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Regional Magnetic Resonance Imaging Lesion Burden and Cognitive Function in Multiple Sclerosis
A Longitudinal Study
Reisa A. Sperling, MD;
Charles R. G. Guttmann, MD;
Marika J. Hohol, MD;
Simon K. Warfield, PhD;
Marianna Jakab, MS;
Marco Parente;
Eli L. Diamond;
Kirk R. Daffner, MD;
Michael J. Olek, DO;
E. John Orav, PhD;
Ron Kikinis, MD;
Ferenc A. Jolesz, MD;
Howard L. Weiner, MD
Arch Neurol. 2001;58:115-121.
ABSTRACT
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Objective To investigate the relationship between magnetic resonance imaging regional
lesion burden and cognitive performance in multiple sclerosis (MS) over a
4-year follow-up period.
Design Twenty-eight patients with MS underwent magnetic resonance imaging and
took the Brief, Repeatable Battery of Neuropsychological Tests in Multiple
Sclerosis at baseline, 1-year, and 4-year follow-up. An automated 3-dimensional
lesion detection method was used to identify MS lesions within anatomical
regions on proton density T2-weighted images. The relationship between magnetic
resonance imaging regional lesion volumes and the Brief, Repeatable Battery
of Neuropsychological Tests in Multiple Sclerosis results was examined using
regression analyses.
Results At all time points, frontal lesion volume represented the greatest proportion
of total lesion volume, and the percentage of white matter classified as lesion
was also highest in frontal and parietal regions. On neuropsychological testing,
when compared with age- and educational level–matched control subjects,
patients with MS showed significant impairment on tests of sustained attention,
processing speed, and verbal memory (P<.001).
Performance on these measures was negatively correlated with MS lesion volume
in frontal and parietal regions at baseline, 1-year, and 4-year follow-up
(R = -0.55 to -0.73, P<.001).
Conclusions Multiple sclerosis lesions show a propensity for frontal and parietal
white matter. Lesion burden in these areas was strongly associated with performance
on tasks requiring sustained complex attention and working verbal memory.
This relationship was consistent over a 4-year period, suggesting that disruption
of frontoparietal subcortical networks may underlie the pattern of neuropsychological
impairment seen in many patients with MS.
INTRODUCTION
COGNITIVE dysfunction is common in patients with multiple sclerosis
(MS), with estimates ranging from 40% to 65% of patients with MS showing impairment
on tests of attention, speed of information processing, and recent memory.1, 2, 3, 4 Several
recent studies5, 6, 7, 8, 9, 10, 11, 12, 13
have investigated the relationship between MS lesion burden as assessed by
magnetic resonance imaging (MRI) and degree of cognitive impairment, with
general agreement that poor cognitive performance is associated with increased
total lesion volume.
The contribution of regional vs total lesion burden to cognitive dysfunction
remains controversial in the literature, and the neuroanatomical basis of
the cognitive dysfunction in MS remains to be fully elucidated. White matter
lesions, which likely affect connections between cortical regions thought
to be crucial for specific cognitive processes, may be particularly difficult
to characterize. Several studies8, 11, 12, 14
have attempted to examine the relationship of regional lesion burden to cognitive
function; however, most of these studies only examined frontal lesion volume.
Even less is known about the relationship of regional or total lesion
volume with specific cognitive deficits over time. Very few studies10, 15, 16 have examined longitudinal
cognitive performance with serial MRI measurements of total lesion volume
and, to our knowledge, there are no longitudinal studies of regional lesion
burden and cognitive function. Because depression is frequent in patients
with MS17 and because depression can have significant
effects on cognitive function, we were also interested in examining the relationship
of depressive symptoms to regional lesion burden and cognitive function.
Our group has been investigating the relationship between serial MS
lesion volumes as assessed on MRI and multiple clinical features in MS.18 We have previously published a report of serial neuropsychological
assessment and MRI measures over a 1-year period,10
demonstrating robust correlations between baseline cognitive test scores and
total lesion volume. In the initial study, only the relationship of total
lesion volume and cognitive test scores was assessed, and no significant changes
in cognitive function were observed at 1-year follow-up. We undertook this
4-year follow-up study to further investigate the relationship between MS
lesion volumes as seen on MRI, examined regionally, and longitudinal cognitive
performance.
SUBJECTS AND METHODS
PATIENTS AND CONTROL SUBJECTS
Forty-four patients with MS were initially enrolled in a National Institutes
of Health–sponsored 1-year study. Four years later, 28 patients consented
to participate in a follow-up study; 9 patients had either moved out of the
area or were too physically incapacitated to participate in follow-up testing;
7 patients declined to participate in the follow-up study. Eligible patients
for the initial study were between 20 and 55 years of age, fulfilled Poser
et al19 criteria for definite MS, had an Expanded
Disability Status Scale20 score of 6.5 or less,
and an MRI of the brain demonstrating lesions consistent with the diagnosis
of MS.21 Patients with a history of other central
nervous system disease or significant medical illnesses were excluded. Patients
with MS were also excluded if they had received immunosupressive, cytotoxic,
or experimental immunomodulatory therapy at any time prior to their initial
enrollment, or corticotropin or corticosteroid therapy within 2 months prior
to enrollment. Treatment with disease-modifying therapy, including corticosteroids
and later interferon beta, was allowed during the course of the study.
Healthy control subjects were recruited from the community for the follow-up
study. Controls were selected to match patients with MS within 3 years of
age and within 2 years of overall educational level. The 2 groups were also
similar in gender composition and handedness. Patient and control demographics
are summarized in Table 1. The
initial and follow-up studies were approved by the Institutional Review Board
of Brigham and Women's Hospital, Boston, Mass. Informed consent was obtained
from all patients and controls.
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Table 1. Demographic and Clinical Data
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MAGNETIC RESONANCE IMAGING
Twenty-eight patients with MS underwent MRI at baseline, 1-year, and
4-year follow-up. Magnetic resonance imaging was performed on a 1.5-T unit
(Signa; General Electric Medical Systems, Milwaukee, Wis). Proton density
and T2-weighted images were obtained using 2 interleaved dual-echo (echo times
= 30 and 80 ms) long repetition (3000-ms) sequences yielding contiguous 3-mm-thick
slices of the whole brain.
Anatomical regions were defined using surface landmarks on a 3-dimensional
display of each patient's baseline MRI study. An operator (R.A.S.) blinded
to patient identity used standard cortical landmarks to divide each hemisphere
into 4 large sectors. A plane was drawn from the superior extent of the rolandic
sulcus to the anterior extent of the brainstem and perpendicular to the midsagittal
plane. A second plane was drawn along the angle of the sylvian fissure also
perpendicular to the midsagittal plane. These intersecting planes resulted
in a crude division of each hemisphere into 4 regions roughly corresponding
to the frontal, parietal, and temporal lobes, and a posterior region that
included the occipital lobe, cerebellum, and brainstem (Figure 1). This procedure was repeated for each hemisphere, yielding
a total of 8 anatomical regions of interest per MRI study.
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Image processing and lesion segmentation. A, T2-weighted magnetic
resonance imaging axial section from the brain of a 33-year-old woman with
multiple sclerosis. B, Segmented image showing tissue classification into
gray matter (gray), cerebrospinal fluid (aqua), normal white matter (green),
and lesion (yellow). C, Anatomical mask showing quadrants corresponding to
right frontal (red), left frontal (green), right parietal (blue), and left
parietal (yellow) regions. D, Overlay of regional lesion labels on T2-weighted
magnetic resonance imaging with corresponding colors mentioned in Figure C.
E, Three-dimensional reconstruction of ventricular cerebrospinal fluid (shown
in light blue) and regional lesion volumes with corresponding colors to anatomical
mask mentioned in Figure C.
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Volumes of abnormal signal intensity (MS lesions) within each of these
regions were identified using an automated image analysis algorithm.22 A template-driven segmentation technique, described
in detail elsewhere,23 was used to identify
major tissue types (gray matter, white matter, and cerebrospinal fluid). Each
white matter voxel was then classified as normal white matter or white matter
with abnormal signal intensity.22 The white
matter classified as having abnormal signal intensity is believed to be consistent
with MS lesions, and is, henceforth, referred to as lesion volume.
A mask defining the anatomical regions on each patient's baseline MRI
was aligned with the segmented images for each time point (baseline, 1 year,
and 4 years) using an automated image registration method.23
This procedure yielded volumes of lesion, healthy white matter, gray matter,
and cerebrospinal fluid for each of the 8 anatomical regions.
NEUROPSYCHOLOGICAL TESTING
The Brief, Repeatable Battery of Neuropsychological Tests in Multiple
Sclerosis (BRB)1 was administered to the patients
with MS at baseline, 1-year, and 4-year follow-up. Alternate, equivalent,
published forms of the revised BRB were used at each follow-up visit to minimize
practice effects. The baseline BRB form was administered to the control subjects
to allow comparison with the initial cognitive performance of the patients
with MS.
The BRB is composed of 5 subtests: (1) The Bushke Verbal Selective Reminding
Test is a measure of verbal learning and delayed recall of a 12-word list.
The Long-Term Storage score represents the sum of words recalled on 2 consecutive
trials without reminding, and the Consistent Long-Term Retrieval (CLTR) is
the sum of words recalled on all subsequent trials without reminding. Total
Delay is the number of words recalled after a 10-minute delay. (2) The 10/36
Spatial Recall Test measures visuospatial learning and delayed recall using
a checkerboard pattern. Three learning trials and 1 delayed trial are scored
for the total number of correct responses. (3) The Symbol Digit Modalities
Test assesses sustained attention and information processing speed. The written
form of the test was used to score the number of correct pairs. (4) The Paced
Auditory Serial Addition Task (PASAT) is a measure of complex attention and
concentration. A prerecorded audiocassette plays a series of single-digit
numbers presented every 3 seconds. The subject is asked to add each number
to the digit immediately preceding it, rather than a cumulative sum. The percentage
of correct additions is recorded. (5) Word List Generation is a measure of
verbal fluency and sustained attention. Subjects are instructed to generate
as many words as possible that begin with a given letter in 60 seconds. The
total number of admissible words is scored.
BECK DEPRESSION INVENTORY
The Beck Depression Inventory (BDI) is a self-reported index of subjective
feelings.24 The BDI consists of 21 groups of
statements, asking the subject to choose the statement in each group that
best describes his or her feelings over the past week. The statements are
assigned numerical value, with higher numbers assigned to more severe symptoms
of depression. The BDI was added to the end of the neuropsychological test
battery for patients with MS at the 4-year follow-up study and was administered
to all controls at the end of their baseline battery.
STATISTICAL METHODS
Nonparametric statistics were used for all comparisons as assumptions
of normality were not uniformly met. Demographic and neuropsychological measures
of patients with MS and controls were compared using the Kruskal-Wallis test.
The Fisher exact test was used to compare dichotomous variables (gender and
handedness). The Wilcoxon signed rank test was used to compare baseline and
follow-up BRB test scores and MRI lesion volumes in patients with MS. All
correlations between MRI lesion volumes and neuropsychological test scores
were examined using the Spearman rank correlation, yielding a Spearman 
coefficient. All significance values were subjected to correction for multiple
comparisons25 where appropriate. All values
are expressed as mean ± SD.
RESULTS
For the 28 patients with MS who participated in the follow-up study,
mean time elapsed from baseline to follow-up assessment was 4.1 ± 0.7
years. Neuropsychological testing of patients with MS was performed within
a mean of 8.3 days (range, 0-32 days) of baseline MRI, 6.9 days (range, 0-22
days) of 1-year follow-up MRI, and 0.2 days (range, 0-3 days) of 4-year follow-up
MRI.
At study enrollment, mean disease duration was 8.3 ± 5.7 years.
Mean Expanded Disability Status Scale score at baseline was 4.0 ± 1.8,
4.2 ± 1.3 at 1-year, and 4.8 ± 1.7 at 4-year follow-up (P = .09, Wilcoxon signed rank test). Fifteen of the patients
with MS were classified as having relapsing-remitting MS and 13 as having
chronic progressive MS at the time of enrollment. Fifteen of the patients
with MS received immunomodulatory therapy at some point during the 4-year
follow-up period. Eight patients received corticosteroid treatment, 3 of these
in combination with cyclophosphamide. Seven patients received interferon beta
therapy.
MRI LESION VOLUMES
Mean total lesion volume was 19.4 ± 15.1 mL at baseline, increasing
to 21.5 ± 15.3 mL at 4-year follow-up (P =
.48 Wilcoxon signed rank test). Frontal lesion volume represented the greatest
percentage of total lesion volume (mean, 51.8% ± 8.3%; P<.01, Wilcoxon signed rank test), and this proportion did not change
over the 4 years. The percentage of white matter classified as lesion was
significantly higher in frontal and parietal regions (6.1% and 7.1%, respectively)
compared with temporal (1.6%) and posterior (3.0%) regions (P<.005, Wilcoxon signed rank test). Regional and total lesion volumes
were highly correlated, particularly frontal and parietal regions with total
lesion volume (R = 0.95-0.97, P<.001 Spearman rank correlation). Relative proportions of white
matter classified as lesion and correlations for regional lesion volumes to
total lesion volume are given in Table 2.
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Table 2. Relationship of Regional to Total Lesion Volumes
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Patients with relapsing-remitting MS had a baseline total lesion volume
of 14.0 ± 5.4 mL compared with 24.1 ± 19.1 mL for the patients
with chronic progressive MS (P<.08, Wilcoxon signed
rank test). The mean change in total lesion volume over 4 years was 0.70 ±
3.2 mL for patients with relapsing-remitting MS and 3.3 ± 4.1 mL for
patients with chronic progressive MS (P<.07, Wilcoxon
signed rank test). We did not find any significant relationship between handedness
and total or regional lesion volumes.
NEUROPSYCHOLOGICAL PERFORMANCE
Patients with MS were impaired on all baseline BRB tests compared with
age- and educational level–matched controls. The most significant differences
were found on tests of sustained attention (PASAT), processing speed (Symbol
Digit Modalities Test), and the sustained working memory component of verbal
memory (CLTR) (P<.001, Kruskal-Wallis test). Table 3 summarizes the BRB results for
controls and patients with MS. Disease duration and Expanded Disability Status
Scale scores were not significantly related to baseline or follow-up cognitive
performance.
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Table 3. Baseline Results for the Brief, Repeatable Battery of Neuropsychological
Tests in Multiple Sclerosis
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Overall, at both 1- and 4-year follow-up, patients with MS did not show
significant changes on neuropsychological testing. Only 1 BRB subtest showed
a modest decline at 4-year follow-up: the Delayed Verbal Memory score on the
Selective Reminding Test (P = .02, Wilcoxon signed
rank test). No significant differences were found in the baseline or follow-up
cognitive performance between patients with relapsing-remitting MS and patients
with chronic progressive MS.
RELATIONSHIP OF MRI LESION BURDEN TO COGNITIVE MEASURES
Cognitive performance was significantly correlated with specific regional
and total lesion volumes at baseline, 1-year, and 4-year follow-up MRI. Poor
performance on tests of complex attention (PASAT), processing speed (Symbol
Digit Modalities Test), and verbal memory (Bushke Verbal Selective Reminding
Test) was associated with greater lesion volume in regions, but not with lesion
volume in the temporal, occipital, brainstem, or cerebellar regions. Even
after stringent correction for multiple comparisons, performance on the PASAT
and Bushke Verbal Selective Reminding Test-CLTR remained significantly correlated
with frontal, parietal, and total lesion burden (R
= -0.55 to -0.74; P<.001, Spearman
rank correlation). We also performed this analysis using lesion volume expressed
as a fraction of the total white matter in each anatomical region with similar
findings. Table 4 gives the correlations
between all regional and total lesion volumes and cognitive performance at
4-year follow-up.
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Table 4. Correlation Between Cognitive Tests Results and Regional Lesion
Volumes at 4-Year Follow-up for Patients With Multiple Sclerosis*
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The relationship between regional lesion volume and neuropsychological
performance was highly stable over the 4-year period. Table 5 gives the correlation between left and right frontal regions
and the PASAT at all 3 time points.
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Table 5. Correlation Coefficients for PASAT With Left and Right Frontal
Regions*
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As above, patients with MS did not demonstrate a significant change
in lesion volume or a significant decline in most cognitive domains over the
4-year period. Overall, we did not find significant correlations between a
change in lesion volume and a change in the BRB scores. The only cognitive
subtest with a statistical trend toward decline over the 4 years, the Bushke
Verbal Selective Reminding Test delayed verbal memory measure, did show a
modest correlation with change in both frontal (R
= -0.40; P<.03, Spearman rank) and total
lesion volumes (R = -0.39; P<.04, Spearman rank), but these were not significant after correction
for multiple comparisons.
BECK DEPRESSION INVENTORY
The BDI was administered at 4-year follow-up to patients with MS, and
at baseline to all controls. Patients with MS reported a significantly higher
BDI score than controls (P<.001, Wilcoxon signed
rank test). However, the BDI scores did not show significant correlation with
cognitive performance or with regional and total lesion volumes.
COMMENT
This longitudinal study demonstrated a robust and highly consistent
association between MRI lesion burden in frontoparietal white matter and cognitive
performance. Our findings suggest that the regional distribution of lesions
in MS is not random, and lesions show a clear predilection for frontal and
parietal regions. Over half the total lesion volume was contained within frontal
regions as we defined them, and frontal and parietal regions showed a significantly
higher percentage of lesioned white matter than temporal and posterior regions.
Lesion volumes in frontal and parietal regions were most strongly associated
with the PASAT, a measure which requires sustained attention, working memory,
and the ability to inhibit automatic responses. We also found a strong correlation
of frontal and parietal lesion burden with the CLTR, a measure of verbal memory
that also requires sustained attention and continuous retrieval of newly acquired
information. Notably, the PASAT and CLTR were also among the tests showing
the greatest impairment in patients with MS compared with age- and educational
level–matched controls.
These findings suggest that the pattern of cognitive dysfunction frequently
observed in patients with MS is directly related to lesion burden in frontal
and parietal white matter. Several previous studies have reported marked dysfunction
in patients with MS on tasks, such as the Wisconsin Card Sort Test, that are
thought to be dependent on the integrity of frontal attentional systems.2, 26 Impairment in sustained attention,
working memory, and executive function is frequently seen in patients with
both cortical and subcortical frontal lobe damage from a variety of neurological
conditions. More recently, functional imaging studies27, 28
have also documented activation in parietal cortical regions with complex
attention and memory tasks. It is also likely that disruption of circuits
traversing the parietal white matter may disconnect frontal areas from other
cortical regions involved in sustained task performance.
Our findings are supported by several other studies that have examined
the relationship of regional MS lesion burden to specific cognitive tests.
Swirsky-Sacchetti et al8 reported that left
frontal lobe lesion burden was associated with poor performance on the Wisconsin
Card Sort Test and several memory tests. Arnett et al26
found that patients with MS who had a "high" frontal lobe lesion burden performed
poorly on the Wisconsin Card Sort Test when compared with patients with a
"low" frontal lesion burden. Foong et al14
found moderately robust correlations between several neuropsychological measures
of executive function and frontal lesion volume, but did not examine lesion
volume in other anatomical regions. Similar to our findings, Foong et al14 did not find a robust relationship between spatial
working memory and frontal lesion burden.
Our data also address the controversy concerning the relative contribution
of regional lesion burden vs total lesion burden to cognitive impairment in
MS. Swirsky-Sacchetti et al8 reported that
total lesion volume was actually the strongest predictor of cognitive function,
despite strong correlations of regional lesion area with specific cognitive
tests. Foong et al14 attempted to elucidate
the specific contribution of frontal lesion volume by controlling for total
lesion volume, which resulted in nonsignificant correlations with all cognitive
measures. We also found a strong relationship between cognitive performance
and total lesion volume. This finding is not particularly surprising, however,
given the extremely high correlation between lesion volumes in frontal and
parietal regions and total lesion volume (R = 0.95
and 0.97, Spearman rank correlation, respectively at both baseline and follow-up).
The most robust associations with cognitive performance were seen with frontal
and parietal regional lesion burden, while temporal, occipital, cerebellar,
and brainstem regions did not show significant correlations with cognitive
performance.
The distribution of regional lesion burden remained consistent over
the 4-year follow-up. Although there was a modest increase in lesion burden
over this time, it was not significantly different from baseline, and concomitantly,
we did not observe much change in cognitive function. Many of our patients
were treated with a variety of therapeutic agents over the course of the 4
years, and this may have influenced the rate of disease progression.
Although the presence of cognitive impairment in MS is well documented,
the course of cognitive decline in MS remains controversial in the literature,
and at least 1 other longitudinal study reported stable cognitive status for
up to 4 years of follow-up.29 There are several
explanations as to why we did not detect significant cognitive deterioration
over the course of this study. First, several of the patients from the original
cohort recruited for this study were unable to participate in the 4-year follow-up
study because of physical incapacity, and may have represented the subgroup
likely to show significant cognitive decline. Another possibility is the "critical
threshold model" first suggested by Rao et al.9
It is conceivable that once this lesion burden threshold has been crossed,
further cognitive deterioration may be slow. At baseline, our patients demonstrated
marked cognitive impairment compared with age- and educational level–matched
controls, and thus we may have missed the "window" of decline. A longitudinal
study of cognitive function with MRI correlation of patients in earlier stages
of the disease would likely yield more change in cognition and in lesion volume
over a similar time period. It is also possible, that although we attempted
to control for "practice effects" by using alternate versions of the BRB testing
materials, repeated exposure or practice effects may have obscured some subtle
decline in cognitive functioning. Finally, the course of cognitive decline
may be variable among patients, and a much larger sample size may be required
to detect a definitive pattern. We did not detect significant differences
between patients with relapsing-remitting MS and patients with chronic progressive
MS in the degree of cognitive impairment at baseline or over time, but had
a small sample of patients in each group. Although we did not detect significant
change on most cognitive measures, interestingly, the only subtest with a
significant decline at follow-up (delayed verbal memory) did show a modest
association with the small increase in frontal and total lesion volume.
Our findings suggest that although mood was clearly affected in many
MS patients, the cognitive impairment seen in MS can not be attributed to
the "pseudodementia" sometimes seen with depression, and that cognitive performance
is independently related to lesion burden. Similar to Foong et al,14 we did not find a significant correlation between
the degree of depressive symptoms and cognitive function or regional lesion
burden. Several of our patients were receiving antidepressants, given either
for depression or nonmood-related symptoms, such as chronic pain or incontinence.
These medications may have affected the self-report of depressive symptoms;
however, our patients did have a significantly higher BDI score than the controls.
One of the strengths of our study is the use of an automated 3-dimensional
lesion detection algorithm. This method allows an unbiased, volumetric assessment
of lesion burden, and was particularly useful for regional analysis. Using
conventional spin-echo imaging, white matter lesions appear as areas of increased
signal intensity. However, the segmentation of these scans can be difficult
because the MRI intensity range of white matter lesions overlaps that of normal
tissue (particularly, of gray matter). Template-driven segmentation allows
automated classification of white matter voxels into healthy white matter
or MS lesion with less interference from gray matter.22
In this study, we chose to use large anatomical divisions, as the exact anatomy
of white matter connectivity is poorly understood. We wanted to devise a method
that was unbiased and easily reproducible across subjects, without requiring
manual editing of subcortical structures. Thus, we chose to divide the hemispheres
into quadrants and group lesions in the occipital lobe, cerebellum, and brainstem
into a posterior region, which did not require any further manual editing.
Future studies with more detailed methods of anatomical lesion localization
may yield better understanding of the regional distribution of lesion burden,
and the relationship to specific patterns of cognitive dysfunction in MS.
AUTHOR INFORMATION
Accepted for publication October 4, 2000.
This study was supported by grants N01-NS-0-2397, NCRR GCRC M01, NIH
NCRR P41 RR13218, and RG 3094A1/T from the National Multiple Sclerosis Society,
New York, NY (Dr Wakefield), and the Nancy Davis Foundation, Boston, Mass
(Dr Weiner).
We thank Sandra Cook, RN, for coordinating patient visits and Mark Anderson
for technical assistance with MRI processing. We also acknowledge the contribution
of Glen Mackin, MD, and Samia Khoury, MD, to the initial study design. We
thank Marilyn Albert, PhD, for her invaluable assistance in reviewing the
manuscript. We gratefully acknowledge the contribution of the patients in
this study.
From the Departments of Neurology (Drs Sperling, Daffner, Olek, and
Weiner and Messrs Parente and Diamond), Medicine (Dr Orav), and Radiology
(Drs Guttmann, Warfield, Kikinis, and Jolesz and Ms Jakab), Brigham and Women's
Hospital, Harvard Medical School, Boston, Mass; and the Department of Neurology,
St Michael's Hospital, Toronto, Ontario (Dr Hohol).
Corresponding author: Reisa A. Sperling, MD, Memory Disorders Unit,
Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115 (e-mail: reisa{at}rics.bwh.harvard.edu).
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