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Correlation of Regional Proton Magnetic Resonance Spectroscopic Metabolic Changes With Cognitive Deficits in Mild Alzheimer Disease
Sophie Chantal, MPs;
Martin Labelle, MSc;
Rémi W. Bouchard, MD, MSc, FRCPC;
Claude M. J. Braun, PhD;
Yvan Boulanger, PhD
Arch Neurol. 2002;59:955-962.
ABSTRACT
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Context The staging of Alzheimer disease (AD) dementia could be improved by
a neurometabolic analysis using magnetic resonance spectroscopy.
Objective To examine the correlation between regional cerebral metabolic alterations
measured by proton magnetic resonance spectroscopy and neuropsychological
dysfunctions in patients with early AD.
Design A case-control study.
Setting University hospital neurology clinic and radiology department.
Participants A cohort of 14 patients with mild AD and 14 control subjects paired
for age and sex.
Interventions Single-voxel proton magnetic resonance spectroscopic brain examination
(60 minutes) and a comprehensive battery of psychometric tests (2 hours).
Main Outcome Measures Metabolite ratios relative to unsuppressed water were calculated for
magnetic resonance spectroscopic metabolites (N-acetylaspartate,
choline, creatine-phosphocreatine, and myo-inositol)
in the medial temporal lobes (MTLs), parietotemporal cortices (PTCs), and
frontal cortices of both hemispheres. Correlations were examined between metabolic
changes in an area and psychometric scores of its known regional function:
MTL and verbal memory, PTC and language and visuoconstructional abilities,
and frontal cortices and executive functions.
Results A significant reduction of N-acetylaspartate/water
(H2O) in the left MTL and of choline/H2O in both MTLs,
as well as a significant increase of myo-inositol/H2O in the right PTC were observed. Metabolic alterations in the left
MTL were correlated with a loss of verbal memory, in the left PTC with language
impairment, and in the right PTC with a loss of visuoconstructional abilities
in the group with AD.
Conclusion These findings are consistent with regional distribution of neuropathologic
changes and cognitive symptoms characterizing early phases of AD, and with
the pattern of lateralization of normal brain function.
INTRODUCTION
ALZHEIMER DISEASE (AD) is a neurodegenerative disorder associated with
a gradual deterioration of cognitive functions, personality, and behavior.
Impairment of recent memory is commonly the first symptom of the disease attributable
to neurochemical and pathologic changes in the medial temporal lobe (MTL).
As AD progresses, language, attention, calculation, visuospatial, visuoconstructional,
and executive functions become impaired because of a dysfunction of the associative
cortices in both cerebral hemispheres.1 The
cause and pathogenesis of AD remain complex but it is always associated with
gray matter atrophy, disruption of neuronal function, and formation of neurofibrillary
tangles and neuritic plaques in the medial temporal limbic regions and isocortex.2-3 Cerebral imaging studies have revealed
hippocampal atrophy consistent with neuronal loss4-5
and predictive of memory performance,5 and
reduced metabolism in the posterior association areas of the neocortex6 as well as in the posterior cingulate gyrus and pericingular
cortex in the early stages of AD.7 However,
heterogeneous metabolic patterns have been reported among patients, reflecting
either frontal or parietotemporal abnormalities8
and right- or left-sided metabolic asymmetries correlated with visuoconstructional
and language discrepancies.9 Neuropsychological
studies of patients with AD have also revealed selective and heterogeneous
patterns of cognitive impairments. For example, some patients present severe
language dysfunction along with milder visuoconstructional dysfunction, whereas
other patients present with the opposite pattern.6
Such differences in the pattern of cognitive deficits suggest a variable distribution
of neocortical abnormalities that can be examined with the proton (1H) magnetic resonance spectroscopy (MRS) technique.
Most in vivo 1H MRS investigations of patients with AD have
demonstrated a reduction of the amount of N-acetylaspartate
(NAA) (neuronal marker)10-22
and an increase of myo-inositol (mI) (glial marker)10-12,14-17
in different brain regions containing both white and gray matter tissues.
Inconsistent results have been reported for choline-containing compounds (Cho),10-11,13-14,16-22
whereas the creatine-phosphocreatine (Cr) signal remains unchanged.13-14,17, 19, 22
Magnetic resonance spectroscopy has been used to assess the association between
regional metabolic abnormalities and cognitive dysfunctions in neurologic
and psychiatric disorders and in healthy individuals.23-26
In patients with AD, conflicting results have been reported concerning
the correlation between the metabolite levels and the degree of cognitive
alteration.11-12,14, 16-17,20, 22
The relevance of the correlations is, however, questionable since either conclusions
were based on nonspecific brief mental evaluations, such as the Mini-Mental
State Examination27 or global scores from the
AD Assessment Scale,28 thereby not reflecting
specific cognitive deficits caused by regional cerebral deterioration, or
the cerebral region examined is not functionally involved in early clinical
symptoms of AD. To our knowledge, no investigation examined specifically the
relationship between local metabolism measured by MRS and associated patterns
of cognitive impairment.
In the present study, MRS data were acquired in 6 cortical regions known
to be affected in patients with AD to evaluate the spatial specificity of
the metabolic impairments. Correlations were established between neurometabolic
variations and specific neuropsychological performances (ie, verbal memory,
executive, language, and visuoconstructional abilities) associated with these
regions. To determine the specificity of correlations, cognitive functions
were tested in the contralateral functional region as control or in the posterior
associative regions in the case of executive functions. The results indicate
that pertinent lateralized correlations can be established in several regions.
PATIENTS AND METHODS
PATIENTS
Fourteen right-handed patients diagnosed as having probable AD of mild
severity according to criteria for dementia of the Alzheimer type of the Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition29 and criteria for probable
AD of the National Institute of Neurologic and Communicative Disorders and
Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)30 were compared with 14 right-handed control subjects
who had no history of cognitive decline or previous neurologic or psychiatric
disorder. They were submitted to physical and neurologic examinations, including
laboratory tests and brain imaging (ie, magnetic resonance imaging or computed
tomography). Clinical assessment of dementia included neurocognitive, behavioral,
and psychiatric interviews conducted by the behavioral neurologist (R.W.B.),
administration of the Mini-Mental State Examination,27
and a neuropsychological evaluation. Controls were evaluated with the same
neuropsychological tests to ensure healthy cognitive functions. Patients presented
with no focal brain lesions detectable by computed tomography or magnetic
resonance imaging, had a global staging score of 1 or less on the Clinical
Dementia Rating31 scale and of less than 4
on the Hachinski Ischemia Scale.32-33
They were not treated with acetylcholinesterase inhibitors or other investigational
drugs to enhance brain cognitive function and were not currently or previously
suffering from significant systemic (including diabetes mellitus) or psychiatric
conditions or traumatic brain injuries that could compromise brain functions.
All controls and patients were individually paired for age and sex.
PROTON MRS
Controls and patients with AD underwent a brain 1H MRS examination
performed using a 1.5-T whole-body scanner (GE Signa; General Electric Medical
Systems, Waukesha, Wis) operating at 63.85 MHz. Proton MRS data were obtained
from 7- to 8-cm3 voxels localized in the left and right MTLs (ie,
amygdala, the anterior half of the hippocampus, and part of the underlying
subiculum, 2 x 2 x 2 cm3), left and right frontal cortices
(FCs) (ie, mixed gray and white matter, 3.1 x 2.3 x 1.0 cm3), and left and right parietotemporal cortices (PTCs) (ie, mixed gray
and white matter, 3.7 x 1.9 x 1.0 cm3). The voxel shapes
of the FC and PTC regions were chosen to maximize their gray matter content
as shown in Figure 1. The point-resolved
spectroscopy pulse sequence was used with the following acquisition parameters:
repetition time, 1200 milliseconds; echo time, 50 milliseconds; number of
acquisitions, 64; spectral width, 2000 Hz; number of points, 1024; and total
acquisition time per voxel, 1.7 minutes. The MRS data were analyzed using
the Magnetic Resonance User Interface (Barcelona, Spain) software and signal
intensities were calculated directly from time-domain data, using the singular
value decomposition 1-dimension model function fitting. The intensity of the
water (H2O) signal was determined from the area of the H2O peak in the H2O-unsuppressed spectra and metabolite/unsuppressed
water ratios were calculated. Owing to the significant overlap with neighboring
signals, the mI signal intensity was estimated from the peak height measured
manually. The mI/H2O ratios were then calculated by dividing the
mI peak height by the NAA peak height and multiplying by the NAA/H2O
ratio. Mean and SD values were calculated for all metabolite ratios.
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Figure 1. T2-weighted magnetic resonance
images of the brain showing the approximate locations of the voxels used for
magnetic resonance spectroscopy. A, Medial temporal lobes (2 x 2 x
2 cm3) B, Frontal cortex (FC) (3.1 x 2.3 x 1.0 cm3) and parietotemporal cortex (PTC) (3.7 x 1.9 x 1.0 cm3). Spectra were obtained from these regions in both the left and right
hemispheres. Voxels in the FC and PTC were positioned to enclose the maximal
amount of gray matter.
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NEUROPSYCHOLOGICAL TESTS
Cognitive domains of verbal memory, language, visuoconstructional abilities,
and executive functions were examined using a battery of standard neuropsychological
tests as listed in Table 1.34-35 The French versions of the original
tests were used and the raw test scores were used for statistical analysis.
For all tests, except Trail Making Test Part A, higher scores indicate better
performance.
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Table 1. Cognitive Tests Administered to Patients With Alzheimer Disease
and Control Subjects
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STATISTICAL ANALYSIS
Metabolite ratios relative to unsuppressed H2O (NAA/H2O, Cho/H2O, Cr/H2O, and mI/H2O) were
compared in all regions between patients with AD and controls by a 2-way repeated
measures analysis of variance followed by a Tukey post hoc test for multiple
comparisons, when allowed. Differences in metabolite ratios between the 2
groups were considered statistically significant when P<.05. The Pearson correlation coefficients followed by a Bonferroni
correction for multiple correlations were used for assessment of the association
between scores in the 4 cognitive domains and metabolite ratios. Correlations
were considered significant at P<.05 (corrected
for 2 neuropsychological tests per functional brain region) with r>0.50. Statistical analyses were performed using SPSS Version 9.0.1
(SPSS Inc, Chicago, Ill) and SIGMASTAT Version 2.03 (Rockware Inc, Golden,
Colo).
RESULTS
DEMOGRAPHICS
The demographic and clinical data of patients with AD and controls paired
for age and sex are summarized in Table
2. Significant differences in Mini-Mental State Examination scores
are measured between patients with AD and controls.
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Table 2. Demographic and Clinical Characteristics of Patients With
Alzheimer Disease (AD) and Control Subjects*
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MRS DATA
Table 3 lists the mean metabolite
ratios of NAA, Cho, mI, and Cr relative to unsuppressed H2O for
all 6 brain regions in patients with AD and controls. The NAA/H2O
ratio was significantly decreased for patients with AD in the left MTL only.
A decrease was also measured in the left FC but the change did not reach statistical
significance. In the other regions, the NAA/H2O ratios were unchanged.
The Cho/H2O ratios of patients with AD were significantly reduced
relative to controls in both the left and right MTLs (Table 3). No statistically significant Cho/H2O changes
were measured in the other regions. In the case of mI/H2O, increases
were measured in all 6 regions, but the changes were statistically significant
in the right PTC only and showed a statistical tendency in the left MTL and
the left PTC. Finally, both increases and decreases were measured for the
Cr/H2O ratio in patients with AD relative to the controls. Statistically
significant decreases were measured in the left MTL and in the left PTC. Figure 2 presents spectra illustrating the
major effects of AD on brain metabolites. No correlation could be established
between metabolite ratios and age for patients with AD and controls.
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Table 3. Metabolite Ratios, Number of Subjects, and Statistical Significance
of the Difference Between Patients With Alzheimer Disease (AD) and Control
Subjects in 6 Brain Voxel Locations*
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Figure 2. Proton magnetic resonance spectra
of the medial temporal lobe of a healthy paired control (A) and a patient
with Alzheimer disease (AD) (B) and of the parietotemporal cortex of a control
(C) and a patient with AD (D). Statistically significant variations recorded
in the patients with AD relative to controls are illustrated by a solid arrow
and nonstatistically significant changes are illustrated by an open arrow
for the metabolites choline (Cho), creatine-phosphocreatine (Cr), myo-inositol (mI), and N-acetylaspartate (NAA).
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CORRELATIONS BETWEEN MRS AND NEUROPSYCHOLOGICAL DATA
Statistically significant Pearson correlations between individual cognitive
test scores and metabolite ratios in specific brain regions in patients with
AD are listed in Table 4 and shown
in Figure 3. Correlations were obtained
between the NAA/H2O ratios measured in the left MTL and the learning
scores and the word recall memory scores measured by the California Verbal
Learning Test (Figure 3A). There
was no significant correlation between these verbal memory scores and other
metabolite ratios and no correlations were found in the right MTL. In Figure 3B, the negative correlation between
language performance measured by the Boston Naming Test (confrontation naming)
and the mI/H2O ratios in the left PTC is shown. No other correlation
was found between Boston Naming Test or verbal fluency scores and any other
metabolite ratio in the left or right PTC. Figure 3C shows the negative correlation between scores obtained
for the copy of Rey Complex Figure 1
Test and mI/H2O ratios in the right PTC. No correlation was found
in the left PTC and no other metabolite ratio was correlated with visuoconstructional
abilities. Executive functions were evaluated with verbal fluency test and
Trail Making Test Part A. Correlations were examined between scores from these
2 tests and all metabolite ratios in the left FC, right FC, bilateral FCs,
and posterior associative cortices as control. A correlation was found between
Trail Making Test Part A and mI/H2O ratios in the right FC (r = 0.55, P = .04, n = 14), the
longer the time spent to complete the test, the higher the mI/H2O
ratio, but this correlation was not statistically significant when the Bonferroni
correction was applied. For all tests, no significant correlation between
neuropsychological performances and age or educational level could be found
for patients with AD.
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Table 4. Statistically Significant Pearson Correlation Data Between
Brain Metabolite Ratios and Cognitive Scores in Specific Regions and in Their
Contralateral Regions for Patients With Alzheimer Disease (AD)*
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Figure 3. Graphs showing statistically significant
Pearson correlations between cognitive scores and 1H magnetic resonance
spectroscopic metabolite ratios in specific brain regions for patients with
Alzheimer disease: A, Between verbal memory performance as measured by the
learning (triangles) and word recall (squares) scores of the California Verbal
Learning Test, and the N-acetylaspartate (NAA)/–water
(H2O) ratio in the left medial temporal lobe. B, Between language
performance as measured by the Boston Naming Test and the myo-inositol (mI)/H2O ratio in the left parietotemporal
cortex. C, Between visuoconstructional abilities as measured by the Rey Complex
Figure Test and the mI/H2O ratio in the right parietotemporal cortex.
Statistical parameters are listed in Table
4. Metabolite ratios are multiplied by 1000 and broken lines serve
merely to guide the eye.
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COMMENT
CORRELATIONS BETWEEN MRS AND NEUROPSYCHOLOGICAL DATA
A strong correlation was found between NAA/H2O ratios and
both the learning and word recall parts of the California Verbal Learning
Test in the left MTL (Figure 3A, Table 4) but not in the right MTL. These
results are consistent with the fact that the left MTL is the site of the
verbal memory function. Although nonverbal visual memory processing has not
been assessed in this study, our results agree with the known laterality of
the mnesic function. In patients with epilepsy, a focus in the left hippocampus
was demonstrated to lead to a verbal memory deficit whereas a focus in the
right hippocampus was associated with a deficit of the nonverbal visual memory.36 More interestingly, verbal memory deficits were observed
in patients with temporal lobe epilepsy following a right-sided excision but
only in those patients who had 1H MRS abnormalities in the contralateral
(ie, left) side.37 Together, these studies
and our results suggest that MRS provides a sensitive measure of neuronal
damage in the MTL that might be undetectable by standard imaging techniques
so early in the disease course. This helps to explain anomalous memory performances
that are most characteristic of the disease.
An increased mI/H2O correlates with lower Boston Naming Test
scores in the left PTC, reflecting impaired language performance (Figure 3B). This correlation is consistent
with the known lateralized language function in the left PTC. Although that
naming function is not exclusively localized in the left posterior associative
cortex and anomia may be observed following frontal dysfunction of the left
dominant hemisphere,38 the absence of correlation
with other brain regions lead us to conclude that the language association
shown is highly specific to left PTC. Moreover, the stronger relationship
between confrontation naming and mI/H2O ratios may be partly explained
by the fact that all our patients were right-handed, thus increasing the probability
of left hemisphere language dominance. Visuoconstructional dysfunction measured
with the Rey Complex Figure 1 Test
correlated with mI/H2O increases (Figure 3C) in the right PTC, in agreement with the known neurophysiological
function of the right PTC.
In the case of executive functions, no relevant correlation was found
between neuropsychological performances and metabolite ratios. Even if the
Trail Making Test Part A and the verbal fluency test are considered to assess
executive capabilities, the entire executive system cannot only be evaluated
by these 2 tests. Indeed, in contrast to limbic cortex and posterior association
areas, the concept of executive functions in the frontal lobe refers to several
cognitive abilities such as planning, judgment, problem solving, abstraction,
etc, that cannot be assessed by a single test. For that reason, the use of
an executive composite z score constructed from specific
tests such as sorting and category tests, the Porteus Maze Test, and the Tower
of London Puzzle would be more accurate to test the executive functions against
metabolite measures.
DISEASE PROGRESSION MODEL
Recent data suggest that initial changes in the pathologic progression
of AD involve an increase in the mI level and that a decrease in the NAA level
and an increase in the Cho level occur later in the disease course.10 A similar hypothesis was made for Down syndrome,39 a progressive neurochemical disorder in which an
mI level increase was found to precede a NAA level loss, suggesting similar
pathologic pathways for both diseases. Our data support these previously reported
studies. The NAA and Cho level reductions along with an mI level increase,
although not always statistically significant, were measured in MTL regions
known to be affected early in AD (Table
3). These results seem to suggest that these regions are affected
to a point where the initial mI level increase is no longer a significant
marker of AD but where neuropathologic processes caused by AD are well established.
Interestingly, a significant mI level increase was observed in the right PTC
region and a strong tendency toward statistical significance of an mI augmentation
was measured in the left PTC. These observations are consistent with Braak
and Braak's model of AD pathophysiology being initiated in the MTL and then
spreading to upper levels of cortical regions.2, 40
In accord with this model, MRS studies have suggested that biochemical changes
in AD are sequential, starting with an mI level increase and followed by decreases
of both NAA and Cho levels.39, 41
Further investigations will be necessary to determine if the NAA and Cho level
modifications are observable in the moderate AD stage following the mI level
increase in the mild stage. Data suggest that the Cr may also be reduced in
the MTL and PTC regions (Table 3).
The regional metabolite pattern observed in patients with AD, compatible
with Braak and Braak's model of pathologic evolution, 2, 40
is also consistent with the progression of cognitive impairment and reflects
a gradual process of brain degeneration. Deficits of episodic memory, that
is, the ability to acquire and retain new information associated with the
medial structures of the temporal lobe (which includes the hippocampus and
the adjacent neocortex),42 usually mark the
onset of clinical symptoms of AD. The correlation observed between decreased
NAA/H2O ratios measured in the left MTL and verbal memory deficits
(learning and word recall memory scores, Figure 3A) in patients with AD supports the role of the MTL in recent
memory function. Moreover, since NAA is a neuronal marker, our results suggest
a correlation between memory dysfunction and the degree of neuronal loss or
damage in the left MTL of patients with AD. This is consistent with previously
reported correlations between memory impairment and hippocampal pathology
determined by neurofibrillary tangle counts43
as well as hippocampal atrophy estimated by volumetric magnetic resonance
imaging in patients with AD.5 Higher cortical
functions such as language, visuoconstructional and executive functions that
decline later in the disease course, are associated with destruction of neocortical
association areas. Although neuronal integrity of the associative cortices
seems preserved, as suggested by the absence of significant changes in NAA/H2O levels in both the PTC and the right FC, the mI/H2O increases
in the left and right PTCs correlated inversely with language and visuoconstructional
performances, respectively, in accord with an early AD phase. In Braak and
Braak's staging model of AD,2, 40
the neocortical stages (V and VI) that correspond to the conventional neuropathologic
criteria for clinical AD diagnosis, are marked by severe destruction of neocortical
association areas while limbic stages (III and IV) show a much less extensive
destruction of the neocortex with no macroscopically detectable atrophy. Since
cognitive functions are impaired, as demonstrated by correlations with increased
mI/H2O ratios (Figure 3B,
C), and since the disease is still in its early stages, as evidenced by the
relatively high Mini-Mental State Examination scores (Table 2) and Clinical Dementia Rating global staging scores, it
seems as if the disease of our patients corresponds to a clinical incipient
AD presumably with mild changes in the associative cortices. Indeed, it is
well known that patients in the early stages of AD present heterogeneous patterns
of cognitive impairment with considerable between-patients score discrepancies
for language, visuoconstructional, and executive dysfunction assessment.6 This cognitive dysfunction variability among patients
tends to fade with the evolution of the disease. Our metabolic-functional
correlations reinforce the hypothesis that the mI level increase characterizes
the initial stages of the disease and precedes the NAA level loss.10
The results of this study demonstrate that clear correlations can be
observed when MRS data are compared with scores from specific cognitive tests
associated with AD-relevant regions. The use of tests measuring specific cognitive
functions instead of a screening test of the general mental status, which
has been used in most reported studies, provides a more detailed characterization
of functional brain abnormalities in AD. Because of the substantial overlap
for some metabolite ratios between the 2 groups, our findings have limited
value for clinical diagnosis in individual patients. However, our data on
specific brain regions support established models of disease progression within
the brain and are consistent with functional laterality of the brain. More
support for understanding the course of neurochemical changes in AD could
be provided by a longitudinal follow-up study of the same cohort of patients.
AUTHOR INFORMATION
Accepted for publication February 11, 2002.
Author contributions: Study concept and design (Ms Chantal, Mr Labelle, and Drs Bouchard, Braun, and Boulanger); acquisition of data (Ms Chantal, Mr Labelle, and
Dr Boulanger); analysis and interpretation of data (Ms Chantal, Mr Labelle, and Dr Boulanger); drafting of the manuscript (Ms Chantal and Dr Boulanger); critical revision of the
manuscript for important intellectual content (Ms Chantal,
Mr Labelle, and Drs Bouchard, Braun, and Boulanger); statistical expertise (Ms Chantal); obtained funding (Ms Chantal
and Dr Bouchard); administrative, technical, and material support (Mr Labelle and Drs Braun and Boulanger); study supervision (Drs Bouchard, Braun, and Boulanger).
This work was supported by grants from the Fondation and Département
de la Recherche, Hôpital de l'Enfant-Jésus du CHA, Quebéc
City, and by a scholarship from the Alzheimer Society of Canada, Toronto,
Ontario (Ms Chantal).
We thank Andrée Morin, RN, for her assistance with patient recruitment
and Abdesslem Khiat, PhD, for helpful discussions.
Corresponding author and reprints: Sophie Chantal, MPs, Centre de
recherche, bureau H-441, Hôpital de l'Enfant-Jésus du CHA, 1401
18e Rue, Quebec City, Quebec G1J 1Z4, Canada (e-mail: sophie.chantal{at}cha.quebec.qc.ca).
From Clinique de la Mémoire/Recherche-Alzheimer, Hôpital
de l'Enfant-Jésus du Centre Hospitalier Affilié Universitaire
de Québec, Université Laval, Quebec City (Ms Chantal and Dr
Bouchard); Centre de Neurosciences Cognitives, Université du Québec
à Montréal, Montreal (Ms Chantal and Dr Braun); and Département
de Radiologie, Hôpital Saint-Luc du Centre Hospitalier de l'Université
de Montréal, Montreal (Mr Labelle and Dr Boulanger), Quebec.
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