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T2 Hypointensity in the Deep Gray Matter of Patients With Multiple Sclerosis
A Quantitative Magnetic Resonance Imaging Study
Rohit Bakshi, MD;
Ralph H. B. Benedict, PhD;
Robert A. Bermel, BA;
Shelton D. Caruthers, PhD;
Srinivas R. Puli, MD;
Christopher W. Tjoa;
Andrew J. Fabiano, BS;
Lawrence Jacobs, MD
Arch Neurol. 2002;59:62-68.
ABSTRACT
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Context While gray matter T2 hypointensity in multiple sclerosis (MS) has been
associated with physical disability and clinical course, previous studies
have relied on visual magnetic resonance imaging (MRI) assessments.
Objective To quantitatively determine if T2 hypointensity is associated with conventional
MRI and clinical findings in MS.
Design Case-control study.
Setting University-affiliated community-based hospital.
Subjects Sixty patients with MS and 50 controls.
Main Outcome Measures T2 intensities of the substantia nigra, red nucleus, thalamus, putamen,
globus pallidus, and caudate; third ventricular width; total brain T1 (hypointense)
and T2 (hyperintense) lesion volumes; Expanded Disability Status Scale (physical
disability) score; and disease course.
Results Deep gray matter T2 hypointensity was present in patients with MS in
all structures (P<.005) except for the substantia
nigra. T2 hypointensity was associated with third ventricle enlargement and
higher T2 but not T1 plaque load. The regression model predicting third ventricle
width included caudate T2 hypointensity (P = .006).
The model predicting T2 lesion load included globus pallidus T2 hypointensity
(P = .001). Caudate T2 hypointensity was the only
variable associated with disability score in regression modeling (P = .03). All T2 hypointensities differentiated the secondary progressive
from the relapsing-remitting clinical courses. The final model (P<.001) predicting clinical course retained T2 hypointensity of
the thalamus, caudate, and putamen but not MRI plaques or atrophy.
Conclusions Gray matter T2 hypointensity in MS is associated with brain atrophy
and is a stronger predictor of disability and clinical course than are conventional
MRI findings. While longitudinal studies are warranted, these results suggest
that pathologic iron deposition is a surrogate marker of the destructive disease
process.
INTRODUCTION
HYPERINTENSE white matter lesions on T2-weighted magnetic resonance
imaging (MRI) scans (T2WI) are useful in diagnosing multiple sclerosis (MS)
in the brain1 and spinal cord2
and can assess disease activity in treatment trials.3
However, bright T2WI lesions are nonspecific in defining the wide range of
pathologic changes in the white matter of patients with MS4
and may be insensitive to microscopic disease.5
While gadolinium contrast enhancement on T1-weighted images may indicate blood-brain
barrier disruption, it is transient, variable, and may not accurately predict
long-term sequelae.6 Both hyperintense and
enhancing lesions show poor correlations with clinical findings in MS and
provide incomplete assessments of therapies.7
Multiple sclerosis is increasingly thought of as a globally destructive
disease process.8-9 Pathologic10 and positron emission tomography imaging studies11 indicate that cortical and subcortical gray matter
involvement is common in MS.12 Recently we
showed that hypointensity on T2WI (purported iron deposition) occurred commonly
in the subcortical gray matter of patients with MS and was associated with
physical disability, disease duration, disease course, brain MRI lesion load,
and brain atrophy.13-14 These
and other studies15-16 of T2 hypointensity
in MS used qualitative (visual) rating systems that limited the findings.
In the present study, we performed a computer-assisted quantitative MRI study
of T2 hypointensity in patients with MS and controls. We compared the degree
of T2 hypointensity with clinical findings and other established quantitative
MRI markers of MS, including brain atrophy and plaque load.
SUBJECTS AND METHODS
SUBJECTS
Sixty patients clinically confirmed to have MS17
and 50 controls were scanned with the same MRI unit at a tertiary care facility.
None of the patients with MS had other major medical illnesses, were younger
than 20 years or older than 60 years, used corticosteroids within 4 weeks,
or had a history of substance abuse. Forty-two patients had the relapsing-remitting
and 18 had the secondary progressive MS clinical disease course.18
Physical disability was assessed by the Expanded Disability Status Scale (EDSS)
within 1 week of the MRI by a single experienced neurologist blind to the
MRI findings.19 Scores ranged from 0 to 8.0
(mean ± SD, 3.7 ± 1.9). The duration of MS ranged from 0.5 to
38 years (mean ± SD, 10.6 ± 9.4 years). The average number of
lifetime courses of high-dose intravenous methylprednisolone taken by all
60 patients with MS was 1.8. Four (7%) were receiving bimonthly intravenous
methylprednisolone for disease progression. Controls included normal volunteers
recruited from hospital staff and consecutive patients referred to the MRI
center for dizziness, headaches, and seizure disorder, who had normal neurologic
and MRI findings. An experienced observer reviewed the scans of controls to
ensure normal findings and discarded 3 controls due to the presence of bright
lesions on T2-weighted images (53 control scans screened, 50 retained). Visual
determination of gray matter T2 intensity was not used to exclude control
scans. Patients with MS and controls were sex-matched (68% women and 70% women,
respectively) and age-matched (mean ± SD age, 42 ± 9 years and
42 ± 10 years, respectively) (P>.9).
MAGNETIC RESONANCE IMAGING
Fast spin-echo T2WI (repetition time [TR]/echo time [TE]/number of signal
averages [NSA] = 2300/120/2; 6-mm slice thickness; 0.6 mm slice gap; echo
train length 18), fast spin-echo fluid-attenuated inversion-recovery (FLAIR)
images (TR/TE/NSA/inversion time = 8000/120/2/2200; 5-mm slice thickness;
interleaved; echo train length 20), and T1-weighted images (TR/TE/NSA = 585/20/1,
5-mm slice thickness, interleaved) were obtained in the axial plane on an
ACS-NT MRI scanner (Philips Medical Systems, Best, the Netherlands). The in-plane
spatial resolution was approximately 1 x 1 mm. The FLAIR protocol was
detailed previously.20 Images were transferred
to Sun workstations (Sun Microsystems, Moutainview, Calif) on which images
were analyzed quantitatively at the Buffalo Neuroimaging Analysis Center (Buffalo,
NY). A trained observer who was blind to clinical information performed the
quantitative MRI analysis. Based on a localization technique,21
standardized circular regions-of-interest (ROIs) were placed on T2WI in the
substantia nigra pars compacta, substantia nigra pars reticulata, red nucleus,
anterior thalamus, posterior thalamus, head of the caudate nucleus, and in
the cerebrospinal fluid (CSF) of the right lateral ventricular body. To sample
the structure while minimizing partial volume effects, the ROIs were 2-mm
in diameter for the substantia nigra pars reticulata, pars compacta, and red
nucleus and were 5 mm for the other structures. Since the lateral ventricular
size varied among subjects, the largest circular ROI (not exceeding 5 mm)
was placed in the ventricle without including the adjacent parenchyma or choroid
plexus. Freehand ROIs were also manually traced for the putamen and globus
pallidus. One axial slice was used for each measurement (the slice showing
the largest part of the structure). Care was taken to avoid placing small
hyperintensities (MS plaques or perivascular spaces) into ROIs. To correct
for potential interscan variations in system scaling and gain, mean signal
intensity in each ROI was divided by mean signal intensity of lateral ventricular
CSF as adapted from Pujol et al.22 Because
T2 intensity was expressed as a ratio to the right lateral ventricular CSF,
it is important to note that absolute right vs left CSF intensities did not
differ in patients (P = .44) or controls (P = .26), and neither right (P = .44) nor
left (P = .27) absolute CSF intensities differed
between the groups. The data from the anterior and posterior thalami ROIs
were averaged to produce a value for the thalamus. The data from the substantia
nigra pars reticulata and pars compacta ROIs were averaged to produce a value
for the substantia nigra. Separate measurements were taken from each hemisphere,
which were then collapsed across both hemispheres by calculating the mean
in each ROI (to reduce the number of statistical variables).
We assessed the validity of right/left collapsing of the variables and
assessed the symmetry of the gray matter signal changes. The Pearson correlation 
values between right and left T2 intensities were 0.92 for the caudate, 0.88
for the thalamus and putamen, 0.90 for the red nucleus, 0.87 for the substantia
nigra, and 0.92 for the globus pallidus. Paired sample t tests showed no significant right vs left difference for the caudate,
thalamus, and red nucleus. While the putamen, substantia nigra, and globus
pallidus showed significant right vs left differences in T2 intensities, the
effect sizes were quite small: 0.3 or less (effect sizes = difference between
means divided by pooled SDs). Thus, in general, the T2 intensity in the gray
matter ROIs showed symmetry in the MS group.
After collapsing the ROIs, a total of 6 ROIs were used for further analysis
(substantia nigra, red nucleus, thalamus, caudate, putamen, globus pallidus).
The typical ROI placement in a patient with MS is shown in Figure 1. The fast spin-echo T2 sequence was used in the analysis
of T2 hypointensity. Previous studies analyzing iron deposition have used
conventional spin-echo to detect T2 shortening.21-24
In this study, we used fast spin-echo T2 because of the faster scanning time
and increased clinical utility in the evaluation of patients with MS (see
"Comment" section).
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Figure 1. Region of interest (ROI) placement
method shown on representative T2-weighted magnetic resonance imaging scans.
Circular ROIs were standardized sizes (see "Subjects and Methods" section)
chosen to maximize signal-to-noise ratio while minimizing partial volume effects.
Freehand ROIs were traced manually. Both right and left hemispheres were assessed
for each ROI, which were then collapsed (see "Subjects and Methods" section).
A, Substantia nigra pars reticulata (SNPR), substantia nigra pars compacta
(SNPC), red nucleus (RN). B, Putamen (PUT) and globus pallidus (GP), manually
traced. C, Head of caudate (CAUD), anterior thalamus (ANT THAL), posterior
thalamus (POST THAL). D, Posterior lateral ventricular cerebrospinal fluid
(CSF).
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The total T2 hyperintense parenchymal plaque lesion load was determined
by manual tracing of lesions on FLAIR images and was the sum of the volume
of each lesion seen on each FLAIR axial slice (area multiplied by slice thickness,
nongapped images); artifacts and other normal hyperintensities seen in the
normal population on FLAIR images were avoided.20
To assess central atrophy, third ventricular width was measured from FLAIR
images using our previously established method.25
The analysis of gray matter and CSF T2 intensity, T2 hyperintense lesion volume,
and third ventricular width was performed using EasyVision software (Release
2.1.2; Philips Medical Systems, Best, the Netherlands). Since hypointense
T1 lesions are difficult to delineate manually, the analysis of T1 lesion
volume was performed using a semiautomated edge finding and local thresholding
technique (Java Image, Version 1.0; Xinapse Systems, Leicester, England [http://www.xinapse.com]). The operator clicks on the edge of hypointense
area and the program examines a region 5 x 5 pixels around the mouse
click and computes the maximum intensity gradient within the region. The pixel
with the highest intensity gradient is then used as the starting point for
contour following, thus outlining the region where the intensity is locally
lower than at the starting pixel.
RELIABILITY
The same individual reanalyzed the MRI scans of 10 randomly chosen patients
with MS at least 2 weeks after the initial analysis. Intraobserver coefficients
of variation for the T2 intensity measurements ranged from 1.0% to 2.7% as
follows: caudate, 1.2% (right)/1.6% (left); anterior thalamus, 2.1%/1.2%;
posterior thalamus, 1.5%/2.2%; red nucleus, 1.4%/1.8%; substantia nigra-pars
reticulata, 2.4%/2.7%; pars compacta, 1.3%/1.8%; putamen, 1.3%/1.1%; globus
pallidus, 1.0%/1.0%; ventricular CSF, 1.2%. The intraobserver coefficients
of variation were 1.2% for total T2 hyperintense parenchymal lesion volume,
1.7% for total T1 hypointense parenchymal lesion volume, and 5.7% for third
ventricular width. A second trained observer analyzed the same 10 patients
for gray matter and CSF T2 intensity; the interobserver coefficients of variation
ranged from 0.6% to 2.9%. To test the stability of the T2 intensity measurement
technique, 2 healthy volunteers, aged 26 (man) and 31 (woman) years, each
underwent the MRI protocol twice (1 week apart). The scan/rescan intrasubject
coefficients of variation for the various gray matter intensities ranged from
1.2% to 2.5%.
ANALYSIS
Group differences were assessed by independent sample t tests. The Pearson r statistic was used
for correlations between continuous variables and the Spearman rank correlation
test was used to compare continuous data with ordinal ratings. We used a conservative
threshold for statistical significance (P<.01)
in all univariate comparisons and controlled for multiple correlations via
regression models. Within the MS group, linear and logistic regression models
were used to predict conventional MRI findings (total hyperintense parenchymal
lesion volume, third ventricular width) and clinical parameters (EDSS, disease
duration, relapsing-remitting [secondary progressive] clinical course) using
only T2 intensity measures as predictors that differed significantly between
patients with MS and controls (ie, abnormal T2 hypointensity). All models
controlled for age by entering age in block 1 and holding age in the final
model. Otherwise, each model used a forward stepwise selection procedure,
with P to enter .05 and P
to exit .10. Two types of analyses were performed. First, regression models
with individual gray matter ROI T2 intensities were fitted to detect significant
predictors of total T1 or T2 parenchymal lesion volume, third ventricular
width, or clinical parameters while controlling only for age. Second, total
T1 and T2 parenchymal lesion volume and third ventricular width were added
to the clinical parameter models.
RESULTS
Univariate comparisons indicated that T2 hypointensity was widespread
throughout the deep gray matter in patients with MS before and after adjusting
for age, affecting the caudate, putamen, globus pallidus, thalamus, and red
nucleus (P<.005) (Table 1). The magnitude of hypointensity was largest in the globus
pallidus, caudate, and putamen (6% to 7% lower than controls, P<.001) (Table 1). Representative
MRIs of T2 hypointensity in patients with MS vs controls are shown in Figure 2. The substantia nigra was the only
structure that did not show abnormal T2 hypointensity in patients with MS
compared with controls. Third ventricular width was larger in patients with
MS (mean ± SD, 4.0 ± 2.4) than in controls (2.2 ± 1.0)
(P<.05), indicating central atrophy in patients
with MS.25
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Gray Matter T2 Hypointensity in Patients With Multiple Sclerosis (MS)
vs Controls
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Figure 2. Four representative subjects illustrating
the deep gray matter T2 hypointensity in multiple sclerosis (MS). A-F, 3 patients
with MS in A 55-year-old healthy female control in G-L. A and B, A 43-year-old
man with secondary progressive MS and moderate physical disability (Expanded
Disability Status Scale [EDSS] score 3.5). Note the hypointensity of the red
nuclei (arrow) in comparison with the normal control scan (G). In figure B,
note the hypointensity of the thalami and lenticular nuclei and enlargement
of the third ventricle (central atrophy) compared with normal control scan
(H). C and D, A 33-year-old woman with relapsing-remitting MS and an EDSS
score of 3.5. Note the hypointensity of the thalami, putamen, and globus pallidus
compared with normal control scans (I, J). E and F, A 28-year-old man with
secondary progressive MS and moderate to severe physical disability (EDSS
score 6.5). Note the hypointensity of the caudate nuclei (arrows) compared
with the normal control scans (K, L).
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Within the MS group, T2 hypointensities in deep gray matter structures
were associated with higher third ventricle width and higher T2 lesion volume.
The regression model predicting third ventricle width included T2 hypointensity
of the caudate (partial r with age = -0.36; P = .006; R2 = 0.23).
The model predicting total T2 lesion load included T2 hypointensity of the
globus pallidus (partial r with age = -0.41; P = .001; R2 = 0.18).
In contrast, T2 hypointensities were not significantly associated with T1
lesion load.
The regression model predicting disease duration retained only T1 lesion
load (partial r with age = 0.32; P = .01; R2 = 0.43). When third
ventricular width, T1, and T2 lesion load were removed from the analysis,
there were no significant T2 hypointensity predictors retained in the model.
Within the MS group, Spearman rank correlations between EDSS score and
MRI variables were as follows: caudate, r = -0.26;
thalamus, r = -0.01; red nucleus, r = -0.03; putamen, r = -0.05;
globus pallidus, r = -0.10; substantia nigra, r = 0.23; whole-brain hyperintense T2 lesion volume, r = 0.23; whole-brain hypointense T1 lesion volume, r = 0.20; third ventricular width, r = 0.30. Caudate T2 hypointensity was retained in the model predicting
EDSS (partial r with age = -0.27; P = .03; R2 = 0.47). Putamen T2
hypointensity was also retained in step 3 of the analysis but the unique variance
contributed by this predictor was provided by a positive correlation and the
partial r with age only was not significant. The
model predicting EDSS included no general MRI measures, indicating that caudate
T2 hypointensity was a stronger predictor of EDSS than were third ventricular
width, T2 lesion volume, and T1 lesion volume.
All T2 hypointensities were significantly associated with the secondary
progressive course after age adjustment. T2 hypointensity in the thalamus
(P = .02) was the strongest predictor of secondary
progressive (vs relapsing-remitting) disease course among the T2 hypointensity
ROIs and general MRI measures. In the final model (R2 = 0.46; P<.001), T2 intensity of the caudate
and putamen were also retained but there were no general measures included.
Thus, gray matter T2 hypointensity was a stronger predictor of secondary progressive
vs relapsing-remitting disease course than were third ventricular width, T2
lesion load, and T1 lesion load.
COMMENT
This quantitative study shows that abnormal hypointensity on T2-weighted
images (BT2 ["black T2"]) is present in MS, occurs throughout the deep gray
matter, and is associated with clinical and MRI markers of disease severity.
BT2 is associated with brain atrophy and is a stronger predictor of disability
and clinical course than are conventional MRI findings. Our findings extend
previous studies that were based on visual (qualitative) assessments of BT2.13-16 A
previous study of 47 patients with MS, using an ordinal rating scale to measure
BT2, found that 25 patients with MS had abnormal hypointensity in the thalamus
and putamen.15 The degree of hypointensity
was correlated with the degree of T2 white matter plaques (also rated visually).
Another group16 used visual rating of BT2 and
reported mild hypointensity in the thalamus (not in the putamen or brainstem).
They used the cortical gray matter as a visual standard of normal T2 intensity
but the cortical gray matter may also develop BT2 in patients with MS,13, 26 so it is not a reliable standard
of reference. Previous studies may have been limited by sample size, lack
of a quantitative approach, or both. In our recent study of BT2 in 114 patients
with MS, we used a visual rating and found that BT2 was commonly detected
in the basal ganglia and thalamus and was related to disease duration, physical
disability, clinical course, MRI lesions, and atrophy.13-14
The present study confirmed that BT2 occurs in patients with MS in previously
recognized areas (ie, the basal ganglia, thalamus) and also in the brainstem
(red nucleus). The degree of BT2 showed a stronger relationship to physical
disability and clinical course than did T1 plaque load, T2 plaque load, or
central atrophy. This suggests that BT2 reflects important disease effects
relating to brain function. These same gray matter structures showed hypometabolism
on positron emission tomography scans of patients with MS.11
BT2 in MS has not yet been correlated with pathologic findings, but
it is probably due to pathologic iron deposition.15
It is not known whether pathologic iron accumulation is a secondary process
(related to neurodegeneration), a primary process contributing to injury,
or both. Previous studies have implicated disturbed iron homeostasis in MS.
Iron accumulates in reactive microglia, microglia, and macrophages in the
brains of patients with MS and ferritin levels are elevated in the CSF of
patients with progressive disease.27-28
The normal pattern of transferrin and ferritin binding was impaired and hemosiderin
and ferritin deposits were identified in the brains of patients with MS.15, 29 Increased chelatable iron can cause
neurotoxicity by transferring electrons to molecular oxygen to produce free
radicals.30 Iron deposition has been described
in a host of neurodegenerative diseases and aging, in which BT2 is also observed
by MRI,21-23,31-32
suggesting a common theme underlying a variety of neurologic conditions. Blood-brain
barrier dysfunction (increased delivery), disrupted clearance of iron byproducts,
or dysregulation of brain iron transport proteins may play a role in iron
deposition,31 potentially offering new therapeutic
opportunities in MS.
While BT2 is most likely due to iron deposition, other possibilities
include magnetization transfer effects, diffusional changes, and tissue oxygenation
differences. If cellular structure is degraded and the free diffusion constant
rises, fast spin-echo T2WI could theoretically show reduced signal. However,
fast spin-echo is relatively insensitive to diffusion effects compared with
echoplanar techniques. Using the moderate echo train length in the present
study, diffusion effects would likely be minimized (if detectable). Deoxyhemoglobin
causes T2 shortening while oxyhemoglobin causes T2 prolongation on heavily
weighted T2WI. Thus, if patients with MS have higher ratios of deoxyhemoglobin
to oxyhemoglobin in gray matter than controls, this might lead to relative
T2 hypointensity. A pathologic correlation of the T2 hypointensity on MRI
is warranted to confirm that iron deposition is the cause.
BT2 was related to third ventricular width, a marker of central brain
atrophy that was previously shown to increase in patients with MS during a
2-year period and to predict physical disability.25
In a recent study, we showed that BT2 was related to third ventricular enlargement
and cortical atrophy but the data were obtained visually.14
In the present study, our quantitative approach confirms that BT2 is associated
with third ventricular width, suggesting a relationship between iron deposition
and atrophy in MS. This might relate to neuronal loss and abnormal iron accumulation
caused by tissue destruction or iron-mediated neurotoxicity. The presence
of BT2 in the deep gray matter and its relationship to brain atrophy in the
brains of patients with MS supports a degenerative disease process.
BT2 was related to the severity of total T2 plaque volume. In a previous
study we showed that visually rated BT2 was related to T2 lesion load and
showed a less robust relationship to T1 lesion load.14
The present study confirms that BT2 is related to total brain T2 lesion load
but not T1 lesion load. Hypointense T1 lesions in MS represent areas of severe
irreversible tissue loss in most instances,4
and less commonly, transient changes. Hyperintense T2 lesions are much more
nonspecific and may include a wide range of pathologic changes, such as Wallerian
degeneration.33 One possible explanation for
the correlation of BT2 with bright T2 lesions but not with dark T1 lesions
is the contribution of tract degeneration, which will prolong T2 but not T1
relaxation time.33 Consistent with this hypothesis,
BT2 showed a close association with brain atrophy in a previous study.14 However, BT2 was not related to gadolinium enhancement.14 These data suggest that iron deposition is a marker
of the global disease process. However future studies should determine if
longitudinal changes in BT2 occur to a degree that could serve as a sensitive
surrogate disease marker.
The reason for the general symmetry of BT2 in MS is not entirely clear.
Multiple sclerosis is increasingly recognized as a global (whole-brain) disease
process that extends beyond focal white matter plaques to include pathologic
changes in normal-appearing white matter,5, 8-9
tract degeneration,33 diffuse brain atrophy,25, 34 and widespread hypometabolism.11-12 Thus, conventional MRI plaques (which
may appear asymmetric) are probably only the "tip of the iceberg" in appreciating
disease effects. Focal T1 hypointensities were not associated with BT2 in
the current study. Other important disease processes that are only weakly
associated with foci of demyelination may be present in the brain, such as
axonal injury, atrophy, and pathologic iron deposition. Thus, global and focal
disease effects may be related but different.
We used fast spin-echo T2 since this is more practical to implement
than conventional spin-echo and has increased sensitivity for MS plaque detection.35 However, conventional spin-echo is more sensitive
to the susceptibility effects of iron.36 Future
studies should compare the 2 spin-echo methods and gradient echo methods in
detecting BT2 in MS.37 We used a method of
estimating T2 relaxation time by calculating intensity as a ratio to the intensity
of CSF, a method shown to accurately reflect T2 relaxation times in iron-containing
gray matter structures.22 It could be argued
that CSF changes related to MS could invalidate the use of CSF T2 intensity
as a standard of reference for gray matter T2 intensity. However, the typical
protein elevations in the CSF of patients with MS do not rise to a threshold
that affects T2 relaxation time,38 and there
was no difference in the absolute intensity of CSF between MS and controls
in our study. Direct measurement of T2 relaxation time is considered the gold
standard for quantitation of iron concentration in gray matter and should
be used in future studies to extend the present findings.21-23,38
AUTHOR INFORMATION
Accepted for publication August 30, 2001.
Author Contributions: Study concept and
design (Drs Bakshi, Benedict, Caruthers, Jacobs); data interpretation (Drs Bakshi, Benedict, and Caruthers); drafting of the manuscript (Dr Bakshi); data analysis and editing of the manuscript
(Dr Benedict, and Caruthers); acquisition of data and technical support (Messers Bermel, Tjoa, and Fabiano); critical revision
(Drs Benedict, Caruthers, Jacobs); supervision (Drs Caruthers,
Jacobs); and obtaining funding (Drs Bakshi, Jacobs).
This research was supported by grant NIH-NINDS 1 K23 NS42379-01 from
the National Institutes of Health, Bethesda, Md (Dr Bakshi), University at
Buffalo State University of New York Pilot Project Program Grant (Dr Bakshi),
American Academy of Neurology Student Interest in Neurology Summer Scholarship,
Minneapolis, Minn (Mr Bermel), Alpha Omega Alpha Medical Student Research
Fellowship, Menlo Park, Calif (Mr Bermel) and University at Buffalo State
University of New York Medical Student Research Fellowship (Mr Bermel).
This work was presented in part at the annual meeting of the Americas
Committee for Treatment and Research in Multiple Sclerosis, Boston, Mass,
October 15, 2000; the annual meeting of the American Academy of Neurology,
Philadelphia, Pa, May 9, 2001; and the annual meeting of the American Neurological
Association, Chicago, Ill, October 1, 2001.
We thank Mark Horsfield, PhD, for developing and installing the neuroimaging
analysis software. We are grateful to Jack Simon, MD, PhD, for critically
reviewing the manuscript.
Corresponding author and reprints: Rohit Bakshi, MD, Buffalo Neuroimaging
Analysis Center, 100 High St, Suite E-2, Buffalo, NY 14203 (e-mail: rbakshi{at}buffalo.edu).
From the Departments of Neurology (Drs Bakshi, Benedict, and Jacobs),
Psychiatry, and Psychology (Dr Benedict), University at Buffalo, State University
of New York; Departments of Neurology (Drs Bakshi, Benedict, and Jacobs) and
Imaging Services (Dr Bakshi), Kaleida Health; Buffalo Neuroimaging Analysis
Center and Jacobs Neurologic Institute (Drs Bakshi, Puli, and Jacobs, and
Messrs Bermel, Tjoa, and Fabiano), Buffalo, NY; and Philips Medical Systems,
Best, the Netherlands (Dr Caruthers).
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