DOI: 10.1093/brain/awh003
Advanced Access publication November 7, 2003
Brain (2004), 127, 65±72
Striatal neural grafting improves cortical
metabolism in Huntington's disease patients
VeÂronique Gaura,1,2 Anne-Catherine Bachoud-LeÂvi,3,4 Maria-Joao Ribeiro,2 Jean-Paul Nguyen,3,4
Vincent Frouin,2 Sophie Baudic,4 Pierre BrugieÁres,3,4 Jean-FrancËois Mangin,2
Marie-FrancËoise BoisseÂ,3,4 SteÂphane Pal®,1,3 Pierre Cesaro,3,4 Yves Samson,2,5 Philippe Hantraye,1,2
Marc Peschanski3,4 and Philippe Remy1,2,3
CEA-CNRS 2210, 4 place du geÂneÂral Leclerc,
91401 Orsay Cedex, 2CEA, Service Hospitalier FreÂdeÂric
Joliot, DRM, 4 place du geÂneÂral Leclerc, 91401 Orsay
Cedex, 3DeÂpartement de Neurosciences, CHU Henri
Mondor, AP-HP et FaculteÂ de MeÂdecine Paris XII,
51 avenue du Mal de Lattre de Tassigny, 94010 CreÂteil
Cedex, 4INSERM U421, IM3, FaculteÂ de MeÂdecine Paris
XII, 8 rue du geÂneÂral Sarrail, 94010 CreÂteil Cedex and
5Urgences Ce
Â reÂbro-Vasculaires, CHU PitieÂ-SalpeÂtrieÁre,
Paris, France
1URA
Huntington's disease is a hereditary disease in which
degeneration of neurons in the striatum leads to motor
and cognitive de®cits. Foetal striatal allografts reverse
these de®cits in phenotypic models of Huntington's
disease developed in primates. A recent open-label pilot
study has shown some clinical improvement or stabilization in three out of ®ve Huntington's disease patients
who received bilateral striatal grafts of foetal neurons.
We show here that the clinical changes in these three
patients were associated with a reduction of the striatal
and cortical hypometabolism, demonstrating that grafts
were able to restore the function of striato-cortical
loops. Conversely, in the two patients not improved by
the grafts, striatal and cortical hypometabolism progressed over the 2-year follow-up. Finally, detailed
anatomical±functional analysis of the grafted striata,
enabled by the 3D fusion of MRI and metabolic images,
revealed considerable heterogeneity in the anatomic and
metabolic pro®les of grafted tissue, both within and
between Huntington's disease patients. Our results
demonstrate the usefulness of PET measurements of
brain glucose metabolism in understanding the effects
of foetal grafts in patients with Huntington's disease.
Keywords: cortex; foetal graft; Huntington's disease; metabolism; striatum
Abbreviations: CMRGlu = absolute glucose metabolic rate; SPM = statistical parametric mapping
Introduction
Huntington's disease is a dominant autosomal neurodegenerative disease beginning during adulthood and leading
to dementia and death within 20 years. To date, no curative
nor neuroprotective therapies are effective to arrest the
progression of this disease. Convergent neuropsychological,
imaging and pathological studies have shown that the
degenerative process in Huntington's disease affects ®rst
and foremost the striatum, and more speci®cally the Golgi
type II (`medium-spiny') neurons (Peschanski et al., 1995;
Cattaneo et al., 2001). This striatal neurodegeneration is
revealed by the progressive atrophy of the caudate and
putamen, and by a decrease of striatal metabolism that
precedes symptom onset in gene carriers (Mazziotta et al.,
1987; Grafton et al., 1992; Antonini et al., 1996). At more
advanced stages of Huntington's disease, the striatal hypometabolism progresses and is associated with a decrease in
cortical metabolism. This cortical hypometabolism has been
attributed to the dysfunction of the cortico-striato-thalamocortical loops induced by the striatal disease (Young et al.,
1986; Berent et al., 1988; Kuwert et al., 1990; Kremer et al.,
1999), but might also be related to the delayed degeneration of
cortical neurons associated with the disease process.
Brain Vol. 127 No. 1 ã Guarantors of Brain 2003; all rights reserved
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Summary
Correspondence to: Philippe Remy, URA CEA-CNRS 2210,
Service Hospitalier FreÂdeÂric Joliot, 4 place du geÂneÂral
Leclerc, 91401 Orsay Cedex, France
E-mail: [email protected]
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V. Gaura et al.
Table 1 Patients' characteristics at baseline (T0)
Patient
Age
(years)/sex
Handedness
CAG repeats
(n)
Disease duration
(years)
TFC
MDRS
1
2
3
4
5
35/M
53/M
43/M
38/M
48/F
Right
Right
Left
Right
Right
49
43
41
51
44
5
7
6
9
4
11
12
12
6
11
130
138
141
113
137
TFC = total functional capacity score (Shoulson, 1981); MDRS = Mattis dementia rating scale score; M =
male; F = female.
Subjects and methods
Subjects
Ethical permission was obtained from the French National Ethics
Committee and the CreÂteil University Hospital Ethics Committee,
and written informed consent was given by all subjects. The followup protocol was based upon the full Core Assessment Program for
Intracerebral Transplantation in Huntington's disease (Quinn et al.,
1996).
Clinical evaluation
Five patients (mean age 43.4 6 7.3 years) with clinical symptoms for
2±7 years and genetically identi®ed Huntington's disease were
included (Table 1) (Bachoud-LeÂvi et al., 2000b). In brief, all patients
had choreic movements, dystonia, gait disturbances, cognitive
de®cits and psychiatric symptoms (irritability, depression). MRI
revealed various degrees of atrophy of striatal nuclei. The patients
had a 2-year clinical follow-up before the ®rst graft in the right
striatum (T0). Twelve months later, they were grafted in the left
striatum (T1), and the ®nal evaluation took place 1 year after this
second graft (T2). Each of these yearly evaluations comprised a large
battery of neuropsychological, motor and psychiatric tests detailed
previously (Bachoud-LeÂvi et al., 2000a, b).
Transplantation procedure
Small blocks of tissue were obtained from the whole ganglionic
eminence of fetuses 7.5±9 weeks post-conception (Bachoud-LeÂvi
et al., 2000b). The tissue was stereotactically grafted in the caudate
and putamen using a needle with a 0.6 mm internal diameter
(Bachoud-LeÂvi et al., 2000a). Two needle tracks aimed at the head of
the caudate and three at the putamen, mainly precommissural.
However, some of these tracks could not be performed in several
patients because of marked striatal atrophy (Bachoud-LeÂvi et al.,
2000a). Immunosuppression with cyclosporine was maintained for
18 months (6 months after the second graft).
MRI and PET scanning procedures
MRI consisted of a T1-weighted SPGR (spoiled gradient recalled
acquisition in the steady state) with inversion-recovery acquisition
allowing a 3D reconstruction with 1.2-mm thick axial slices. The
PET examination was performed with a high-resolution EXACT
HR+ tomograph (CTI/Siemens) using a 3D acquisition, before
transplantation and at T2. Twenty minutes prior to PET examination,
we inserted a radial arterial line under local anesthesia to allow blood
measurements of radioactivity and glucose concentrations. The
subject was positioned in the tomograph with the head maintained
using an individually molded headholder. The room was quiet and
light dimmed during the whole examination. Metabolic images were
acquired 30±50 min after intravenous injection of 118±280 MBq of
[18F]FDG (¯uorodeoxyglucose), and the absolute glucose metabolic
rate (CMRGlu) was calculated using the classical model proposed by
Sokoloff and revised for human PET studies (Fontaine et al., 1999).
Image analysis
First, we used the statistical parametric mapping (SPM) software
(SPM99; Wellcome Department of Cognitive Neurology, London,
UK) (Friston, 1996) to perform a voxel-by-voxel t-test comparison
of pre- and post-graft brain metabolism of each patient with the brain
metabolism obtained in 17 age-matched controls (mean age 42.0 6
8.1 years). In order to have enough power for the statistical analysis
and to avoid any bias, we compared the pre- and post-graft scans of
each patient with the same normal database obtained in 17 controls
to ensure that the changes between both comparisons could only be
related to changes that occurred in the patients, rather than changes
in the normal controls dataset. For that purpose, individual PET
images were transformed to ®t the Talairach's standard stereotaxic
space (Talairach and Tournoux, 1988). The images were then
smoothed with a 8 3 8 3 8 mm Gaussian ®lter to compensate for
intersubject variability of brain anatomy (Friston, 1996). The
statistical threshold of each comparison was set at a conservative
value of P < 0.0005, with an extent threshold >20 voxels (1 voxel =
8 mm3). We then counted the number of voxels in which the
metabolism was signi®cantly lower than in controls at this statistical
level, both in the striatum and in the cortex. These numbers were
compared individually at baseline (T0) and at the end of the study
(T2).
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The implantation of foetal striatal neuroblasts into the
striatum of animal models of Huntington's disease induced
the reconstruction of impaired neural circuits (Clarke et al.,
1988; Sirinathsinghji et al., 1988; Wictorin, 1992), as well as
motor and cognitive improvement (Kendall et al., 1998; Pal®
et al., 1998). Our group recently reported the results of an
open-label pilot study in which ®ve Huntington's disease
patients were grafted with striatal neuroblasts (Bachoud-LeÂvi
et al., 2000b), showing that three of the patients had some
clinical improvement after the graft. Here, we report the
results of follow-up of striatal and cortical metabolism in
these ®ve patients.
PET in grafted Huntington's disease patients
In addition, we quanti®ed the striatal glucose consumption
(CMRGlu) in each patient before and after the graft, using individual
regions of interest (ROIs). For that purpose, metabolic images were
coregistered with the individual MRI obtained at the same timepoint (Mangin et al., 1994). Anatomic ROIs delineating the head of
the caudate nucleus and the putamen in each hemisphere were drawn
on individual MRIs, on all slices where these structures were visible.
We copied all ROIs onto corresponding PET images and calculated
CMRGlu values in each striatal structure.
Finally, we performed a qualitative analysis of the metabolic
pro®le within the striatum of each subject using a 3D superimposition of metabolic images onto the corresponding MR
images. The striatal structures and grafts were also extracted
using an MRI segmentation of the brain of patient 1 to better
individualize the metabolic pro®le of both the grafts and the
surrounding putamen.
Results
Clinical results
Extent of hypometabolism in patients compared
with controls in whole-brain SPM analysis
The number of hypometabolic voxels decreased after the
graft in the striatum and in the cortex of patients 1 and 2,
with most of the cortical improvement occurring in the
frontal lobes. In patient 3, the extent of striatal hypometabolism decreased whereas the cortical hypometabolism
was stable at a low level. In contrast, the striatal hypometabolism worsened after the grafts in patients 4 and 5,
which was associated with a marked spread of the cortical
hypometabolism (Fig. 1).
ROI analysis of the striatal CMRGlu
The amplitude of CMRGlu changes in the striatum between
T0 and T2 differed markedly among patients (Fig. 2).
Compared with baseline values, CMRGlu values averaged
over the right and left striatum increased by 69.8, 28.8 and
7.3% after the grafts in patients 1, 2 and 3, respectively.
Conversely, the striatal CMRGlu values decreased over these
2 years by 25.6 and 38.1% in patients 4 and 5, respectively.
The changes in CMRGlu were highly correlated (r = 0.99, P <
0.0005) with the changes in the number of hypometabolic
voxels in the stiatum measured using SPM (see above). The
global brain rate of glucose consumption increased from T0
to T2 in patients 1, 2 and 3 (from 5.69 to 8.56, 5.19 to 5.75 and
5.75 to 6.38 mmol/min/100 g, respectively), whereas it
decreased in patients 4 and 5 (from 4.88 to 4.64 and 5.53 to
3.99 mmol/min/100 g, respectively).
Qualitative analysis of the striatal metabolism
The superimposition of each metabolic image to the corresponding MRI was used to determine the anatomical±
functional pro®les of the grafted striata (see Fig. 3). In
patient 1, two implants grew markedly in the left putamen
(Fig. 4). These grafts have absolute metabolic values in the
range of the control mean, corresponding to 2.4- and 2.1-fold
over the baseline striatal values in this patients for the anterior
and posterior grafts, respectively. Other grafts in patient 1 and
in the other patients were smaller, and were dif®cult to
discriminate from the host striatum on MRI. Some of these
grafts were associated with a focal increase of metabolism in
the corresponding structure (patient 1, left caudate and right
putamen; patient 2, left caudate and right putamen; patient 3,
right putamen; Fig. 3), while others did not prevent a
progressive decrease of striatal metabolism (patients 4 and 5;
Figures 3 and 5). Finally, one implant formed a hypometabolic cyst in the left putamen of patient 4 (Fig. 3).
Discussion
The follow-up of brain metabolism in Huntington's disease
patients bilaterally grafted with striatal neuroblasts provided
two main results. First, the parallel improvement of clinical
status, striatal metabolism and cortical metabolism in patients
1±3 demonstrates that foetal grafts in the striatum of
Huntington's disease patients are able to reconstruct the
impaired cortico-striato-thalamo-cortical loops. Secondly,
striatal grafts show heterogeneous anatomic and metabolic
pro®les both within and between patients.
After bilateral grafts, patients 1 and 2 were clinically
improved, patient 3 was stabilized, and the disease progressed
in patients 4 and 5 despite the grafts (Bachoud-LeÂvi et al.,
2000b). These clinical changes perfectly match the changes
observed in brain metabolism. In patients 1, 2 and 3 the mean
striatal CMRGlu increased after the grafts, respectively, by
69.8, 28.8 and 7.3%. Moreover, the extent of the cortical
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The clinical results have been detailed elsewhere (BachoudLeÂvi et al., 2000b). In brief, patients 1 and 2 were improved
by the grafts on global cognitive abilities, tests of executive
functions, verbal ¯uency and motor performances. In patient
3, whose main performances were in the normal range at
baseline, a slight decline was observed in some tests of global
cognitive abilities or executive functions, but other tests, such
as verbal ¯uency, improved, and he was able to perform again
daily activities that he previously gave up. Conversely,
patients 4 and 5 did not bene®t from the grafts and performed
markedly worse at the end of follow-up in nearly all tests of
cognitive and motor functions. Clinical outcome was not
clearly related to the degree of striatal atrophy measured at
baseline, though patient 4, who had the more advanced
disease, had a more severe atrophy than the other patients.
The whole striatal volume (left + right) was 4412, 5354, 6759,
2777 and 6504 mm3 in patients 1±5, respectively.
Accordingly, we were not able to identify any relationship
between the technical aspects (e.g. tissue preparation, number
of needle tracks, etc.) of the grafts that were performed in
each patient and the clinical outcome.
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V. Gaura et al.
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Fig. 1 Topography and extent of the brain hypometabolism in each patient before and after the graft compared with a group of 17 agematched controls, revealed by the SPM99 analysis at a statistical level of P < 0.0005. All visible voxels have a metabolic value lower than
control mean minus 4.01 SD, darkest voxels have the highest difference from control values (Z score). The arrows in patients 1 and 2
indicate the improvement of frontal hypometabolism after the graft. The graphs on the right side indicate the number of hypometabolic
voxels before (empty columns) and after (®lled columns) the graft in the striatum, and in the whole cerebral cortex.
PET in grafted Huntington's disease patients
hypometabolism was reduced in patients 1 and 2 and
stabilized in patient 3. These changes were symmetrical
despite the fact that grafts were performed 1 year apart. These
improvements are unlikely to occur by chance considering
the amplitude of the metabolic changes in a region where a
14% decrease is expected on average over this time (Kremer
et al., 1999). The evolution of cortical hypometabolism in
symptomatic Huntington's disease patients has not been
systematically studied, but the parallelism of striatal and
cortical changes in these patients is striking, and therefore
unlikely to occur by chance. Indeed, in the two patients who
were not clinically improved, striatal and cortical hypometabolism worsened. These results support the fact that the
clinical bene®t provided by the grafts in the ®rst three patients
is related to the functional improvement in the impaired
striato-cortical loops. Indeed, it is widely accepted that most
of the motor, cognitive and emotional symptoms observed in
the early stages of Huntington's disease re¯ect fronto-striatal
dysfunction (Brandt and Butters, 1986; Lawrence et al., 1998;
Joel, 2001). In patients 1 and 2, the improvement of frontal
hypometabolism after transplantation is associated with the
improvement of cognitive functions involving striato-frontal
pathways, for example those measured using the verbal
¯uency task or the trail-making tests (Bachoud-LeÂvi et al.,
2000b). This is in line with the results obtained in primate
models of Huntington's disease, in which striatal grafts
improve motor and cognitive de®cits induced by a striatal
lesion (Kendall et al., 1998; Pal® et al., 1998). Finally, it has
been shown in animal models that striatal grafts are able to
reconnect both the striatal afferents and efferents (for a
review see Wictorin, 1992). Bringing together these experimental results and the present study has two major
implications. First, it is possible to improve the function of
striato-cortical loops by grafting foetal cells in the striatum,
which demonstrates that these cells partially replace the
degenerated neurons in the local circuitry. Secondly, the
cortical hypometabolism is reversible in Huntington's
Fig. 3 Striatal metabolism in ®ve patients with Huntington's disease, before (T0) and after (T2) bilateral neural graft in the caudate and
putamen. In each individual, the normalized metabolic images have been superimposed on the corresponding MRI. The right side of the
brain is on the left in the images. In patients 1±3, the arrows indicate grafted tissue in which metabolism increased compared with the
baseline striatal metabolism. In patients 4 and 5, none of the graft was associated with a noticeable increase of metabolism. Note that in
patient 4, a cystic cavity appeared in the grafted left putamen (arrow).
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Fig. 2 Absolute CMRGlu values (mg/100 g tissue/min) in the
whole striatum of the ®ve patients before (empty columns) and
after (®lled columns) the graft. The plain and dotted lines indicate
the normal mean and the normal mean minus 2 SD, respectively.
69
70
V. Gaura et al.
disease, at least at this early stage of the disease, which means
that it is not related only to the degeneration of cortical
neurons. Moreover, this speci®c remote improvement of
frontal cortical metabolism after the striatal grafts supports
the rationale for intrastriatal grafting in Huntington's disease
(Peschanski et al., 1995).
However, a potential limitation of this experimental
treatment is the heterogeneity of clinical and PET changes
after the grafts. In their study, Hauser and colleagues found no
signi®cant worsening in seven patients after bilateral foetal
grafts in the striatum (Hauser et al., 2002). In this group, the
mean striatal metabolism did not change signi®cantly (±2%)
1 year after the second graft; however, no individual data
have been provided. In our study, despite the consistency of
the technique used in the ®ve patients, we found that the
foetal tissue implanted in the striatum of Huntington's disease
patients may have variable anatomical±functional pro®les
even in the same individual, while using a unique suspension
of foetal cells. For example, some grafts grew markedly in the
host striatum, whereas others were dif®cult to distinguish
from the host striatal tissue. Changes in striatal metabolism
were not consistently associated with signal changes on MRI.
In addition, in patient 4, who was initially improved by the
graft, a cyst developed from the graft in the left putamen. If
this cyst was caused by graft rejection, it is important to note
that it was not associated with any increase of glucose
metabolism. These heterogeneous anatomic and metabolic
pro®les of the grafts are in line with the post mortem
observation of the grafts surviving in a single Huntington's
disease patient reported by Freeman et al. (2000). The
explanation of this heterogeneity in graft development and
metabolism remains speculative. It might be related to the
number of surviving cells and to the proportion of striatal
tissue included in each implant, or to the degree of
reconnection of striatal grafted tissue with the host systems
(Clarke et al., 1988; Dunnett et al., 1988; Sirinathsinghji et al.,
1988). The fact remains that the uptake of FDG is mainly
related to synaptic activity, and that clinical improvement
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Fig. 4 Anatomical aspect and metabolic pro®le of the foetal grafts in the left putamen of patient 1. (a) Axial (top), sagittal (middle) and
coronal (bottom) views of the MRI and corresponding metabolic slices with the two grafts which grew markedly reversing the atrophy of
this structure (hyposignal in T1-weighted MRIs). The most anterior of these grafts (arrow 1) is associated with a strong peak of
metabolism, reaching +135% compared with the baseline (T0) metabolism in this structure. The posterior graft in the left putamen of this
patient is associated with a +107% metabolic increase. (b) 3D reconstruction of the MRI in which the left striatal metabolism has been
fusioned with the segmented and reconstructed structure. The cortex of the right hemisphere is shown, as well as the left lateral ventricle
(pale blue). The dark lines indicate the two needle tracks leading to the two grafts individualized in the left putamen of this patient. Both
grafts are visible and have a higher metabolism than the surrounding host striatum. The size of the anterior graft is indicated. The colour
scale indicates the level of brain metabolism.
PET in grafted Huntington's disease patients
71
Fig. 5 MRI and PET images for patient 5. The grafts in the upper striatum (arrows) do not induce a noticeable increase of metabolism.
The colour scale indicates the level of brain metabolism.
Acknowledgements
The authors wish to thank ReÂgine TreÂbossen and Fabrice
Poupon for invaluable help in image analysis, the nurses and
radiochemistry staff in Orsay for technical assistance, and
Dr Ken Moya for his review of the manuscript. This work was
supported in part by a grant from the MinisteÁre de la SanteÂ
(PHRC) and V.G. was supported by a grant from the
Fondation pour la Recherche MeÂdicale.
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Received May 9, 2003. Revised July 10, 2003
Accepted July 17, 2003
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