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Dopaminergic Function and Dopamine Transporter Binding Assessed With Positron Emission Tomography in Parkinson Disease
Maria-Joao Ribeiro, MD, PhD;
Marie Vidailhet, MD;
Christian Loc'h, BS;
Corinne Dupel, MD;
Jean Paul Nguyen, MD;
Michel Ponchant, BS;
Frédéric Dollé, PhD;
Marc Peschanski, MD, PhD;
Philippe Hantraye, PhD;
Pierre Cesaro, MD, PhD;
Yves Samson, MD;
Philippe Remy, MD, PhD
Arch Neurol. 2002;59:580-586.
ABSTRACT
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Background Measuring progression of Parkinson disease (PD) using positron emission
tomography may help demonstrate the efficacy of neuroprotective treatments.
To date, 18F-dopa has been the gold standard to measure presynaptic
dopaminergic function in PD, but this tracer might overestimate the rate of
neuronal death in PD because its uptake also depends on dopamine turnover
rather than exclusively on the density of dopaminergic terminals in the striatum.
The latter might be assessed using newly developed ligands of the membrane
dopamine transporter.
Objective To compare the striatal uptakes of 18F-dopa and 76Br-FE-CBT,
a dopamine transporter ligand, in patients with PD.
Patients and Methods The striatal uptakes of 76Br-FE-CBT and 18F-dopa
were compared using positron emission tomography in 10 patients with early
PD and 8 with advanced PD. Correlation of uptakes with motor performance was
investigated.
Results The reduction in 76Br-FE-CBT binding to 43% of control values
was more severe than the reduction in 18F-dopa uptake (63% of control
values) in the putamen of patients with early PD. No significant difference
was found between either tracer's uptake in the putamen of patients with advanced
PD. Motor performance was highly correlated to 18F-dopa uptake,
whereas correlation to 76Br-FE-CBT binding was weak.
Conclusions Uptake of 18F-dopa may be up-regulated in early PD, suggesting
a compensatory increase of dopamine synthesis in surviving dopaminergic terminals.
Positron emission tomography dopamine transporter ligands and 18F-dopa
give complementary information on the presynaptic status of the nigrostriatal
dopaminergic system and might be associated to investigate the efficacy of
neuroprotective treatments in PD.
INTRODUCTION
EVALUATING neuroprotective treatments designed to slow down the progressive
loss of dopaminergic neurons is a crucial step for the development of therapeutic
strategies in Parkinson disease (PD). A major drawback faced by previous neuroprotection
studies in PD was that the potential neuroprotective effect was indistinguishable
from the symptomatic improvement provided by the drug on trial.1-2
To overcome this limitation, a biological marker of disease progression could
be valuable to evaluate the efficacy of neuroprotective drugs. Until now,
positron emission tomography (PET) using 18F-dopa has been the
gold standard tool for measuring disease progression in patients with PD.3-5 However, 18F-dopa
uptake reflects the density of striatal dopaminergic terminals6
and the conversion of 18F-dopa into 18F-dopamine in
these terminals.5, 7-8
It has been suggested that in PD, the loss of dopaminergic synapses was partially
compensated for by increased dopamine metabolism in the surviving terminals
(for review see Zigmond et al,9 Hornykiewicz,10 and Bezard and Gross11).
Thus, 18F-dopa uptake might overestimate the number of striatal
dopaminergic nerve terminals in these patients.12-13
Ligands that bind to the presynaptic membrane dopamine transporter (DAT),
which reflect the density of striatal dopaminergic nerve terminals,14-16 might be more suitable
for assessing disease progression and the efficacy of neuroprotective treatments.
To test this, it is necessary to compare the striatal uptakes of PET DAT ligands
and 18F-dopa at different stages of PD. In addition, the relationships
between each tracer's uptake in the striatum and motor performance remain
to be investigated in the same cohort of patients with PD. We compared the
striatal uptake of 18F-dopa with a highly specific DAT tropane
ligand in patients with early and advanced PD and investigated the correlations
between these tracers' uptakes and motor performances of these patients.
PATIENTS AND METHODS
PATIENTS
Eighteen patients (mean ± SD age, 53.7 ± 6.0 years) fulfilling
the UK Parkinson's Disease Brain Bank criteria for prospective diagnosis of
PD17 were selected. They were divided into
2 groups: (1) 10 patients with early PD (mean ± SD age, 51.7 ±
4.4 years; mean ± SD disease duration, 1.9 ± 0.6 years; Hoehn
and Yahr stage I-II) without atypical signs18
who were drug naive at the time of the PET study but responded to treatment
after it was initiated and (2) 8 patients with more advanced PD (mean ±
SD age, 56.1 ± 6.6 years; mean ± SD disease duration, 12.5 ±
6.7 years; Hoehn and Yahr stage  III) who were all dopa responders according
to the criteria of the Core Assessment Program for Intracerebral Transplantations
and the Core Assessment Program for Surgical Interventional Therapies (Table 1).19-20
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Table 1. Clinical Profile of 18 Patients With Parkinson Disease*
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All patients were assessed in the "defined off" state19-20
using the Unified Parkinson's Disease Rating Scale 3 (UPDRS-3) motor score
and the Purdue Pegboard task. The latter estimates bradykinesia and has been
shown to correlate with striatal dopaminergic function.21
Briefly, for this task, patients were asked to put as many unmarked rods as
possible into aligned holes using a single hand in 30 seconds. The number
of rods accurately placed was registered.
Patients were scanned using 2 different PET tracers: (1) 18F-dopa
and (2) 76Br-FE-CBT (fluorethyl-methyl-2ß-carboxymethoxy-3ß-4-bromophenyl-tropane),
a ligand of the presynaptic plasma membrane DAT.22
This highly specific tracer has the advantage of reaching an equilibrium 30
minutes after injection. Patients with PD were compared with 25 control subjects
(22 men and 3 women; mean ± SD age, 49.7 ± 13.0 years) with
no neurological history, no clinical abnormality, and normal findings on brain
magnetic resonance imaging. Of these 25 controls, 7 were examined with 18F-dopa only, 8 with 76Br-FE-CBT only, and 10 with both
PET tracers. All patients and controls were part of ongoing protocols in our
center (Orsay, France) that were approved by the local ethics committee, and
they gave their written informed consent after the nature of the procedure
had been fully explained.
MAGNETIC RESONANCE IMAGING AND PET ACQUISITION
Brain magnetic resonance images were obtained using a 1.5-T imager (Signa;
General Electric Co, Milwaukee, Wis). T2-weighted images from each patient
were used to reveal brain lesions and signal abnormalities in the basal ganglia.
In addition, a T1-weighted SPGR (spoiled gradient acquisition at the steady
state) acquisition with inversion recovery was performed to allow 3-dimensional
reconstruction of magnetic resonance images.
Positron emission tomographic examinations in patients with early PD
were performed using the ECAT EXACT HR+ tomograph (CTI-Siemens, Knoxville,
Tenn), which collects 63 simultaneous 2.4-mm-thick slices with an intrinsic
in-plane resolution of 4.3 mm.23 Patients with
advanced PD were studied using the ECAT 953B/31 tomograph (CTI-Siemens), which
acquires 31 simultaneous 3.4-mm-thick slices with an intrinsic transaxial
resolution of 6.0 mm.24 For all PET examinations,
patients were positioned in the tomograph using 3-dimensional laser alignment
and a thermoplastic mask molded to each patient's face to restrain head movements.
Tissue attenuation was measured using 3 68Ge rod sources.
For 18F-dopa studies, patients with advanced disease discontinued
taking antiparkinsonian medications at least 12 hours before PET examination.
In all patients, 100 mg of carbidopa was given 1 hour before tracer administration,
and 9 time frames were acquired for 90 minutes after intravenous injection
of 143.9 ± 55.1 MBq of 18F-dopa. For 76Br-FE-CBT
studies, we tested the effect of dopaminergic medications in 2 patients who
were studied twice: (1) after 12-h drug withdrawal and (2) during administration
of medication. Drug withdrawal had no significant effect on striatal tracer
uptake of the 76Br-FE-CBT, confirming previous results25 and unpublished data obtained in rats at our center
(Orsay) (C.L. and P.H., 1996). Accordingly, all PET studies with 76Br-FE-CBT
were performed without drug withdrawal in the 8 patients with advanced PD.
For these studies, 13 time frames were acquired more than 90 minutes after
intravenous injection of 34.8 ± 9.9 MBq of 76Br-FE-CBT.
IMAGE ANALYSIS
For both radiotracers, the time frames collected between 30 and 90 minutes
after injection were summed to create an integrated image. This image was
used to define regions of interest in the striata and the occipital lobe in
4 to 6 contiguous planes where these structures could be visualized.6 Circular regions of interest 10 mm in diameter were
drawn, 1 on the head of the caudate nucleus and 3 on the putamen in each hemisphere.
A 25-mm-diameter region of interest was drawn on the occipital region using
the same image slices as those used for the striata. The mean activity concentration
values in the region of interest for the left and right caudate, the occipital,
and the left and right putamen were then calculated and used to obtain regional
time-activity curves. From these curves, the 18F-dopa uptake values
(Ki) were determined using multiple-time graphical analysis, with the occipital
activity as a nonspecific input function.6
The specific uptake of 76Br-FE-CBT reaches equilibrium 30 minutes
after tracer injection,26 allowing calculation
of the striatal binding potential (BnP) values of this tracer using the graphical
analysis described by Logan et al27 and using
the occipital activity as a nonspecific input function.
Considering that patients were studied using 2 different scanners, the
Ki and BnP values obtained in each patient were normalized to the mean Ki
and BnP values obtained in age-matched controls studied using the same tomograph.
Specifically, the values obtained in patients with early PD were normalized
to values obtained using the ECAT EXACT HR+ in 7 controls (mean ± SD
age, 49.4 ± 12.2 years) for 18F-dopa uptake and 6 controls
(mean ± SD age, 53.3 ± 7.2 years) for 76Br-FE-CBT,
whereas the values obtained in patients with more advanced PD were normalized
to values in 10 controls (mean ± SD age, 49.9 ± 14.2 years)
for 18F-dopa uptake and 10 controls (mean ± SD age, 53.9
± 5.6 years) for 76Br-FE-CBT.
STATISTICAL ANALYSIS
The 3 groups (controls and patients with early and severe PD) were compared
for Ki and BnP values in the caudate and putamen using a Kruskal-Wallis test
(1-way nonparametric analysis of variance). For that purpose, values obtained
in the right and left hemispheres were averaged. In addition, normalized Ki
values were compared with normalized BnP values in the putamen of patients
on the more and less affected hemispheres using a Friedman test (2-factor
nonparametric analysis of variance). Finally, correlations between Ki and
BnP values and motor performance (motor score of the UPDRS-3 scale and Purdue
Pegboard) were analyzed using the nonparametric Spearman test. For the latter
analysis between PET values and Purdue Pegboard scores, right and left values
were averaged to avoid any statistical bias related to the lack of independence
of the variables. Data are given as mean ± SD.
RESULTS
18F-DOPA AND 76BR-FE-CBT IN PATIENTS AND CONTROLS
Figure 1 shows examples of
images obtained in a control subject, a patient with early PD, and a patient
with advanced PD for 18F-dopa Ki and 76Br-FE-CBT BnP.
Because Ki and BnP values were normalized to the mean of control values (Table 2), they are expressed as percentages
of the normal mean.
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Figure 1. Images of 18F-dopa
and 76Br-FE-CBT uptake at the level of the striatum in a control
subject, a drug-naive patient with early Parkinson disease (PD), and a patient
with advanced PD. Uptake of both tracers is asymmetrically decreased in patients
with PD and is less in the posterior than in the anterior striatum. In the
patient with early PD, the decrease of 76Br-FE-CBT uptake is more
severe than the 18F-dopa uptake reduction in the left posterior
putamen and in the right putamen.
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Table 2. Individual Positron Emission Tomography Results in 18 Patients
With Parkinson Disease*
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In patients with early PD, normalized Ki values averaged over both hemispheres
were reduced to 87% ± 13% in the caudate nucleus and 63% ± 21%
in the putamen, and the corresponding BnP values were 70% ± 14% and
43% ± 17%. In patients with advanced disease, Ki values were 46% ±
11% and 33% ± 9% of control values in the caudate and putamen, respectively,
whereas BnP values were decreased to 32% ± 7% and 27% ± 5% in
these regions. The Kruskal-Wallis analysis of variance comparing patients
with early PD, patients with severe PD, and controls revealed significant
differences among groups for Ki values (caudate: H = 18.50; putamen: H = 18.97)
and BnP values (caudate: H = 18.21; putamen: H = 18.12) (P<.001 for all).
In the patient groups, we compared the normalized Ki values with the
normalized BnP values in the putamen contralateral to the less and more clinically
affected sides (Figure 2). The Friedman
analysis of variance revealed that Ki values were significantly higher than
BnP values in patients with early PD in the less affected (Ki = 74% ±
19% and BnP = 48% ± 14%) and more affected (Ki = 51% ± 25% and
BnP = 37% ± 20%) hemispheres ( 2 = 20.43; P<.001). In patients with severe PD, the difference between Ki and
BnP values was not significant in the less affected (Ki = 34% ± 12%
and BnP = 27% ± 5%) and more affected (Ki = 31% ± 9% and BnP
= 27% ± 5%) hemispheres (2 = 3.75; P = .29).
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Figure 2. Normalized 18F-dopa
and 76Br-FE-CBT uptake in the putamen of patients with early and
advanced Parkinson disease (PD) in the less and more affected sides. The difference
between tracer uptakes is significant in patients with early but not advanced
PD (P<.001, Friedman test). Error bars represent SD.
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CORRELATIONS
The Ki values in the putamen averaged over both hemispheres in patients
with PD were significantly correlated with motor performance, measured using
the motor score of the UPDRS-3 scale (r = -0.78; P<.003, Spearman) and the Purdue Pegboard (r = 0.78; P<.005) (Figure 3). There was a trend toward a correlation between the corresponding
BnP values and the motor scores (UPDRS-3: r = -0.61; P = .01; Purdue Pegboard: r =
0.51; P = .05) (Figure 3), although the latter correlations were not significant
after Bonferroni correction. Patient 2 has high Ki and BnP normalized values
and good motor performance (Figure 3)
and therefore might be considered an outlier. However, this patient has clear
parkinsonian symptoms, including a rest tremor. If we make the correlation
analysis after excluding patient 2, Ki values are correlated with UPDRS-3
(r = -0.73; P = .003)
and Pegboard (r = 0.74; P
= .006) scores, whereas BnP values are correlated with UPDRS-3 (r = -0.54; P = .03) but not Pegboard
(r = 0.41; P = .12) scores.
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Figure 3. Correlations between motor performance
and each tracer's normalized uptake in the putamen of patients with Parkinson
disease (Spearman rank test). For the Unified Parkinson's Disease Rating Scale
3 (UPDRS-3) motor score, increasing values indicate decreasing performances,
whereas for the Purdue Pegboard, the number of digits correctly placed in
30 seconds is measured. The correlations between motor performance and 18F-dopa uptake (Ki) are statistically significant, whereas those observed
using 76Br-FE-CBT binding potential (BnP) do not reach the P<.05 level after Bonferroni correction.
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COMMENT
In this study, we compared the striatal binding of 2 different presynaptic
dopaminergic PET tracers: 18F-dopa, which has been widely used
to study striatal dopaminergic function, and 76Br-FE-CBT, a recently
developed highly specific ligand of the membrane DAT. The binding of both
tracers is reduced in parkinsonian patients, but this reduction is significantly
greater with 76Br-FE-CBT than with 18F-dopa. Specifically,
in the putamen of drug-naive patients with early PD, 18F-dopa uptake
is decreased to 63% of control values on average, whereas 76Br-FE-CBT
BnP is reduced to 43% of control values. For each tracer, this value estimates
the symptomatic threshold, which is the level of tracer uptake for which the
clinical signs of PD appear. The symptomatic threshold found using 18F-dopa is similar to that reported in previous PET studies.12-13,28-29 Only
2 PET studies12-13 have compared 18F-dopa and a PET DAT ligand in the same parkinsonian patients. As
in the present study, it was reported that the binding of the DAT ligand was
significantly lower than the 18F-dopa uptake in the putamen of
patients with early PD.12-13 Altogether,
these results confirm that DAT ligands are more sensitive than 18F-dopa
to detect the early stages of PD because they reflect the loss of dopaminergic
nerve terminals.14-16
Indeed, the mean 57% reduction in 76Br-FE-CBT in the putamen of
patients with early PD is in line with the decrease in dopaminergic neurons
in the substantia nigra pars compacta extrapolated from the postmortem analysis
of brains from patients with PD.30-31
In addition, in our group of patients with advanced PD with a mean disease
duration of 12.1 years, the 73% loss of 76 Br-FE-CBT uptake in
the putamen is comparable to the 75% nigral cell loss observed by German et
al32 in patients with an average disease duration
of 14 years.
Comparatively, 18F-dopa uptake seems to be up-regulated in
the surviving dopaminergic terminals of patients with early PD.12-13
The striatal 18F-dopa uptake depends on the integrity of the nigrostriatal
dopaminergic pathway6 and on the activity of
the aromatic L-amino acid decarboxylase in these nerve terminals.5, 8 An L-amino acid decarboxylase overactivity
is supposed to occur in the surviving dopaminergic terminals of patients with
PD to compensate for the loss of dopaminergic neurons.9-11
This compensatory mechanism might be similar to that observed in normal aging,33-34 in which the progressive loss of
nigrostriatal dopaminergic neurons30, 35
is associated with a decrease in striatal DAT ligand binding,36-37
without any reduction of 18F-dopa uptake.38-39
This compensatory process, suggested by results obtained in patients
with early PD, seems not to persist in patients with advanced PD. The difference
between 18F-dopa uptake and 76Br-FE-CBT BnP is less
and is not significant in the putamen of patients with advanced disease (Figure 2). Recently, Lee et al12
found that up-regulation of 18F-dopa uptake was on average 18%
of control values compared with DAT ligand binding in untreated patients with
early PD (20% in our data) and 12% in patients with PD who have reached stage
II to III of the Hoehn and Yahr scale. Our patients with advanced PD are between
stages III and V on this scale, and the apparent difference between 18F-dopa and 76Br-FE-CBT uptake in the putamen is only 6%.
Thus, our results and those obtained in 2 recent PET studies12-13 suggest that compensatory mechanisms
to dopaminergic neuronal degeneration are present in the early stages of the
disease and might be less important in patients with more advanced PD, all
of which are similar to observations made in a rat model of PD.40
Results of previous studies9 suggest that the
compensatory increase of dopamine synthesis in PD mainly occurs at a later,
although still presymptomatic, stage of neuronal degeneration. This hypothesis
is based on the widely accepted observation that parkinsonian symptoms appear
when striatal dopamine is reduced to 20% to 30% of normal levels,41-42 whereas dopaminergic neurons in the
nigra are reduced to approximately 50% of normal values.30-31
However, measurements of postmortem striatal dopamine levels should be cautiously
interpreted considering the instability of this molecule.43-44
In rats given PD using the 6-OHDA toxin, the level of striatal dopamine measured
in vivo is much higher than that found in the postmortem analysis of the same
animals.45-46 One simple explanation
for this phenomenon is that dopamine turnover would rise in PD, leading to
an increase in the dopamine released in the extracellular space but a decrease
in the dopamine stored in the presynaptic vesicles, which is the dopamine
measured in postmortem analyses. Accordingly, nearly all experimental and
human studies have shown that the turnover of dopamine was increased in PD
as demonstrated by the rise in the level of dopamine metabolites in the striatum.9-11 Thus, increased synthesis
of dopamine in the surviving striatal terminals of patients with early PD
would be accompanied by an increased transformation of 18F-dopa
into 18F-dopamine in these terminals because of the overactivity
of L-amino acid decarboxylase.9, 34
The PET results fit with the latter hypothesis. Although this metabolic response
might not be the only compensatory change during neuronal degeneration in
early PD,11 it likely plays a role in delaying
the onset of symptoms during the early stage of disease. Conversely, the loss
of such metabolic compensations in more severely affected patients, which
remain to be confirmed in further studies, might play a major role in the
motor fluctuations observed in these patients.47-48
Prospective study of the striatal uptake of both tracers during disease progression
may help confirm this.
Finally, in all patients with PD, the relationships between motor performance
and putamenal tracer uptake were stronger with 18F-dopa than with 76Br-FE-CBT BnP. The correlations between 18F-dopa uptake
and motor performance have been emphasized in several studies.21, 49-50
In addition, correlations between PD severity and striatal uptake of DAT ligands
have been reported using either PET or single-photon computed tomography.36, 51-52 However, the relationships
between the 2 different PET tracers and motor performance have not been analyzed
previously in the same patients. The present results suggest that the motor
abilities of patients with PD depend more on the functional status of putamen
dopaminergic terminals, measured using 18F-dopa, than on the density
of these terminals, evaluated using a DAT ligand. This result, emphasizing
the functional meaning of 18F-dopa uptake, is also in line with
the hypothesis that the compensatory increase of dopamine synthesis in the
early stages of PD might be responsible for delaying motor symptom onset in
these patients.
Altogether, our results suggest that 18F-dopa and 76Br-FE-CBT are complementary markers of the presynaptic dopaminergic
nigrostriatal system and thus may be useful to assess neuroprotection therapies.
However, this is based on the hypothesis that there is no down-regulation
of 76Br-FE-CBT binding in hyperactive dopaminergic neurons or in
relation to dopaminergic medications. If this hypothesis is true, DAT ligands
might more accurately measure dopaminergic neuronal degeneration than 18F-dopa and could be appropriate to evaluate neuroprotective strategies
in PD.
AUTHOR INFORMATION
Accepted for publication November 29, 2001.
Author contributions: Study concept and design (Drs Vidailhet, Nguyen, Peschanski, Hantraye, Cesaro, Samson,
and Remy); acquisition of data (Drs Ribeiro, Dupel,
and Dollé and Messrs Loc'h and Ponchant); analysis and interpretation
of data (Drs Ribeiro, Vidailhet, and Remy); drafting
of the manuscript (Drs Ribeiro, Vidailhet, Dupel, Dollé,
and Remy and Messrs Loc'h and Ponchant); critical revision of the manuscript
for important intellectual content (Drs Vidailhet, Nguyen,
Peschanski, Hantraye, Cesaro, Samson, and Remy); statistical expertise (Dr Remy); obtained funding (Drs Vidailhet,
Dupel, Nguyen, Samson, and Remy); administrative, technical, and material
support (Mr Loc'h and Dr Dollé); and study
supervision (Drs Vidailhet, Peschanski, Hantraye, Cesaro,
and Remy).
This work was supported by grant PHRC IDF-96138 from the French Ministère
de la Santé, Paris; the Association France Parkinson; grant PRAXIS
XXI/BD/2657/94 from the Fundaçãopara a Ciência e Tecnologia
and a grant from the ARS and Universidade de Coimbra, Portugal (Dr Ribeiro);
and the Fondation pour la Recherche Médicale, Paris (Dr Dupel).
We thank the radiochemists and nurses at the Service Hospitalier Frédéric
Joliot for their assistance and Ken Moya, MD, PhD, for his critical reading
of the manuscript.
Corresponding author and reprints: Philippe Remy, MD, PhD, URA CEA-CNRS
2210, Service Hospitalier Frédéric Joliot, 4, place du Général
Leclerc, 91401 Orsay, CEDEX, France (e-mail: remy{at}shfj.cea.fr).
From Commissariat à l'Energie Atomique (CEA), Service Hospitalier
Frédéric Joliot, Orsay, France (Drs Ribeiro, Dupel, Dollé,
Samson, and Remy and Messrs Loc'h and Ponchant); Service de Neurologie, Hôpital
Saint-Antoine, Paris, France (Dr Vidailhet); Institut National de la Santé
et de la Recherche Médicale (INSERM) U289, Paris (Dr Vidailhet); Département
de Neurosciences, Centre Hospitalier Universitaire (CHU) Henri Mondor, Assistance
Publique-Hôpitaux de Paris & Université Paris 12, Créteil,
France (Drs Nguyen, Peschanski, Cesaro, and Remy); INSERM U421, IM3, Faculté
de Médecine, Créteil (Drs Nguyen, Peschanski, and Cesaro); Unité
de Recherche Associée CEA–Centre National de la Recherche Scientifique
2210, Orsay (Drs Hantraye and Remy); and Urgences Cérébro-Vasculaires,
CHU Pitié-Salpétrière, Paris (Dr Samson)
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