1. health and fitness
2. disease

DepArtMeNt of Neurology · tHe NeuroScIeNce ceNtre ·
copeNHAgeN uNIverSIty HoSpItAl · rIgSHoSpItAlet · copeNHAgeN, DeNMArk ·
www.MS-reSeArcH.Dk
Danish
Multiple Sclerosis center
Annual report
2010
DANISH Mult Iple ScleroSIS ceN ter ANNuAl report 2010
1
Utrecht University, utrecht, the Netherlands (professor Hub
Schellekens)
Innsbruck Medical University, Innsbruck, Austria (professor Florian Deisenhammer)
Heinrich-Heine-University, Düsseldorf, Germany (professor
Hans-peter Hartung)
General Charles University, prague, czech republic (professor eva Havrdova)
Ospedale Universitario San Luigi, torino, Italy (professor
Auturio Bertolotto)
Hospital Universitari Vall d’Hebron, Barcelona, Spain (professor Xavier Montalban)
Queen Square, london, the united Kingdom (professor
Gavin Giovannoni)
Collaboration with pharmaceutical
companies on clinical trials
DMSC staff seminar 2010.
Novartis, Denmark
Merck Serono Nordic, Denmark, Norway and
Sweden
Biogen idec, Denmark and uSA
teva/Aventis, Israel and Denmark
Sanofi-aventis, Denmark
Bayer Schering, Germany
Genmab, Denmark
Genzymes, Holland
Glaxo Smith-Kline
ovamed, Germany
Swedish orphan, Sweden
Acknowledgements
Danish Multiple Sclerosis Research Center has received generous support from a number of
public and private research funds:
Danish Medical research council
Danish MS Society
Warwara larsen Foundation
rigshospitalets Scientific Board
eu Sixth Framework programme
Brdr. røjne Holding
Jeppe Juel Memorial legacy
roFar Foundation
roche Denmark
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DANISH MultIple Sclero SIS ceNter AN NuAl report 2010
the Danish Strategic research council
the Johnsen Memorial Foundation
the lounkær Foundation
Biogen idec
Sanofi-aventis
Merck Serono
ejner Jonasson og Hustrus mindelegat
Fondsbørsvekselerer Henry Hansen og Hustrus
legat
DANISH Mult Iple ScleroSIS ceN ter ANNuAl report 2010
31
Table of contents
5
A short review of 2010 in the Danish Multiple Sclerosis Center
6
Missions and aims
8
About the Danish Multiple Sclerosis Center
12
Organization diagram
14
Research activities 2010
16
Clinical research
18
Neuroimaging
19
Neurogenetics
20
Neuroimmunology
22
Neuropathology
23
Routine analyses in Neuroimmunology Laboratory
24
Scientific publications 2009-2010
26
Peer reviewed original papers 2009
27
Peer reviewed original papers 2010
29
Prizes
29
Honorary offices
30
Scientific collaboration
30
National
30
International
31
Pharmaceutical companies on clinical trials
31
Acknowledgements
Annual
Report
2010
DA NISH Mu ltip le scl erosis CENTER ann ual rep ort 2010
3
Publisher:
Danish Multiple Sclerosis Center
Authors:
Per Soelberg Sørensen
Morten Blinkenberg
Finn Sellebjerg
Annette Oturai
Helle Bach Søndergaard
Poul Erik H. Jensen
Photos:
Morten Blinkenberg
Concept, design, graphic
­production and print:
Stibo Zone
Njalsgade 19 D
DK-2300 København S
Tlf.: +45 89 39 88 33
www.stibozone.com
4
DANISH Mult iple sclerosis CEN TER annual report 2010
Professor Per Soelberg Sørensen,
MD, DMSc
Director of the Danish Multiple
Sclerosis Center (DMSC)
A short review of 2010
in the Danish Multiple
Sclerosis Center
2010 was the year when we expected to be able to offer our patients the first
tablet to treat multiple sclerosis. However, one of the expected drugs, Cladribine, received a negative opinion of the European Medicines Agency (EMA) and
the decision on the other tablet, Gilenya, was delayed. Late in 2010 Gilenya
achieved a positive opinion by EMA but only for treatment of patients who did
not respond satisfactorily to the injectible drugs, interferon-beta and glatiramer
acetate. Gilenya will be marketed from May 2011.
The activity in Danish Multiple Sclerosis Center (DMSC) has continued to
increase in 2010 despite the fact that DMSC had the same number of MS
specialist nurses and a reduced staff of MS neurologist compared with 2009.
This has only been possible due to the extra-ordinary efforts by all members
of the DMSC staff. The number of patients receiving highly specialized therapy
has increased and by the end of 2010 more than 350 patients were receiving monthly infusions of Tysabri, meaning that more than 20 patients attend
the outpatient clinic every day for intravenous infusion of disease modifying
drugs. It has been a logistic challenge to accommodate patients’ wishes for
infusions on particular days. Fortunately we have had the opportunity to equip
a second infusion room in 2010.
In 2010 we completed a multi-center, international trial organized and directed
from DMSC using add-on treatment of Simvastatin to interferon-beta. Unfortunately we did not see any beneficial effects of this combination. We have
continued our efforts to find effective therapy for patients with progressive
forms of MS and have initiated 2 new clinical trials in patients with progressive
MS investigating Tysabri and monthly pulses of methylprednisolone.
We have continued our search for biomarkers that can tell if a patient respond
to a certain therapy, and in pathological studies we have described differences
between primary progressive and secondary progressive MS in inflammation
and demyelination in the brain. We have described the pathological processes
responsible for the steady worsening of symptoms in patients with progressive
forms of MS and found the explanation why symptoms often seem to recur
with the same localization.
I hope you will enjoy reading the annual report of DMSC.
Per Soelberg Sørensen
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
5
DMSC missions and aims
The mission of Rigs­hospitalet is to be the
leading hospital in Denmark for patients in need
of highly specialized treatment
The missions of the
­Danish Multiple Sclerosis Center (DMSC) are:
To be the leading multiple sclerosis (MS) center
in Denmark
To be at the forefront of highly specialized
management of MS
To carry out research and development in MS
at an advanced international level
To collaborate scientifically and exchange
knowledge in MS research
To educate staff to a highly specialized level in
their relevant fields
To contribute with professional advice on MS
to the healthcare community
To meet people with MS at their terms with
openness and respect
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DANISH Mult iple sclerosis CEN TER annual report 2010
The aims of
the DMSC are:
To provide the optimal interdisciplinary patient
care to all MS patients in the region and to
patients from other regions in need of highly
specialized therapy
To carryout high quality research in MS with
focus on clinical research, new therapies, MS
genetics, neuroimmunology and MS pathology
To teach undergraduate students and PhDstudents and stimulate their interest in MS
research
To educate post docs, MS physicians, nurses,
secretaries and other professionals to a high
level of knowledge of MS in their relevant
expert fields
To lead the national research in Denmark in
partnership with other Danish researchers and
to establish a broad international collaboration
with MS research groups in Europe and from
overseas.
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
7
About
The Danish Multiple
Sclerosis Center
8
DANISH Multi ple sclero sis CENTER ann ual report 2010
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
9
The Danish Multiple Sclerosis Center
About The Danish Multiple
Sclerosis Center
The Danish Multiple Sclerosis Center (DMSC)
is offering highly specialized therapy and is the
leading center for MS research in Denmark. Together with Danish colleagues we are responsible
for the vast majority of clinical and translational
MS research in Denmark, and we collaborate with
MS researchers from all over the world.
DMSC is composed of a multidisciplinary
MS clinic and a research unit. The MS Clinic is
located on the 8th floor of the main complex of
Rigshospitalet and comprises the offices of the
professor and consultants, the nurses’ offices, the
reception desk and the secretary offices as well as
the outpatient consultation rooms and facilities
for intravenous therapy with disease modifying
drugs and rooms for invasive procedures. DMSC
provides multidisciplinary care for more than 1900
MS patients, and offers both basic and highly
specialized therapy.
The National Board of Health has appointed
DMSC to perform highly specialized therapy such
as Tysabri, strong immunosuppression and experimental therapies. DMSC is a center for children
and adolescence with MS in Eastern Denmark and
has a highly specialized function in treating neuromyelitis optica, once thought to be a variant of
MS, but now considered to be a separate disease
entity. DMSC also offers treatment of severe spasticity with an intrathecal baclofen pump, not only
to patients with MS but also to other patients
with diseases or traumatic injuries causing severe
spasticity.
It is the aim of the MS Clinic to provide high
quality multi-disciplinary care for all our patients
with openness and respect. Our staff comprises a
professor, 5 consultants, 2 staff neurologists and
several external consultants working part time in
the MS Clinic. There is one leading nurse and 7
MS specialist nurses, 3 secretaries, a neuropsychologist, a physiotherapist and a medical social
counselor. We serve patients from the Copenhagen capital region and many patients from
neighbouring regions and from all over Zealand
are referred for highly specialized therapy.
The MS Research Unit is partly located in the
proximity of the MS Clinic, where most patients
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DANISH Mult iple sclerosis CEN TER annual report 2010
related to clinical research takes place and where
the offices of 3 research nurses and 1 research
secretary are embedded. The remaining part of
the MS Research Unit is located on the first floor
in the Michaelsen Building 63 and in the basement of building 93. These facilities contain the
Neuroimmunology Laboratory and offices for the
research staff. The laboratory is equipped with
an 8-color flow cytometer and facilities for doing
real-time polymerase chain reaction (PCR). Further, the facilities contain the MS Biobank and the
neurogenetics laboratory for DNA preparation and
facilities for making routine tests.
The focus of the research in DMSC is clinical
research including neuroimaging, neuroimmunology, neurogenetics and neuropathology of MS.
ACtive patientS iN DMSC
2.000
1.800
1.600
1.400
1.200
1.000
800
600
400
200
0
1994
2004
2008
2010
2011
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
11
Organization
Director: Professor Per Soelberg Sørensen
MS clinic
MS Research Unit
Neurologists
Professor Per Soelberg Sørensen
Consultant Morten Blinkenberg
Consultant Finn Sellebjerg
Consultant Annette Oturai
Consultant Karen Schreiber
Consultant Ana Voldsgaard
Staff neurologist Melinda Magyari
Staff neurologist Henrik Mathiesen
Clinical research
Professor
Per Soelberg Sørensen
Consultant Karen Schreiber
Staff neurologist Ana Voldsgaard
Staff neurologist
Melinda Magyari
Neuropsycologist
Agnete Jønsson
PhD student Stephan Bramow
PhD student Lars Börnsen
PhD student Jeppe Romme Christensen
PhD student Rikke Ratzer
Junior physician Morten Møller
Research nurses
Vibeke Jespersen
Joan Pietraszek
Sidsel Nielsen
MS nurses
Leading nurse Anne Hansen
Dorte Stauning Rasmussen
Anette Husted Pedersen
Lene Almind
Julie Yoon S. Moberg
Louise Nathalie Christiansen
Maj Daae Christensen
Sidsel Nielsen
Secretaries
Annette Larsen
Malene Møllesøe
Helle Vilhelmsen
PhD students
Lars Börnsen
Jeppe Romme Christensen
Rikke Ratzer
Julie Maria Hejgaard
Dan Hesse
Junior research fellow
Marianne Hansen
Research secretary
Annette Larsen
Neuroimaging research
Consultant
Morten Blinkenberg
Staff neurologist
Henrik Mathiesen
Genetic research
Consultant Annette Oturai
Senior research fellow
Helle Bach Søndergaard
Neuropsychologist
Agnete Jønsson
Physiotherapist
Lis Albrechtsen
Medical social counselor
Keld Nissen
12
Neuroimmunology
research
Ass. professor Finn Sellebjerg
Senior research fellow
Helle Bach Søndergaard
DANISH Mult iple sclerosis CEN TER annual report 2010
Neuropathology
research
Professor
Per Soelberg Sørensen
Ph.d. student
Stephan Bramow
Neuroimmunology
Laboratory
Laborarory leader
Poul Erik Hyldgaard Jensen
Laboratory technicians
Leading Laboratory technician
Joy Mendel-Hartvig
Marie Koefoed
Anne Mette Hedegaard Nielsen
Michael Jensen
Vibeke Fuglholt
Professor
Per Soelberg
Sørensen
Ass. professor
Finn Sellebjerg
Consultant
Morten
­Blinkenberg
Consultant
Annette Oturai
Staff neurologist
Henrik
Mathiesen
Laboratory
leader Poul Erik
Hyldgaard
Jensen
Consultant
Karen Schreiber
Consultant
Ana Voldsgaard
Staff neurologist
Melinda
Magyari
Senior research
fellow
Helle Bach
Søndergaard
Leading laboratory technician
Joy MendelHartvig
Leading nurse
Anne Hansen
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
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Research
activities 2010
Clinical research
Clinical research
Neuroimaging
Neurogenetics
Neuroimmunology
Neuropathology
Routine analyses in Neuroimmunology Laboratory
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DANISH Multi ple sclero sis CENTER ann ual report 2010
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
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Research activities 2010
Clinical research
Clinical research group:
Per Soelberg Sørensen, Morten Blinkenberg, Finn
Sellebjerg, Annette Oturai, Ana Voldsgaard, Karen
Schreiber, Henrik Mathiesen, Melinda Magyari,
Lars Börnsen, Jeppe Romme Christensen, Rikke
Ratzer, Julie Maria Hejgaard, Agnete Jønsson,
Vibeke Jespersen, Joan Pietraszek, Sidsel Walther
Nielsen, Anne Hansen, Annette Larsen.
Therapeutic trials
In 2010 we completed the SIMCOMBIN study,
which is a Nordic multi-center study directed from
DMSC and conducted in 42 MS Centers in Denmark,
Norway, Sweden and Finland. The study investigated
simvastatin as add-on therapy to interferon-beta in
de novo treated patients with relapsing-remitting
MS. More than 300 patients participated in the trial.
Unfortunately the results showed that there was no
benefit of add-on of simvastatin to interferon-beta.
We have recently conducted another combination trial, which is a multi-center European trial
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DANISH Multi ple sclero sis CENTER ann ual report 2010
exploring the effect of Minocycline as add-on
therapy to interferon-beta in de novo treated
patients. The trial was completed in April 2011,
and the results will be available in the summer of
2011.
We are currently performing several single-center
studies in patients with progressive MS in order
to try to find treatment options for this phase of
the disease that currently lags effective therapy. In
this regard we study the effect of erythropoietin
(EPO) on disability in patients with progressive MS
and the aim is to include 56 patients and to finalize
inclusion in 2011.
We have performed a small safety study with
eggs of the pig whipworm (Trichuris suis). This
small trial has been completed, and the data are
currently under examination. If the result is positive we will embark a phase II trial with inclusion of
80 patients.
In patients with progressive MS, we are testing
the effect of erythropoietin (EPO) on permanent
MS symptoms, and we are conducting an exploratory trial of natalizumab (Tysabri) in patients with
progressive MS and are planning a similar trial
investigating the effect of monthly cycles of methylprednisolone tablets.
Other clinical research trials
In 2010 we initiated a study exploring the role
of vitamin D on clinical disease activity in MS. Vitamin D seems to yield some protection against encountering MS and may also influence the disease
activity in established MS.
MS is increasing particularly in women. Whereas
the incidence of MS has been almost unchanged
in men, it has doubled in women since 1985. In
collaboration with the Danish MS Register we embarked on an extensive analysis of possible factors
that might have contributed to the increase of MS in
women. We will explore demographic factors, such
as changes in working conditions, merital status,
childbirth, smoking habits and vitamin D intake.
DMSC is among the leading centers in the world
regarding studies of antibodies against biological agents. We have extensively studied the effect
of neutralizing antibodies against interferon-beta,
most recently in a EU supported European study
of neutralizing antibodies against interferon-beta
(NABINMS study). We have introduced a new assay
for detecting neutralizing antibodies based on a luciferase reporter gene under control of interferon-beta.
Recently we have implemented an analysis of
antibodies against natalizumab (Tysabri) and have
conducted and international study of the frequency
of occurrence of antibodies against natalizumab
together with MS centers in Sweden, Norway and
Germany. We were able to show that fewer patients
developed persistent antibodies against natalizumab compared with the observation in clinical
studies. We have also shown that the propensity
to develop antibodies against interferon-beta does
not carry an excess risk of developing antibodies
against natalizumab.
We are currently doing a study of interferonalpha in patients who have developed neutralizing
antibodies against interferon-beta to see whether
these patients have maintained a full biological
response to interferon-alpha and therefore might
be treated with interferon-alpha.
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
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Research activities 2010
Neuroimaging
Neuroimaging research group:
Morten Blinkenberg, Henrik Mathiesen,
Per Soelberg Sørensen
PET
During the last decades, functional imaging have
improved our understanding of the neurodegenerative processes in MS.
Former positron emission tomography (PET)
studies, carried out in Danish Multiple Sclerosis
Center (DMSC), have shown that cerebral activation in MS patients, is severely reduced as a consequence of disease progression.
A PET study focusing on the early relapsing
remitting phase of the disease and the corresponding changes in cerebral activation has recently
been performed in DMSC. The study shows, that
reductions in PET are associated with reduced magnetic resonance spectroscopy (MRS) measures of
N-acetyl-aspartate (NAA) normalized to Creatine
(NAA/Cr), reflecting neuronal dysfunction or loss
in MS. In this way there seem to be a relationship
between these two different measures of cerebral
neuronal integrity in MS, which have implication
for the further use of MRS in MS.
MRI
In collaboration with Danish Research Centre for
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DANISH Multi ple sclero sis CENTER ann ual report 2010
Magnetic Resonance, we have previously shown,
that MRS measurements of NAA/Cr correlate with
cognitive dysfunction in MS. This cohort has now
been re-evaluated and analyzed for longitudinal
changes in MRS. Preliminary data show, that MRS
decrease in the early stage of MS, predicts disease
progression after 5 years. MRS may therefore be
used as a clinical marker, to determine disease
course in MS.
Another study focuses on the pathophysiological
mechanisms underlying changes in cerebral activation in MS patients.
Resting-state fMRI is a new approach to assess
functional brain connectivity by measuring the
synchronous fluctuation in the blood-oxygenlevel dependent signal between remote brain
regions at rest. PhD-student, Anne-Marie
Dogonowski, uses this method to study, whether
changes in functional connectivity of the motor
network, reflect disease severity in patients with
MS.
Preliminary results show, increased coupling
between premotor cortex and the motor network,
which might reflect an adaptive mechanism to
maintain motor function with increasing clinical
disability. These data highlight the potential of
resting-state fMRI to study disease-related functional reorganization of distinct brain networks in
multiple sclerosis and encourage further research
in this field.
Neurogenetics
Neurogenetics research group:
Annette Bang Oturai, Helle Bach Søndergaard,
Finn Sellebjerg, Julie Maria Hejgaard
The ultimate cause of multiple sclerosis (MS) is still
unknown. Probably a combination of hereditary
and environmental factors trigger a defect in the
immune system that will lead to MS. The frequency
of MS varies geographically and between ethnic
groups, with the greatest risk in white northern
Europeans living in temperate regions. From family studies we have known for many years that
genes plays a role, and that MS susceptibility is
influenced by genetic variations within the major
histocompatibility complex (MHC).
We have previously performed linkage studies
investigating Danish and Nordic sib pair families,
and later participated in the ultimate MS linkage
study investigating >700 European MS families
revealing MHC as the only genome-wide linkage
signal in MS with a lod score of 11,7, dominated by
the DR2 (DRB1*15:01-DQB1*06:02) haplotype.
We have collected DNA for more than 15 years,
and today we have DNA from more than 1,800
Danish MS patients and 1,200 controls, all kept
in the »Danish Multiple Sclerosis Biobank« in our
department at Rigshospitalet. In order to increase the sample size for genetic testing, we have
participated in the »Nordic MS Genetic Network«
since 1994, and today the Nordic material consists
of more than 6,000 MS cases and 6,000 controls.
Local research is focused on the candidate gene
approaches and the genetic influence on the differences in treatment response.
We are part of the IMSGC (International Multiple
Sclerosis Genetic Consortium) – and the Wellcome
Trust Case Control Consortium (WTCCC), where
23 research groups from 15 countries are performing the largest set of MS genome-wide association
study (GWAS), genotyping 11,000 cases and 11,000
controls using 500,000 SNP chip. Primary results
have elucidated associations to more than 100
gene variations (SNPs). Following this collaboration we are joining the Immunochip Consortium,
where 1,000 Danish cases and 1,000 Danish
controls participate in a large scale genetic analysis,
investigating best genes/regions/SNPs in MS as
well as 9 other autoimmune diseases, together with
other international MS groups, looking for shared
autoimmune genes.
The risk of MS has been increasing over the last
50 years, especially among women older than 40.
On this background we have initiated a PhD project
looking at aspects of gender differences, including
different treatment responses.
Furthermore, we have initiated a large-scale vitamin D PhD project, investigating gene variations
within the vitamin D pathway, and the importance
of vitamin D in clinical and immunological disease
activity.
In addition, we have collected more than 800
questionnaires from MS patients dealing in detail
with lifestyle and environmental exposure, giving the possibility to study gene-environmental
interaction.
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
19
Research activities 2010
Neuroimmunology
Neuroimmunology research group:
Finn Sellebjerg, Helle Bach Søndergaard, Poul Erik
Hyldgaard Jensen, Jeppe Romme Christensen, Lars
Börnsen, Rikke Ratzer, Per Soelberg Sørensen
Immunological studies
It is becoming increasingly clear that relapsing-remitting MS is caused by repeated attacks of inflammatory demyelination and axonal damage. These
attacks are initiated by inflammatory cells that are
activated within the immune systems, recirculate
in blood, and access the brain and spinal cord by
crossing the different blood-brain barrier systems.
Based on animal experiments, MS has been thought
to be mainly a T cell-driven disease. Clinical trials
do, however, show that in addition to treatment
with natalizumab, that blocks the migration of all
mononuclear cells into the CNS, B cell depletion is
also efficacioius in relapsing-remitting MS. More
recent studies have suggested that even in progressive MS, which has been thought to be caused
mainly by neurodegenerative processes, inflammation may be crucial in the pathogenesis.
We study the mechanism of immune activation
in MS, addressing the reactivity of subsets of T cells
and B cells to autoantigens expressed in the brain
and spinal cord, and address how these and other
leukocytes contribute to the activation of T cells.
We also study the effect of immunomodulatory
treatment on these processes, and focus specifically
on the mechanism of action of interferon-beta since
recent studies from our laboratory have suggested
that endogenous production of this cytokine may
have a protective role in MS.
In other studies we use flow cytometry to
study the phenotype of individual, circulating
lymphocytes by measuring the binding of fluorochrome-coupled, monoclonal antibodies to distinct
molecules. By combining the analysis of different
molecules expressed on the cell surface, these cells
can be divided into a large number of functionally
relevant subtypes, which can be quantitated both
in relative and absolute terms. We are currently
studying an array of activation and differentiation
markers on T cell subsets, B cells, NK cells, monocytes and dendritic cells to explore the activation
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DANISH Mult iple sclerosis CEN TER annual report 2010
status of these cell types in patients with relapsingremitting, primary and secondary progressive MS.
These studies will provide novel insights into immune activation in subtypes of MS.
Molecular biology
Activation of immune responses depends on
interactions between different immune cells and
coordinated, tightly regulated expression of a
vast number of molecules within single cells.
Gene expression is controlled by the activity of
transcription factors that are either constitutively
expressed in active forms, expressed in forms that
require activation by other signals, or are inducible on cellular activation. The transcription factors
direct the expression of messenger RNA (mRNA)
from the genes encoded by the DNA sequence,
and after export from the nucleus the mRNA
provides a template for protein synthesis on
ribosomes in the cytosol. Within the last decade
it has become apparent that endogenous, small
RNA molecules termed microRNA (miRNA) have
a key role in regulating the translation of protein
from mRNA in the cytosol. MiRNA can either
induce the degradation of mRNA, or can inhibit
the translation of mRNA into protein by binding
to the 3’ untranslated region of mRNA molecules.
Furthermore, the accessibility of a genomic region
can be regulated by epigenetic modifications of
the DNA strand.
Recent studies have identified miRNA molecules
that are differentially expressed in MS patients
and healthy controls, and it has been suggested
that pathogenic immune activation in MS may,
indeed, reflect changes in miRNA expression.
We have studied miRNA expression in MS, and
have found that even patients with MS in clinical
remission show clear changes in the expression
of miRNA compared to healthy control subjects.
Furthermore, we have identified miRNA molecules
that are specifically regulated by treatment with
interferon-beta. We are now studying the extent
to which miRNA expression changes in pregnant
women with MS, as pregnancy is known to dampen
disease activity in relapsing-remitting MS. These
studies are complemented by mRNA expression
studies in subtypes of mononuclear cells, isolated
by immunomagnetic technology, from patients
with relapsing-remitting, primary and secondary
progressive MS.
Taken together our studies provide novel insights
into the molecular mechanisms of the pathogenic
immune responses in MS. As miRNA can now be
therapeutically introduced into specific human cells,
the identification of miRNAs that can modulate
pathogenic immune responses have a strong potential for the treatment of MS in the future.
Biomarker studies
The term biomarker is used for gene products or
proteins that can be measured in blood or other
body fluids, and reflects a pathogenetically or therapeutically relevant in vivo process. Immunological
and molecular biology studies provide the platform
for the development of biomarkers, but the validation of these also requires access to collections of
well characterized samples from MS patients, who
are followed prospectively. Such biomarker studies
can provide insights into the pathogenesis of MS
and our understanding of the therapeutic effects of
immunomodulatory and immunosuppressive treatments. The development of biomarkers that can
serve as surrogate outcomes in clinical trials is an
important aim of the ongoing biomarker research at
our center.
We have studied the immunological effects of
treatment with natalizumab, interferon-beta and
glatiramer acetate. The studies have resulted in the
validation of biomarkers that may reflect the therapeutic effect of treatment better than the currently
used biomarkers, and are now being studied in
clinical trials of patients with primary and secondary progressive MS.
We continue to study the mechanisms and effects of antibodies to biopharmaceutical therapies
– interferon-beta and natalizumab – in MS. Most
recently we have shown that although antibody
responses to glatiramer acetate develop during therapy, they do not appear to influence the response to
therapy. Finally, we have identified immune activation markers that are upregulated in a subgroup of
patients treated with interferon-beta. This response
is associated with increased disease activity during
interferon-therapy. We are now exploring how this
response is induced and how it may increase the
pathogenic processes in MS.
With the introduction of a number of new MS
therapeutics in the coming years, a better understanding of the different therapies is urgently
needed. Indeed, some patients may do well on a
safe first-line therapy with moderate efficacy, others require more efficacious therapies which are
usually associated with an increased risk of severe
side effects. We will continue to study how genetic
markers and other biomarkers can be used to tailor
individual MS therapy.
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
21
Research activities 2010
Neuropathology
Neuropathology research group:
Per Soelberg Sørensen, Stephan Bramow,
(Henning Laursen, Laboratory of Neuropathology)
In 2010 we published a scientific work showing
that whereas demyelination was less profound in
brains of primary progressive patients compared to
secondary progressive patients, demyelination in
the spinal cord was similar.
We also demonstrated that remyelinated areas
had increased vulnerability and recurrent demyelination in the remyelinated areas were more
frequent than appearance of new demyelinating
plaques. This could explain why patients often
develop recurrence of symptoms in new relapses.
We also showed that diffuse new inflammation correlated with active focal demyelination emphasizing the necessity of an action on both sides of the
blood-brain-barrier for new treatments of progressive MS.
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DANISH Multi ple sclero sis CENTER ann ual report 2010
Routine analyses in
Neuroimmunology
Laboratory
Neuroimmunology Laboratory
research group:
Poul Erik H. Jensen, laboratory technicians: Joy
Mendel-Hartvig, Michael Kolbjørn Jensen, Vibeke
Fuglholt, Rikke Larsen.
Diagnostic evaluation
The presence in CSF of oligoclonal IgG-bands is of
interest in the diagnosis of Multiple Sclerosis (MS).
In 2010 we have analyzed 813 patient samples,
using isoelectric focusing of CSF and corresponding plasma samples for the characterization of IgG
bands.
In the autoimmune disease Myasthenia gravis
(MG), autoantibodies against the acetylcholine
receptor (AChR) may cause a diminished binding of ACh on muscular surfaces and thereby a
reduced impulse transmission to the postsynaptic
membrane of the neuromuscular endplate occurs.
For diagnostic and therapeutic purposes, we
measure the concentrations of these autoantibodies from patient serum samples, using a radioimmunoassay kit, and in 2010 we analyzed 1324
patient samples.
Measurement of neutralizing antibodies
Subgroups of MS patients, treated with Interferonbeta or Tysabri, generate neutralizing antibodies,
which diminish the therapeutic effects. Interferonbeta molecules bind to leucocytes and a specific
up-regulation of MxA mRNA in the cells occur.
Neutralizing antibodies may abolish this effect,
and therefore we measure the neutralization of
Interferon-beta by antibodies in new cell-culture
assay based on luciferase-induced expression, and
further by the MxA mRNA-expression as a biological response to treatment with Interferon-beta. In
2010 we have analyzed 1029 patient samples for
neutralizing antibodies, and 151 patient samples
for MxA mRNA expression. Furthermore, we have
screened 165 patient samples for Interferon-beta
binding antibodies using an ELISA-assay.
The action of Tysabri differs from Interferonbeta, since it blocks mononuclear cell binding to
endothelial cells (alpha-4 integrin antagonist). In
this way Tysabri inhibits mononuclear cells from
entering the central nervous system. The generation
of neutralizing antibodies to Tysabri in MS patients
blocks the biological effects of Tysabri. In 2010 we
analyzed 572 blood samples for the presence of
antibodies to Tysabri by ELISA.
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
23
Scientific
publications,
prizes,
collaboration,
acknowledgements
Scientific publications 2009-2010
Prizes
Honorary offices
Scientific collaboration
Acknowledgements
24
DANISH Multi ple sclero sis CENTER ann ual report 2010
DA NISH Mu lti p le sclerosis CENTER ann ual rep ort 2010
25
Scientific publications
Publications 2009
Peer reviewed original papers
Kemppinen A, Suvela M, Tienari PJ, Elovaara I, Koivisto
K, Pirttilä T, Reunanen M, Baumann P, Hillert J,
Lundmark F, Oturai A, Ryder L, Harbo H, Celius EG,
Palotie A, Daly M, Peltonen L, Saarela J. MYO9B
polymorphisms in multiple sclerosis. Eur J Hum Genet
2009;17(6):840-3.
Khademi M, Börnsen L, Rafatnia F, Andersson M,
Brundin L, Piehl F, Sellebjerg F, Olsson T. The effects
of natalizumab on inflammatory mediators in multiple
sclerosis: prospects for treatment-sensitive biomarkers. Eur J Neurol 2009;16: 528-36.
Sellebjerg F, Börnsen L, Khademi M, Krakauer M, Olsson T, Frederiksen JL, Sorensen PS. B cell chemokine
CXCL13 in cerebrospinal fluid in active MS. Neurology 2009;73: 2003-10.
Sellebjerg F, Börnsen L, Khademi M, Krakauer M, Olsson
T, Frederiksen JL, Sørensen PS. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in
active MS. Neurology 2009;73(23):2003-10.
Koch-Henriksen N, Sorensen PS, Bendtzen K, Flachs EM.
The clinical effect of neutralizing antibodies against
interferon-beta is independent of the type of interferon-beta used for patients with relapsing-remitting
multiple sclerosis. Mult Scler 2009;15(5):601-5.
Hedegaard CJ, Chen N, Sellebjerg F, Sørensen PS, Leslie
RG, Bendtzen K, Nielsen CH. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in
patients with multiple sclerosis: a role in regulating
cytokine responses to MBP. Immunology 2009;128(1
Suppl):e451-61.
Nielsen TR, Rostgaard K, Askling J, Steffensen R,
Oturai A, Jersild C, Koch-Henriksen N, Sørensen
PS, Hjalgrim H. Effects of infectious mononucleosis
and HLA-DRB1*15 in multiple sclerosis. Mult Scler
2009;15(4):431-6.
Hesse D, Sellebjerg F, Sorensen PS. Absence of MxA
induction by interferon beta in patients with MS
reflects complete loss of bioactivity. Neurology
2009;73(5):372-7.
O’Connor P, Comi G, Montalban X, Antel J, Radue EW,
de Vera A, Pohlmann H, Kappos L; FTY720 D2201
Study Group. Oral fingolimod (FTY720) in multiple
sclerosis: two-year results of a phase II extension
study. Neurology 2009;72(1):73-9.
Sellebjerg F, Krakauer M, Hesse D, Ryder LP, Alsing I,
Jensen PE, Koch-Henriksen N, Svejgaard A, Soelberg
Sørensen P. Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation. Eur J Neurol 2009;16(12):1291-8.
Hesse D, Frederiksen JL, Koch-Henriksen N, Schreiber
K, Stenager E, Heltberg A, Ravnborg M, Bendtzen
K, Sellebjerg F, Sorensen PS. Methylprednisolone
does not restore biological response in multiple
sclerosis patients with neutralizing antibodies against
interferon-beta. Eur J Neurol 2009;16(1):43-7.
Enevold C, Oturai AB, Sørensen PS, Ryder LP, KochHenriksen N, Bendtzen K. Multiple sclerosis and
polymorphisms of innate pattern recognition receptors TLR1-10, NOD1-2, DDX58, and IFIH1. J Neuroimmunol 2009;212(1-2):125-31.
Ravnborg M, Bendtzen K, Christensen O, Jensen PE,
Hesse D, Tovey MG, Sørensen PS. Treatment with
azathioprine and cyclic methylprednisolone has little
or no effect on bioactivity in anti-interferon beta
antibody-positive patients with multiple sclerosis.
Mult Scler 2009;15(3):323-8.
Sorensen PS, Mellgren SI, Svenningsson A, Elovaara I,
Frederiksen JL, Beiske AG, Myhr KM, Søgaard LV,
Olsen IC, Sandberg-Wollheim M. NORdic trial of oral
Methylprednisolone as add-on therapy to Interferon
beta-1a for treatment of relapsing-remitting Multiple
Sclerosis (NORMIMS study): a randomised, placebocontrolled trial. Lancet Neurol 2009:519-29.
Oturai AB, Koch-Henriksen N, Petersen T, Jensen PE,
Sellebjerg F, Sorensen PS. Efficacy of natalizumab
in multiple sclerosis patients with high disease
activity: a Danish nationwide study. Eur J Neurol
2009;16(3):420-3.
26
Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF,
Rauschka H, Schmidbauer M, Laursen H, Sorensen
PS, Lassmann H. The relation between inflammation
and neurodegeneration in multiple sclerosis brains.
Brain 2009;132(Pt5):1175-89.
DANISH Mult iple sclerosis CEN TER annual report 2010
Giovannoni G, Barbarash O, Casset-Semanaz F, King J,
Metz L, Pardo G, Simsarian J, Sørensen PS, Stubinski
B; Rebif New Formulation Study Group. Safety and
immunogenicity of a new formulation of interferon
beta-1a (Rebif New Formulation) in a Phase IIIb
study in patients with relapsing multiple sclerosis:
96-week results. Mult Scler 2009;15(2):219-28.
Jagodic M, Colacios C, Nohra R, Dejean AS, Beyeen AD,
Khademi M, Casemayou A, Lamouroux L, Duthoit
C, Papapietro O, Sjöholm L, Bernard I, Lagrange D,
Dahlman I, Lundmark F, Oturai AB, Soendergaard
2009
2010
HB, Kemppinen A, Saarela J, Tienari PJ, Harbo HF,
Spurkland A, Ramagopalan SV, Sadovnick DA, Ebers
GC, Seddighzadeh M, Klareskog L, Alfredsson L,
Padyukov L, Hillert J, Clanet M, Edan G, Fontaine
B, Fournié GJ, Kockum I, Saoudi A, Olsson T. A
role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis. Sci Transl Med
2009;1(10):10ra21.
Other publications
Waldemar G, Boysen GM, Høgenhaven H, Knudsen GM,
Sørensen PS, Vissing J. Neurologi. I: Schaffalitzky de
Muckadell OB; Haunsø S, Vilstrup H (red.). Medicinsk
Kompendium 17. Udgave, Nyt Nordisk Forlag Arnold
Busck, København 2009; pp.2418-2623.
Sorensen PS. How effective is natalizumab as second-line
treatment for multiple sclerosis in daily clinical praxis?
Eur J Neurol 2009;16(3):287-8.
Sorensen PS. Management of patients with neutralizing
antibodies against interferon-beta: stop Interferon-beta
therapy or wait for the antibodies to go away? Eur J
Neurol 2009;16(1):1-2.
Publications of clinical trials
in which we have been
investigators:
Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O,
Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J,
King J, Komoly S, Lubetzki C, Montalban X, Myhr KM,
Ravnborg M, Rieckmann P, Wynn D, Young C, Filippi
M; PreCISe study group. Effect of glatiramer acetate on
conversion to clinically definite multiple sclerosis in
patients with clinically isolated syndrome (PreCISe
study): a randomised, double-blind, placebo-controlled
trial. Lancet. 2009 Oct 31;374(9700):1503-11.
Publications 2010
Peer reviewed original papers
Kemppinen A, Suvela M, Tienari PJ, Elovaara I, Koivisto
K, Pirttilä T, Reunanen M, Baumann P, Hillert J,
Lundmark F, Oturai A, Ryder L1, Harbo H, Celius
EG, Palotie A, Daly M, Peltonen L, Saarela J. MYO9B
polymorphisms in multiple sclerosis. Eur J Hum Genet
2009;17(6):840-3.
Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N,
Lucchinetti CF, Sørensen PS, Laursen H. Demyelination
versus remyelination in progressive multiple sclerosis.
Brain. 2010 Oct;133(10):2983-98.
Polman CH, Bertolotto A, Deisenhammer F, Giovannoni
G, Hartung HP, Hemmer B, Killestein J, McFarland
HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold
SC, Schellekens H, Sørensen PS. Recommendations
for clinical use of data on neutralising antibodies to
interferon-beta therapy in multiple sclerosis. Lancet
Neurol. 2010 Jul;9(7):740-50.
Enevold C, Oturai AB, Sørensen PS, Ryder LP, KochHenriksen N, Bendtzen K. Polymorphisms of innate
pattern recognition receptors, response to interferonbeta and development of neutralizing antibodies in multiple sclerosis patients. Mult Scler. 2010
Aug;16(8):942-9.
International Multiple Sclerosis Genetics Conssortium
(IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are
novel multiple sclerosis susceptibility loci. Genes Immun. 2010 Jul;11(5):397-405.
Ravnborg M, Sørensen PS, Andersson M, Celius EG, Jongen
PJ, Elovaara I, Bartholomé E, Constantinescu CS, Beer K,
Garde E, Sperling B. Methylprednisolone in combination
with interferon beta-1a for relapsing-remitting multiple
sclerosis (MECOMBIN study): a multicentre, doubleblind, randomised, placebo-controlled, parallel-group
trial. Lancet Neurol. 2010 Jul;9(7):672-80. Epub 2010
Jun 9. Erratum in: Lancet Neurol. 2010 Aug;9(8):759.
Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z,
Montalban X, Du Pasquier RA, Polman CH, Sorensen
PS, Hemmer B. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010
Aug;17(8):1019-32.
Hesse D, Krakauer M, Lund H, Søndergaard HB, Langkilde
A, Ryder LP, Sorensen PS, Sellebjerg F. Breakthrough
disease during interferon-[beta] therapy in MS: No
signs of impaired biologic response. Neurology. 2010
May 4;74(18):1455-62.
Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology.
Lancet Neurol. 2010 May;9(5):520-32. Review.
DA NISH Mu ltip le scl erosis CENTER ann ual rep ort 2010
27
Scientific publications
Radue EW, Stuart WH, Calabresi PA, Confavreux C,
Galetta SL, Rudick RA, Lublin FD, Weinstock-Guttman
B, Wynn DR, Fisher E, Papadopoulou A, Lynn F,
Panzara MA, Sandrock AW; SENTINEL Investigators.
Natalizumab plus interferon beta-1a reduces lesion
formation in relapsing multiple sclerosis. J Neurol Sci.
2010 May 15;292(1-2):28-35.
Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P,
Hamlett A, Musch B, Greenberg SJ; CLARITY Study
Group. A placebo-controlled trial of oral cladribine for
relapsing multiple sclerosis. N Engl J Med. 2010 Feb
4;362(5):416-26.
Comi G, O’Connor P, Montalban X, Antel J, Radue
EW, Karlsson G, Pohlmann H, Aradhye S, Kappos L;
FTY720D2201 Study Group. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results.
Mult Scler. 2010 Feb;16(2):197-207.
Ockinger J, Stridh P, Beyeen AD, Lundmark F, Seddighzadeh M, Oturai A, Sørensen PS, Lorentzen AR,
Celius EG, Leppä V, Koivisto K, Tienari PJ, Alfredsson L, Padyukov L, Hillert J, Kockum I, Jagodic M,
Olsson T. Genetic variants of CC chemokine genes in
experimental autoimmune encephalomyelitis, multiple
sclerosis and rheumatoid arthritis. Genes Immun. 2010
Mar;11(2):142-54.
Jakkula E, Leppä V, Sulonen AM, Varilo T, Kallio S, Kemppinen A, Purcell S, Koivisto K, Tienari P, Sumelahti ML,
Elovaara I, Pirttilä T, Reunanen M, Aromaa A, Oturai
AB, Søndergaard HB, Harbo HF, Mero IL, Gabriel SB,
Mirel DB, Hauser SL, Kappos L, Polman C, De Jager PL,
Hafler DA, Daly MJ, Palotie A, Saarela J, Peltonen L.
Genome-wide association study in a high-risk isolate for
multiple sclerosis reveals associated variants in STAT3
gene. Am J Hum Genet. 2010 Feb 12;86(2):285-91.
Mero I-L, ÅR Lorentzen, Ban M, Smestad C, Celius EG,
Aarseth J, Myhr K-M, Link J, Hillert J, Olsson T,
Kockum I, Masterman T, Oturai AB, Søndergaard HB,
Sellebjerg F, Saarela J, Kemppinen A, Elovaara I, Spurkland A, Dudbridge F, Lie BA, Harbo HF. A rare variant
of the TYK2 gene is confirmed to be associated with
multiple sclerosis. Eur J Hum Genet 2010;18:502-4.
28
DANISH Mult iple sclerosis CEN TER annual report 2010
2010
Nohra R, Beyeen AD, Guo JP, Khademi M, Sundqvist E,
Hedreul MT, Sellebjerg F, Smestad C, Oturai AB, Harbo
HF, Wallström E, Hillert J, Alfredsson L, Kockum I,
Jagodic M, Lorentzen J, Olsson T. RGMA and IL21R
show association with experimental inflammation and
multiple sclerosis. Genes Immun. 2010;11(4):279-93.
Ghezzi A, Banwell B, Boyko A, Amato MP, Anlar B,
Blinkenberg M, Boon M, Filippi M, Jozwiak S,
Ketelslegers I, Kornek B, Lim M, Lindstrom E, Nadj C,
Neuteboom R, Rocca MA, Rostasy K, Tardieu M, Wassmer E,Catsman-Berrevoets C, Hintzen R. The management of multiple sclerosis in children: a European view.
Mult Scler. 2010 Oct;16(10):1258-67.
Other publications
Paulson OB, Gjerris F, Sorensen PS (eds.). Klinisk
Neurologi og neurokirurgi, 5. udgave. FADL’s Forlag,
København 2010, ISBN 978-87-7749-550-2.
Sorensen PS, Paulson OB, Gjerris F (eds.). Nervesystemets sygdomme, 3. udgave. Gads forlag, København
2010, ISBN 978-87-12-044472-7.
Publications of clinical trials
in which we have been
investigators:
Radue EW, Stuart WH, Calabresi PA, Confavreux C,
Galetta SL, Rudick RA, Lublin FD, Weinstock-Guttman
B, Wynn DR, Fisher E, Papadopoulou A, Lynn F,
Panzara MA, Sandrock AW; SENTINEL Investigators.
Natalizumab plus interferon beta-1a reduces lesion
formation in relapsing multiple sclerosis. J Neurol Sci.
2010 May 15;292(1-2):28-35.
Comi G, O’Connor P, Montalban X, Antel J, Radue
EW, Karlsson G, Pohlmann H, Aradhye S, Kappos L;
FTY720D2201 Study Group. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results.
Mult Scler. 2010 Feb;16(2):197-207.
Prizes and honorary offices
Prizes
Annette Oturai
»Roseliv-Prize« 100.00 DDK donated for many years of scientific work within multiple
sclerosis (2009/2010)
Honorary offices
A: National
Finn Sellebjerg
Chairman of the Danish Society for Research in Multiple Sclerosis (DAREMUS)
Chairman and board member of The Research Committeé of the Danish Multiple Sclerosis
Society
Annette Oturai
Board member of the Danish Society for Research in Multiple Sclerosis (DAREMUS)
Board member of the Torben Fogh and Erik Trier foundation. 2006Per Soelberg Sørensen
Board member of the Gangsted Foundation, 2008Morten Blinkenberg
Board member of The Research Committeé of the Danish Multiple Sclerosis Society
B: International
Finn Sellebjerg
Member of the European Federation of Neurological Societies »Scientist Panel on MS and
Demyelinating Diseases«. Member of the European Council for Treatment and Research in
Multiple Sclerosis council.
Per Soelberg Sørensen
Treasurer, European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS),
2010Member of the editorial board, Multiple Sclerosis Journal, 2010Member of the editorial board, European Journal of Neurology, 2003Chairman, Teaching Course Committee, European Committee for Treatment and Research in
Multiple Sclerosis (ECTRIMS), 2010
DA NISH Mu ltip le scl erosis CENTER ann ual rep ort 2010
29
Scientific collaboration
Scientific collaboration
National
The Danish Multiple Sclerosis Register, Copenhagen
University Hospital, Rigshospitalet, Copenhagen, (Nils
Koch-Henriksen, MD)
Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, (Peter Garred, Jacob
Larsen MD, Lars Ryder , Klaus Rieneck, MD, Hans O.
Madsen, MD)
Institute for Inflammatory Research, Copenhagen
University Hospital, Rigshospitalet, (Christian EnevoldJohansen MD, Professor Klaus Bendtzen)
Department of Clinical Neuroscience and Centrum
for Molecular Medicine Karolinska Insitutet at
Karolinska University Hospial, Solna 171 76 Stockholm,
Sweden (Professor Tomas Olsson, associate Professor
Ingrid Kockum)
Department of Neurology, Lund University Hospital,
Lund, Sweden (Professor Magnhild Sandberg-Wollheim)
Department of Epidemiology Research, Statens Serum
Institut, Copenhagen, (Trine Rasmussen Nielsen, MD,
Henrik Hjalgrim, MD, professor Mads Melbye, Peter
Michael Bager, ph.d.)
Department of Neurology, Gothenburg University Hospital, Gothenburg, Sweden (Professor Oluf Andersen,
Professor Jan Lycke)
Department of Human Genetics, Aarhus University,
Denmark (Bjørn Andersen Nexø)
Sankt Joseph Hospital and Ruhr University, Bochum,
Germany (Professor Ralf Gold)
Laboratory of Neuropathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, (Henning
Laursen, MD)
Department of Neurology, Turku and University of
Turku (Associate Professor Juha-Pekka Erälinna)
Danish Research Center for Magnetic Resonance,
Hvidovre Hospital, (Professor Olaf Paulsen, Professor
Hartwig Siebner, Ellen Garde, MD, Henrik Lund, MS)
30
Department of Neurology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden (Professor
Jan Hillert, Eva Åkesson, MD, Helena Modin, MD,
Associate Professor Anna Fogdell-Hahn)
Department of Neurology, Hôpital Henri Mondor,
Créteil, France.
University of Helsinki, Finland (Professor Markus
Färkkilä)
Faculty of Life Sciences, University of Copenhagen,
Denmark (Professor Christian M.O. Kapel, Professor
Allan Roepstorff, Professor Stig Milan Thamsborg)
Institute for Molecular Medicine Finland, University
of Helsinki, Finland (Janna Saarela)
Cell Therapy Unit, The Blood bank, Department of Clinical Immunology, Rigshospitalet (Anne Fischer-Nielsen,
MD, Roberto Oliveri, MD)
University of Cambridge, Neurology Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom (Stephen Sawcer, MD, Professor Alastair Compston)
International
International Multiple Sclerosis Genetic Consortium
(IMSG): MS Genetic collaboration between 15 countries
from Europe, USA, Canada and Australia
Nordic MS Genetic Network: Collaboration between the
Nordic countries: Sweden (Huddinge, Lund, Gothenburg, Stockholm), Norway (Oslo, Bergen), Finland
(Helsinki) and Denmark (Copenhagen)
Immunochip Consortium: Autoimmune diseases genetic
collaboration between 15 countries from Europe, USA,
Canada and Australia
Institute of Immunology, Rikshospitalet, University
Hospital, Oslo, Norway (Anne Spurkland, MD, Hanne F.
Harbo, MD, professor Frode Vartdal)
Department of Immunopathology, Brain Research
Center, Medical University of Vienna, Vienna, Austria.
(Professor Hans Lassmann and Josa Frischer, MD)
Department of Neurology, Ullevål University Hospital,
Oslo, Norway (Elisabeth G Celius, MD)
Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA (Professor Claudia F. Lucchinetti)
Department of Neurology, Haukeland Hospital, Bergen,
Norway (Professor Kjell-Morten Myhr)
VU Medical Centre, Amsterdam, The Netherlands (Professor Chris Polman)
DANISH Mult iple sclerosis CEN TER annual report 2010
Utrecht University, utrecht, the Netherlands (professor Hub
Schellekens)
Innsbruck Medical University, Innsbruck, Austria (professor Florian Deisenhammer)
Heinrich-Heine-University, Düsseldorf, Germany (professor
Hans-peter Hartung)
General Charles University, prague, czech republic (professor eva Havrdova)
Ospedale Universitario San Luigi, torino, Italy (professor
Auturio Bertolotto)
Hospital Universitari Vall d’Hebron, Barcelona, Spain (professor Xavier Montalban)
Queen Square, london, the united Kingdom (professor
Gavin Giovannoni)
Collaboration with pharmaceutical
companies on clinical trials
DMSC staff seminar 2010.
Novartis, Denmark
Merck Serono Nordic, Denmark, Norway and
Sweden
Biogen idec, Denmark and uSA
teva/Aventis, Israel and Denmark
Sanofi-aventis, Denmark
Bayer Schering, Germany
Genmab, Denmark
Genzymes, Holland
Glaxo Smith-Kline
ovamed, Germany
Swedish orphan, Sweden
Acknowledgements
Danish Multiple Sclerosis Research Center has received generous support from a number of
public and private research funds:
Danish Medical research council
Danish MS Society
Warwara larsen Foundation
rigshospitalets Scientific Board
eu Sixth Framework programme
Brdr. røjne Holding
Jeppe Juel Memorial legacy
roFar Foundation
roche Denmark
2
DANISH MultIple Sclero SIS ceNter AN NuAl report 2010
the Danish Strategic research council
the Johnsen Memorial Foundation
the lounkær Foundation
Biogen idec
Sanofi-aventis
Merck Serono
ejner Jonasson og Hustrus mindelegat
Fondsbørsvekselerer Henry Hansen og Hustrus
legat
DANISH Mult Iple ScleroSIS ceN ter ANNuAl report 2010
31
DepArtMeNt of Neurology · tHe NeuroScIeNce ceNtre ·
copeNHAgeN uNIverSIty HoSpItAl · rIgSHoSpItAlet · copeNHAgeN, DeNMArk ·
www.MS-reSeArcH.Dk
Danish
Multiple Sclerosis center
Annual report
2010
DANISH Mult Iple ScleroSIS ceN ter ANNuAl report 2010
1