gonzalez,
James E. Bryant, Jeffrey Killen, Robert C. Knowlton, Erwin B.
Montgomery, Gary C. Cutter, Abidin Yildirim, Barton L.
Guthrie and Ray L. Watts; Birmingham, AL
T1766. REM Sleep without Atonia and Freezing of Gait
in Parkinson’s Disease
Aleksandar Videnovic, Clare C. Marlin, Joni Planetta, Laila
Alibiglou, David E. Villancourt and Colum D. MacKinnon;
Chicago, IL and Gainesville, FL
Background: Idiopathic RBD (iRBD) frequently precedes
motor features of PD, including freezing of gait (FOG).
Despite the common neuroanatomical networks involved in
the pathophysiology of iRBD and FOG in PD, associations
between iRBD and FOG remain poorly understood.
Methods: Twenty age- and sex-matched participants
(iRBD n ¼ 5, PD without FOG n ¼ 5, PD with FOG n
¼ 5, controls n ¼ 5) underwent polysomnography. The
amount of excessive phasic and tonic muscle activity during
REM sleep was quantified using the method by Cygan and
colleagues (Cygan, J Clin Sleep Med, 2010). Freezing of
gait was assessed by the FOG Questionnaire.
Results: There was a significant group effect for tonic (p
¼ .001) and phasic (p ¼ .008) muscle activity during REM
sleep. Tonic and phasic muscle activity was significantly
increased relative to control subjects in both the iRBD and
PD with FOG groups. There were no significant differences
in REM-related muscle activity between the iRBD and PD
with FOG groups. A trend toward statistical significance
was observed for increased tonic EMG activity in PD with
FOG versus PD without FOG (p ¼ .072).
Conclusions: PD with co-existent FOG may be associated
with increased tonic muscle activation during REM sleep.
Study supported by: Michael J Fox Foundation for Parkinson Reserach
Deep brain stimulation (DBS) relieves symptoms of neuropsychiatric diseases when medical treatments fail, yet its
therapeutic mechanism is unknown. We hypothesized that
ventral intermediate nucleus (VIM) DBS for essential
tremor activates cortex at short latencies and that this
potential is related to suppression of tremor. Electroencephalography measured cortical activity in 5 subjects (7 brain
hemispheres) across a range of DBS settings. Reversal of the
anode and cathode contacts minimized stimulus artifact,
allowing visualization of brain activity. Regression quantified
the relationship between the event related potentials (ERPs)
and tremor. DBS generated a polyphasic ERP in ipsilateral
sensorimotor cortex with peaks at latencies beginning less
than one millisecond after the stimulus (mean latencies
0.960.2, 5.660.7, and 13.961.4 milliseconds, denoted R1,
R2, and R3, respectively). R1 amplitude and frequency were
both closely associated with tremor suppression (p<0.0001,
respectively). We demonstrate short latency cortical activation by symptomatically effective VIM DBS, which suggests
that DBS may improve essential tremor by synchronizing
the precise timing of discharges in nearby axons to the stimulation frequency or one of its subharmonics.
Study supported by: United States National Institutes of
Health / National Institutes of Neurological Disorders and
Stroke (K23 NS067053-01)
T1767. Clinical and Immunological Features with
Glycine Receptor Antibodies
Angela Vincent, M. Isabel Leite, Alexander Carvajal, Patrick
Waters and Mark Woodhall; Oxford, United Kingdom
T1769. Can Proton and Phosphorus MR Spectroscopy
Be Used for Early Diagnosis in Parkinson’s Disease?
Nora Weiduschat, M. Flint Beal, Xiangling Mao, Melissa J.
Nirenberg, Dikoma C. Shungu and Claire Henchcliffe;
New York, NY
Progressive encephalomyelitis with rigidity and myoclonus
(PERM) has been described with GlyR antibodies. We studied patients referred for testing whose IgG antibodies bound
to GlyR alpha1 expressed in human embryonic kidney
(HEK) cells. 42 sera (60% males; 2-77y, median 51y) were
Background: If mitochondrial dysfunction is an early event
contributing to Parkinson disease (PD) development, then
non-invasive quantitation of energy metabolism indices
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would be a useful tool for early diagnosis and treatment
monitoring. The present study aimed at assessing indices of
brain energy metabolism at rest in subjects with early Parkinson’s disease (PD) using proton and phosphorus magnetic resonance spectroscopy.
Methods: During this cross-sectional study including 20
subjects with early PD (Hoehn and Yahr stage 1-2) and 15
age-matched healthy volunteers (HV), ventricular lactate,
and regional levels of N-acetylaspartate, phosphocreatine,
free phosphate and ATP were determined.
Results: Metabolite levels were not significantly different
between PD and HV nor between unmedicated PD subjects
and those receiving levodopa. In the PD group, there were
no significant correlations between MRS markers and age,
disease duration, or UPDRS motor scores.
Conclusion: In early PD and under resting conditions,
proton and phosphorus MRS do not appear to reliably
detect metabolic abnormalities. MRS under dynamic conditions might uncover latent energy deficits in early PD,
which needs to be investigated in future studies.
Study supported by: Dana Foundation
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Methods: Sixteen PPAOS subjects were age and gendermatched to 16 PSP subjects and 20 controls. All subjects
were prospectively recruited, underwent detailed neurological and speech evaluations, and 3T head MRI including diffusion tensor imaging. Atrophy and white matter tract
degeneration were assessed.
Results: The PSP subjects had typical occulomotor/gait
impairments but not speech apraxia. Both syndromes showed
grey matter loss in supplementary motor area, white matter
loss in posterior frontal lobes and degeneration of corpus callosum. In PPAOS, lateral grey matter loss was focal involving
superior premotor cortex, while volume loss extended into the
prefrontal cortex in PSP. Caudate nucleus volume loss and
superior cerebellar peduncle degeneration was observed in PSP.
Interestingly, midbrain area was decreased in both syndromes
compared to controls, although this was greater in PSP.
Conclusions: Although neuroanatomical differences were
identified between these distinctive clinical syndromes, there
was overlap, such as midbrain atrophy, suggesting that these
two syndromes may have common pathogenetic
underpinnings.
Study supported by: NIH grant R01-DC010367 and the
Dana Foundation
T1770. Structural Abnormalities in the Brain Associated
with Rapid Onset Dystonia-Parkinsonism: A Preliminary
Investigation
Christopher T. Whitlow, Allison Brashear, Bernardino Ghetti,
Matthew C. Hagen, Kathleen J. Sweadner and Joseph A.
Maldjian; Winston-Salem, NC; Indianapolis, IN; Cincinnati,
OH and Boston, MA
T1772. Subacute Combine Degeneration of the Cord
Due to Functional B12 Deficiency
Subhashie Wijemanne, Sui Li and Michal Vytopil; Boston,
MA
Introduction: Subacute combine degeneration of the
cord(SCDC) is a well known clinical entity due to Vitamin
B12 deficiency. The diagnosis is made in the appropriate
clinical setting with a low or low normal B12 level, confirmed by high serum Methylmalonic acid and homocystein.
We present a case of functional B12 deficiency with supra
normal B12 level.
Case report: 64 year old male with Parkinson’s disease
presented with progressive gait disorder of several months
duration. He had slow cognitive processing, loss of joint
position and vibration sense in both lower and upper
extremity with sensory ataxia.
Results: CBC: WBC 1.41, Hg 8.5 HCT 25.1 platelet
63, MCV 104, Blood smear macrocystic anemia with
hypersegmented neutrophils. Vitamin B12 levels since 2008
>1200, never on supplements. Methylmalonic acid 23.53
(0-0.4), Intrinsic factor antibody positive.MRI spine showed
T2 hyperintensity in the dorsal column without any evidence of myelopathy.
Conclusion: Functional B12 deficiency is a rare cause of
SCDC. It can present with a supra normal B12 level. If the
clinical picture is suggestive, should proceed with Methylmalonic acid and Homocystein levels even if the B12 level
is supra normal. Transcobolamine II deficiency is a potential
etiology.
Study supported by: None
Rapid-onset dystonia-parkinsonism (RDP) is a rare inherited form of dystonia characterized by bradykinesia, postural
instability and dystonic movements. In this preliminary
investigation, we hypothesize that RDP may affect components of the cortico-striato-pallidothalamocortical (CSPTC)
and cerebello-thalamo-cortical (CbTC) pathways, thought
to be involved in other movement disorders. Standard voxel
based morphometry and diffusion tensor imaging MRI
methods were used to obtain voxel-wise measures of gray
matter (GM) volume, as well as GM and white matter
(WM) fractional anisotropy (FA) from 3 patients with RDP
and 18 age-matched controls. Statistical Parametric Mapping analyses demonstrated GM volume decreases in RDP
patients compared to controls in the right dentate nucleus,
with decreased FA in the right superior cerebellar peduncle,
known to subserve the dentate nucleus and send cerebellar
feedback via efferent fibers to the motor cortex. RDP
patients demonstrated additional FA decreases compared to
controls in corpus callosum, as well as in bilateral striatum,
extra-nuclear WM tracts, dentate nuclei and middle cerebellar peduncles. These data demonstrate RDP-associated
abnormalities in GM and WM, including components of
the CSPTC and CbTC, suggesting a heterogeneous distributed pattern of central nervous system disease.
Study supported by: R01NS058949
T1773. MRI Signal Intensity in Dystonic Muscle
Kathleen V. Woschkolup, Gonzalo J. Revuelta and Kenneth
Spicer; Charleston, SC
T1771. MRI Comparison of Primary Progressive Apraxia
of Speech and PSP
Jennifer L. Whitwell, Joseph R. Duffy, Edythe A. Strand, Mary
M. Machulda, Matthew L. Senjem, Jeffrey L. Gunter, Kejal
Kantarci, Scott D. Eggers, Clifford R. Jack and Keith A.
Josephs; Rochester, MN
Background: The term Dystonia encompasses a heterogeneous group of disorders that share one common feature: sustained muscular contraction. Currently there is a great need
for a tool that can objectively measure dystonia severity.
Objective:This is a pilot study to establish utility of muscle-MR in the assessment of dystonia.
Methods: Records of 11 CD patients, with Sternocleidomastoid (SCM) involvement were reviewed. Population age
Background: Primary progressive apraxia of speech
(PPAOS) and progressive supranuclear palsy (PSP) are both
motor disorders with similar patterns of cortical atrophy.
We compared, for the first time, neuroanatomical features
between these two syndromes.
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mean: 48.9; SD: 22.2; 8 Female. MRI C-spine obtained
prior to treatment for Dystonia and while symptomatic,were
reviewed.Excluding patients with unclear diagnosis or history. Sternocleidomastoid muscles(SCM) in each patient
were viewed in axial T2 sequences. Signal intensity
determined by gray scale per SCM at three different but
consistent slices for each patient.Volumes adjusted for
consistency.Values in both groups were compared using
two-tailed paired TTest.
Results: The effect size, Cohensd, corrected for a paired
sample design does fall within the small effect range and
should not be dismissed as insignificant.
Conclusion: Our preliminary findings suggest muscleMR may be a useful tool in the study of dystonia. Further
prospective studies using this technique are warranted.
Study supported by: None
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mice injected with AAV-14-3-3H-GFP showed a 37%
increase in dopamine neuron counts compared to MPTPtreated AAV-GFP mice (p<0.05). Conversely, we tested the
effect of 14-3-3 inhibition on MPTP toxicity by injecting
transgenic mice expressing the 14-3-3 peptide inhibitor
difopein with saline or MPTP. Difopein mice had a 15%
increase in dopamine cell loss compared to wildtype upon
MPTP treatment. Our studies suggest that 14-3-3s may be
a target for PD therapeutics.
Study supported by: NINDS;
Parkinson Association of Alabama;
CCTS/COCD Translational Research Intramural Grant
Program
T1776. Short Latency Afferent Inhibition: A Biomarker
for Mild Cognitive Impairment in Parkinson’s Disease?
Alison J. Yarnall, Lynn Rochester, Rachel David, Tien K.
Khoo, Gordon W. Duncan, Brook Galna, Mark R. Baker and
David J. Burn; Newcastle, United Kingdom
T1774. Evaluation of Smelling Function, F-DOPA PET
Study and Transcranial Sonography of Substantia Nigra
in Asymptomatic Carriers of Common LRRK2 Risk
Variants: A Longitudinal Case-Control Study
Ruey-Meei Wu, Chin-Yi Yu, Kai-Yuan Tzen and Meng-Ling
Chen; Taipei, Taiwan
Background: Mild cognitive impairment in Parkinson’s
disease (PD-MCI) is common and predicts those at risk of
dementia. Cholinergic dysfunction, which can be assessed
using short latency afferent inhibition (SAI), may contribute
to the pathophysiology of PD-MCI.
Methods: 22 PD (11 cognitively normal (PD-CN); 11
PD-MCI) patients and 22 age-matched controls participated. MCI was determined as <26 on the Montreal Cognitive Assessment. SAI was measured by conditioning motor
evoked potentials, elicited by transcranial magnetic stimulation (TMS) of motor cortex, with electrical stimuli delivered
to the contralateral median nerve at intervals ranging from
N20 (predetermined) to N20þ4ms. A generalised linear
model (GLM) was used to compare SAI (% difference
between test and conditioned response expressed as grand
mean) between-groups after controlling for age.
Results: There was no significant difference between the
PD-CN and controls for SAI (62.8 6 30.3% versus 55.7 6
21.7%, p ¼ 0.447). The PD-MCI group showed significantly less inhibition (88.4 6 25.8%) than both PD-CN (p
¼ 0.021) and controls (p ¼ 0.01). These differences
remained after controlling for age.
Conclusions: Cholinergic dysfunction occurs early in
PD-MCI. SAI may be a useful biomarker of increased risk
of dementia in PD patients.
Study supported by: M J Fox Foundation
Objectives: the aim of this study was to determine the value
of smelling test, 18F-dopa PET and sonography of substantia nigra (SN) as the tools of premotor diagnosis of Parkinson’s disease in asymptomatic carriers of LRRK2 G2385R
in a Taiwanese cohort.
Methods: Fifteen asymptomatic G2385R carriers and fifteen controls were included. University of Pennsylvania
Smell Identification Test, 18F-dopa PET and TCD of SN
were performed on enrollment and after 2-years follow-up.
Results: There were no difference of striatal uptake of
18F-dopa in PET or olfactory function between groups
neither on enrollment nor after 2 yrs follow up. Logistic
regression analysis revealed G2385R carrier status were
significantly associated with the manifestation of hyperechogenicity of SN, while the protective haplotype N551KR1298H-K1423K was negatively associated with the
echofeature. One of the G2385R carriers who had SN
hyperechogenicy developed parkinsonism and decreased
striatal 18F-dopa uptake was noted in the PET study.
Interpretation: Our study suggested hyperechogenicity of
SN might be a valuable tool for premotor diagnosis for
asymptomatic carriers of LRRK2 risk variants.
Study supported by: National Science council of Taiwan
T1777. Normal Striatal D1 Dopamine Receptor
Binding in Primary Focal Dystonias
Morvarid Karimi, Joanne Markham, Hubert Flores, Stephen
Moerlein, Tom Videen and Joel S. Perlmutter; St. Louis, MO
T1775. Modulation of 14-3-3 Proteins in the MPTP
Parkinson’s Disease Model
Huiping Ding, Sunny Slone and Talene Yacoubian;
Birmingham, AL
Dystonia is characterized by repetitive patterned or sustained
muscle contractions causing abnormal postures. Several lines
of evidence implicate abnormalities of dopaminergic pathways. We have recently demonstrated that the abnormal
striatal spiperone (nonspecific D2/D3 ligand) binding in
focal dystonia is not due to a D2-receptor abnormality since
the highly D2-specific NMB binding was not altered. This
suggests that an abnormality in D3-receptor may be associated with focal dystonia. Interestingly, accumulating evidence indicates a synergistic interaction between D1 and
D3-receptors. Thus, this study will investigate the role of
D1 receptors that primarily mediate the direct pathway in
the basal ganglia prior to validating a D3-specific ligand for
human use.
We compared striatal binding potential of NNC112
([11C](þ)-8-chloro-5-(7-benzofuranyl)-7-hydroxy-3-methyl-
Disruption of 14-3-3 expression and function has been
implicated in Parkinson’s disease (PD). 14-3-3s are regulators of cell survival, and we have shown that 14-3-3 overexpression protects in cellular and invertebrate PD models.
Validation of 14-3-3s in mammalian models is the next step
in translating these studies into potential therapy development. We tested the consequences of 14-3-3 modulation in
the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
model. We tested the effect of 14-3-3H overexpression using
an adeno-associated virus (AAV). Mice were stereotactically
injected with AAV-green fluorescent protein (GFP) or AAV14-3-3H-GFP into the substantia nigra, and four weeks
later were treated with saline or 30 mg/kg MPTP intraperitoneally for five days. 21 days later, brains were collected for
dopamine neuronal counts by stereology. MPTP-treated
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2,3,4,5-tetrahydro-1H-3-benzazepine, a D1-radioligand) in
primary cranial, cervical or arm dystonia to age, gender and
smoking status matched healthy controls.
Data from 7 healthy and 7 dystonic subjects (age:
58.4þ/- 10) did not reveal any significant difference in
striatal BPND between the two groups. This study had 86%
power to detect 16% difference between two groups (CI:
0.08-0.44).
We aim to enroll 20 subjects in each group as originally
planned to improve the statistical power.
Study supported by: 1K23NS069746-01A1
compared to controls within pilomotor nerves at all sites
(0.7660.19 vs. 0.2660.13, P<0.001) and within sudomotor
nerves at all sites (0.2060.11 vs. 0.0260.01, P<0.005).
Discussion: Patients with PD have a distal sensory and
autonomic neuropathy and elevated levels of a-synuclein in
both sympathetic adrenergic pilomotor and sympathetic
cholinergic sudomotor fibers. These findings suggest the asynuclein ratio may be a potential biomarker in patients
with PD.
Study supported by: NIH NINDS K23NS050209
(CHG) and the RJG Foundation (CHG)
T1778. Dopaminergic Modulation of Basal Ganglia
Connectivity in Parkinson’s Disease
Kathleen L. Poston, William Shire, Richard Joseph, Vinod
Menon and Michael Greicius; Stanford, CA
T1780. Circadian Rhythm of Melatonin Secretion Is
Altered in Parkinson’s Disease
Aleksandar Videnovic, Angelica Marconi, Charleston Noble,
Katherine Reid, Teresa Kuhta, Tanya Simuni, Cindy Zadikoff
and Phyllis Zee; Chicago, IL
Objective: To identify changes in basal ganglia and cortical
connectivity in Parkinson’s disease (PD) ON and OFF medication using resting state fMRI.
Design/Methods: We acquired resting state fMRI data
on 30 participants: 15 early PD (MDS-UPDRS-III 26.9þ/9.8) and 15 age-matched controls (HC). PD patients were
scanned both OFF and ON medications (PD-OFF and
PD-ON). We performed a region-of-interest (ROI) based
functional connectivity analysis, selecting regions in the
caudate (CAU), and putamen (PUT). We conducted twosample t-tests and paired-sample t-tests for each ROI to
identify significant connectivity differences in PD-OFF versus controls and PD-OFF versus PD-ON, respectively.
Results: For the CAU ROI, PD-OFF had decreased
connectivity in the contralateral caudate compared to HC;
PD-ON had increased connectivity within the contralateral
caudate and ipsilateral putamen compared to PD-OFF. For
the PUT ROI, PD-OFF had decreased connectivity with
the bilateral motor cortex compared to HC; PD-ON had
increased connectivity with the ipsilateral putamen and
bilateral motor cortex compared to PD-OFF.
Conclusions: PD-OFF showed reduced connectivity
within regions associated with motor function with strengthened connectivity when patients were ON medication.
These findings suggest cortical-subcortical connectivity could
serve as objective biomarkers of PD motor function.
Study supported by: K23 NS075097 (KP), R01
MH084164 (VM), R01 NS073498 (MG), Michael J. Fox
Foundation for Parkinson’s disease Research (KP)
Objective: To examine circadian melatonin secretion in PD.
Background: Clinical studies in PD report diurnal fluctuations of motor and non-motor symptoms, suggesting
modifications of circadian system in PD.
Design/Methods: Rest-activity cycles of PD participants
and age/gender matched controls were assessed by actigraphy and sleep diaries over 14 days. This was followed by
blood sampling at 30-minute intervals for 24 hours, under
constant routine conditions. Serum melatonin levels were
measured by immunoassay. The area-under-the-curve
(AUC) and circadian phase were calculated. Group differences were assessed using independent group t test.
Results: 20 PD participants (9M/11F), age 6568.2 years,
and 12 controls (1M/11F), age 6366.3 years participated in
this study. 24-hour AUC of melatonin secretion was significantly diminished in PD participants compared to controls
(p ¼ 0.01). Both daytime and nighttime AUC were significantly diminished in the PD group (p ¼ 0.03; p ¼ 0.01).
Melatonin midpoint was significantly delayed in PD participants (circadian time 19.4) relative to the control group
(circadian time 16.6) (p ¼ 0.02).
Conclusions/Relevance: Circadian melatonin secretion is
reduced, and phase of the melatonin rhythm delayed in PD.
These results suggest that approaches aimed to improve circadian function have potential as complementary therapies
for PD.
Study supported by: NIH/NINDS; American Academy
of Neurology Foundation; Parkinson’s Disease Foundation
T1779. Alpha Synuclein as a Cutaneous Biomarker of
Parkinson Disease
Christopher H. Gibbons, Ningshan Wang and Roy Freeman;
Boston, MA
Autoimmune Neurology
T1801. A Case of Bilateral Horizontal Gaze
Ophthalmoplegia: The 1þ1 Syndrome
Nadeem Akhtar and Sumeet Singhal; Nottingham, United
Kingdom
Background: Parkinson’s disease (PD) is a multisystem neurodegenerative disease characterized by the deposition of a-synuclein in the central, peripheral and enteric nervous system.
Objective: To develop a biomarker for Parkinson’s
disease.
Methods: Eighteen patients with PD and 10 matched
controls underwent skin biopsies at the distal leg, distal
thigh and proximal thigh. Skin biopsies were stained for
PGP9.5, tyrosine hydroxylase, vasoactive intestinal peptide
and a-synuclein. The density of nerve fiber subtypes within
specific dermal organelles (pilomotor muscles and sweat
glands) and the ratio of a-synuclein deposition within nerve
fibers was calculated.
Results: Patients with PD had a distal neuropathy expressed
by loss of intra-epidermal, pilomotor and sudomotor fibers
(P<0.05). Patients with PD had higher a-synuclein ratios
We describe an unusual case of complete horizontal gaze paralysis presenting as a relapse of Multiple Sclerosis. A-young
woman, a known case of relapsing and remitting MS presented with sudden onset of binocular diplopia. On examination there was a complete horizontal gaze paralysis. Vertical
eye movements were normal. Oculocephalic reflex failed to
improve horizontal eye movement. No nystagmus and no
other sign of brainstem dysfunction were observed. Visual
acuity was normal in both eyes. Brain MRI scans showed
white matter T2-hypersignal abnormalities. A plaque of demyelination was noted in the posterior part of the medial
pontine tegmentum. Complete bilateral horizontal gaze paralysis has been exceptionally reported. To our knowledge, only
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two cases of complete horizontal bilateral ophthalmoplegia in
multiple sclerosis have been reported in the literature.
Study supported by: No one
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and psychiatric symptoms that often progresses to include
dyskinesia, decreased level of consciousness, and autonomic
instability. The condition was classically described in women
with ovarian teratomas, however has more recently been recognized to have a wider range of presentations. We report
the case of a 38 year old woman without past medical history who presented with auditory hallucinations, headache
and what was described as a non-epileptic seizure. She was
felt to have had an initial psychotic break and was referred
for inpatient psychiatric admission. Brain MRI and EEG
were normal, but CSF was notable for mild pleocytosis.
Abdominal imaging later revealed an ovarian teratoma. After
removal of the mass and treatment with steroids and IVIg,
she demonstrated a complete resolution of symptoms. AntiNMDA receptor antibodies were later found in the patient’s
CSF. As this case demonstrates, it is important to consider
paraneoplastic encephalitis - even with normal MRI and
EEG - as a cause of initial psychiatric symptoms in patient
populations not typical for initial psychotic break as the
condition is reversible if recognized early.
Study supported by: Residency program
T1802. Chronic Microglial Encephalomyelitis (CME)
Allen J. Aksamit, Brian G. Weinshenker and Joseph E. Parisi;
Rochester, MN
Six patients presented with a unique corticosteroid responsive disabling subacute encephalomyelitis evolving to chronic
cognitive and behavioral dysfunction, tremor, myoclonus,
and optic nerve swelling. Five patients also had myelopathy
with longitudinally extensive T2 hyper-intensity on MRI of
the spinal cord. MRI head was characteristic with periventricular diffuse T2 white matter abnormalities with a prominent pattern of radially oriented, linear perivascular
increased signal, that enhanced after gadolinium. All had
spinal fluid pleocytosis. All had a poorly defined systemic
autoimmune illnesses. Brain biopsy in each case revealed
prominent perivascular microglial activation and lymphocytic cuffing without demyelination or other specific features. The initial outcome after high dose corticosteroid
therapy was favorable. Chronic immunosuppressive therapy
was required to prevent relapse. We propose to call this syndrome chronic microglial encephalomyelitis (CME).
Whether this condition represents a single disease entity or
a common syndrome of many causes is unknown. However,
it can be recognized and differentiated from CNS sarcoidosis, lymphoma, vasculitis, and multiple sclerosis. It can be
treated effectively, but requires long term immunomodulatory therapy to prevent relapse.
Study supported by: NONE
T1805. Patients Can Adequately Report Their MS
Severity Online; Implications for Online Research
Platforms
Riley Bove, Timothy Vaughan, Brian C. Healy, Elizabeth
Secor, Alexander Musallam, Bonnie Glanz, Howard Weiner,
Paul Wicks, Tanuja Chitnis and Philip L. De Jager; Boston,
MA and Cambridge
Online research platforms such as PatientsLikeMe (PLM)
offer promise for research in multiple sclerosis (MS), but
their patient-reported outcomes (PROs) and patient samples
require clinical validation.
We sought first to compare the PRO used by PLM members to rate disease severity (MS Rating Scale, revised:
MSRS-R) with clinically validated tools, and second to
assess biases in the PLM MS population.
We deployed the MSRS-R to 122 patients and their
physicians at the Partners MS Center (PMSC) in Boston.
Patient- and physician-derived MSRS-R scores revealed
good agreement (weighted kappa 0.483, Spearman’s r ¼
0.732). Patient-derived MSRS-R scores showed high correlation with physician-derived EDSS, Timed 25 Foot Walk
and Ambulation Index (0.50<r<0.61, p<0.001 for each).
We then compared 4,039 PMSC patients to 10,255
PLM members. PLM subjects were younger, more educated,
more often female, and less often white. Disease course was
more often relapsing remitting, presenting at younger age,
with shorter disease duration (p<0.001 for all comparisons).
These differences were small in absolute terms.
Large prospective datasets collected online may accelerate
research studies, particularly in tracking the relationship
between clinical outcomes (relapses, progression) and fluctuations in PROs (fatigue, quality of life).
Study supported by: N/A
Drs Vaughan and Wicks are employees of PatientsLikeMe, Inc, and own stock options in the company.
T1803. Elevated IFNa Activity in Patients with a
History of Lyme Disease and Persistent Symptoms
Elzbieta Jacek, Brian Fallon, Mary K. Crow and Armin
Alaedini; New York, NY
Some Lyme disease patients suffer from persistent symptoms
of pain, fatigue, and/or cognitive deficits despite recommended courses of antibiotic treatment. The mechanisms responsible for these symptoms, collectively referred to as
post-Lyme disease syndrome (PLDS), remain unclear. IFNa
is a cytokine that is produced in response to inflammation
by a variety of cells. Several studies have shown a correlation
between increased IFNa activity and neurocognitive impairment. We carried out a longitudinal analysis of serum IFNa
activity in PLDS patients prior to and following treatment
with ceftriaxone b-lactam antibiotic by detection of changes
in IFNa target genes, including IFIT1, IFI44, and IFIT3,
using a functional cell-based assay and qRT-PCR. Sera from
PLDS patients caused significantly higher induction of
IFIT1 (p<0.01) and IFI44 (p<0.05) than post-Lyme
healthy controls, indicating elevated IFNa activity. However,
patient serum IFNa activity did not moderate in response
to ceftriaxone. The results provide further evidence for the
existence of an immune-mediated disease process in PLDS
and suggest a possible mechanism for some of the associated
neurocognitive deficits.
Study supported by: National Institutes of Healthy
Time for Lyme
T1806. Comparison of Disease Activity in SPMS and
PPMS in the Context of Multicenter Clinical Trials
Diego Cadavid, Rotem Orbach and Zhenming Zhao;
Cambridge, MA and Tal Hashomer, Israel
T1804. Anti-NMDA Receptor Antibody Encephalitis
Presenting as Acute Psychosis
Matthew B. Bevers, Isabel C. Arrillaga-Romany and Bradford
C. Dickerson; Boston, MA
Retrospective natural history studies have shown similarities
in disease progression for primary (PPMS) and secondary
(SPMS) progressive multiple sclerosis, suggesting these may
be phenotypic variations of the same disease. We compared
Limbic encephalitis caused by antibodies to the NMDA receptor is associated with a syndrome of headache, seizure
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longitudinal disease activity in SPMS and PPMS in the context of international multicenter clinical trials. We analyzed
outcome measures collected over 2 years for subjects
randomized to placebo in one SPMS and one PPMS clinical
trial. Disease activity was analyzed across 3 categories:
intermittent activity, progression, and improvement. MRI
measures and quality-of-life measures were included when
available. We found 17,963 disease activity measurements
corresponding to 101 outcome variables from 206 SPMS
subjects and 9,798 disease activity measurements from 78
outcome variables from 135 PPMS subjects. Subjects with
SPMS and PPMS exhibited remarkably similar disease activity except for sensory worsening (more common in PPMS)
and 9-Hole Peg worsening (more common in SPMS).
Intermittent activity was the most common pattern of disease activity; clinical worsening and improvement occurred
at similar frequencies in both. These analyses demonstrating
similar disease activity patterns in SPMS and PPMS support
the concept that these forms of MS are essentially the same.
Study supported by: Biogen Idec
DC and ZZ are full-time employees of Biogen Idec and
own stocks/options in Biogen Idec. RO was a paid intern at
Biogen Idec.
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mental factors and we wondered if this also occurs in
NMO.
Methods: We retrospectively analysed relapse data of 128
aquaporin-4 antibody-positive NMO/NMO spectrum disorder patients from the UK (n ¼ 81) and Japan (n ¼ 47).
The month of onset attack and months in which all subsequent relapses occurred were recorded.
Results: 475 relapses (including onset attack) occurred in
128 patients. There was no obvious seasonal variation in
NMO onset attacks. However, subsequent relapses were
most frequent during the summer months, with fewest
relapses during the winter months. This trend was seen in
both the UK and the Japanese cohorts and was also seen
when only relapses occurring prior to initiation of longterm immunosuppression were analysed.
Discussion: Our data suggest that NMO relapses in
aquaporin-4 positive patients are most frequent in summer.
This is likely to be related to environmental factors that
may include temperature, sunlight exposure and seasonal
prevalence of various infectious agents. Larger studies are
indicated to confirm our findings.
Study supported by: PC-L has no disclosures. JK has
received support for scientific meetings from Biogen Idec,
Teva and Novartis and is supported by the NHS National
Specialised Commissioning Group for Neuromyelitis Optica.
MIL is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica and by the National
Institute for Health Research Oxford Biomedical Research
Centre and has received speaking honoraria from Novartis.
LE and AJ are supported by the NHS National Specialised
Commissioning Group for Neuromyelitis Optica. IN has
received funding for travel and received speaker honoraria
from Bayer Schering Pharma, and Biogen Idec; has received
research funding from Mitsubishi Chemical Medience Corporation, and the Grants-in-Aid for Scientific Research from the
Ministry of Education, Science and Technology of Japan. KF
serves on scientific advisory boards for Bayer Schering
Pharma, Biogen Idec, and Merck Serono; has received funding for travel and received speaker honoraria from Bayer
Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe
Pharma Corporation, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, and Asahi Kasei Kuraray Medical
Co., Ltd.; serves on the editorial board of Clinical and Experimental Neuroimmunology; receives royalties from the publication of Clinical Practice Guide of Orthopedic Surgery
(Bunkodo, 2007); and has received research support from
Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research
Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe
Pharma Corporation, Teijin Pharma, Eisai Inc., and Kowa
Pharmaceuticals America, Inc., and the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and
Technology of Japan. JP has received unrestricted grants and
support for scientific meetings and scientific advisory honorariums from Merck Serono, TEVA, Biogen, Bayer Schering
and Novartis, has held MS society grants and is a clinical
lead for the UK Department of Health Risk Sharing Scheme.
T1807. The MS-STAT Trial: A Phase II Trial of High
Dose Simvastatin for Secondary Progressive Multiple
Sclerosis (SPMS): Initial Results
Jeremy S. Chataway, Ali Alsanousi, Dennis Chan, David
MacManus, Kelvin Hunter, Jo Foster, Charles Bangham,
David Wilkie, Jennifer Nicholas, Virginia Calder, John
Greenwood, Chris Frost and Richard Nicholas; London,
United Kingdom and Brighton, United Kingdom
Background: No current treatments are proven to reduce
the rate of progression in secondary progressive MS
(SPMS). Simvastatin is an attractive potential therapy which
is well tolerated, with an excellent safety profile, that has
both immunomodulatory and neuroprotective effects. This
investigator-led study is the first trial of a statin in SPMS.
Results: 140 patients were randomised as planned and
129 were followed up to year 2 (92%). At baseline mean
age was 51yrs (range 35 to 65), MS duration 21.2 (8.6),
SPMS duration 7.2 (5.2), and 69% were female. At baseline
the median (IQR) EDSS was 6 (5.5 to 6.5) and at 24
months 6.5 (6 to 6.5). At baseline, MSIS-29 was 68.2
(14.6) and at 24 months 72.4 (16.6). The total cohort had
474 new or enlarging T2 lesions (1.9 per patient per year),
with 1 relapses experienced by 34 participants.
Conclusion: This 2 year trial of a novel agent in SPMS
has now completed. In addition to the results above, brain
atrophy and full unblinded data will be presented. ClinicalTrials.gov, number NCT00647348
Study supported by: Multiple Sclerosis Trials
Collaboration
Moulton Foundation
T1808. Seasonal Variation of Relapses in Neuromyelitis
Optica
Peter Chater-Lea, Joanna Kitley, Liene Elsone, Yoshiki Takai,
Anu Jacob, Ichiro Nakashima, M. Isabel Leite, Kazuo
Fujihara and Jackie Palace; Oxford, United Kingdom;
Liverpool, United Kingdom and Sendai, Japan
T1809. PK11195-PET Enhancement in Black Holes
Correlates with Disability and Outcome in Progressive
Multiple Sclerosis
Paolo Giannetti, Marios Politis, Paul Su, Federico E.
Turkheimer, Omar Malik, Shiva Keihaninejad, Kit Wu,
Richard Reynolds, Richard Nicholas and Paola Piccini;
London, United Kingdom
Introduction: NMO is an autoimmune inflammatory disease of the CNS, which is often relapsing. The trigger for
relapses is unknown. In MS, variations in relapse rates
throughout the year are seen, suggesting a role for environ-
The pathophysiological correlates and contribution to persisting disability of MS black holes (BH) are still unclear. In
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order to study their in vivo pathological correlates, we used
PK11195-PET to investigate changes in microglial activity.
Ten relapsing and 9 progressive MS subjects had a
PK11195-PET and MRI scans, alongside a clinical assessment. We studied the PK11195 binding potential, specifically bound relative to the non-displaceable radioligand in
tissue (BPND), in BH. Out of a total of 1,242 BHs identified, 947 were PK11195 enhancing. The PK11195 BPND
was correlated with EDSS (r ¼ 0.818; p<0.01) only in the
progressive group. In the relapsing patients there was an
inverse correlation between PK11195 BPND and BH lesion
load (r ¼ -0.781; p<0.01). The progressive patients’ total
PK11195 BPND at baseline was found to be a significant
outcome predictor of disability at the 2 years FU assessment
(p<0.01). Our findings show that MS patients have heterogeneous patterns of microglial activity in BHs. In progressive subjects PK11195 BPND was associated with disability
and outcome, whereas in relapsing patients higher PK
BPND was present in subjects with a smaller BH lesion load
and was not associated with disability.
Study supported by: PG received an EFNS (European
Federation of Neorological Societies) Scientific Fellowship
in 2009 and a Research Fellowship from the Fondazione
Italiana Sclerosi Multipla – Cod. 2010/B/7.
FT was funded by the PET Methodology Programme
Grant from the Medical Research Council (UK).
The Multiple Sclerosis Society of Great Britain and
Northern Ireland (747/02 to RR, RN).
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maintenance of neurologic function. We have observed
hippocampal injury that compromises cognitive function
and induces seizures following acute infection of C57BL/6
mice with the Theiler’s murine encephalomyelitis virus.
Injury is independent of direct neuronal infection with the
virus and precedes the onset of an adaptive immune
response, leading us to hypothesize that an early innate
immune response causes the damage. Flow cytometric
analysis of brain-infiltrating leukocytes indicated that mice
experiencing hippocampal injury mount a robust inflammatory monocyte and neutrophil response in the brain
within hours of infection. Immunodepletion of inflammatory monocytes but not neutrophils protected the hippocampus from injury, preserved cognitive function, and
reduced seizure activity. Adoptive transfer of inflammatory
monocytes into hosts with a defective innate immune
response recapitulated the hippocampal injury and triggered seizures. We conclude that hippocampal injury and
seizures during acute picornavirus infection of the brain
are the result of bystander pathology triggered by infiltration of inflammatory monocytes.
Study supported by: This work was supported by grant
NS64571 from the NIH/NINDS.
T1813. Faciobrachial Dystonic Seizures Are
Immunotherapy-Responsive and Treatment May Prevent
Amnesia
Sarosh R. Irani*, Susanne A. Schneider, Rosemary Pettingill,
Philippa Pettingill, Bethan Lang, Shelagh J.M. Smith, Michael
R. Johnson and Angela Vincent; Oxford, United Kingdom and
London, United Kingdom
T1810. Withdrawn.
T1811. Natal Natalizumab
Daniel Lashley, Kevin Gormley and Timothy Harrower;
Exeter, United Kingdom
Faciobrachial dystonic seizures (FBDS) have been recently
described as a prodrome to LGI1-antibody encephalitis.
Here we detail serial clinical and serological outcomes in 10
prospectively identified cases.
The ages at onset varied widely (28-92 years) and all
had LGI1-antibodies. Videos will be used to
show FBDS affected arm (100%), face (90%) and leg
(40%) and occurred between 8 and 200 times per day
(mean ¼ 75).
FBDS were the first feature in nine cases, but only five
had normal cognition upon presentation to neurology. All
these five cases were commenced on anti-epileptic drugs and
three progressed to develop amnesia, 45, 60 and 89 days after FBDS onset. By contrast, two cases also treated with
immunotherapies (at 30 and 108 days), retained normal
cognition (ACE-R >93). Overall, immunotherapies were far
more effective than AEDs in FBDS control (p ¼ 0.0002),
and in three cases FBDS ceased with corticosteroids after
only 10 days. In patients with persistent LGI1-antibodies,
immunotherapy cessation commonly produced FBDS recurrence. Overall, time to immunotherapy administration correlated with time to return of function (r2 ¼ 0.74; p ¼
0.0013).
FBDS are the first adult-onset epilepsy with a consistent
immunotherapy-response and their effective treatment may
prevent amnesia.
Study supported by: Nil
Conflict of interest: AV and the University of Oxford
receive royalties and payments for antibody assays and AV is
the inventor on patent application WO/2010/046716 entitled ‘‘Neurological Autoimmune Disorders’’. The patent has
been licensed to Euroimmun AG for the development of
assays for Lgi1 and other VGKC-complex antibodies. SRI
and BL are coapplicants on the patent.
The risk of rebound severe relapse on discontinuation of
natalizumab therapy in relapsing-remitting Multiple Sclerosis (RRMS) remains undetermined. Similarly, there is limited data regarding safety of natalizumab use in pregnancy.
The post-natal period is independently associated with an
increased risk of MS relapse.
We present a case of a 32 year old woman with RRMS and
a 15 month history of natalizumab treatment, stopped during
pregnancy. She suffered relapses at 15 and 34 weeks antenatal,
then an untypical, severe, disabling relapse at 2 weeks postnatal. Sequential MRI imaging showed evolution of a diffuse
leucoencephalopathy on T2, with multiple gadolinium enhancing lesions in a pattern consistent with aggressive MS. Serological testing and cerebrospinal fluid studies were negative for JC
virus and in the presence of clinical improvement, natalizumab
was re-introduced. The gadolinium enhancement resolved and
she made rapid clinical improvement.
The combination of natalizumab withdrawal and post-natal immune reconstitution may have contributed to the
severe relapse. Appropriate patients should be counselled on
this risk at time of treatment initiation and on diagnosis of
pregnancy. If discontinued, early reintroduction of immunosuppressive treatment should be considered immediately
upon delivery.
Study supported by: TH has received educational grants
to attend conferences from Biogen.
T1812. Brain-Infiltrating Inflammatory Monocytes
Injure the Hippocampus and Induce Seizures during
Acute Picornavirus Infection of the CNS
Charles L. Howe; Rochester, MN
Immune control of acute viral infection in the CNS requires
a careful balance between efficient clearance of the virus and
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T1814. Withdrawn.
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Conclusion: aMSC transplantation is a safe procedure in
ALS patients, with a beneficial effect on the progression of
ALS and improvement in survival.
Study supported by: No support
T1815. Evaluation of Blood Anti-JCVirus Antibodies of
Natalizumab Treated Multiple Sclerosis Patients
Themistoklis Kalamatas, Nikolaos Protopapas, Ioannis
Doumos, Aimilia Lafioniati, Athina Nella, Anastasios Graigos
and Klimentini Karageorgiou; Athens, Attiki, Greece
T1817. Chronic Pain as a Manifestation of Potassium
Channel-Complex Autoimmunity
Christopher J. Klein, Vanda A. Lennon, Paula A. Aston,
Andrew McKeon and Sean J. Pittock; Rochester, MN
Objective: The main goal of our study is to evaluate the
measurements of anti-JCV antibodies found in the blood of
Natalizumab treated MS patients.
Design/Methods: 263 MS patients were tested with the
Stratify(TM) two step ELISA assay for serum anti-JCV antibodies. Blood samples were drawn previous to Natalizumab
Infusions and were sent to Unilabs. We analysed demographics data (age, sex, years of Natalizumab treatment, history of immunosuppression treatment) and results of the
anti-Jcv test.
Results/Conclusion: 163 patients were female and 100
patients were male and their ages varied from 15 to 72 years
(mean 45.8,SD:11.30 years). The duration of Natalizumab
treatment varied from 0,5 to 7 years (mean 3,17,SD:1,08).
226 patients were never treated with immunosuppressants.
37 were treated with immunosuppressants. 152 patients
were found positive for serum anti-JCV and 111 were found
negative (57.7% positive, 42.3% negative). We found that
with aging the prevalence of positive serum anti-JCV
increases (p<0.005). No other statistical significant relations
could be found.
Discussion: Although no significant relations were found
we suggest that testing forAnti-JCV as a basic biomarker
should always be performed before initiation of treatment
with Natalizumab.
Study supported by: Stratify (TM) JCV test kits were
provided by Genesis Pharma. Genesis Pharma also financed
the courier service for the transfer of blood samples to
Unilabs.
Autoantibodies targeting voltage-gated potassium channel
(VGKC)-complexes cause a spectrum of neuronal hyperexcitability disorders. We investigated pain as a manifestation
of VGKC-complex-IgG autoimmunity. VGKC-complex-IgG
was identified in 1,992 patients of 54,853 tested (4%). Of
316 evaluated neurologically at Mayo Clinic, 159 (50%)
had pain, in isolation (28%) or with accompanying neurological manifestations (72%). Pain was subacute in onset,
chronic in course, neuropathic, nociceptive, regional or diffuse and sometimes attributed to fibromyalgia (6%) or psychogenic cause (13%). Neuropathy impairment scores and
nerve-conductions, were normal in most patients. Evidence
of neuronal hyperexcitability (hyperhidrosis, quantitative
heat-pain hyperalgesia or electromyographic excitability) was
25-fold more common in pain patients. Pain management
required multiple medications in 70% (narcotics, 30%); 13
of 16 patients reported pain relief with immunotherapy.
Pain was significantly associated with CASPR2-IgG-positivity (16% positive with pain, 7% without pain; p ¼ 0.014)
but not with LGI1-IgG. Less than 10% of 167 patients
with neural autoantibodies other than VGKC-complex-IgG
reported pain. Chronic pain is a syndromic manifestation of
VGKC-complex autoimmunity. Hyperexcitability of nociceptive pathways is implicated. CASPR2-IgG significantly
associates with pain, but in most patients the VGKC-complex target molecule remains to be determined.
Study supported by: Mayo Foundation and a
National Institutes of Health grant (NS065007, C.J.K.)
and Mayo Clinic CTSA through grant number UL1
RR024150 from the National Center for Research Resources (NCRR), a component of the National Institutes of
Health (NIH).
T1816. Intrathecal Autologous Mesenchymal Stem Cell
Transplantation in Patients with Amyotrophic Lateral
Sclerosis: A Four Year Case Control Follow-Up Study
Clementine E. Karageorgiou, Ioanna Chatzi, Athanasia
Alexoudi, George Gortzolidis, Elissaios Karageorgiou, Helen
Papageorgiou, George A. Tagaris, Theofanis Chatzistamatiou,
Aikaterini Stavropoulou-Gioka and Aikaterini StavropoulouGioka; Athens, Greece and Minneapolis
T1818. Targeting Innate Receptors with MIS416
Reshaped Autoimmune T Cell Responses and Suppressed
CNS Inflammation and Disease
Anne C. La Flamme, Gill Webster, David O’Sullivan,
Madeleine White and Sarrabeth Stone; Wellington,
New Zealand and Auckland, New Zealand
Objective: To study the clinical course of patients with
Amyotrophic Lateral Sclerosis (ALS) four years after initiation of autologous mesenchymal stem cell (aMSC)
transplantation.
Patients: Thirty seven patients with definite ALS who
had undergone intrathecal delivery of aMSC were compared
to nine ALS patients matched for age, type, and severity of
ALS. Between group comparisons of the ALSFRS progression, requirement for ventilator support and number of
deaths over four years were performed using analysis of variance and survival analysis.
Results: No significant side effects were noticed after the
aMSC injection and the main adverse effect was low grade
fever.
During the four year follow-up period there were five
deaths (13.5%) in the aMSC group and 8 deaths (88,8%)
in the control group The decrease of the ALSFRS score was
significantly less in the aMSC group than in the control
group (p<0,001).Ventilatory support required two patients
from aMSC group(6.06%) and seven patients from the control group(77,7%).
Modification of innate immune cells has recently been recognized as a viable treatment strategy for reducing autoimmune disease pathology. MIS416 is a microparticle targeting
the innate receptors, NOD2 and TLR9, and is a promising
new therapeutic for progressive multiple sclerosis currently
in phase 2a trial. However, the precise mechanism for disease reduction in patients is unknown. Using mouse models
we investigated the pathways by which activation of TLR9
and NOD2 modify the innate immune environment and
subsequent T cell-mediated autoimmune responses. We
found that MIS416 had profound effects on the Th subset
balance by depressing Th17 and Th2 development, sustaining Th1 responses, and augmenting splenic regulatory T
cells. These effects coincided with increased levels of serum
IFN-c induced by MIS416 treatment. We believe that this
enhanced systemic IFN-c is key to MIS416-mediated protection as serum levels correlated strongly with disease
reduction and the protective effect of MIS416 was
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abrogated in IFN-c-deficient animals. Together, these studies
indicate that administration of MIS416, which initially targets innate cells, reshapes autoimmune T cell responses and
in an IFN-c-dependent manner leads to a reduction in
CNS inflammation and disease.
Study supported by: This work has been supported by
Victoria University of Wellington, the Great New Zealand
Trek, and Innate Immunotherapeutics.
GW and Innate Immunotherapeutics have financial and
commercial interest in MIS416.
GW may have financial benefit from MIS416. ACL, DO,
MW, and SS have no financial interest or benefit.
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T1821. Phase Imaging in Marmoset EAE at 7T
Demonstrates Heterogeneity within Focal Lesions
Pietro Maggi, Pascal Sati, Emily Leibovitch, Maria I. Gaita´n,
Jillian Wholer, Sheila Macri, Luca Massacesi, Susan
Westmoreland, Steve Jacobson, Afonso Silva and Daniel S.
Reich; Bethesda, MD and Boston, MA
‘‘Phase’’ imaging at 7T demonstrates that MS lesions
appearing similar on conventional ‘‘magnitude’’ images are
often remarkably heterogeneous (Hammond et al., Ann
Neurol 2008; Yao et al., Radiology 2012). In the marmoset
EAE model, induced with human white matter homogenate
(n ¼ 4), we investigated the biological origin of intralesional
phase variations. A multi-gradient-echo sequence performed
at 7T generated magnitude T2*-weighted (T2*w) and phase
images. Animals were scanned prior to and every two weeks
after immunization, and then weekly after the first lesion
appeared. We observed two lesion patterns: (1) Lesions that
appeared similar on magnitude and phase (homogeneous
hyperintense T2*w signal and hypointense phase signal); (2)
Lesions that appeared different on magnitude and phase
(homogeneous hyperintense T2*w signal but heterogeneous
phase signal with areas of hypointensity and isointensity).
We conclude that phase imaging in marmoset EAE might
provide more specific information about the pathology
underlying tissue damage within lesions. Possible sources of
phase heterogeneity include variations in water content,
myelination, and iron deposition; histopathology is underway to investigate these possibilities.
Study supported by: Intramural Research Program of
NINDS/NIH;
National Center for Research Resources and the Office of
Research Infrastructure Programs/NIH
T1819. Treatment of MS with ACTHar Gel – Clinical
Experience and Case Presentation
Gerard M. Lehrer; New York, NY
ACTH has been known to be effective in treating MS exacerbations after the study by Rose et al. The half life after IV
administration is less than 8 hours, and it had to be
repeated twice daily. The presumed effect was via glucocorticoid from the adrenal cortex. Because ACTHar prepared
first by Armour as a porcine anterior pituitary extract in a
gelatin base was to have extended activity, I began using it
as a single, subcutaneous injection of 80-120u. Surprisingly
a single injection often resulted in almost total reversal of
symptoms, lasting 4-6 days, with no or few repeats for complete return to usual function. Patients will be examples in
whom total loss of vision, documented by loss of VEP,
returned to 20/20 within 24 hours. It appeared that other
components of the gene product, pro-opiomelanocortin, e.g.
melanocortin, MSH, lipotropin, and 39 aminoacid ACTH
might be responsible for a direct effect on immune and
inflammatory processes. Colleagues confirmed this impression. Synthetic ACTH prepared similarly was only minimally effective. Data from approximately 600 patients will
be reviewed.
Study supported by: Questcor
T1822. Cognitive Function and Visual outcome
Measures in Patients with Early MS
Amir H. Maghzi, Laura Julian, Jackie Marcus, Jennifer
Graves, Ellen M. Mowry, Rebecca Spain, Ari Green, Michelle
K. Mass, Daniel Pelletier and Emmanuelle Waubant; San
Francisco, CA; Baltimore; Prtland and New Haven
T1820. Blood Brain Barrier Changes Prior to Lesion
Formation in a Primate Model of Multiple Sclerosis
Pietro Maggi, Emily Leibovitch, Maria I. Gaita´n, Jillian
Wholer, Govind Nair, Luca Massacesi, Steve Jacobson, Afonso
Silva and Daniel S. Reich; Bethesda, MD
Objectives: In search of the best outcome to measure neuroprotection,we aimed to study the correlation of cognitive
function with optical coherence tomography(OCT) measurements in a cohort of patients with early MS.
Methods: Patients with relapsing-remitting MS or clinically isolated syndromes seen within 12 months of onset
and naive to disease-modifying therapies were enrolled in a
trial of neuroprotection with riluzole vs. placebo. Baseline
clinical, demographic, OCT, MRI and neuropsychological
data were obtained at least four weeks after corticosteroid
treatment. Linear regression analysis with adjustment for age
and educational level were performed.
Results: Baseline OCT and neuropsychological evaluations were available for 31 patients (77.4% females; mean
age 37.02; median EDSS 2.0; mean disease duration 7.4
months). 32% of patients had impairment on at least one
cognitive test. Mean retinal nerve fiber layer thickness
(96.63þ/-12.04 microns, normal 88.5-111.7) and mean
macular volume (6.59þ/-0.39 mm3, normal 6.1-7.0) for
both eyes were not correlated with information processing
speed, learning and memory, executive functioning, attention, working memory, and visuospatial capacities.
Conclusion: Although based on small numbers, OCT
measurements do not seem to be associated with cognitive
deficits in early MS.Correlations with measures of brain atrophy and interocular differences are ongoing.
Changes in BBB permeability are associated with inflammation in MS and EAE. We used quantitative MRI to investigate processes associated with lesion formation in marmoset
EAE induced with human white matter homogenate (n ¼
4). Animals underwent brain MRI on a 7T scanner, including T1 maps before and after gadolinium injection. Animals
were scanned prior to and every two weeks after immunization, then weekly after the first lesion appearance. Prolongation of the longitudinal relaxation rate (R1 ¼ 1/T1) following gadolinium injection was used to estimate BBB changes
at each time point. In areas that later became focal lesions,
we found that DR1 increased over time (p ¼ 0.0024),
4.461.3 (mean6standard error) fold over baseline in the
10 days prior to lesion appearance. Slight further increases
in DR1 at the time of and shortly after lesion appearance
were also observed. There was no change in DR1 in the cortex or extralesional white matter. We conclude that focal
BBB changes occur during the initial stages of lesion development in marmoset EAE. This suggests that inflammation
in this MS model is primarily a multifocal process rather
than a diffuse one.
Study supported by: Intramural Research Program of
NINDS/NIH;
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Study supported by: This study was supported by the
national MS Society (RG3932-A-2). Biogen Idec and Sanofi
Aventis have provided free medication for this trial. Dr.
Maghzi was supported through a McDonald’s Fellowship
from MSIF.
Dr. Marcus was supported by a fellowship from national
MS society and Biogen Idec.
Dr. Waubant has received has received honorarium for
educational presentations from Biogen Idec. She is ad hoc
consultant for Sanofi Aventis. She has received free study
medication from Biogen Idec and Sanofi Aventis. She has
received an educational grant from Biogen Idec.
Dr. Green served as ad hoc consultant for Novartis and
Biogen Idec.
All other authors have nothing to disclose regarding this
study.
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Results: In all BD cases, Cx43, Cx32 and Cx47 were
extensively diminished. In the leading edge of Baló’s lesions,
Cx43 and AQP4 loss preceded Cx47 loss. Two cases with
MS and six with NMO showed preferential Cx43 and AQP4
loss far beyond the demyelinated areas, and vasculocentric
deposition of immunoglobulin or complement was observed
in four of the six NMO cases. The other cases showed AQP4
and Cx43 preservation, even in actively demyelinating lesions.
Some NMO cases showed preferential MAG loss in AQP4and Cx43-diminished active lesions.
Conclusion: Our findings indicate that antibody-independent astrocytopathy can occur in MS, BD and NMO,
and could be a common denominator.
Study supported by: This work was supported in part by
a Health and Labour Sciences Research Grant on
Intractable Diseases (H22-Nanchi-Ippan-130 and H23Nanchi-Ippan-017) from the
Ministry of Health, Labour, and Welfare, Japan, by a Scientific Research B Grant (No.
22390178) and a Challenging Exploratory Research
Grant (No. 23659459) from the
Ministry of Education, Culture, Sports, Science, and
Technology (Japan), by the
Kaibara Morikazu Medical Science Promotion Foundation (Japan), and by the Japanese Multiple Sclerosis Society.
T1823. Clinical Information of Four Men with Anti-NMethyl D-Aspartate Receptor Encephalitis
Makoto Samukawa, Makito Hirano, Hikaru Sakamoto,
Shuichi Ueno, Toshiharu Maekura, Harutoshi Fujimura,
Susumu Kusunoki and Yusaku Nakamura; Osaka-Sayama,
Osaka, Japan; Sakai, Osaka, Japan and Toyonaka, Osaka,
Japan
Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis
is a female-predominant disease often associated with tumors
such as ovarian teratoma. Male patients have been also
reported but their clinical information is not well-known.
Thus, we report four men who had anti-NMDAR encephalitis with characteristic symptoms. All patients had prodromal
symptoms such as fever and headache, and then developed
psychiatric changes. No patients had tumors. Cerebral spinal
fluid in all patients contained NMDAR antibody. Characteristic complications include: venous thrombosis (2/4),
hippocamps involvement (2/4), hypersexuality (2/4), and
joint contracture (1/4). Venous thrombosis, generally more
frequent in men than in women, caused fatal pulmonary
embolism in one of our patients. Joint contracture has been
found previously in only one man. Hippocampus is consistently affected in this disease, however, one of our patients
had atrophy of hippocampus severely progressed on MRI
even after recovery of psychiatric problems. Hypersexuality is
common in limbic encephalitis, but detail description has not
been reported previously. This symptom in men can threaten
female nurses. We suggest that these characteristic features are
not necessarily male-specific, but should be properly managed
in consideration of gender differences.
Study supported by: N/A
T1825. The Role of Manganese Enhanced MRI
(MEMRI) in Theiler’s Murine Encephalitis Virus
(TMEV) Induced CNS Inflammatory Disease Models
Istvan Pirko, Jeffrey Gamez, Emily R. Shearier, Mekala
Raman, Aaron J. Johnson and Slobodan I. Macura; Rochester,
MN
MEMRI is a unique tool utilized in CNS tractography.
Manganese can be directly microinjected to CNS foci for
connectivity studies utilizing its T1 relaxation enhancement
properties. When administered systemically, it crosses the BBB
at specific locations and visualizes corresponding neuronal
structures. While DTI scrutinizes physical connectivity by
assessing water diffusion directionality, MEMRI provides
‘‘functional tractography’’ by visualizing tract connectivity via
transsynaptic uptake. Dose dependent toxicity limits its longterm use. MEMRI has never been utilized in the TMEV
model of MS. We studied IP administration in TMEV
infected C57BL6/J mice, in uninfected controls, and in a previously reported hemorrhagic demyelination model.Tract
enhancement was noted at 24 hours with maximal uptake in
hippocampi, olfactory bulbs, and cerebellum. In infected
mice, characteristic T1 black holes, thinning and focal disruption of tracts were detected. BBB disruption and resultant Mn
uptake were also demonstrated. Manganese also exerted an
unexpected therapeutic effect: hemorrhagic demyelination was
suppressed with manganese adnimistration, likely as a result of
direct effects on infected neurons.We conclude that MEMRI
enables unique functional tractography, with a capacity to provide important structural and functional information.
Study supported by: NIH NINDS R0 1NS058698 and
Mayo Clinic Department of Neurology intramural funds
T1824. Connexin Astrocytopathy in Multiple Sclerosis,
Baló’s Disease and Neuromyelitis Optica
Katsuhisa Masaki, Satoshi O. Suzuki, Takuya Matsushita,
Takeshi Matsuoka, Toshihiko Suenaga, Takeshi Tabira, Toru
Iwaki and Jun-ichi Kira; Fukuoka, Japan; Nara, Japan and
Tokyo, Japan
Background: Recently, we reported AQP4 loss without
perivascular deposition of either activated complement or immunoglobulin in patients with multiple sclerosis (MS), neuromyelitis optica (NMO) and Baló’s disease (BD). To investigate
the relationship between astrocytopathy and demyelination, we
examined the expression of connexins (Cx), which form gap
junction channels between astrocytes and oligodendrocytes.
Methods: We evaluated astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 expression relative to AQP4 and
GFAP expression, and extents of demyelination in 11 autopsied cases with NMO, five with MS, four with BD.
T1826. Pilot Clinical Trial of Eculizumab in
AQP4-IgG-Positive NMO
Sean J. Pittock**, Andrew McKeon, Jay N. Mandrekar, Brian
G. Weinshenker, Claudia F. Lucchinetti and Dean M.
Wingerchuk; Rochester, MN and Scottsdale, AZ
Objective: Investigate safety and efficacy of blocking
terminal complement activation in reducing frequency of
neuromyelitis optica (NMO) relapses. We conducted an
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open-label study of eculizumab, an inhibitor of C5 cleavage,
in patients with aggressive NMO.
Methods: 14 adults with NMO spectrum disorder ( 2
relapses in the preceding 6 months or 3 in the preceding 12
months) were treated with eculizumab for 1 year. 7 had
failed standard immunosuppressant treatments.
Results: After 12 months treatment, 12 of 14 were
relapse-free. The median annualized attack rate declined
from 3 (pre-eculizumab) to 0 (on-eculizumab; p<0.0001).
Two subjects had single attacks: one had back pain only
(<30 hours after first infusion, without objective clinical/radiological evidence of myelitis) and received corticosteroids
for a ‘‘possible’’ attack; the other had optic neuritis. At 12
months, no subject had worsened disability by any outcome
measure. Median EDSS score declined from 4.3 (pre-eculizumab) to 3.5 (on-eculizumab; p <0.01). One patient was
successfully treated for meningococcal meningitis. Otherwise, the treatment was well tolerated.
Conclusions: Apparent stabilization of disease activity in
this cohort selected for aggressive disease activity supports a
central role for complement activation in NMO. Eculizumab warrants further investigation as NMO therapy.
Study supported by: Alexion Pharmaceuticals, Inc.
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substantial so disabling sequelae are rare. Permanent disability from progressive disease is more common but this usually evolves very slowly. Rare case reports have suggested
there may also be a fulminant variant (first proposed by
Otto Marburg in 1906) of ‘‘unrelenting progressive disease
that typically leads to death within a few months to a year.’’
To clarify the early course of MS, we analyzed all 1,854
patients who met McDonald diagnostic criteria for MS seen
at our MS Center from 1994-2011. None had fulminant
disease. Only 4 patients reached an EDSS of 6.0 (requiring
assistance to walk) within the first year and all these were
alive and stable 10 years later. No patient died within 5
years of onset and fewer than 10% of patients reached an
EDSS of 6.0 within 5 years. (Analysis of these patients will
be presented.) We conclude that fulminant MS is rare. The
low rate of disability in the first few years of MS has important implications for counseling newly diagnosed patients
and discussing therapeautic options.
Study supported by: No outside support.
T1829. Demographic and Clinical Features of
Participants in a VA Longitudinal Study of MS
Walter Royal, Mitchell Wallin, Terry Lee-Wilk, Heidi Maloni,
William J. Culpepper, Joseph Finkelstein, Jong-Chaur Shieh,
Michael Levin, Micheline McCarthy, William Tyor, Jonathan
Leigh, Min Zhan, Robert Kane and Christopher Bever;
Baltimore, MD; Washington, DC; Buffalo, NY; Memphis,
TN; Miami, FL; Atlanta, GA and Cleveland, OH
T1827. Growth Factors PDGF and FGF-2 Are Required
for Human Recombinant IgM-Mediated Stimulation of
Oligodendrocyte Proliferation and Survival
Jens O. Watzlawik, Arthur E. Warrington and Moses
Rodriguez; Rochester, MN
Objectives: To describe results of a cross-sectional analysis
of clinical and demographic characteristics for military veterans participating in a longitudinal study of MS.
Methods: MS patients recruited from 8 VA medical centers were assessed using the Kurtzke EDSS, the Multiple
Sclerosis Functional Composite, and questionnaires to
obtain demographic information.
Results: 96 patients were enrolled, 83% treated with a
MS disease modifying therapy. The patient mean age was
47.5 þ 8.7, male: female ratio was 2.6:1, and 59.5% were
non-white. 59.4% had relapsing-remitting, 28.1% secondary
progressive, 8.3% primary progressive and 4.2% had relapsing progressive MS. Females were younger at the time of
their first MS symptom (p ¼ 0.005). Non-white patients
were younger at enrollment (p ¼ 0.008) and borderline
younger at their first MS symptom (p ¼ 0.06) than white
patients. EDSS scores showed a bimodal distribution with
peaks at EDSS 2.5 and 6.0. Progressive disease was associated with older age at the time of study enrollment (p ¼
0.018) and a borderline later onset of MS symptoms than
relapsing-remitting patients (p ¼ 0.05).
Conclusions: Some cohort characteristics differ from
those of non-VA patient groups, but several features are similar. Ongoing and more detailed studies are underway.
Study supported by: Veterans Administration
Authors are paid salaries by the VA.
RHIgM22 is a recombinant human IgM, which targets
myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. Co-factors required for
rHIgM22 to promote remyelination are unknown and, it is
unclear whether remyelination is driven by stimulation of
oligodendrocyte progenitor cell (OPC) proliferation/survival,
or by survival of mature OLs. RHIgM22 has completed
safety studies in animals and is likely soon being tested in
MS patients.
We assessed IgM-induced OL proliferation, differentiation, apoptotic and intracellular signaling in vitro by radiolabeling, immunohistochemistry and Western blots.
RHIgM22 promotes OPC proliferation in mixed glia cultures, but not in isolated OPCs. Proliferation in mixed glia
is blocked by inhibition of PDGFaR kinase. RHIgM22
inhibits apoptotic signaling and differentiation in isolated
OPCs in a PDGF-/FGF-2-dependent manner, but does not
influence survival in mature OLs.
Our findings demonstrate that glial growth factors are
necessary for rHIgM22-mediated effects and suggest that
astrocytes and microglia play important beneficial roles for
IgM-induced in vivo remyelination. Our data support the
hypothesis that OPCs are responsible for remyelination following a demyelinating insult such as MS rather than
mature oligodendrocytes.
Study supported by: This work was supported by grants
from the National Institutes of Health (R01s - GM092993,
NS024180, NS032129, NS048357, R21 - NS073684), the
National Multiple Sclerosis Society (CA1060A11), the
Applebaum Foundation, the Hilton Foundation, the Peterson Foundation and the Minnesota Partnership for Biotechnology and Medical Genomics.
T1830. Unusual Presentation of Paraneoplastic StiffPerson Syndrome with Underlying Breast Cancer
Alvin Shrestha, Tatiana Mihalova, Daniel Burns, Hannah
Jennens and Roland Etti; Birmingham, West Midlands, United
Kingdom
A 46 year old lady presented to the Neurologists with constant itching and burning sensation of the left arm followed
by the right. An MRI of the head and neck and nerve conduction study was normal. Five months later, she developed
persistent stiffness of the neck and shoulders, and found
head movement restrictive. Routine bloods were
T1828. Does ‘‘Fulminant’’ Multiple Sclerosis Exist?
Loren A. Rolak and Susan Anderson; Marshfield, WI
Disability seldom occurs early in the course of MS. Relapses
can produce severe deficits but remissions are usually
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unremarkable; however anti-amphiphysin antibody was positive. She was given a diagnosis of partial stiff-person syndrome. At 11 months from the initial symptoms, the
patient herself reported an abnormal lump in her right
axilla. A CT whole body confirmed the lymph node, but
did not show any other malignancy or lymphoma. A lumbar
puncture showed an acellular CSF with normal CSF/serum
glucose ratio, protein level and cytology. She was reviewed
in the Breast Clinic, where the node was aspirated. The cytology unfortunately revealed large numbers of malignant
cells, ER, PGR and cytokeratin positive, in keeping with
metastatic breast cancer.
This case describes an unusual initial presentation of
burning sensation and itching, before the occurrence of classical stiffness in keeping with stiff-person syndrome, which
preceded the detection of the underlying malignancy by several months.
Study supported by: Conflict of interest: nil
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antibody staining. Using stage specific antisera to monitor
differentiation, we observed maturation of OL from Akt1-/mice was arrested prior to differentiation. Staining specific
for galactocerebroside (GalC), an early marker of differentiation, was absent. Western blot analysis confirmed the loss
Akt1. Akt2-/- and Akt3 -/- mice displayed normal differentiation in vitro. These results suggest that Akt1, the predominant isoform during development, is required for oligodendrocyte maturation in vitro.
Study supported by: This work was supported by the
Grace R Loeb Endowed Chair in Neuroscience Children’s
Hospital of Philadelphia
T1833. Profound Alternating Corticospinal Tract
Enhancement in Neuro-Behcet’s Disease
April A. Erwin, Carlo Tornatore and Mark Lin; Washington,
DC
Introduction: A typical MRI presentation of neuro-Behcet’s
is corticospinal tract T2 hyperintensities. We present a case
with profound corticospinal tract enhancement, alternating
sides on successive relapses. We also present for comparison
a more conventional case of neuro-Behcet’s with nonenhancing brainstem T2 hyperintensities.
Cases: A 30 year old female presented with dysarthria
and hemiparesis on three occasions. MRI brain during each
event revealed enhancing brainstem and basal ganglia corticospinal tract lesions, alternating right to left on successive
exacerbations, and remitting after administration of steroids.
CSF oligoclonal bands and rheumatological serum screening
tests were negative. Further history-taking revealed patient
had recurrent bipolar ulcers and papulopustular skin lesions,
qualifying her for a diagnosis of Behcet’s per International
Study Group criteria. In another case, a 42 year old Yemeni
male presented with hemisensory loss and bipolar ulcers.
His MRI brain showed a more typical pattern of nonenhancing T2 hyperintensities in the right midbrain and
pons.
Conclusions: Neuro-Behcet’s is known to cause T2
hyperintensities in the brainstem and basal ganglia which
may briefly enhance in the acute phase. However, the degree
of enhancement and recurrent, alternating corticospinal tract
lesions seen in our patient have not been described.
Study supported by: None
T1831. The Prevalence of Cardiovascular Risk Factors
in Multiple Sclerosis Patients
Zohara Sternberg, Christopher Leung, Daniel S. Sternberg and
Elad Levy; Buffalo
Objectives: This retrospective study examined the prevalence of CV risk factors in patients with multiple sclerosis
(MS).
Methods: CV risk factors were compared with non-MS
patients who were diagnosed with non-autoimmune diseases
of the brain. Correlation between CV risk factors and indicators of disease severity were carried out for MS patients.
Results: After adjusting for confounding factors, MS
patients had significantly higher TC (P ¼ 0.01), higher
plasma HDL (P <0.001), but lower plasma glucose (P
<0.001) and systolic BP (P ¼ 0.001) compared to non-MS
patients. Gender differences in CV risk factors among MS
patients were observed. Multiple regression analysis showed
a positive correlation between plasma glucose and the EDSS
(P ¼ 0.008), and the rate of clinical relapse (P ¼ 0.001),
while diastolic BP and serum albumin were inversely related
to the EDSS and MSSS (Ps < 0.05).
Conclusion: MS patients present with low CV risk factors. Lowe plasma glucose and BP may be associated with
autonomic nervous dysfunction in MS.
Study supported by: Jog for the Jake, a local philanthropic foundation
T1834. Anti-CD52 Therapy in Experimental
Autoimmune Encephalomyelitis
Michael J. Turner, Nathalie Chretien, Evis Havari, Michael
LaMorte, Bruce Roberts, Johanne Kaplan and William M.
Siders; Framingham, MA
T1832. Akt1, Not Ak2 or Akt3, Regulates
Oligodendrocyte Maturation In Vitro
Jennifer A. Minarcik, Mary V. Reid, Morris J. Birnbaum,
Chen Po, Judith B. Grinspan and Gihan I. Tennekoon;
Philadelphia, PA and Baltimore, MD
Alemtuzumab is a humanized monoclonal antibody that
binds to the human CD52 molecule present at high levels
on T and B lymphocytes. Administration of alemtuzumab
results in lymphocyte depletion thereby altering the circulating lymphocyte pool in RR-MS patients. A recently developed depleting murine CD52 (muCD52)-specific antibody
was evaluated in a mouse EAE model to expand our understanding of anti-CD52 therapy. Following immunization to
induce EAE mice were treated with anti-muCD52 antibody,
characterized with respect to disease severity and mechanism
of action of the antibody. Results from these studies
demonstrated a profound impact of anti-muCD52 therapy.
Specifically, prophylactic treatment effectively prevented the
development of disease while therapeutic intervention inhibited disease progression and reversed existing symptoms.
Longitudinal flow cytometric evaluation demonstrated a
decrease in the number of MOG35-55 specific CD4þ T
Myelin formation around axons by oligodendrocytes (OL)
enables proper conduction of nerve impulses and ensures
axonal integrity. Axonal signals that initiate and maintain
myelination require the activation of several signal transduction pathways. The Akt (serine/threonine protein kinase B)
pathway contributes to cell survival, proliferation, and lineage specificity of OL, along with the production of myelin
through the phosphorylation of the mammalian target of
rapamycin (mTOR). We investigated the importance of Akt
and its 3 isoforms in the regulation of OL differentiation in
cell culture.
To study the effects of the specific Akt isoforms, we
isolated OL from newborn mice (Akt1-/-, Akt2-/-, Akt3-/-,
heterozygote and WT). OL were isolated by differential
adhesion and purity was established using A2B5/GFAP
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cells as determined by IFNg intracellular cytokine staining.
Histological evaluation also showed a reduction in the level
of lymphocytic infiltrate in the CNS of anti-muCD52
treated animals compared to control animals that received
the vehicle. These results demonstrated the therapeutic efficacy of anti-muCD52 treatment as exhibited by a reduction
in MOG-reactive pathogenic T cells and decreased lymphocyte infiltration in the CNS of mice with EAE.
Study supported by: Genzyme, a Sanofi Company
Dr. Turner and all co-authors receive personal compensation as an employees of Genzyme.
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scientific meetings and scientific advisory honorariums
from Merck Serono, TEVA, Biogen, Bayer Schering and
Novartis, has held MS society grants and is a clinical lead
for the UK DOH RSS.
T1836. Serum Proteomic Analysis of a Presymptomatic
MS Cohort
Mitchell Wallin, Unsong Oh, Julius Nyalwidhe, Thomas
Kislinger, O. John Semmes, John Kurtzke, Parisa Coffman and
Steven Jacobson; Washington, DC; Richmond, VA; Norfolk,
VA; Bethesda, MD and Toronto, ON, Canada
Objective: Susceptibility to MS is determined by environmental and genetic factors, but the cause remains unknown.
Changes to the proteome prior to first symptom onset may
reflect the underlying pathophysiology of the disease.
Methods: Pre and post-symptomatic serum from 100
US military veterans with MS along with 100 matched
healthy veterans and 50 other neurological disease controls
were obtained from Department of Defense Serum Repository. Multidimensional protein Identification Technology
Liquid Chromatography Tandem Mass Spectrometry analysis was performed on tryptic peptides of lectin-captured
glycosylated serum proteins following albumin/IgG
depletion.
Results: The mean collection interval between MS presymptomatic and post-symptomatic serum was 6.0 and
1.1 years, respectively. Pre-symptomatic proteins from the
MS group were differentially regulated compared to that
of both control groups indicating that proteomic changes
are detected prior to symptom onset. Pathway analysis
showed that proteins involved in the complement and
coagulation pathways and lipid transport are significantly
altered in the serum of subjects with MS compared to
healthy donors.
Conclusions: Compared with controls, differential proteomic changes were noted in the serum of patients with
MS that preceded the onset of symptomatic disease.
Study supported by: National MS Society
T1835. MOG Antibodies in Adult and Pediatric
Demyelinating Diseases
Joanna Kitley, Mark Woodhall, Patrick Waters, M. Isabel
Leite, Jackie Palace and Angela Vincent; Oxford, United
Kingdom
Antibodies that bind to extracellular domains of myelin-oligodendrocyte glycoprotein (MOG), expressed on human
embryonic kidney cells, have only recently been identified
in patients with demyelinating diseases, and have been
reported most consistently in children with ADEM. We
have started performing MOG-antibody testing as a clinical
service, and from 125 patient samples referred, 14 patients
were positive for MOG-antibodies; all were negative for
aquaporin-4-antibodies. 4/14 were children aged 3-16, 3/4
were male. The remainder were 6 male and 4 female adults.
Here we report the clinical phenotypes of 8 of these
patients.
The presentations varied between ADEM-like (two children), monophasic LETM (two adults) and simultaneous
ON and LETM typical of monophasic NMO (four adults).
Overall, all the adults had features consistent with a diagnosis of NMO or NMO spectrum disorder. 7/8 patients made
excellent recovery with immunotherapies and relapses were
uncommon. We conclude that, although the full spectrum
and long-term course of MOG-antibody-disease are not
entirely established, MOG-antibodies will be helpful in the
diagnosis and management of children and adults with
demyelinating conditions, and that they might account for
some of the aquaporin-4-antibody-’’seronegative’’ cases that
have previously been described as NMO.
Study supported by: JK has received support for scientific
meetings from Biogen Idec and is supported by the NHS
National Specialised Commissioning Group for Neuromyelitis Optica. MW, PW and MIL are involved in AQP4 and
MOG antibody testing, supported by the NHS National
Specialised Commissioning Group for Neuromyelitis Optica
and by the NIHR Oxford Biomedical Research Centre. AV
and the Nuffield Department of Clinical Neurosciences
hold patents and receive royalties and payments for antibody tests. JP has received unrestricted grants and support
for scientific meetings and scientific advisory honorariums
from Merck Serono, TEVA, Biogen, Bayer Schering and
Novartis, has held MS society grants and is a clinical lead
for the UK DOH RSS.
JK has received support for scientific meetings from Biogen Idec and is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica.
MW, PW and MIL are involved in AQP4 and MOG antibody testing, supported by the NHS National Specialised
Commissioning Group for Neuromyelitis Optica and by
the NIHR Oxford Biomedical Research Centre. AV and
the Nuffield Department of Clinical Neurosciences hold
patents and receive royalties and payments for antibody
tests. JP has received unrestricted grants and support for
T1837. Guillain-Barré Syndrome and Its Association
with the 1976 ‘‘Swine Flu’’ Immunisation Programme
James N.R. Wyatt; Liverpool, United Kingdom
Introduction: In 1976, the US government suspected an
influenza pandemic. In response, they set up a national vaccination programme. This was soon disbanded, as a rise in
the incidence of Guillain-Barré syndrome was reported.
Years after, it is still a matter of debate whether there was a
causal relationship.
Objective: To use the Bradford-Hill criteria(1) of causality to determine the presence or absence of a causal relationship between GBS and the 1976 ‘‘swine flu’’ programme.
Method: PubMed and Medline were searched using
phrases such as ‘‘Guillain-Barre syndrome AND influenza
vaccine’’ or ‘‘1976 swine flu AND Guillain-Barre syndrome’’. Current and past literature obtained in this way
was reviewed and formed the basis for my research.
Conclusion: 5 out of 9 of the Bradford-Hill criteria were
satisfied. Thus, there is some, but not overwhelming
evidence to support a causal relationship. Using present
literature it is not possible to reach a definite conclusion.
However, there is enough evidence to suggest caution in
future mass vaccination programmes.
1.Bradford-Hill A. The environment and disease: Association or causation? Meeting of section of occupational medicine; 1965; 7; 295-300
Study supported by: None
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T1838. Leveraging Electronic Health Records for
Studying Multiple Sclerosis
Zongqi Xia, Tianxi Cai, Suchun Cheng, Raul N.G. Perez,
Vivian S. Gainer, Shwan N. Murphy, Pei J. Chen, Guergana
K. Savova, Katherine P. Liao, Elizabeth W. Karlson, Ashwin
N. Ananthakrishnan, Peter Szolovitis, Susanne E. Churchill,
Issac S. Kohane, Robert M. Plenge and Philip L. De Jager;
Boston, MA; Cambridge, MA and Charlestown, MA
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PR3-ANCA. Serum IgG4 was increased in 7/26 cases measured. The most frequent cause of secondary HP was
ANCA-associated
vasculitis/Wegener
granulomatosis
(59.3%). The most frequent initial symptoms were headache (33.4%) and visual disturbance (11.9%), with headache and cranial nerve involvement present in 70.8% and
61.8% of cases during the entire course.
Interpretation: ANCA-associated HP is the most common type of HP observed in Japan.
Study supported by: This work was supported in part by
a Health and Labour Sciences Research Grant on Intractable
Diseases (H23- Nanchi-Ippan-086) from the Ministry of
Health, Labour, nd Welfare, Japan
Electronic Health Records (EHR)-derived virtual cohorts
complement conventional cohort studies. We developed an
EHR algorithm to identify patients with multiple sclerosis
(MS). We built a ‘‘data-mart’’ that includes the complete
medical records of 193,895 patients from Partners HealthCare who either underwent a magnetic resonance imaging
study (brain, cervical spine) or had a related ICD9 code for
MS. The mart contains codified and narrative data extracted
using natural language processing. We randomly selected
595 subjects to develop a training set where MS diagnosis
was established by neurologist chart review. The LASSO
logistic regression model was developed on the training set
and selected informative variables for the MS algorithm,
which was then applied to the entire mart. The algorithm
yielded AUC ¼ 0.962, sensitivity ¼ 83%, PPV ¼ 92% and
NPV ¼ 89% with specificity set at 95%. In total, the algorithm captures 5,537 MS patients, including 86% of the
1,341 subjects from a gold-standard MS cohort. We are
testing the portability of the MS algorithm in other EHR
systems and leveraging the EHR-derived MS cohort to
study predictors of conversion from the presymptomatic
phase to clinical MS, disease activity in MS, and response
to disease-modifying therapy.
Study supported by: National Institutes of Health Office
of the Director, National Library of Medicine and the
National Institute of General Medical Sciences
(2U54LM008748)
T1840. Caspr2 Autoantibodies Target CNS and PNS
Axons
Eric Lancaster, Josep Dalmau and Steven S. Scherer;
Philadelphia, PA and Barcelona, Spain
Background: Caspr2 is an axonal protein that localizes voltage gated potassium channels (VGKC) to the juxtaparanodes of myelinated axons. A subset of patients with antibodies to the VGKC complex, Caspr2 is the actual antigen.
Caspr2 autoantibodies are associated with acquired peripheral nerve hyperexcitability (Isaacs’ syndrome) and/or encephalitis. The mechanisms by which Caspr2 antibodies
cause disease are unknown.
Methods: Peripheral and central nervous system tissues
were immunolabeled with patients’ Caspr2 antibodies.
Results: Caspr2 is expressed in the soma and dendrites of
CNS neurons, but surface Caspr2 is expressed only on
axons. Accordingly, Caspr2 autoantibodies labeled the axons,
but not soma or dendrites, of cultured hippocampal
neurons. This labeling did not co-localize with a synaptic
marker (Bassoon). In brain slices, stained was observed
predominantly in white matter tracts, specifically on the
juxtaparanodes of myelinated axons. In the PNS, Caspr2
antibodies labeled the juxtaparanodes of axons of sciatic
nerve fibers, and spinal nerve roots, as well as the somata of
dorsal root ganglia neurons.
Conclusions: While other antibodies to cell surface proteins (e.g. the NMDA receptor) target synapses, Caspr2
antibodies predominately target CNS and PNS axons.
Study supported by: This work is supported in part by
grants from the National Institutes of Health
RO1NS077851, RO1MH094741, and the National Cancer
Institute RO1CA089054 (JD); and Fundació la Marató
TV3 and Fondo de Investigaciones Sanitarias (FIS, PI11/
01780) (JD); and grants from the National Organization
for Rare Disorders (EL), NINDS (EL) and the Dana Foundation (EL). Dr. Dalmau has received a research grant from
Euroimmun, and receives royalties from patents for the use
of Ma2 and NMDAR as autoantibody test.
Dr. Dalmau has received a research grant from Euroimmun, and receives royalties from patents for the use of Ma2
and NMDAR as autoantibody test.
T1839. The First Nationwide Survey of Hypertrophic
Pachymeningitis in Japan
Tomomi Yonekawa, Katsuhisa Masaki, Takuya Matsushita,
Shinya Sato and Jun-ichi Kira; Fukuoka, Japan
Objective: To clarify clinico-epidemiological features of hypertrophic pachymeningitis (HP) in Japan through the first
nationwide survey of this disease.
Methods: Cases with HP diagnosed from January 1,
2005 through December 31, 2011 were collected nationwide. We excluded HP cases associated with malignancy
and those with intracranial hypotension.
Results: A preliminary survey reported 330 HP cases
(34.8% response rate), with detailed data collated for 184
of these cases. The prevalence of HP was 0.282 per 100,000
people, with a male to female ratio of 1.2:1. Mean age of
onset was 58.6615.7 years. Of the 184 detailed cases, 152
had cranial HP, 11 had spinal HP, 9 had both. Idiopathic
HP was seen in 103 cases, secondary HP in 67 cases. 45
cases of 117 examined were positive for MPO-ANCA or
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2012 Annual Meeting Works in
Progress Poster Session Abstracts
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criteria were finally enrolled in this study. The diagnosis of
fatty liver was made based on the findings of liver ultrasound, while the presence of ICAD was decided according
to the interpretation of MRA data.
Results: Of 6146 participants, the prevalence of NAFLD
and ICAD was 46.4% (n¼2853)and 4.6% (n¼282), respectively. After the adjustment for atherosclerosis risk factors,
NAFLD was independently associated with increased risk of
ICAD (OR: 1.89, 95% CI: 1.45-2.46). In addition,
NAFLD was still associated with increased risk of ICAD in
another multiple regression model adjusting for metabolic
syndrome and other risk factors (OR: 1.91, 95% CI: 1.462.50).
Conclusions: The present study suggested that the detection of NAFLD was independently associated with the
increased risk for ICAD among asymptomatic Korean.
Posters will be displayed in Arlington, located on the 3rd
floor in the Back Bay Hall of the Marriott Copley Place
from 11:30 am – 7:00 pm.
Authors will be present during the following times:
WIP100-WIP1001: Sunday, October 7, 5:30 – 7:00 pm
WIP1100-WIP1409: Monday, October 8, 5:30 – 6:30 pm
WIP1500-WIP1804: Tuesday, October 9, 5:30 – 7:00 pm
The Works in Progress category emphasizes ongoing clinical or basic research of an extraordinary nature, which warrants expediated presentation. These abstracts were selected
based on scientific merit, timeliness, and anticipated interest
to the membership. Key aspects of research must have been
conducted after the regular abstract deadline.
NOTE: Two asterisks designates an abstract selected for oral presentation in the Derek Denny-Brown New Member Symposium.
WIP103. Hydrogen Sulfide Increases Angiogenesis and
Improves Functional Outcome after Stroke
Mi-Young Oh, Hyunduk Jang, Wi-Sun Ryu, Seung-Hoon Lee
and Byung-Woo Yoon; Seoul, Korea
Objective: Hydrogen Sulfide is a potent inducer of angiogenesis. In this study, we investigate whether NaHS (H2S
donor) induces angiogenesis and thereby improves functional outcome in rat cerebral ischemic/reperfusion model.
Methods: Adult male rats were subjected to middle cerebral artery occlusion and were treated with 5mg/kg of
NaHS or normal saline starting 48 hours after middle cerebral artery occlusion and daily for 14 days. Neurological
functional tests were performed. The volume of von willebrand factor(vWF)- positive area was measured. Newly proliferated vascular endothelial cell were counted. Angiogenic
factor expressions were measured by immunohistochemistry
and western blot. In vitro, endothelial tube formation was
examined.
Results: NaHS significantly promoted vWF-positive area
(30.16% vs. vehicle, 12.3 %, p<0.01) and proliferation of
vascular endothelial cell (7.3/2*105 um2 vs. vehicle, 3.1/
2*105um2, p<0.01) in the ischemic brain. and improved
functional outcome after stroke. Mechanisms underlying the
NaHS-induced vascular remodeling were investigated.
NaHS increased the expression of vascular endothelial
growth factor (VEGF), angiopoietin-1 (Ang1), angiopoietin2(Ang-2) and phosphorylation of Akt, and ERK-1/2.
Conclusion: NaHS promoted angiogenesis, which may
contribute to improvement of functional outcome after
stroke. The VEGF/VEGF receptor, phosphoinositide 3-kinase/Akt, and ERK-1/2 pathways appear to mediate NaHSinduced angiogenesis.
Behavioral Neurology
WIP101. The Detrimental Effect of Aging on
Leptomeningeal Collaterals in Ischemic Stroke
Atay Vural, Murat E. Arsava, Erhan Akpinar, Rahsan
Gocmen, Seray Akcalar, Kader K. Oguz and Akif M.
Topcuoglu; Ankara, Turkey
Background and Purpose: Aging is associated with
decreased penumbral salvage in patients with ischemic
stroke. Another critical factor that determines the fate of penumbra tissue is the degree of collateral circulation, which
decreases significantly with aging in experimental models of
stroke. In this study we sought to identify whether these
observations could be translated to humans.
Methods: Computed tomography angiography (CTA)
source images were used to assess the degree of collateral circulation in a retrospective series of patients with proximal
middle cerebral artery occlusion. Bivariate and multivariate
analyses were used to explore the relationship between
patient age and degree of collateral irculation.
Results: A total of 70 patients were included into the
study. Older age (p¼0.005), history of hypertension
(p¼0.036), higher admission NIHSS scores (p¼0.013) and
increased time to CTA (p¼0.013) were associated with
inadequate collaterals in bivariate analyses. In multivariate
analysis, older age (p¼0.008) and higher NIHSS scores
(p¼0.032) remained as the only significant independent
variables that were associated with inadequate collaterals. A
10-year increment in patient age increased the odds of inadequate collateral circulation by 1.87 (95% CI, 1.18-2.97).
Conclusions: Our findings show that there is a significant interplay between patient age and adequacy of leptomeningeal collateral circulation in patients with proximal middle cerebral artery occlusion.
WIP104. Retinal Microvascular Abnormalities Predict
Brain Microvascular Disease Progression: An ARIC
Study
Thomas C. Hanff, A. Richey Sharrett, Tom H. Mosley, Dean
Shibata, David S. Knopman, Ronald Klein, Barbara Klein
and Rebecca F. Gottesman; Baltimore, MD; Jackson, MS;
Seattle, WA; Rochester, MN and Madison, WI
WIP102. The Association between Non-Alcoholic Fatty
Liver Disease and Intracranial Atherosclerotic Disease
Hyun-Suk Jung, Byung-Su Kim and Yoon Ho Choi; Seoul,
Republic of Korea
Background: Brain microvascular disease (BMVD) exists
for years before visible on MRI. Retinal microvascular
changes may be an even earlier marker of BMVD. We
tested this association by 1)using a continuous measure of
white matter hyperintensity progression (WMP) and 2)combining WMP and lacunar infarcts into one comprehensive
measure of brain microvascular disease.
Methods: Participants underwent initial brain MRIs and
retinal photography, and 10 year follow-up brain MRIs.
Background: The purpose of this study is to examine an
association between non-alcoholic fatty liver disease
(NAFLD) and intracranial atherosclerotic disease (ICAD).
Methods: From January 2008 to December 2010, 6146
asymptomatic study participants met full study inclusion
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Retinal microvascular changes (e.g., retinopathy and arteriovenous nicking), were evaluated relative to: 1)volume of
WMP (change in leukoaraiosis volume) and 2)global microvascular disease (lacunes on follow-up MRI þ WMP).
Results were adjusted for vascular risk factors including
blood pressure and diabetes.
Results: Any retinopathy was associated with 3.06 cc
(95% CI 0.39-5.73) more WMP, and arteriovenous nicking
was independently associated with 2.98 cc (95% CI 1.134.81) more WMP. Furthermore, combining lacunar infarcts
and WMP yielded associations between brain and retinal
changes that were stronger than has been previously
reported.
Discussion: This combined brain vascular score may be
useful in efforts to identify early markers of BMVD.
graphics, vascular risk factors, comorbidities, trauma severity
and trauma mechanism compared to controls.
Results: The cohort included a total of 1,173,431 subjects (436,541 TBI), with a mean age of 49.9. Recurrent
stroke was identified in 1.1% of the TBI group and 0.9%
of the non-TBI trauma group in 2.4 years of mean followup. After adjustment, TBI was independently associated
with ischemic stroke (hazard ratio 1.34, 95% CI 1.28-1.39).
Conclusions: TBI is associated with ischemic stroke,
independently of other major predictors.
Study supported by: Dr. Burke is supported by a VA
advanced fellowship.
WIP105. Racial and Ethnic Differences in Post-Stroke
Depression among Community Dwelling Adults
Lesli Skolarus, Lynda Lisabeth, Lewis Morgenstern, Deborah
Levine and Devin Brown; Ann Arbor
WIP201. The Association of Non-Clinical Factors with
Head CT Use in Emergency Department Dizziness
Visits: A Population-Based Study
Kevin A. Kerber, James F. Burke, Lesli E. Skolarus, Brian C.
Callaghan, Devin L. Brown, William J. Meurer, Lynda D.
Lisabeth, A. Mark Fendrick and Lewis B. Morgenstern; Ann
Arbor, MI
Education
Background: African Americans (AAs) and Hispanics have
a higher incidence of stroke than non-Hispanic whites
(NHWs). Post-stroke depression (PSD) is associated with
greater disability and mortality. We sought to explore racial
and ethnic differences in PSD.
Methods: National Health Interview Survey (NHIS) data
from 2000-2010 were used to identify 8,413 community
dwelling adults with self-reported stroke. Depression was
identified by the Kessler-6 scale using a standard cut-off of
13. Logistic regression was used to assess racial/ethnic
associations with PSD after adjusting for demographics,
comorbidities, disability, socioeconomic status (education,
insurance) and US nativity.
Results: Overall, 9% had PSD. Hispanics (14%) were
more likely to have PSD than AAs (9%) and NHWs (9%,
p<0.01). After full adjustment, AAs were less likely
(OR¼0.76, 95% CI 0.65-0.89) while Hispanics were
equally likely to have PSD compared with NHWs
(OR¼1.05, 95% CI 0.83-1.33). Age and socioeconomic
factors were confounders of the race/ethnicity-PSD association for both AAs and Hispanics.
Discussion: Among US stroke survivors, Hispanics had
more PSD than NHWs. This ethnic association was driven
by age and socioeconomic status suggesting that younger,
more disadvantaged Hispanics may be an important target
for PSD intervention efforts.
Study supported by: NINDS K23 NS073685
Efforts to optimize HCT utilization in emergency department dizziness (ED) visits require understanding the factors
that contribute to their use. From a population-based study
of dizziness, we aimed to explore associations of non-clinical
factors with HCT use.
From May 8, 2011 to May 7, 2012, adult patients who
presented to EDs in Corpus Christi, Texas, with dizziness,
vertigo, or imbalance as a reason for the visit were identified. Clinical and non-clinical information was abstracted
from source documents. Adjusting for clinical factors, a
hierarchical logistic regression model with provider as a
random effect was used to explore the associations of nonclinical factors with use of a head CT.
To date, 1,126 visits meeting the study criteria have been
abstracted. A HCT was performed in 44.4%. In the hierarchical model (c-statistic, 0.80), significant non-clinical factors included having insurance (OR, 2.2; 95%CI, 1.4-3.4),
physician use of a documentation template having a preprinted HCT item (OR 2.4, 95%CI, 1.6-3.6), and provider
(intraclass correlation coefficient, 0.07).
This ongoing work suggests that non-clinical factors likely
have an important role in the use of a HCT in ED dizziness
presentations.
Study supported by: NIH K23 RR024009.
WIP106. Association between TBI and Ischemic Stroke
James F. Burke, Jessica L. Stulc, Lesli E. Skolarus, Darin B.
Zahuranec and Lewis B. Morgenstern; Ann Arbor, MI
WIP202. Quantifying Neurologist Outpatient Test
Utilization and Costs
James F. Burke, Brian Callaghan, Lesli E. Skolarus and Kevin
A. Kerber; Ann Arbor, MI
Introduction: A substantial proportion of stroke in the
young is unexplained. We explored whether traumatic brain
injury (TBI) is a risk factor for subsequent ischemic stroke
given that TBI causes vascular changes that augment thrombosis and diffuse hypercoagulability.
Methods: Patients with any emergency department visit
or hospitalization for TBI (exposed group) or non-TBI
related trauma (control) based on statewide emergency
department and inpatient databases in California from
2005-2009 were included in a retrospective cohort. TBI was
defined using the Center for Disease Control definition.
Our primary outcome was subsequent hospitalization for
ischemic stroke (ICD-9-CM 433.x1, 434.x1, 436). The
association between TBI and stroke was estimated using
Cox proportional hazards modeling adjusting for demo-
Introduction: Specialty societies are collaborating to limit
healthcare expenditures by identifying overutilized services.
To inform this process for neurology, we are quantifying utilization and aggregate cost of tests ordered by neurologists.
Methods: Serial cross sectional study of the 2009
National Ambulatory Medical Care Survey – a nationally
representative survey of ambulatory medical care services.
Utilization of imaging, lab and electrophysiological tests by
neurologists was tabulated across all visits and the visit
ICD-9-CM codes were aggregated across primary neurological subspecialties. Costs of care were estimated using average
Medicare payments.
Results: In 2009, there were an estimated 14,800,000
neurologist visits, resulting in 2,170,000 MRIs, 1,100,000
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EMGs, 570,000 EEGs and 460,000 PSGs. The mean cost
of diagnostic tests ordered per visit is $212 (95% CI $177$247). MRI and EMG were the two largest cost centers,
accounting for 53% and 32% of total estimated costs. The
largest number of MRIs were performed for headache and
neuromuscular disorders, while EMG was used most for
neuromuscular disorders and pain complaints.
Conclusions: MRI and EMG are the largest contributors
to diagnostic test costs attributable to neurologists in the
outpatient setting. These tests should be carefully scrutinized
in efforts to identify overutilization.
Study supported by: Dr. Burke is supported by a VA
advanced fellowship.
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neurofibromas are near-universal in NF1, but tumor-burden
can vary greatly.
We tested the hypothesis that there are single nucleotide
polymorphisms (SNP’s) or copy number variants (CNV’s)
associated with extremes of cutaneous tumor-burden. Threehundred NF1-subjects were identified for the top or bottom
15% of cutaneous tumor-burden. Subjects were genotyped
using the Affymetrix Genome-Wide Human SNP array 6.0,
containing 909,622 markers and >946,000 CNV probes.
The association analysis shows several SNP’s with p-values
near genome-wide significance. The CNV investigations
reveal three deletions in high tumor-burden cases in a
region encompassing a gene that may play a role in cell division and growth regulation.
We will identify novel genetic variants impacting cutaneous tumor-burden in NF1 by whole-exome-sequencing of
those subjects with high and low cutaneous tumor burden.
We will test whether each variant identified has an impact
on severity of disease by analyzing each SNP for association
to the severity of cutaneous tumor-burden. Further processing of variants in whole-exome-sequencing will follow our
informatics pipeline to identify potential common or rare
modifying variants.
Study supported by: Departmental
NF-Midwest
NF-Northeast
K12 CA090354 Training Grant
PI: Tracy Batchelor, M.D.
Harvard Medical School Center for Neurofibromatosis
and Allied Disorders (CNfAD).
Neuro-oncology
WIP301. Malignant Glioma Genotyping by CSF
2-Hydroxyglutarate Oncometabolite and IDH1
Mutation Analysis
Leonora Balaj, Edwin Lok, Kenneth D. Swanson, John M.
Asara, Clark C. Chen, Fred Hochberg, Xandra O. Breakefield
and Eric T. Wong; Boston, MA and San Diego, CA
IDH1 mutation in gliomas results in a gain-of-function for
the isocitrate dehydrogenase enzyme causing markedly
increased kinetics of NADPH-dependent reduction of a-ketoglutarate to 2-hydroxyglutarate. Glioma cells also secrete
small membrane vesicles termed exosomes and exosomederived nucleic acids can be utilized for the detection of
tumor-specific biomarker such as the G395A mutation in the
IDH1 mRNA. We report a 42-year-old patient with biopsyproven low-grade fibrillary astrocytoma located in left insula,
which had 1p and 19q deletions. The tumor had a partial
response to neoadjuvant temozolomide lasting 2 years but
later progressed and was treated with temozolomide chemoirradiation. CSF was collected at the time of disease progression. Targeted mass spectrometry (LC-MS/MS) detected at
least a 4-fold increase in the oncometabolite 2-hydroxyglutarate compared to 10 control samples obtained from patients
without malignancy. Exosomes were isolated from the CSF
by high-speed centrifugation and highly sensitive BEAMingqRT-PCR detected the G395A mutation commonly found in
IDH1-mutated tumors. This is the first documentation of
oncometabolite accompanied by the identification of the
IDH1 G395A genotype in patient CSF. CSF oncometabolite
profiling and IDH1 genotyping of malignant gliomas could
potentially facilitate their timely diagnosis and treatment.
Study supported by: A Reason To Ride research fund
Xandra O Breakefield serves on the Scientific Advisory
Board for Exosome Diagnostics, Inc. Leonora Balaj, Edwin
Lok, Kenneth D Swanson, John M Asara, Clark C Chen,
Fred Hochberg, and Eric T Wong have no conflict of interest.
Neurogenetics
WIP501. Dark Xavier, Zebrafish Model of MADD
Seok-Hyung Kim, Robert Carson, Michael J. Bennett, Sarah
A. Scott, H. Alex Brown and Kevin C. Ess; Nashville, TN and
Philadelphia, TN
Multiple acyl-CoA dehydrogenase deficiency (MADD) is
a genetic disease caused by mutations in electron transfer
flavoprotein complex (ETFA/ETFB) or ETF dehydrogenase (ETFDH). Impairment of these genes impairs mitochondrial function resulting in accumulation of acyl-CoA
esters. Patients with MADD are classified as Type I
(neonatal-onset, congenital abnormalities), Type II (neonatal onset without congenital abnormities) and Type III
(milder symptoms). Severe neurological manifestations are
seen including encephalopathy and leukodystrophy as
well as hypoglycemia, metabolic acidosis, heart disease
and hepatomegaly. There are no animal models of
MADD that recapitulate the clinical spectrum seen in
MADD.
Using forward genetics, we identified mutant zebrafish
with a fatty liver phenotype. These zebrafish (dark xavier,
dxa) have a nonsense mutation in Etfa. Homozygous dxa
zebrafish have abnormalities of brain, liver, kidneys and
heart. Marked accumulation of lipids, acyl-esters and
cholesterol in multiple organs was seen. Brain abnormalities include hypomyelination and increased numbers of
neural progenitor cells. Interestingly, dxa mutants had
increased cell size in multiple organs. This suggests activation of target of rapamycin complex 1 (TORC1) signaling, this was confirmed using biochemical assays. Dxa
zebrafish will be invaluable for future in vivo chemical
screens to identify therapeutic compounds efficacious for
MADD.
Study supported by: Dept. of Defense Grant TS093052
WIP302. Genetic Modifiers Affecting Neurofibromatosis
(GMAN): Cutaneous Tumor Burden in
Neurofibromatosis Type 1
Fawn Leigh, Lan Kluwe, Victor Mautner, Douglas R. Stewart,
Conxi Lazaro, Neale Benjamin, Bergen Sarah, Scott R.
Plotkin, Alexander Pemov, Jennifer Sloan, Lee Kaplan,
Maragaret P. Wallace, Meena Upadhyaya, Ludwine Messiaen,
Bruce Korf, Andre Bernards and James Gusella; Boston, IL;
Hamburg, Germany; Rockville, MD; Barcelona, Spain;
Gainesville, FL; Birmingham, AL and Cardiff, United
Kingdom
Neurofibromatosis type 1 (NF1) is the most common
neuro-cutaneous syndrome, affecting 1 in 3,000. Cutaneous
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WIP502. Driving Selection Against Heteroplasmic
Mitochondrial DNA Mutations by Rapamycin
Ying Dai, Kangni Zheng, Joanne Clark, Russell H. Swerdlow,
Stefan M. Pulst, James P. Sutton, Leslie A. Shinobu and David
K. Simon; Boston, MA; Kansas City, KS; Salt Lake City, UT;
Oxnard, CA and Fujisawa, Kanagawa, Japan
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UDRS scores suggests a possible clinical application. Work
is ongoing to correlate results to neuropathology.
Study supported by: PFC is an Honorary Consultant
Neurologist at Newcastle upon Tyne Foundation Hospitals
NHS Trust, is a Wellcome Trust Senior Fellow in Clinical
Science (084980/Z/08/Z), and a UK NIHR Senior Investigator. PFC receives additional support from the Wellcome
Trust Centre for Mitochondrial Research (096919Z/11/Z),
the Medical Research Council (UK) Centre for Translational
Muscle Disease research, the Association Française contre les
Myopathies, EU FP7 TIRCON, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease
award to the Newcastle upon Tyne Foundation Hospitals
NHS Trust.
Mitochondrial DNA (mtDNA) mutations cause a variety of
mitochondrial diseases, and may contribute to aging and
neurodegenerative disorders, but there are no effective treatments to counteract the effects of these mutations. Selective
degradation of dysfunctional mitochondria through autophagy (mitophagy) plays a critical role in mitochondrial quality control. Rapamycin activates mitophagy by inhibiting
mTOR kinase activity. We hypothesized that enhancing
mitopahgy would cause the preferential degradation of mitochondria harboring relatively greater levels of mtDNA
mutations, thereby driving mutation levels lower over time.
We examined the effect of rapamycin on mtDNA mutation
levels in human cybrid cell lines carrying a heteroplasmic
mtDNA G11778A mutation, the most common cause of
Leber’s hereditary optic neuropathy (LHON). We confirm
that chronic rapamycin inhibits mTOR kinase and induces
mitophagy, as indicated by colocalization of LC3 positive
autophagosomes with mitochondria. This is accompanied
by a striking progressive reduction in G11778A mutation
levels. The decreased mutational burden is not due to rapamycin-induced cell death, as there is no significant difference in cytotoxicity between rapamycin and vehicle-treated
cells. These data suggest that pharmacological induction of
mitophagy may have therapeutic potential for the treatment
of disorders associated with heteroplasmic mtDNA
mutations.
Study supported by: This work was supported by the
National Institute of Neurological Disorders and Stroke
(1R21NS077758; DKS) and the United Mitochondrial Disease Foundation (UMDF11-095; YD).
WIP504. Early Neuropsychiatry Features in
Neuroferritinopathy
Michael J. Keogh, Baldev Singh and Patrick F. Chinnery;
Newcastle upon Tyne, Tyne and Wear, United Kingdom
Introduction: Neuroferritinopathy is an autosomal dominant movement disorder caused by iron accumulation
within the basal ganglia. Early clinical descriptions stressed
the absence of neuropsychiatric features until the very late
phase, distinguishing the disorder from Huntington’s disease. However, these anecdotal reports have not been
substantiated.
Methods: Systematic review of 22 neuroferritinopathy
patients.
Results: 45% (n¼10) had objective measures of an abnormality on Addenbrooke’s Cognitive Examination (ACER) or neuropsychometric testing. The mean age of onset for
neuropsychiatric features was 48.6 years old (sd¼10.3
years), 4.2 years (sd¼3.9 years) after the development of
motor symptoms. Mean ACE scores were 74.7 (sd ¼ 7.3),
with verbal fluency particularly affected. Neuropsychiatric
abnormalities were present in 6 patients (60%) at the time
of presentation with a movement disorder. During follow
up, two patients required anti-psychotic medication and
psychiatric institutional care. Significant clinical heterogeneity was noted.
Discussion: Contrary to previous reports, neuropsychiatric symptoms are often present on clinical presentation, and
usually develop within 5 years of onset. Although there is
marked clinical heterogeneity, defects of verbal fluency are
most common. These findings redefine the phenotype of
neuroferritinopathy. The absence of neuropsychiatric features is not a reliable feature discriminating the disease from
other inherited movement disorders.
WIP503. Voxel Based Morphometry and Voxel Based
Relaxometry in Neuroferritinopathy
Michael J. Keogh, Andrew M. Blamire and Patrick F.
Chinnery; Newcastle upon Tyne, Tyne and Wear,
United Kingdom
Neuroferritinopathy is an autosomal dominant movement
disorder resulting in iron deposition in the basal ganglia
which is visible on MRI imaging. However, MRI changes
correlate poorly with clinical features, and the extent of tissue abnormalities outside the basal ganglia is poorly defined.
Voxel based morphometry (VBM) and relaxometry (VBR)
are quantitative MRI techniques which can assess brain
morphology and suggest regional tissue anomalies respectively; they have never been applied in a large cohort of
patients with any neurodegeneration with brain iron
(NBIA) disorder.
Methods: VBM and VBR analysis of 10 patients with
neuroferritinopathy were compared with clinical rating
scales and age matched controls.
Results: VBM detected extensive signal alteration in the
basal ganglia, cerebellum, motor cortex and brain stem
(threshold p<0.001, uncorrected) compared to controls.
Unified Dystonia Rating Scale scores correlated with VBM
signal in the caudate, lentiform and globus pallidus. T1 and
T2 VBR changes were seen in the cerebellum, brainstem
and several deep cortical regions.
Conclusions: VBM and VBR suggest that anatomical
and tissue abnormalities outside the basal ganglia may be
present in neuroferritinopathy. VBM correlation with
Pediatric Neurology
WIP801. Anti-NMDA Receptor Encephalitis, a Series of
208 Children
Maarten J. Titulaer**, Lindsey McCracken, Thais Armangue,
Inigo Gabilondo, Eugenia Martinez-Hernandez, Takahiro
Iizuka, Lawrence S. Honig, Susanne Benseler, Myrna R.
Rosenfeld, Rita Balice-Gordon, Francesc Graus, Carol Glaser
and Josep Dalmau; Barcelona, Spain; Philadelphia, PA;
Sagamihara, Japan; New York, NY; Toronto, Canada and
Richmond, CA
Objective: To report the syndrome and suggest treatment
guidelines for this disorder.
Methods: Cohort study, analysis of symptoms, treatment,
and long-term follow-up (24 months).
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Results: 73% were girls. 42% of girls 12 years had
ovarian teratoma(s) versus 6% <12; 0% in boys. In patients
<12, initial symptoms were seizures, abnormal behavior,
and movement disorders (36%-33%-14%), while in patients
12 were abnormal behavior and seizures (57%-23%).
Within one month, the syndrome was similar to that
reported in adults, although with less frequent autonomic/
breathing dysfunction. Immunotherapy (94%) and tumor
removal (when appropriate) resulted in full/good recovery in
79% of the patients; 3% died. Early treatment and no ICU
admission associated with better outcome (p¼0.018 and
p<0.0005). 52% responded to steroids, IVIg and/or plasmapheresis, 100% with good outcome. If these treatments
failed (48%), rituximab/cyclophosphamide (second-line
therapy) improved outcome (79% vs 67% without secondline therapy). Relapses occurred in 15%.
Conclusions: Pediatric and adult phenotypes of antiNMDAR encephalitis are similar, but tumor association,
symptom onset and frequency of some symptoms vary.
Prompt treatment improves outcome. If initial immunotherapy fails, second-line treatment is usually effective. 79% of
children have good outcome although complete recovery
can take >24 months.
Study supported by: The current work is supported in
part by a KWF fellowship 2009-4451 of the Dutch Cancer
Society (MT), the National Institutes of Health
RO1NS077851 (JD), RO1MH094741 (RB-G and JD),
Fundació la Marató TV3 (JD), Fondo de Investigaciones
Sanitarias (FIS, PI11/01780 to JD, FI08/00285 to EMH,
and PS09/0193 to FG), and a McKnight Neuroscience of
Brain Disorders award (RB-G and JD).
Dr. Dalmau receives royalties from the editorial board of
Up-To-Date; from Athena Diagnostics for a patent for the use
of Ma2 as autoantibody test. Dr. Dalmau holds a patent application for the use of NMDA receptor as autoantibody test.
Dr. Dalmau has received a research grant from Euroimmun.
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Trauma/Injury
WIP1001. Predicting Return to FunctionalIndependence by 12-15 Months after Severe Traumatic
Brain Injury on Discharge from Inpatient-Rehabilitation
David S. Kushner, Jasmine Martinez-Barrizonte and Myrlynn
Delille; Miami, FL
Inpatient rehabilitation (IR) case series to evaluate usefulness
of bowel/bladder continence status and improvement in
Functional-Independence-Measure (FIM) cognitive score at
discharge in predicting return to functional-independence at
12-15months in 7 patients having severe traumatic brain
injury (STBI). Patients had initial emergency department
Glasgow Coma Scale scores of 3-6, post-traumatic amnesia
durations of 18-115 days, time to follow commands of 16100 days, abnormal initial brain CT scans, and initial pupil
abnormalities. IR ranged 20-42 days. Outpatient rehabilitation ranged 20days-8months. IR FIM cognitive and sphincter/(bowel/bladder continence) score improvements were
compared to national normative STBI FIM data from Uniform Data Systems for Medical Rehabilitation (UDSMR)
for 2010 (n¼15,808). All 7 patients resumed ability to live
independently/drive by 12-15 months; 4 are now employed
as a physician, accountant, lawyer and a banker. CognitiveFIM scores improved an average of 11 points, compared to
5.9 points for UDSMR. Sphincter-FIM scores improved an
average of 6.3 points, compared to 3 points for UDSMR.
IR FIM cognitive and sphincter score improvements approximately twice the national average are associated with favorable functional outcomes at 12-15months after STBI.
Dementia and Aging
WIP1101. Dementia Hospital Length-of-Stay and Cost
Leslie S. Wilson; San Francisco, CA
Alzheimer’s prevalence is 5.1 million; expected to double by
2050. Medicare spends $160 billion.
Objective: Compare care patterns for hospitalized dementia vs non-dementia patients longitudinally in an integrated
healthcare system.
Methods: 106,283 hospitalized dementia (predominantly
Alzheimers) and matched non-dementia patients from Kaiser Northern California. Analysis was random effects GLS
regression.
Results: Mean age 77 with 31% dementia vs 10% nondementia patients over 85 years. 82% dementia vs 69%
non-dementia hospitalizations were urgent. Dementia diagnosis code was primarily the third listed. Dementia diagnosis is a significant predictor of hospital LOS, increasing stay
by 0.46 days (CI:0.5403-0.3831;p¼0.000). Alzheimers diagnosis accounted for less LOS increase than cerebral vascular
dementia. Pneumonia was the most frequent DRG diagnosis
for dementia and second for non-dementia hospitalizations.
Costs for the most frequent principal diagnosis were the
same, but for the second most frequent ICD9:599.0 (urinary tract infection), dementia patients stayed 1.57 days
longer; costing $1,000 more than non-dementia patients.
LOS differences are significantly affected by co-morbidities
(p¼0.000).
Conclusion: Dementia is a significant predictor of LOS
but varies by dementia type. Efficient management of hospitalized dementia patients should focus on selected associated
co-morbidities.
Study supported by: Elan Pharmaceuticals, now Johnson
an Johnson gave an unrestricted grant for this work.
WIP802. Tolerability and Efficacy of rTMS in Children
with ASD
Lindsay M. Oberman, Brittany Irish, Lidya Poni, Alvaro
Pascual-Leone and Alexander Rotenberg; Boston, MA
Autism spectrum disorders (ASD) are the most prevalent developmental disorder. Current interventions offer moderate
success in some individuals, though many continue to have
life-long impairments. Specific repetitive transcranial magnetic stimulation (rTMS) protocols have recently been
developed and in the case of major depression, FDAapproved, for treatment of multiple neuropsychological disorders. However, since most rTMS studies have focused on
adults, the tolerability and efficacy in children is unknown.
Previous findings from our lab suggest that applying rTMS
to suppress right pars opercularis (increasing excitability in
left pars opercularis, a region critical to language and socialskills, through transcollosal connections) leads to improvements in these domains in adults with Asperger’s Syndrome.
We have now extended this study to children with ASD
(N¼6 at time of submission) and find that rTMS is both
tolerable, with only one minor headache, and potentially
effective with three of six children showing improvement in
pragmatic language and social-skills on both standardized
measures and subjective reports after a single session of
rTMS. Future studies should explore rTMS in pediatric disorders as a novel, well-tolerated, nonpharmacologic and
potentially efficacious avenue for therapeutic interventions.
Study supported by: Harvard Catalyst KL2 mentored
award to L.M.O., A.P-L. Mentor.
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WIP1102. The Auditory Event-Related Oscillations Are
Diminished, and Correlate with Hippocampal Volumetry
in Mild Cognitive Impairment
Gorsev G. Yener, Pinar Kurt, Berrin Cavusoglu, Derya D.
Emek, Gulsah Aktas, Emel Ada, Bahar Guntekin and Erol
Basar; Izmir, Turkey and Istanbul, Turkey
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Study supported by: NIH R01 NS052305, and the
UNM Clinical Translational Science Center
WIP1104. Behavioral Deficits in APP Transgenic Mice
Reversed by mGluR Inhibitor with Pro-Neurogenic,
Ab-Reducing, and Anxiolytic Properties
Sam Gandy, John W. Steele, Star W. Lee, Dane Clemenson,
Reto Gadient, Pam Wedel, Charles Glabe, Carrolee Barlow,
Michelle Ehrlich, Fred H. Gage and Soong Ho Kim; New
York, NY; La Jolla, CA and Irvine, CA
Background: Amnestic mild cognitive impairment (MCI) is
a pre-dementia stage in majority. Event-related oscillations
(ERO) might be used for detection of cognitive deficits.
Our group showed decreased delta target ERO in AD previously. We investigated whether the same prevails for MCI,
and ERO correlate to brain volumetry.
Method: MCI subjects (n¼22) and age-matched healthy
controls (HC) (n¼21) were investigated by auditory ERO.
The maximum target delta peak-to-peak amplitudes (0.52.2 Hz) were measured in þ300-800 msec. Volumetric
measurements of magnetic resonance images were performed
using a semi-automatic lesion annotation and volume measurement tool (LAVA, mimlabs) in 11 MCI and 10 HC
subjects.
Results: The oddball target delta response was 47-62%
lower in MCI over fronto-central-parietal regions. Left hippocampal and total brain volumes were lower in MCI.
Left hippocampal volume correlated to C3, Tp8 beta; F3
gamma ERO; and right hippocampal volume to C3 beta
ERO.
Discussion: The auditory target delta ERO are lower in
fronto-central-parietal regions as accordant with our earlier
findings in AD. Moreover, correlation of ERO to hippocampal volumetry gives a rise the neurophysiological methods to be searched as a potential biomarker in future.
Study supported by: Istanbul Kultur University
Görsev G. Yener was in the advisory boards of Lundbeck
and Novartis. She received honorarium from Pfizer for
speaking activities.
One hallmark of Alzheimer’s disease is accumulation of
neurotoxic amyloid beta (Ab) oligomers in the brain. Activation of Group II metabotropic glutamate receptors (Gp
II mGlu receptor: mGlu2, mGlu3) triggers release of Ab
peptides from isolated synaptic terminals and is selectively
suppressed by antagonist pretreatment. We have assessed
the therapeutic potential of chronic pharmacological
inhibition of Gp II mGluR in APP (Alzheimer’s amyloid
precursor protein) transgenic mice. To achieve inhibition
of Gp II mGluR in the brain, orally bioavailable prodrug
BCI-838 was used to deliver its active metabolite BCI632. Chronic (3 month) treatment with BCI-838 was
associated with reduction in levels of brain Ab monomers
and oligomers, correction of transgene-related behavioral
deficits, reduction in transgene-related anxiety behavior,
and stimulation of hippocampal neurogenesis. Group II
mGluR inhibition may offer a unique package of relevant
properties as an AD therapeutic by providing acute symptomatic benefit, attenuation of neuropathology, and stimulation of repair.
Study supported by: BCI-838 and BCI-631 were provided by BrainCells Inc.
Gadient and Wedel are employees of BrainCells Inc.
Gage is a founding scientist of BrainCells Inc.
WIP1105. Transcranial Magnetic Stimulation of Deep
Brain Regions in Alzheimer’s Disease: A Pilot Study
Elissa L. Ash, Veronika Vakhapova, Irena Bova, Ely Simon,
Moran Korem, Moran Eldad, Amos D. Korczyn and Avraham
Zangen; Tel Aviv, Israel and Beersheva, Israel
WIP1103. Biomarkers of Neuroinflammation in
Subcortical Ischemic Vascular Disease
Gary A. Rosenberg, Yi Yang, Richard R. Reichard, Jillian
Prestopnik and John C. Adair; Albuquerque, NM and
Albququerque, NM
rTMS is a non-invasive technique using magnetic coils to
painlessly stimulate brain regions to influence cortical activity. Deep-rTMS allows for stimulation of deeper and wider
brain areas, thereby potentially providing more significant
effects on brain activity and function. Basic and clinical
rTMS studies suggest that stimulation can produce long
term changes in cortical synapses akin to LTP and LTD,
and might influence neuronal regulation and network
patterns, in addition to other, non-neuronal effects. In a placebo-controlled pilot study we evaluated the safety and feasibility of high frequency and low frequency deep-rTMS to
the prefrontal areas of AD patients receiving stable doses of
accepted AD medications. Results from this feasibility study
demonstrate the safety of the method, as well as a trend
toward improvement in cognitive and clinical measures in
patients treated with high frequency deep-rTMS that lasted
through a 2 month, post-treatment phase; this effect was
not evident with low frequency stimulation. Given the small
sample size, no conclusions can be drawn regarding efficacy.
Further studies are warranted.
Study supported by: Brainsway Inc.
Prof. Avraham Zangen is an inventor of deep TMS coils
that have been patented by the NIH and the Weizmann
Institute. He serves as a consultant for and has financial interest in Brainsway Inc. that purchased an exclusive license
of these patents.
Background: Subcortical ischemic vascular disease (SIVD)
is a form of vascular cognitive impairment (VCI) secondary
to small vessel arteriolosclerosis. Matrix metalloproteinases
(MMPs) are increased in cerebrospinal fluid (CSF) and
brain tissue in SIVD. We report an association between
CSF MMPs and immunohistochemistry.
Methods: Four patients in a long-term study of VCI
underwent autopsy. They had neurological and neuropsychological testing and MRI. Albumin index, MMP-2,
MMP-3, MMP-9, Ab1-42, phospho Tau (P-Tau) and totaltau (T-tau) were measured in CSF. Brain was immunostained for MMPs and co-localized with astrocytes and
microglia/macrophages.
Results: Histology showed gliosis in white matter in all
patients; three had SIVD and one AD. CSF in SIVD
patients showed altered levels of MMPs. Ab1-42/1og (PTau) was reduced in AD. SIVD patients had MMP-2
immunostaining in white matter. In AD, gray matter
showed MMP-9 and MMP-3. All brains had Iba-1 immunostaining consistent with an inflammatory response.
Conclusions: This is the first report to show an association of MMPs in CSF with immunostaining in brain. This
small sample suggests inflammation is important in SIVD,
and supports further study of MMPs as biomarkers in VCI.
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Study supported by: Research on Neurodegenerative Diseases/ALS from Ministry of Health, Labor and Welfare,
Japan
Neuromuscular Disease
WIP1401. Non-Human Primate Model of Amyotrophic
Lateral Sclerosis with Cytoplasmic Mislocalization of
TDP-43
Takuya Ohkubo, Mio Tajiri, Azusa Uchida, Hiroki Kimura,
Nobuyuki Sasaguri, Toshiki Uchihara, Hidehiro Misusawa
and Takanori Yokota; Tokyo, Japan and Tsukuba, Japan
WIP1403. Miller-Fisher Variant of Guillain-Barre: Is
Treatment Cost-Effective?
Li Yang, Harrison X. Bai, Li-Ming Tan and Bo Xiao;
Changsha, Hunan, China and New Haven, CT
Objective: The purpose of the study is to determine
whether treatment affects the rate and speed of recovery of
Miller Fisher Syndrome.
Methods: We identified 44 patients diagnosed with MFS
from 10/2004-5/2012.
Clinical data were collected from charts. Statistical analysis was performed by using Student’s t test and chi-square
analysis.
Results: Median age 47, 66% male, 66% preceded by
prodromal symptoms: 55% respiratory, 5% GI. Patients
received no treatment (41%), corticosteroids (39%), IVIg
(18%) or plasmapheresis (7%). The average follow up period is 38 months. Patients receiving treatment stayed in the
hospital longer than those who did not receive treatment
(20.0 vs.12.8 d, p¼0.045), but did not have higher rates of
resolution in opthalmoplegia (p¼0.192), ataxia (p¼0.608)
or areflexia (p¼0.519). There is no significant difference in
duration between neurological onset and beginning of recovery of ataxia (18.2 vs.26.2 d, p¼0.33) or opthalmoplegia
(19.1 vs.26.1 d, p¼0.43).
Conclusions: Immunomodulating treatment slightly hasten the alleviation of ataxia and opthalmoplegia, but does
not affect recovery outcome. Considering the side effect of
corticosteroids and the high cost of IVIg, their use would
not be necessary for patients with MFS since they have a
natural good recovery over time.
TDP-43 was found to be a major component of abnormal
aggregation in the motoneuron in sporadic ALS. We
injected an AAV vector expressing human wild-type TDP43 to the spinal cord in non-human primate, cynomolgus.These monkeys developed progressive motor weakness
and muscle atrophy. They also showed regional cytoplasmic
TDP-43 mislocalization with loss of nuclear TDP-43 staining in the lateral nuclear group of spinal cord and cystatin
C-positive cytoplasmic aggregates, reminiscent of the spinal
cord pathology of patients with ALS. TDP-43 mislocalization was an early or presymptomatic event and was later
associated with neuron loss. These findings suggest that
TDP-43 transactive response deoxyribonucleic acid-binding
protein 43 mislocalization leads to a-motoneuron degeneration. Furthermore, truncation of TDP-43 was not a prerequisite for motoneuronal degeneration, and phosphorylation
of TDP-43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed TDP-43 only
in the nucleus of motoneurons. There is thus a species difference in TDP-43 pathology, and our monkey model recapitulates ALS pathology to a greater extent than rodent
models, providing a valuable tool for studying the pathogenesis of sporadic ALS. Furthermore, we discuss the mechanism of propagation of TDP-43 protein.
Study supported by: Grants-in-Aid for Scientific Research
(A) (#22240039, to T.Y. and H.M.) and Grant-in-Aid for
Young Scientists (A) (#24689039 to T.O.) by the Ministry
of Education,Culture,Sports,Science and Technology
(MEXT), Japan
WIP1404. Completion and Outcomes of a Phase 1
Intraspinal Stem Cell Transplantation Trial for ALS
Eva L. Feldman, Nicholas M. Boulis, Karl Johe, Seward B.
Rutkove, Thais Federici, Meraida Polak, Crystal Kelly and
Jonathan D. Glass; Ann Arbor, MI; Atlanta, GA; Rockville,
MD and Boston, MA
WIP1402. Regional Spread of ALS Lesion – Multifocal
Hits and Local Propagation?
Teruhiko Sekiguchi, Tadashi Kanouchi, Kazumoto Shibuya,
Yuichi Noto, Masanori Nakagawa, Satoshi Kuwabara,
Hidehiro Mizusawa and Takanori Yokota; Tokyo, Japan;
Chiba, Japan and Kyoto, Japan
The FDA-approved trial, ‘‘A Phase 1, Open-label, First-inhuman, Feasibility and Safety Study of Human Spinal
Cord-derived Neural Stem Cell Transplantation for the
Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,’’ has been completed in 18 ALS subjects.
Cohorts followed a ‘‘risk escalation’’ paradigm including
unilateral (n¼5) or bilateral (n¼10 total) lumbar or cervical
injections. The final 3 subjects receiving cervical injections
previously received bilateral lumbar injections. All injections
delivered 100,000 cells, for a dosing range up to 1.5 million
cells. The procedure utilized a novel spinal-mounted stabilization and injection device that includes a floating cannula
to prevent spinal cord shearing. The procedure was well-tolerated with minimal perioperative or postoperative complications. Cervical kyphosis developed in one subject following the multi-level laminectomy. Some subjects did not
tolerate immunosuppression. Disease progression continued
in all but one subject who exhibited clinical and electrophysiological improvements. Four subject deaths have
occurred and postmortem analyses are underway. Results
demonstrate that intraspinal transplantation of neural progenitor cells in ALS subjects is feasible and well-tolerated,
and supports future trial phases examining therapeutic
efficacy.
Study supported by: Neuralstem, Inc. Rockville, MD.
To investigate whether or not the lesions in sporadic ALS
spread contiguously from a focal onset site in rostrocaudal
direction along the spinal cord, as in the manner hypothesized by a prion-like propagation from single seed. Thirtytwo sporadic ALS patients with initial symptom in the bulbar or upper limb regions were studied. The presence of
abnormal spontaneous activities in needle electromyography
(nEMG), were compared among the muscles innervated by
different spinal segments, especially between T10 and L5
paraspinal muscles and between vastus medialis and biceps
femoris. These paired muscles have almost the same axon
length and motoneuronal property. Thirteen of 32 patients
showed non-contiguous distribution of nEMG abnormality
from the onset site. In 8 (61.5%) of the 13 patients, the
non-contiguous pattern was also evident between the paired
muscles with same motoneuronal vulnerability. The motoneuron pool with skipped nEMG abnormality seemed to
form a cluster in the lumbosacral cord in 4 of the 8
patients. In sporadic ALS, involvement of the lower motoneurons cannot be explained by the ‘‘single seed and simple
propagation’’, and we propose a hypothesis, ‘‘multifocal hits
and local propagation’’.
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Dr. Boulis is the inventor of the intraspinal stabilization
and injection device. Neuralstem, Inc. has purchased an
exclusive license to this technology. Dr. Boulis received an
inventors share of this fee, and has the rights to royalty payments for distribution of this technology.
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PMP22 may be more common than previously thought in
causing CMT1A.
Study supported by: Grant from NINDS R01NS066927.
WIP1409. Prevalence of Small-Fiber Polyneuropathy in
Fibromyalgia
Anne Louise Oaklander, Daniela Herzog, Heather Downs and
Siena Napoleon; Boston, MA
WIP1405. Congenital Myasthenic Syndrome (CMS),
Autophagic Myopathy, and Cognitive Dysfunction
Caused by Mutations in DPAGT1
Duygu Selcen**, XinMing Shen, Ying Li, Eric Wieben and
Andrew G. Engel; Rochester, MN and Rochester
Fibromyalgia is a chronic-pain disorder of unknown pathogenesis which currently can only be symptomatically managed. Small-fiber polyneuropathy (SFPN) can have similar
symptoms, but objective diagnostic tests, etiologic causes,
and some disease-modifying treatments exist for SFPN. This
ongoing study tests the hypothesis that some fibromyalgia
patients have undiagnosed SFPN. Twelve diagnosed and
screened (American College of Rheumatology-2010 criteria)
fibromyalgia patients were studied along with 14 normal
controls; neuropathy patients were excluded. The consensusrecommended diagnostic tests for SFPN were applied and
blindly analyzed; including PGP9.5-immunolabeled distalleg skin biopsy, autonomic-function testing (AFT) (WR
Electronics), and the Utah Early Neuropathy Scale. Intraepidermal nerve-fiber densities (IENF) were normalized to
values from 240 normal volunteers. Among fibromyalgia
subjects IENF averaged 24 6 0.10% of predicted norm vs.
64 6 0.07% among controls (p 0.01). 50% of fibromyalgia vs. 0% of control skin-biopsies were definitively
diagnostic (IENF <5th centile). Among fibromyalgia
subjects 22% of AFT were diagnostic of SFPN with 67%
borderline vs. 0% diagnostic and 38% borderline among
controls. UENS scores averaged 4.3 among fibromyalgia
subjects vs. 0.4 among controls (p 0.02). Multiple preliminary results suggest that substantial numbers of fibromyalgia patients meet rigorous diagnostic criteria for SFPN.
Study supported by: Funded in part by the Public Health
Service NIH-K24NS59892 and a charitable donation from
Ms. Jane Cheever Powell.
We recently identified two CMS patients with CNS involvement. Patient 1 is a16-year-old mentally retarded girl
with severe generalized CMS since infancy. One of her
siblings is also affected and has autistic features. Patient 2 is
a 14-year-old girl with mild cognitive deficits and progressive limb-girdle CMS since infancy. Both respond poorly to
anti-AChE therapy. Intercostal muscle specimens in both
show small tubular aggregates in type 2 fibers, type1 fiber
atrophy, and a vacuolar myopathy with autophagic features.
Endplate studies reveal that quantal release, postsynaptic
response to acetylcholine quanta, and endplate AChR content are reduced to 50% of normal. Quantitative EM of
65 endplate regions shows hypoplastic endplates, very small
nerve terminals, and poorly differentiated postsynaptic
regions. Neither patient harbors mutations in currently recognized CMS disease genes but exome sequencing in each
identifies two heteroallelic mutations in DPAGT1 coding
for dolichyl-phosphate N-acetylglucosamine phosphotransferase, an enzyme subserving protein N-glycosylation.
Immunoblots of muscle extracts probed by two different
antibodies demonstrates reduced to absent glycosylation of
70 kDa proteins. We hypothesize that hypoglycosylation
of synapse-specific proteins causes defects in motor as well
as central synapses.
Study supported by: NIH Grant NS6277 and a Research
Grant from the MDA.
WIP1406. Withdrawn.
WIP1407. Withdrawn.
Behavioral Neurology
WIP1408. DNA Replication, but Not Chromosomal
Unequal Exchange, as an Alternative Mechanism That
Results in CMT1A Mutation
Brett A. Parker, Ryan Alexander, Xingyao Wu, Michael Shy,
Nathalie Schnetz-Boutaud, Jonathan Haines, Jun Li and
Bryan Burnette; Nashville, TN and Iowa City, IA
WIP1501. Cognitive Remediation (CR) Combined with
Transcranial Magnetic Stimulation (TMS) in Alzheimer’s
Disease (AD)
Lukas Schilberg, Anna-Katharine Brem, Catarina Freitas,
Natasha Atkinson, Ilya Vidrin, Leonie Asboth, Daniel Z. Press
and Alvaro Pascual-Leone; Boston, MA
Charcot-Marie-Tooth disease type-1A (CMT1A) is caused
by the trisomy of chromosome 17p12 bearing the PMP22
gene. We have identified a CMT1A family with a proband
carrying a tetrasomy of the chromosome 17p12, while the
proband’s mother has the classical trisomy and his father has
no mutation. Although, the proband has had difficulties in
walking since birth, his two siblings with the trisomy of
PMP22 are asymptomatic, and his mother only has a mild
sensory loss, supporting a gene-dosage effect. By mapping
the high-variant SNPs in the chromosome 17p, we showed
that the three copies of the PMP22 in the mother and the
four copies of PMP22 in the proband were of identical origin. We then expanded this observation in an additional 39
patients with CMT1A. Single origin of the PMP22 was
identified in seven of the 39 patients. 32 patients showed
different origins of the PMP22 trisomy as predicted by the
traditional ‘chromosomal unequal exchange mechanism’.
Our results suggest that in addition to the unequal exchange
mechanism, DNA replication producing identical copies of
Existing AD treatments show limited benefit and have sideeffects. We are evaluating a novel, non-pharmacologic
intervention merging TMS with computer-based CR in
mild-moderate AD (MMSE 18-26). To date, we have 12
patients randomized to active or sham TMS-CR. Patients
undergo 6 weeks of daily one-hour sessions of TMS-CR as
adjunct to their stable pharmacologic therapy (5 sessions/
week, total 30 sessions). A short train of repetitive TMS is
applied to a given brain region immediately before CR tailored to engage the targeted brain circuit. Six different brain
regions engaged in major cognitive functions affected by
AD are targeted, as identified using the patient’s own brain
MRI. Relative to baseline, five patients in the active group
who have completed the study have improved by 2.9 points
on the Alzheimer’s Disease Assessment Scale (ADAS-Cog),
whereas two who have undergone sham worsened by 2.7
points: mean difference in ADAS-Cog between groups of
5.6 points. Importantly, all patients in the active TMS-CR
group to date show an improvement, and none in the sham
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group. These results are extremely promising, and show
markedly greater benefits than reported for existing
treatments.
Study supported by: Harvard Catalyst | The Harvard
Clinical and Translational Science Center (National Center
for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health
Award #UL1 RR 025758); Berenson-Allen Foundation;
Neuronix Ltd.
Dr. Pascual-Leone serves as scientific advisor of Neuronix
globus pallidus and substantia nigra all had significant connectivity changes with the left parietal lobe. The anterior
putaminal change in connectivity correlated with the change
in UPDRS-III scores (r¼0.5869).
Interpretation: The connectivity change between basal
gangliar components and the left parietal lobe in this population could reflect the loss of a compensatory mechanism
after levodopa administration, or a pathological hypersynchronicity that improved with levodopa.
Study supported by: The Paul Ruby Foundation for Parkinson’s Research
Movement Disorder
WIP1703. Distinct Progressive Genotype-Related
Neurodegeneration in Spinocerebellar Ataxia Types 1, 3
and 6 – A Longitudinal Study
Kathrin Reetz, Shahram Mirzazade, Anna Lehmann, Agnes
Juzek, Anna Costa, Till K. Hauser, Heike Jacobi, Thomas
Klockgether, Jorg B. Schulz and On Behalf of the Ataxia Study
Group; Aachen, Germany; Tu¨bingen, Germany and Bonn,
Germany
WIP1701. A Diagnostic Questionnaire Discriminates
between Psychogenic and Neurogenic Movement
Disorders
David S. Glosser, Nathan A. Taylor, Lori Sheehan, Daniel
Kremens and Tsao-Wei Liang; Philadelphia, PA
Introduction: We developed a questionnaire that discriminates neurogenic from psychogenic movement disorders
(NMD vs. PMD). PMDs are defined as stereotyped behaviors misattributed to a NMD. PMDs can be regarded as
distress displays, or escape/avoidance behaviors, and may
trigger invasive therapies and disability. PMDs may mimic
disorders of gait, tremor, speech, speed, coordination, &
their diagnosis is challenging.
Methods: Sixty five sequential movement disorder referrals were administered a 15 minute 7-risk factor interview
assessing: 1. movement consistency, onset rate, stereotypy 2.
hx of psych treatment, self-injury, abuse, drug/ETOH,
somatizations/medicolegal. All subjects were independently
diagnosed by 2 movement disorders neurologists as NMD
(n¼43) vs. PMD (n¼18).
Results: Mean # risks of PMD S’s ¼ 7.83; NMD S’s ¼
4.69, (t¼4.272; p¼.000).
Diagnostic sensitivity @ 4 risks ¼ 88%; @ 5 risks ¼
55%. Selectivity @ 4 risks ¼ 55%; @ 5 risks ¼ 91%.
Conclusions: The instrument discriminates between
NMD & PMD patients. Its use may facilitate early diagnosis and reduce the social and economic costs of the condition as well as medical and psychiatric morbidity.
Study supported by: Departmental funds, Thomas Jefferson U. Hospital, Dep’t of Neurology
Background: EUROSCA is a multicentric longitudinal
cohort study that examines disease progression in Spinocerebellar Ataxias (SCA) SCA1, SCA3 and SCA6.
Methods: In the EUROSCA study sites Belgium, France,
Germany, Italy, Poland and Spain clinical and magnetic resonance imaging (MRI) data were collected at baseline and
after a two-year follow up for a complementary approach of
quantitative three-dimensional (3D) volumetry and
observer-independent longitudinal voxel-based morphometry
(VBM).
Results: 37 SCA1, 19 SCA3 and 7 SCA6 patients completed follow-up and were compared to respective agematched healthy control groups. Overall, volumetric data
demonstrated an increase of atrophy in the brainstem, cerebellum and basal ganglia in all genotypes over time. Rate of
progression was greatest in SCA1 and SCA3 in pons, in
SCA1 in cerebellum and in SCA1 and SCA3 in putamen.
Compared to healthy controls longitudinal VBM revealed
greatest increase in gray matter atrophy in the cerebellum
and brainstem in SCA1, in the putamen and pallidum in
SCA3 and to a lesser extent also in the cerebellum in SCA6.
Discussion: Quantitative volumetry and VBM imaging
demonstrated specific SCA genotype-related neurodegenerative longitudinal progression in SCA1, SCA3 and SCA6.
Study supported by: Research Grant from the European
Commission (6th Framework)
WIP1702. Resting State Functional Connectivity
Pharmaco-MRI of Parkinson’s Disease
Peter S. Pressman, Darren R. Gitelman and Tanya Simuni;
San Francisco, CA and Chicago, IL
WIP1704. Cerebellar Ataxia with Neuronopathy and
Bilateral Vestibular Areflexia Syndrome (CANVAS)
David J. Szmulewicz, John A. Waterston, Hamish G.
MacDougall, Stuart Mossman, Andrew M. Chancellor,
Catriona A. McLean, Saumil Merchant, Peter Patrikios, Leslie
Roberts, Elsdon Storey and G. Michael Halmagyi; Melbourne,
Australia; Sydney, Australia; Wellington, New Zealand; Boston
and Brisbane, Australia
Objective: Resting state functional connectivity MRI
(fcMRI) has demonstrated significant differences between
controls and patients with Parkinson’s disease (PD). Few
studies have investigated the effects of dopaminergic medication on resting state fcMRI in PD. This study investigated
how basal gangliar functional connectivity differed on and
off levodopa in this population.
Methods: Patients arrived off all prescribed medications,
and received standardized testing as well as a resting MRI
study. Imaging and testing was repeated one hour after medication administration. A seed-to-voxel analysis from basal
gangliar components was performed, and the MRI results
compared with the Unified Parkinson’s Disease Rating Scale
(UPDRS).
Results: Our subjects were predominantly symptomatic
on the right side. The anterior and posterior putamen, ventral lateral and ventral anterior nuclei of the thalamus,
We report a novel cerebellar ataxia with characteristic clinical features and atrophy of the cerebellum and of cranial
and spinal nerve sensory ganglia. In 2004 we reported the
association of bilateral vestibulopathy with cerebellar ataxia
as a distinct syndrome with a characteristic clinical sign - an
absent visually-enhanced vestibulo-ocular reflex. Later we
showed in 18 patients that a non-length dependent
peripheral neuropathy was an integral part of CANVAS
(Cerebellar Ataxia Neuropathy bilateral Vestibular Areflexia
Syndrome). We now have data from 41 patients with CANVAS, and brain and spine neuropathology from one and
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show that the underlying pathology is in sensory ganglia in other word it is a ‘‘neuronopathy’’ rather than a ‘‘neuropathy’’. Brain and temporal bone pathology in another
patient showed marked loss of Purkinje cells and of vestibular, trigeminal and facial ganglion cells. All patients had
brain MRI and 36/41 had evidence of cerebellar atrophy
involving anterior and dorsal vermis, and hemispheric crus
I. Clinical presentation may mimic that of SCA 3. There
are 5 sets of sibling pairs, inferring CANVAS is a late-onset
recessive disorder and identification of the culprit gene is
currently a target of investigation.
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hybridization using specific oligoprobes and riboprobe for
preprodynorphin. Subthalamotomy had beneficial effects on
the motor symptoms in the four lesioned monkeys,
increased LIDs, increased the duration of antiparkinsonian
response to L-DOPA, and allowed a 40% reduction of LDOPA. In the striatum, no change was observed in the dopamine transporter, levels of D2 receptor and its mRNA, as
well as in preproenkephalin. The striatal increases of D1 receptor levels, its mRNA, and changes in preprodynorphin
mRNA induced by subthalamotomy may explain the potentiation of the response to L-DOPA following surgery.
Study supported by: CIHR
WIP1705. N-Acetylcysteine Increases Cerebral
Glutathione as Measured by 7T Magnetic Resonance
Spectroscopy in Patients with Gaucher or Parkinson’s
Disease
Mary J. Holmay, Melissa Terpstra, Lisa Coles, Usha Mishra,
Matthew Ahlskog, Gulin Oz, James C. Cloyd and Paul J.
Tuite; Minneapolis, MN
WIP1707. A Novel Alpha-Synuclein Missense Mutation
in Parkinson’s Disease
Christos Proukakis, Maria Katsianou, Angelika Hummel,
Timothy Brier, Henry Houlden, Jonathan Mark Cooper and
Anthony H. Schapira; London, United Kingdom and London,
United Kingdom
Decreased glutathione (GSH) in postmortem Parkinson’s
disease (PD) brains and increased reactive oxygen species in
fibroblasts from individuals with Gaucher disease (GD)
have been observed, indicating oxidative stress in both conditions. The objective of this study was to determine if an
intravenous dose of N-acetylcysteine (NAC), a GSH precursor, alters blood redox status and brain GSH levels.
Patients with PD, GD, and age-matched healthy controls
(N¼3 per group) participated. Reduced (GSH) and oxidized glutathione (GSSG) were measured in whole blood by
HPLC/MS and brain GSH was measured by MRS as
described previously (Oz & Tkac, MRM, 2011) at 7T prior
to and up to 120 minutes following the start of a 1-hour
infusion of NAC (150mg/kg). Blood GSH/GSSG ratios
increased, peaking at 60-75 minutes after the start of infusion with a maximal change from baseline of 502-1624%.
Brain GSH peaked at 105-120 minutes with a maximal
change from baseline of 20-82%.
This pilot study shows that a single, intravenous high
NAC dose alters peripheral and brain GSH levels. Further
study will help determine dosage regimens of this potentially useful antioxidant for PD and GD.
Study supported by: This pilot study was funded by a
grant from the Lysosomal Disease Network, protocol
#6721.
Ms Holmay is an employee of Lundbeck US. However
the Company had no involvement in this research.
Background: Although alpha-synuclein (SNCA) is crucial
in the pathogenesis of Parkinson’s disease (PD), only three
missense mutations have been reported. The possibility of
somatic mutations has not been investigated.
Methods: SNCA exons were analysed in DNA from 28
PD patient brains by sequencing and high resolution melting (HRM) analysis. Restriction digests, and subcloning of
PCR products were used to confirm a mutation, and determine its phase. Transfection was used to generate a cell
model.
Results: A novel missense mutation (c.150T>G,
p.H50Q) was detected in DNA from one case. This was
absent in databases and controls. The mutation changes a
highly conserved residue which is within one turn of the
a-helix from E46 and A53, and is a copper binding site.
The mutant peak appeared lower than the wild type on
sequencing, but no evidence of mosaicism was found. HRM
analysis, which can detect low level mosaicism, did not
reveal mutations in other samples. Stably transfected neuroblastoma cell lines overexpressing HA-tagged mutant SNCA
were generated. No colocalisation of mutant SNCA with
cellular organelles was found.
Conclusions: We propose H50Q as the fourth SNCA
missense mutation. The cell lines are being analysed for
changes in copper toxicity and mitochondrial function.
Study supported by: Royal Free Peter Samuel Fund, Wellcome Trust/MRC joint call in Neurodegeneration award
(WT089698), the Kattan Trust, Parkinson’s UK
WIP1706. Changes in D1 Receptor Are Associated with
the Potentiation of Response to Levodopa Following
Subthalamotomy in Parkinsonian Monkeys
Vincent A. Jourdain, Laurent Gregoire, Marc Morissette,
Nicolas Morin, Martin Parent and Therese Di Paolo; Quebec,
QC, Canada
WIP1708. The Discharge of Striatal Neurons Is
Profoundly Altered in Patients with Parkinson’s Disease
Arun Singh, Lisa F. Potts, Klaus Mewes, Robert Gross, Mahlon
R. DeLong and Stella M. Papa; Atlanta, GA
Loss of striatal dopaminergic modulation in Parkinson’s disease (PD) presumably leads to abnormal discharges of striatal output neurons (medium spiny neurons, MSNs). To
examine the MSN firing in PD, we analyzed data obtained
during electrophysiologic mapping for DBS treatment
including PD, dystonia and essential tremor (ET) patients
for comparison. Strict criteria were applied for MSN classification. The mean firing rate of MSNs was significantly
higher in PD (30612 Hz) than dystonia (1065 Hz) and
ET (<3 Hz). In PD, a larger fraction of striatal neurons
also exhibited burst activity. These findings are aligned with
recent data from parkinsonian monkeys (Liang, J. Neurosci.,
2008), challenging the classic functional model of PD. The
less increased frequencies in dystonia highlight the relevance
Subthalamotomy is offered to parkinsonian patients presenting disabling L-DOPA-induced dyskinesia. A potentiation
of response to L-DOPA is observed following subthalamotomy. We investigated the dopaminergic D1 and D2 systems
and associated neuropeptides in four MPTP-treated
dyskinetic monkeys receiving a unilateral subthalamotomy
and compared these results to four control and four MPTPtreated monkeys. The concentration of dopamine was
measured by high-performance liquid chromatography. Dopamine transporter, D1, and D2 receptors levels were quantified by autoradiography using [125I]RTI, [3H]SCH23390 and [3H]raclopride binding, respectively. The D1,
D2 and preproenkephalin mRNAs were measured by in situ
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of specifically high MSN activity to PD, but also suggest
that there may be grounds for the frequently alluded Dystonia-PD continuum. The very low firing rates in ET resemble MSN activity in normal monkeys, suggesting a parallel
with normal humans. These findings demonstrate profound
alterations of the MSN discharge in patients with PD, and
point to the importance of investigating its molecular basis
to develop function-restorative therapies.
Study supported by: NS045962
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Patients’ antibodies were found specific for DPPX, without
reacting with DPP10 or Kv4.2. The unexplained diarrhea led
to demonstrate a robust expression of DPPX in the myenteric
plexus. The course of neuropsychiatric symptoms was prolonged and often associated with relapses while decreasing
immunotherapy. Long-term follow-up showed substantial
improvement in 3 patients (1 is lost to follow-up).
Interpretation: Antibodies to DPPX associate with a protracted encephalitis characterized by CNS hyperexcitability
(agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy.
Study supported by: Supported in part by a KWF fellowship
2009-4451 of the Dutch Cancer Society (MT), the National
Institutes of Health RO1NS077851 (JD), RO1MH094741
(RB-G and JD), Fundació la Marató TV3 (JD), Fondo de
Investigaciones Sanitarias (FIS, PI11/01780 to JD, FI08/00285
to EMH, and PS09/0193 to FG), and a McKnight Neuroscience of Brain Disorders award (RB-G and JD).
Dr. Dalmau receives royalties from the editorial board of
Up-To-Date; from Athena Diagnostics for a patent for the use
of Ma2 as autoantibody test. Dr. Dalmau holds a patent application for the use of NMDA receptor as autoantibody test.
Dr. Dalmau has received a research grant from Euroimmun.
Autoimmune Neurology
WIP1801. Elevated Micro RNAs in Cerebrospinal Fluid
of Multiple Sclerosis Patients Contribute to Neuronal
Injury
Neha Patel, Elliot Choi, Marie Medynets, Scott Newsome,
Peter Calabresi, Avindra Nath and Tongguang Wang;
Bethesda, MD and Baltimore, MD
Neurodegeneration in patients with progressive forms of
multiple sclerosis (MS) may continue despite immunomodulatory therapy and its pathophysiology is poorly
understood. Since micro RNAs (miR) play a critical role in
maintaining cellular homeostasis, levels of 88 miRs in cerebrospinal fluid (CSF) samples from 7 relapsing-remitting, 9
secondary progressive MS (SPMS) patients and 9 controls
were determined using PCR array. The levels of 12 miRs
were significantly up-regulated and one, miR423-3p, downregulated in SPMS compared to control. Among them,
miR150 also increased in relapsing-remitting MS compared
to control. Using cellquanti-blue assay and beta-III-tubulin
immunostaining, the effects of increased miRs on cultured
human fetal neurons were studied with mimics. Among
them, miR-16 and miR-29 induced significant neurotoxicity
compared to control. These observations indicate that miRs
can be detected in CSF from MS patients and are maximally dysregulated in patients with SPMS. Change in miR
levels in different categories of MS could be used as biomarkers for the disease diagnosis and prognosis. These miRs
may also play a role in the pathogenesis of the progressive
forms of MS and could serve as potential targets for the
therapy.
Study supported by: NIH intramural funding.
WIP1803. Human Aquaporin 4 281-300 Is the
Immunodominant Linear Determinant in the Context
of HLA-DRB1*03:01 – Relevance for Diagnosing and
Monitoring Patients with Neuromyelitis Optica
Benjamin Arellano, Rehana Hussain, Tresa Zacharias, Doris
Lambracht-Washington and Olaf Stuve; Dallas, TX
Objective: Human aquaporin 4 (hAQP4) is thought to be
the autoantigen in patients with neuromyelitis optica
(NMO). HLA haplotype analyses in NMO patient cohorts
suggest a positive association with HLA-DRB1*03:01. This
study aimed to identify immunodominant linear determinants of hAQP4 in the context of HLA-DRB1*03:01.
Design: HLA-DRB1*03:01 transgenic mice were immunized with whole-protein hAQP4. To test cellular immune
responses, lymph node cells and splenocytes were cultured
in vitro with twenty-amino acid-long peptides that overlap
by ten amino acids across the entirety of hAQP4. The frequency of Th1, Th17, and Th2 cytokines was determined
by ELISPOT assay.
Results: Peptide hAQP4281-300 generated a significantly
(P-value<0.01) greater Th1 and Th17 immune response
than any of the other linear peptides screened. This 20mer
peptide contains two dominant immunogenic 15mer peptides. hAQP4281-300 did not interfere with recombinant
AQP4 autoantibody binding.
Conclusion: hAQP4281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLADRB1*03:01. Within hAQP4281-330 are two dominant
immunogenic determinants that induce differential Th phenotypes. hAQP4 determinants identified in this study may
serve as diagnostic biomarkers in NMO patients.
Study supported by: Doris Duke Charitable Foundation
with collaborations with lab funded by the Guthy-Jackson
Charitable Foundation.
WIP1802. Encephalitis and Antibodies to DPPX, a
Regulatory Subunit of Kv4.2 Potassium Channels
Anna Boronat, Jeffrey M. Gelfand, Nuria Gresa-Arribas, HyoYoung Jeong, Michael Walsh, Kirk Roberts, Eugenia MartinezHernandez, Myrna R. Rosenfeld, Rita Balice-Gordon, Francesc
Graus, Bernardo Rudy and Josep Dalmau; Barcelona, Spain;
San Francisco; New York; Brisbane, Australia and
Philadelphia
Objective: To report a novel cell-surface autoantigen in 4
patients that is a critical regulatory subunit of the Kv4.2 potassium channels.
Methods: Techniques included immunoprecipitation,
mass spectrometry, cell-base experiments with Kv4.2 and
several dipeptidyl-peptidase-like protein-6 (DPPX) plasmid
constructs, and brain immunostaining of DPPX-null mice.
Results: Immunoprecipitation studies identified DPPX as
the target autoantigen. Symptoms included agitation, confusion, myoclonus, tremor, and seizures. All patients had
pleocytosis, and three severe prodromal diarrhea of unknown
etiology. Given that DPPX ‘‘tunes up’’ the Kv4.2 potassium
channels, we determined the epitope distribution in DPPX,
DPP10 (a protein homologous to DPPX) and Kv4.2.
WIP1804. Treatment Patterns in Co-Occurring Multiple
Sclerosis and Sarcoidosis
Dorlan J. Kimbrough, Justin C. McArthur and Carlos A.
Pardo; Baltimore, MD
Recent reports (Carbonelli et al., 2012 and Chakravarty
et al., 2012) suggest that interferon (IFN) beta may trigger
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pulmonary sarcoidosis in multiple sclerosis (MS) patients. We
retrospectively identified six patients with concurrent or
sequential MS/sarcoidosis among 300 patients from the Neurosarcoidosis (NS) and MS clinics at Johns Hopkins Hospital
between 2000 and 2011. Medical records were reviewed. All
six patients were women, age 39.8 þ/ 10.8 years at diagnosis. Three had biopsy-proven pulmonary sarcoidosis; in two
cases, MS was initially diagnosed (treatments included glatiramer, natalizumab, and mycophenolate mofetil for one case;
IFN beta-1a alone for the second). In the third case, pulmonary sarcoidosis was treated with prednisone and preceded
neurologic symptoms by twenty years. Among the three cases
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without biopsy, one MS patient was treated with IFN beta1b, glatiramer, and IFN beta-1a before developing sarcoidosis.
One NS patient used prednisone and mycophenolate mofetil
before MS was reconsidered; a third case was diagnostically
uncertain and treated with mycophenolate mofetil. Co-occurring MS/sarcoidosis cases are rare in our patient population.
IFN therapy preceded sarcoidosis in three cases, but confounding treatments and rarity of cases prevented strong
inferences about association.
Study supported by: Project RESTORE Bart McLean
Fund for Neuroimmunology Research. National Institutes
of Health.
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NINDS/ANA Career Development
Symposium Poster Session
Abstracts
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(b) 75 BAVMþ(with) aneurysm cases vs. 504 controls, and
(c) 150 BAVM-(without) aneurysm cases vs. 504 controls.
Results: rs10757278-G was marginally associated with
BAVM (OR¼1.23, 95% CI¼0.99-1.53, P¼0.064). Compared to controls, the association was stronger in
BAVMþaneurysm (OR¼1.50, 95% CI¼1.03-1.89,
P¼0.035) than in BAVM-aneurysm cases (OR¼1.03, 95%
CI¼0.77-1.33, P¼0.832). Similar effects were observed for
other SNPs in linkage disequilibrium (r2>0.8) with
rs10757278.
Conclusion: Common 9p21.3 variants showed similar
effect sizes as previously reported for aneurysmal disease.
The SNP association with BAVM appears to be explained
by known association with aneurysms, suggesting that
BAVM associated aneurysms share similar vascular pathology mechanisms.
Study supported by: K23 NS058357 (HK), R01
NS034949 (WLY), and P01 NS044155 (WLY)
Each year, recipients of K awards are invited to attend the
NINDS/ANA Career Development Symposium, designed to
provide them with the essential tools to enhance their ability
to write successful grant proposals and to obtain grant funding from the NIH and other institutions. The NINDS/ANA
Career Development Symposium was set up to foster the success of young members of the faculty who had obtained career development awards (K08, K12, or K23) from the NIH.
Career Development posters will be presented during the
wine and cheese reception of the Career Development Symposium from 5:00 pm – 7:00 pm on Saturday, October 6.
The K-awardee participant’s name is in bold.
CD503. Metabolomics Identifies Alterations in the
Tricarboxylic Acid Cycle in Acute Ischemic Stroke
W. Taylor Kimberly, Yu Wang, Ly Huong Pham and Robert
E. Gerszten; Boston, MA
CD501. Directional EEG Connectivity Method
Demonstrates Complex, Reciprocal Information Flows
during Praxis Performance
Joshua B. Ewen, Anna Korzeniewska, Balaji M. Lakshmanan,
Stewart H. Mostofsky and Nathan E. Crone; Baltimore, MD
Background: There is limited information about changes in
metabolism during acute ischemic stroke. The identification
of circulating plasma metabolites modulated during cerebral
infarction may provide insight into pathogenesis and identify novel biomarkers.
Methods: We performed filament occlusion of the middle cerebral atery of Wistar rats compared to sham controls,
collecting plasma and CSF two hours after onset of ischemia. Samples were analyzed using liquid chromatography
followed by tandem mass spectrometry. Polar metabolites
including organic acids, sugars and bile acids were quantified using electrospray ionization followed by scheduled
multiple reaction monitoring.
Results: Several metabolites were altered in the setting of
cerebral infarction. We detected a 38% rise in lactate
(P¼0.03), and a 41% accumulation of pyruvate (P¼0.04)
in the plasma of stroke animals. We also detected increases
in several metabolites in the tricarboxylic acid (TCA) cycle,
including succinate (47%, P¼0.03), malate (64%, P¼0.03),
alpha-ketoglutarate (64%, P¼0.03), fumarate (28%,
P¼0.03) and aconitate (61%; P¼0.005) but not in citrate
(P>0.20).
Conclusions: Taken together, these data highlight alterations in metabolites that are related to the TCA cycle during
acute ischemic stroke. Validation in human cohorts may
confirm their potential utility as biomarkers of stroke.
Study supported by: 1K23NS076597-01;
The Clinical Investigator Training Program: Beth Israel
Deaconess Medical Center – Harvard Medical School, in
collaboration with Pfizer Inc. and Merck & Co.
Praxis function is known from lesion studies to depend on
left parietal and premotor regions. While the typical physiological model suggests that praxis ‘‘commands’’ are sent from
the left parietal region to left premotor regions and then to
primary motor cortex, EEG studies of go/no-go praxis tasks
suggest more complex interactions between bilateral anterior
and posterior brain regions. Using a high density EEG array,
we recorded data from a praxis task and analyzed them with
Event Related Causality (ERC; Granger-Causality-based
method which estimates dynamical changes in brain activity
flow). Because the ERC method has been not previously
been applied to scalp EEG, we investigated optimal analysis
parameters. Data from the mental rehearsal portion of the
task demonstrated activity flows between left and right posterior regions and flows from both posterior regions toward left
frontal regions. Data from the initiation of the pantomime
portion demonstrated reciprocal flows, suggesting feedback
from left anterior regions to bilateral posterior regions. These
results demonstrated the utility of ERC in analyzing scalp
EEG recordings and suggest generally that systems-level neural complex motor circuits function with reciprocal information flows.
Study supported by: NIH/NINDS
CD502. Genetic Variants on 9p21.3 Are Associated with
Brain Arteriovenous Malformations with Associated
Flow-Related Arterial Aneurysms
Helen Kim, Nasrine Bendjilali, Jeffrey Nelson, Shantel M.
Weinsheimer, Mark Segal, Charles E. McCulloch, Ludmila
Pawlikowska and William L. Young; San Francisco, CA
CD504. Perception among African Americans towards
Calling 911 for Acute Stroke
Lesli E. Skolarus, Jillian S. Murphy, Marc A. Zimmerman,
Sarah Bailey, Sophronia Fowlkes and Lewis B. Morgenstern;
Ann Arbor and Flint
Background: The 9p21.3 locus is associated with risk of
coronary artery disease and intracranial and abdominal aortic aneurysms (rs10757278). We investigated whether previously reported 9p21.3 SNPs are associated with risk of brain
arteriovenous malformations (BAVM), which often have
accompanying flow-related arterial aneurysms.
Methods: Genotypes for 6 SNPs, including rs10757278,
were imputed using 1000 Genomes Phase 1 CEU data
(R2>0.9). We tested for association using logistic regression
of imputed dosages adjusting for age, sex and top 3 components of ancestry in: (a) 338 BAVM cases vs. 504 controls,
Background: African Americans receive acute stroke
treatments less often than European Americans. We used a
community-based participatory research approach to explore
perceptions of emergency stroke care among urban African
American youth and adults.
Methods: Community partners, church health teams/
leaders identified and recruited focus group participants
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from 3 African American churches in Flint, MI. Nine focus
groups were conducted from November 2011 to March
2012; we took a grounded theory approach to analysis.
Results: Thirty nine youth (64% women) and 38 adults
(90% women) participated. Adults and youth endorsed their
inability to recognize stroke warning signs. Adult barriers
also included finances. Adult facilitators included widespread acceptance of stroke as an emergency and perceived
social approval for calling 911for stroke. Youth barriers to
calling 911 for stroke included emotional state (fear, liability), lack of empowerment, anxiety about talking to EMS
dispatchers and perceptions that the medical community
does not care to help them. Youth also identified community factors, including violence and limited city resources as
barriers.
Conclusion: Designing behavioral interventions to
increase 911 calls for acute stroke should be cognizant of
and sensitive to barriers specific to the community.
Study supported by: NINDS K23 NS073685
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Methods: SPOTRIAS (Specialized Program of Translational Research in Acute Stroke) centers prospectively collected data on all patients treated with IVrtPA or IAT from
1/1/2005 to 12/31/2010. IAT was categorized as bridging
therapy (BT: IAT after IVrtPA), and endovascular therapy
alone (ETA). In-hospital mortality was compared in (1)
patients age 80 versus <80, and (2) IAT/BT/ETA versus
IVrtPA only among those age 80 using multivariable logistic regression.
Results: 3378 were treated with IVrtPA, 808 with IAT
(383 with ETA and 425 with BT). Patients 80 (n¼1182)
had a higher risk of in-hospital mortality compared to
younger counterparts. Among those age 80, IAT (OR
0.95, 95%CI 0.60-1.49), BT (OR 0.82, 95%CI 0.47-1.45),
and ETA (OR 1.15, 95%CI 0.64-2.08) versus IVrtPA were
not associated with increased in-hospital mortality.
Conclusions: IAT does not appear to increase the risk of
in-hospital mortality among those over age 80 compared to
intravenous thrombolysis alone
Study supported by: SPOTRIAS is funded by the
National Institutes of Neurological Diseases and Stroke
(NINDS P50 NS049060). JZW was funded by NINDS
1K23 NS 073104-01A1 and the NIH Loan Repayment
Program (AG 31009).
CD505. High Resolution Magnetic Resonance Imaging
(HRMRI) in Intracranial Atherosclerosis
Tanya N. Turan, Truman R. Brown, Zoran Rumboldt and
Robert J. Adams; Charleston, SC
Introduction: HRMRI can identify prognostically important plaque features (intraplaque hemorrhage (IPH), fibrous
cap, and lipid core) in extracranial carotid disease, but plaque features in intracranial atherosclerosis (ICAS), a more
common cause of stroke worldwide, have not been systematically examined. This study aimed to refine a HRMRI
protocol that will consistently visualize the arterial lumen,
vessel wall, and atherosclerotic plaque components in
patients with ICAS.
Methods: 36 patients with 50-99% ICAS underwent a
brain MRI using a 3Tesla Siemens scanner with a 32 channel head coil. Stepwise adjustments to the imaging protocol
were made to refine the image quality. Images were assessed
using a grading scale based on visualization of the vessel
wall, lumen, and plaque components.
Results: The final imaging protocol was selected from
the sequences that provided the best image quality without
unacceptable scan duration. The final sequences include 3D
acquisition of T1 weighted images (pre- and post-contrast),
T2 weighted images, and FLAIR sequences.
Summary: HRMRI can be used to identify IPH, fibrous
cap, and lipid rich core in ICAS. Further studies are planned
using this protocol to determine inter-rater reliability and the
prognostic value of these plaque features in ICAS.
Study supported by: NIH/NINDS 1K23NS069668
CD507. Induction of Autophagy Protects Against
TDP43-Mediated Neurodegeneration
Sami Barmada, Aaron Daub, Michael Ando, Andrea Serio,
Andrey Tsvetkov, Arpana Arjun, Siddharthan Chandran and
Steve Finkbeiner; San Francisco, CA and Edinburgh, United
Kingdom
TDP43, a nuclear DNA- and RNA-binding protein, plays a
prominent role in the pathogenesis of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
We demonstrated previously that expression of wild-type
and mutant TDP43 in primary rodent cortical neurons
recapitulates key features of ALS and FTD, including nuclear mislocalization, cytoplasmic aggregation, and mutantspecific neuronal loss. Two important predictors of cell
death in this model were TDP43 levels and cytoplasmic
mislocalization. Because stimulation of autophagy could
potentially address both factors, we investigated a family of
small-molecule compounds capable of inducing autophagy
for their ability to prevent TDP43-mediated neurodegeneration. Using a novel method of measuring protein turnover
in living cells, we first confirmed that the compounds
enhance autophagy in neurons. We then demonstrated that
the compounds lower TDP43 half-life, prevent cytoplasmic
mislocalization, and decrease overall levels of TDP43. Not
only did the compounds prevent TDP43-mediated cell
death in primary neurons, but they were also beneficial in
human stem cell-derived neurons carrying TDP43 mutations. Our data strongly suggest that induction of autophagy
through the use of small molecules may be a promising and
effective therapy for many patients suffering from ALS and
FTD.
Study supported by: NIH/NINDS (5-K08-NS072233-02)
CD506. Impact of Acute Ischemic Stroke Treatment in
Patients over Age 80: The SPOTRIAS Consortium
Experience
Joshua Z. Willey, Santiago Ortega-Gutierrez, Nils Petersen,
Pooja Khatri, Andria L. Ford, Natalia S. Rost, Latisha K. Ali,
Nichole R. Gonzales, Jose G. Merino, Brett C. Meyer and
Randolph S. Marshall; New York, NY; Cincinnati, OH; St.
Louis, MO; Boston, MA; Los Angeles, CA; Houston, TX;
Bethesda, MD and San Diego, CA
CD508. Sex Chromosomes Modulate Longevity and
Susceptibility to Alzheimer Disease
Dena B. Dubal, Nino Devidze, Kurtresha Worden, Daniel
Kim, Julie Harris, Gui-Qiu Yu, Jorge Palop, Art Arnold,
Bruce Miller and Lennart Mucke; San Francisco, CA and Los
Angeles, CA
Background: Few acute stroke studies have included
patients 80 years. We outline in-hospital outcomes in (1)
patients 80 years versus <80, and (2) those 80 receiving
intra-arterial therapy (IAT) compared to those treated with
intravenous recombinant tissue plasminogen activator
(IVrtPA).
Women live longer in normal aging and with Alzheimer’s
disease (AD). Men with AD progress to death faster and
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Path: N:/3b2/ANA#/Vol00000/120257/APPFile/JW-ANA#120257
J_ID: ZAY Customer A_ID: BKLT2012_CD_Abstracts Cad