Gray Matter Atrophy in Patients With Ischemic Stroke

With Cognitive Impairment

Glenn T. Stebbins, PhD; David L. Nyenhuis, PhD; Changsheng Wang, PhD; Jennifer L. Cox, PhD;
Sally Freels, PhD; Katherine Bangen, PhD; Leyla deToledo-Morrell, PhD; Kumar Sripathirathan, PhD;
Michael Moseley, PhD; David A. Turner, MD; John D.E. Gabrieli, PhD; Philip B. Gorelick, MD
Background and PurposePatients with ischemic stroke are at risk for developing vascular cognitive impairment ranging
from mild impairments to dementia. MRI findings of infarction, white matter hyperintensities, and global cerebral
atrophy have been implicated in the development of vascular cognitive impairment. The present study investigated
regional gray matter volume differences between patients with ischemic stroke with no cognitive impairment and those
with impairment in at least one domain of cognitive function.
MethodsNinety-one patients with ischemic stroke participated. Detailed neuropsychological testing was used to
characterize cognitive functioning in 7 domains: orientation, attention, working memory, language, visuospatial ability,
psychomotor speed, and memory. High-resolution T1-weighted 3-dimensional fast-spoiled gradient recalled structural
MRIs were processed using optimized voxel-based morphometry techniques while controlling for lesions. Whole brain
voxelwise regional differences in gray matter volume were assessed between patients with stroke with no impaired
cognitive domains and patients with stroke with at least one impaired cognitive domain. Logistic regression models were
used to assess the contribution of demographic variables, stroke-related variables, and voxel-based morphometry results
to classification of cognitive impairment group membership.
ResultsFifty-one patients had no impairments in any cognitive domain and 40 patients were impaired in at least one
cognitive domain. Logistic regression identified significant contributions to cognitive impairment groups for demographic variables, stroke-related variables, and cognitive domain performance. Voxel-based morphology results
demonstrated significant gray matter volume reductions in patients with stroke with one or more cognitive domain
impairment compared with patients with stroke without cognitive impairment that was seen mostly in the thalamus with
smaller reductions found in the cingulate gyrus and frontal, temporal, parietal, and occipital lobes. These reductions were
present after controlling for group differences in age, education, stroke volume, and laterality of stroke. The addition of
voxel-based morphometry-derived thalamic volume significantly improved a logistic regression model predicting
cognitive impairment group membership when added to demographic variables, stroke-related variables, and cognitive
domain performance.
ConclusionsThese results suggest a central role for the thalamus and lesser roles for other cortical regions in the
development of cognitive impairment after ischemic stroke. Indeed, consideration of thalamic volumes adds significant
information to the classification of cognitive impaired versus nonimpaired groups beyond information provided by
demographic, stroke-related, and cognitive performance measures. (Stroke. 2008;39:785-793.)
Key Words: cognition disorders MRI vascular cognitive impairment

atients with ischemic stroke are at increased risk of

developing vascular cognitive impairment, which ranges
in severity from mild and/or isolated cognitive impairment to
vascular dementia.1 Vascular cognitive impairment may affect half of all stroke survivors.2 The prevalence of vascular
cognitive impairment has been estimated to be 50 per 1000

population with a higher prevalence of mild or isolated

impairment (26 per 1000) compared with vascular dementia
(15 per 1000).3 Studies demonstrate similar rates of institutionalization, mortality, and other adverse outcomes among
patients with stroke with cognitive impairment but no dementia and patients with stroke with dementia.3 In addition,

Received October 15, 2007; accepted November 8, 2007.

From the Departments of Neurological Sciences (G.T.S., C.W., L.d.T.-M., K.S.) and Diagnostic Radiology (D.A.T.), Rush University Medical Center,
Chicago, Ill; the Department of Neurology and Rehabilitation (D.L.N., P.B.G.), University of Illinois, Chicago, Ill; Buffalo Neuroimaging Center (J.L.C.),
Buffalo, NY; the School of Public Health (S.F.), University of Illinois, Chicago, Ill; Neurosciences (K.B.), University of California at San Diego, San
Diego, Calif; the Department of Radiology (M.M.), Stanford University, Stanford, Calif; and the Department of Brain and Cognitive Sciences (J.D.E.G.),
Massachusetts Institute of Technology, Cambridge, Mass.
Correspondence to Glenn T. Stebbins, PhD, Department of Neurological Sciences, Rush University Medical Center, 1725 W. Harrison, Suite 309,
Chicago, IL 60612. E-mail gstebbin@rush.edu
2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.107.507392

785
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patients with stroke with cognitive impairment but no dementia have an increased 5-year risk of developing vascular
dementia or other dementias.4 If patients with stroke with
cognitive impairment but no dementia are at increased risk of
dementia, identification of markers for developing cognitive
impairment might prove useful for interventions designed to
prevent the progression to vascular dementia.
Involvement of the thalamus in cognitive disturbances is
well established. Impairments in sensory function, motor
abilities, language, executive function, and long-term memory are associated with vascular syndromes in the thalamus.5
In a study of 10 patients with isolated thalamic lesions,
impairments in long-term memory were associated with
lesions of the mammillothalamic tract and impairments in
working memory were associated with lesions of the medial
dorsal, midline, and intralaminar nuclei.6 Strategic lesions of
the thalamus were found to be related to the development of
vascular dementia in 8 patients after infarction of the paramedian nucleus and the anterior nucleus. These findings
suggest that the precise location of thalamic lesions influences the type of cognitive deficit observed.
General cerebral atrophy has also been associated with the
development of cognitive impairment after stroke. Cortical
gray matter atrophy correlated with dementia severity in a
sample of patients with subcortical ischemic vascular disease7
and was an independent predictor of cognitive decline in a
sample of patients with subcortical cerebrovascular brain
injury.8 The exact mechanism of this atrophy is not known
but may reflect secondary degeneration after ischemic events.
Voxel-based morphometry (VBM) provides an automated,
voxelwise comparison of gray matter volume between
groups.9,10 The procedure involves the normalization of
individual subjects MRI to a common template so that group
comparisons can be conducted. Because the individual MRIs
are registered into the same space, they can be combined into
relevant groups and compared. Since no a priori regions of
interest are defined, VBM provides an unbiased whole brain
comparison between groups, making it an ideal method for
exploratory cross-sectional studies. As VBM techniques require the warping of individual brains to a common template,
the presence of lesions may result in incorrect tissue type
classifications at the site of the lesion during this normalization process. One method of adjusting for the presence of
lesions during normalization is to mask out the lesions from
consideration during the warping process so as to remove the
influence of the lesions in the calculations of the required
image warping.11 This process allows for the calculation of
parameters required to accurately normalize individual lesioned brains to a template without the potentially confounding influence of the infarcted tissue. The normalizing parameters developed from the lesion-masked scans can then be
applied to the scans with the lesions unmasked. In the present
study, we used whole brain, voxel-based analyses to investigate regional differences in gray matter volume in a sample of
patients with ischemic stroke without cognitive impairment
compared with those with impairment in one or more cognitive domains. We used a costfunction technique11 to adjust
the warping of individual brains to a common template. We
sought to determine the usefulness of this approach to

classifying gray matter changes after ischemic stroke and to

better understand the relationship between gray matter
changes and cognitive function.

Materials and Methods

Participants
Participants were patients with ischemic stroke who presented to the
Stroke and Neurologic Critical Care Service at Rush University
Medical Center. The study was explained to all potential participants
and their families while they were inpatients at the time of stroke.
Those who met study criteria and who agreed to be contacted at a
later date were asked to participate once they entered the 3- to
6-month poststroke time window. A priori inclusion criteria were age
50 or older (including persons closer to age 50 than 49); ischemic
stroke defined by the National Institute of Neurological and Communicative Disorders and Stroke Stroke Data Bank12 criteria 3 to 6
months before study entry; sufficient English language skills for
psychological tests; and availability of a proxy or relative knowledgeable about the participant. Standard clinical CT or MRI scans
during hospitalization were available and aided in stroke subtyping
and in ruling out cerebral hemorrhage. Approximately one third of
potential subjects approached agreed to participate; exact numbers of
nonparticipants and a comparison of persons who did and did not
participate was not possible, because Institutional Review Board
regulations prevented the gathering of nonparticipant data.
Exclusion criteria included patients with aphasia who scored less
than 50% correct on the Boston Diagnostic Aphasia Examination
Commands Subtest13 or who otherwise could not complete psychological testing because of a language disorder; diagnosed chronic or
degenerative disease or condition before stroke affecting the central
nervous system (eg, Alzheimer disease); active substance abuse
disorders as defined by the Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition14; intracranial hemorrhage; difficult to
control epilepsy that could present with cognitive impairment; or
temporal lobe epilepsy. In addition, patients with temporal lobe
stroke were excluded because the study original hypotheses sought to
compare Alzheimer disease markers (eg, medial temporal lobe
atrophy) to markers of cerebral vascular disease. Three patients, who
otherwise met study participation requirements, were excluded due
to the presence of temporal lobe infarcts. Prior stroke was not
exclusionary. Although patients with preexisting Alzheimer disease
or other diagnosed neurodegenerative conditions were excluded,
exclusion criteria did not include the presence of undiagnosed
prestroke cognitive impairment. The study was completed under the
guidance and approval of the Institutional Review Board at Rush
University Medical Center and the University of Illinois at Chicago.

Study Instruments and Examination Procedures

All study participants completed formal neuropsychological assessment administered by a trained neuropsychological technician under
the supervision of the study neuropsychologist. The examination
took approximately 90 to 120 minutes to administer and included the
following tests: Boston Diagnostic Aphasia Examination, Commands subtest13; Controlled Learning and Enhanced Recall, Immediate and Delayed15; Self-Ordered Pointing Task16; Wechsler Memory Scale, Third Edition: Paragraph I and Digit Span subtests17;
Wechsler Memory Scale, Form I Mental Control18; Symbol Digit
(Oral Version)19; portions of the Behavioral Dyscontrol Scale20;
Mini-Mental State Examination21; Figural Recognition Test22;
CERAD Boston Naming Test and Verbal Fluency23; Brief version of
the Ravens Progressive Matrices24; Grooved Pegboard Test25; the
Chicago Multiscale Depression Inventory26; and the Informant
Questionnaire on Cognitive Decline in the Elderly (IQCODE)27 as an
estimate of change in cognitive function from premorbid levels.
The subjects also completed an unstructured neurologic interview
to determine history of, number of, timing, symptoms, and recovery
from stroke; a history of memory loss and other symptoms of
dementia; and a structured neurologic interview to determine the
history of dementia onset and symptoms of cognitive dysfunction.

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Stebbins et al
Table 1. Neuropsychological Test Scores (means SDs),
Listed by Domain, and Compared Across Patients With and
Without Cognitive Impairment

Tests Listed by Domain

Patients Without
Cognitive
Impairment

Patients With
Cognitive
Impairment

9.66 (0.55)

9.03 (1.28)

Digits Forward

6.26 (1.08)*

5.58 (1.44)

WMS Mental Control

5.00 (1.26)

4.03 (1.86)

15.19 (1.42)

13.87 (1.53)

5.92 (1.85)

4.55 (2.21)

11.75 (1.09)

9.97 (2.79)

Attention

Working Memory
Self-ordered Pointing
Test total score
Digits Backward
Behavioral Dyscontrol Scale

787

and independently rated 25 subjects chosen at random from the study

sample. He therefore made 175 impairment/nonimpairment ratings
(25 subjects7 cognitive domains). There was independent agreement on 166 of 175 ratings yielding a kappa score of 0.79 suggestive
of substantial agreement29 between the 2 raters and reliable
placement of subjects into impairment categories.

MRI Image Acquisition

Orientation
MMSE Orientation Items

Gray Matter Atrophy in Ischemic Stroke

Language

All MRIs were acquired using a 1.5-Tesla General Electric Signa

scanner (General Electric Medical Systems, Milwaukee, Wis) at
Rush University Medical Center. A high-resolution 3-dimensional
spoiled gradient recalled T1-weighted MRI scan was acquired for
each subject. One hundred twenty-four gapless coronal slices with a
thickness of 1.6 mm were obtained with the following parameters:
repetition time 34 ms, minimum echo time 7 ms, one acquisition, flip
angle 35, matrix size 256192, field of view 22 cm, and inplane
resolution 0.8594 mm. Additionally, a coronal 3-dimensional fast
spin echo T2-weighted MRI scan was acquired with the following
parameters: repetition time 2900 ms, echo time 102 ms, 2 acquisitions, matrix size 256192, field of view 22 cm, slice thickness
3.0 mm with no gap, 48 slices, and inplane resolution 0.8594 mm.

BDAE Commands

14.85 (0.41)

14.26 (1.39)

Lesion Identification

Boston Naming Test

14.43 (0.97)

12.82 (2.46)

17.7 (4.82)

12.89 (5.99)

The study neurologist (P.B.G.) classified the etiologies of the

presenting strokes at the time of study entry using Stroke Data Bank
Criteria12 and the total number of visible lesions, including both the
lesion from the presenting stroke and those from previous stroke
events, were counted using Cardiovascular Health Study criteria.30
The lesion volumes were traced on the axial, coronal, and sagittal
orientations of 3-dimensional T1 spoiled gradient recalled scans
using the Analyze Software package (AnalyzeAVW; Mayo Clinic
Foundation, Rochester, Minn). The 3-dimensional T2 fast spin echo
scans were used to assist in identifying the lesions and tracing the
lesion volume. The lesion maps were saved in a format acceptable
for VBM processing.

Animal Naming
Visuospatial
Figural Recognition Test
Ravens Matrices

8.00 (0.00)*

7.68 (0.90)

11.94 (1.34)

10.08 (2.37)

Psychomotor
Grooved Pegs Domain (pegs/sec)

0.25 (0.07)

0.17 (0.09)

42.46 (11.03)

28.03 (11.46)

CLTR Total Immediate Recall

30.96 (6.03)

23.32 (6.64)

CLTR Delayed Recall

12.38 (2.32)

8.95 (3.16)

Voxel-Based Morphometry Image Preprocessing

WMS Paragraph Immediate

Recall

13.08 (3.56)

9.08 (4.05)

WMS Paragraph Delayed Recall

11.74 (3.28)

6.97 (3.99)

Images were analyzed using SPM2 (Wellcome Department of

Cognitive Neurology, London, UK) implemented in Matlab 6.5
(Mathworks, Natick, Mass). A modified optimized VBM technique
was used following the method of Good and colleagues.9,10 We used
a costfunction modification11 of the optimized VBM technique to
adjust for the presence of infarcted tissue during VBM processing.
Because infarcted tissue leads to tissue misclassification, the presence of lesions can affect calculation of segmentation and normalization parameters required in VBM. The costfunction modification
removes infarcted tissue from the calculation of these parameters,
thus removing the potential for tissue misclassification during
segmentation and normalization.
The first step in VBM processing involved the construction of a
customized sample-specific brain template. This template was developed by using the lesion maps identifying the volume and
locations of infarcts to mask out these regions on the individual
3-dimensional T1 spoiled gradient recalled volumes and normalizing
the lesion-masked volumes of all participants to the standard brain
template of the Montreal Neurological Institute using a 12-parameter
affine transformation with nonlinear adjustments with 787 basis
functions.31 Masking the lesions from the individual volumes removed the potential misclassification of tissue type during the affine
transformation and nonlinear adjustments. The spatial transformation
parameters for this normalization were then applied to the individual
nonmasked volumes and the resultant normalized images were
resampled to a 111-mm voxel size smoothed with a 8-mm full
width half maximum Gaussian kernel and then averaged to produce
the sample-specific whole brain template. Templates for gray matter,
white matter, and cerebrospinal fluid were computed by segmenting
the sample-specific whole brain template into the 3 components
based on image intensity classification and probability of tissue class
membership.10

Symbol Digit Oral Score

Memory

*P0.05.
P0.01.
P0.001.
MMSE indicates Mini-Mental State Examination; WMS, Wechsler Memory
Scale; BDAE, Boston Diagnostic Aphasia Examination; CLTR, Controlled Learning and Enhanced Recall, Immediate and Delayed.

Diagnostic Procedures
Neuropsychological tests were classified into the following domains:
orientation, attention, working memory, language, visuospatial
skills, psychomotor speed, and memory as described elsewhere28
(Table 1 ). Patients were classified as impaired or not impaired by an
experienced, board-certified neuropsychologist (American Board of
Professional Psychology/American Board of Clinical Neuropsychology) based on normative data and subject demographic characteristics. When normative data were applicable, test performance was
judged as impaired if it was below the fifth percentile for people of
similar age and educational background. Corrections were applied if
subjects differed significantly from a tests standardization sample
(eg, if there was a large deviation between the subjects reported
education and that of the normative sample or for subjects for whom
English, although fluently spoken, was a second language). The
overall performance rating in a domain was based on the preponderance of scores within the domain taking into account the degree of
impairment severity on each test and the number of impaired tests in
the domain. To assess the interrater reliability of the impairment
ratings, a second neuropsychologist was trained in study methods

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The second step in VBM processing involved the normalization of

individual scans to the sample-specific template. The individual
3-dimensional T1 spoiled gradient recalled scans were masked for
lesions and segmented into gray matter, white matter, and cerebrospinal fluid components using information from the sample-specific
tissue classification templates. The individual gray matter segments
were spatially normalized to the sample-specific gray matter template created during the sample-specific template creation using a
12-parameter affine transformation and nonlinear adjustments with
787 basis functions.31 Masking out the location of infarcts
allowed for the calculation of tissue segmentation and normalization
parameters absent the potential for tissue misclassification and
normalization distortion induced by the presence of the lesions. The
spatial transformation parameters obtained from the lesion-masked
gray matter normalization were applied to the nonmasked 3-dimensional T1 spoiled gradient recalled volumes and resampled to a
111-mm voxel size to produce lesion-adjusted normalized volumes. Individual lesion-adjusted normalized whole brain volumes
were then segmented again into gray matter, white matter, and
cerebrospinal fluid partitions using a Markov random field model32
to improve tissue type classification. As a consequence of spatial
normalization, the volumes of some regions may increase or decrease in size. To correct for these volume changes, the normalized
gray and white matter segments were modulated to preserve the
amount of tissue from the nonnormalized gray and white matter
segments. In the modulation step, voxel values are multiplied by the
Jacobian determinants derived from the normalization process. The
segmented, normalized, and modulated individual lesion-adjusted
brain segments were smoothed with an 8-mm full width half
maximum Gaussian kernel. Application of the smoothing kernel
compensates for interindividual variability and conforms the data
more closely to Gaussian random field theory, which provides for
corrected statistical inference.

Statistical Analyses
Group differences in demographic and stroke-related variables and
cognitive performance domain scores were assessed using a
2-sample t test or 2 test where appropriate. The segmented,
normalized, modulated, smoothed lesion-adjusted MRI images were
analyzed in SPM2 to evaluate gray matter differences between the
patients with no cognitive impairment and patients with impairment
in one or more cognitive domains. A binary logistic regression was
used to assess the relative contributions of each cognitive domain to
the classification of no cognitive impairment/at least one impaired
cognitive domain after controlling for group differences in demographic and stroke-related variables. To assess regional differences
in gray matter volume between the 2 groups, voxel-by-voxel comparisons were performed using the general linear model controlling
for total brain volume and selected stroke-related, cognitive, and
demographic variables. Significant differences in gray matter tissue
volume between the groups were detected at a statistical threshold of
P0.005. Additionally, clusters of significant differences were
required to have an extent of at least 50 voxels. To assess if gray
matter volume differences significantly increased the accuracy of
classification of participants to cognitive impairment groups above
that obtained with cognitive performance measures alone, the binary
logistic regression was repeated with gray matter volume values
added to the list of independent variables.

Results
One hundred four participants were enrolled. MRI scans were
available on 91 of the subjects (3 scans missing due to subject
refusal, 4 due to severe movement artifact, and 6 due to
technical failure). Results for these 91 examinations are
presented.
Etiologies of the presenting strokes at the time of study
entry were determined using Stroke Data Bank Criteria.12
Infarctions due to atherosclerosis or tandem arterial pathology accounted for 26.6% of the strokes, 23% were classified

as lacunar infarctions, 4.3% as cardiac emboli, 4.3% as

infarctions of unknown cause, and 41.5% as unknown. Lesion
locations were 28.7% in the left hemisphere, 36.2% in the
right hemisphere, 9.6% in the brain stem, 10.6% in the pons,
and 14.9% of the locations were unknown. Cardiovascular
Health Study criteria30 were used to count the total number of
visible lesions. The number of lesions ranged from 0 to 8 with
an average of 1.63 (SD, 1.78) per subject. Cortical lesions
were present in 26.9% of the participants and 44.1% had at
least one subcortical lesion.
Fifty-one of the 91 subjects were unimpaired in any
cognitive domain with the remaining 40 impaired in one or
more cognitive domains. The cognitively impaired group had
the following distribution of involved domains: 4.3% impaired orientation, 6.4% impaired attention, 9.6% impaired
working memory, 8.5% impaired language, 3.2% impaired
visuospatial abilities, 25.5% impaired psychomotor speed,
and 13.9% impaired declarative memory. The nonimpaired
and impaired groups did not differ in gender distribution,
handedness, total number of strokes, number of cortical
strokes, number of subcortical strokes, or estimated change
from premorbid function. The cognitively impaired group
was significantly older, had fewer years of formal education,
more left-sided strokes, lower mental status scores, and
increased stroke volume compared with the noncognitiveimpaired group. Gray matter, white matter, and cerebrospinal
fluid volumes, derived from the VBM processing, were not
significantly different between the groups (Table 2). Contribution of cognitive domain performance to group classification was examined using a binary logistic regression. In this
model, demographic and stroke-related variables demonstrating significant group differences were entered as a first block
of variables (age, years of education, presence of left-sided
stroke, and total lesion volume) with cognitive domain
performance entered as a second block of variables. The
overall model was significant (21152.42, P0.0005) with
only psychomotor processing speed cognitive domain performance significantly determining the model (Wald16.59,
P0.01).
Examination of VBM-derived gray matter volume differences was conducted using the analysis of covariance model
in SPM2. Age, years of education, presence of left-sided
strokes, total brain volume, and total lesion volume were
entered as covariates of no interest. Decreased gray matter
volume was detected in the cognitively impaired group
compared with the unimpaired group in multiple regions, but
mostly in the bilateral thalamus. Additional regions of decreased gray matter volume in the cognitive impairment
group were found in the bilateral superior, middle and medial
frontal lobes, the right superior temporal lobe, the bilateral
middle temporal lobes, the right central gyrus, the right
anterior cingulate gyrus, the left posterior cingulate gyrus,
bilateral inferior parietal lobe, the left cuneus, the bilateral
precuneus, the left superior occipital lobe, and the right
lingual gyrus. No regions of decreased gray matter volume
were detected in the noncognitive-impaired group compared
with the cognitive impairment group (Table 3; Figure).
Although many regions were identified as having decreased
gray matter volume in the cognitive impairment group, the

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Stebbins et al
Table 2. Demographic Variables and Stroke-Related Variables
(means SDs) for Patients With Stroke With and Without
Cognitive Impairment
Patients Without
Cognitive
Impairment
(n51)

Patients With
Cognitive
Impairment
(n40)

Age

63.1 (8.2)*

67.4 (9.7)

Education

15.4 (3.8)

12.5 (3.7)

24/27

21/19

Demographic Variables

Gender (female/male)
Handedness (left/right)

2/49

2/38

IQCODE

51.3 (5.4)

53.4 (6.9)

MMSE

28.7 (1.1)

25.8 (3.6)

Stroke variables
Total stroke no.

1.35 (1.55)

1.85 (2.02)

Total no. of cortical

strokes

0.31 (0.86)

0.67 (0.93)

Total no. of subcortical

strokes

0.67 (1.07)

0.95 (1.47)

5083.2* (11 097.1)

14 703.4 (24 665.7)

16/35*

22/18

1.20 (1.36)

2.23 (2.42)

Total stroke
volume, mm3
Left-sided stroke?
(yes/no)
Stroke severity scale
score
VBM gray matter
volume (ml3)

641.2 (76.2)

608.3 (99.9)

VBM white matter

volume (ml3)

408.0 (68.8)

395.7 (66.0)

VBM CSF volume, mL3

467.5 (116.5)

483.3 (167.5)

*P0.05.
P0.01.
IQCODE indicates Informant Questionnaire on Cognitive Decline in the
Elderly; MMSE, Mini-Mental State Examination.

majority of differences were in the bilateral thalamus.

Indeed, there were over 5100 voxels in the thalamus
demonstrating a significant loss of volume compared with
the right post central gyrus, which had less than 2000 such
voxels. Six subjects had radiologically confirmed thalamic
lesions (3 no cognitive impairment, 3 cognitive impairment). These patients were excluded and the VBM analyses were recomputed without significantly altering the
results (Table 3; Figure).
The distribution of thalamic sub nuclei involvement was
examined by using the Talairach Daemon (http://ric.uthscsa.
edu/projects/talairachdaemon), which provides structural location based on Talairach coordinates.33 Significantly decreased
gray matter volumes in thalamic subnuclei in the cognitive
impairment group compared with the noncognitive-impaired
group were found in the left medial dorsal nucleus, ventral
lateral nucleus, ventral anterior nucleus, and pulvinar.
Individual participants normalized gray matter volume
values were extracted from the thalamic regions demonstrating significant group differences on SPM analyses. As
expected, these values were significantly lower in patients
with cognitive impairment compared with patients without
cognitive impairment (no cognitive impairment mean0.264

Gray Matter Atrophy in Ischemic Stroke

789

[0.044]; cognitive impairment mean [SD]0.210 [0.054];

F[21, 89]27.32, P0.0005).
To assess if thalamic volume provided additional information for cognitive group classification, beyond that found for
demographic, stroke-related, and cognitive domain performance, the binary logistic model analyzing the contribution
of these variables was repeated with thalamic volume included in the analysis. For this binary logistic regression,
demographic and stroke-related variables were entered first in
the model, cognitive domain performance scores were entered second in the model, and normalized thalamic gray
matter volume was entered last in the model. As previously
found, demographic and stroke-related variables significantly
contributed to the model (model 2[4]12.65, P0.013) with
a significant increase in the model accuracy with the addition
of the cognitive domain performance measures (model
252.41[11], P0.0005. Importantly, the addition of thalamic gray matter volume significantly improved the model
using only demographic, stroke-related, and cognitive domain performance (model 2[12]63.95, P0.005). Of all the
variables entered in the final model, normalized thalamic
volume provided the greatest separation between patients
with any cognitive impairment and patients with no cognitive
impairment (Wald16.50, P0.01). The next most discriminating variable was psychomotor speed cognitive domain
performance (Wald15.44, P0.02) followed by patient age
(Wald15.14, P0.02) and spatial cognitive domain performance (Wald14.06, P0.04).

Discussion
In the present study, gray matter volume was compared
between patients with ischemic stroke with no cognitive
impairment and patients with impairment in one or more
cognitive domains. The cognitively impaired group was
older, had fewer years of education, more left-sided strokes,
greater lesion volumes, and deficits in multiple cognitive
domains, including orientation, attention, working memory,
language, visuospatial skills, psychomotor speed, and memory. Given these variables, patient psychomotor processing
speed cognitive domain demonstrated the strongest relationship to the cognitive impairment classification.
In addition, we found significant decreases in gray matter
volume in patients with ischemic stroke with cognitive
impairment compared with those without impaired cognitive
functioning in the thalamus, frontal, temporal, parietal, and
occipital lobes. The major region of decreased gray matter
volume was in the thalamus. These differences were not due
to effects of age, educational levels, presence of left-sided
lesions, total lesion volume, total brain volume, nor differences in change from premorbid function. Instead, the decreased gray matter volume appears to relate to differences in
cognitive status as reflected by performance on neuropsychological tests.
The vast majority of gray matter reduction in the cognitive
impairment group was in the thalamus. This reduction in gray
matter volume reflected group differences in multiple cognitive domains, including orientation, attention, working memory, visuospatial abilities, language, and declarative memory.

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Table 3. Stereotactic Locations and Brodmanns Areas (BA) of Significant (P<0.001 With a 50-voxel
extent threshold) Differences in Gray Matter Volume Between Patients With Stroke With No Cognitive
Impairment and Patients With Stroke With Impairment in at Least One Cognitive Domain
Talairach Coordinates
Location

BA

No. of Voxels

16

25

4.7

0.001

5053

3.28

0.001

10

713

30

54

4.09

0.001

453

10

25

60

14

3.59

0.001

218

44

43

4.15

0.001

995

11

58

21

3.58

0.001

431

10/11

38

56

10

3.76

0.001

218

38

14

30

3.66

0.001

160

Left thalamus
Right thalamus
Left superior frontal gyrus
Right superior frontal gyrus
Left middle frontal gyrus

Maximum

Right middle frontal gyrus

55

42

3.33

0.001

103

Left medial frontal gyrus

10

66

3.61

0.001

480

10

57

3.21

0.001

308

11

36

28

3.45

0.001

71

11

59

18

3.19

0.001

100

Right medial frontal gyrus

9/10

61

3.49

0.001

849

Right superior temporal gyrus

42

68

28

3.56

0.001

475

Left middle temporal gyrus

39

49

59

2.99

0.001

184

Right middle temporal gyrus

37

50

45

3.74

0.001

329

39

51

75

11

3.19

0.001

67

Right post-central gyrus

58

22

31

3.46

0.001

1840

Right anterior cingulate

32/10

48

3.10

0.001

159

Left posterior cingulate

23/30

13

52

14

3.04

0.001

126

40

46

55

47

3.45

0.001

452

40

64

36

29

3.42

0.001

272

40

47

55

51

4.05

0.001

545

Left inferior parietal lobe

Right inferior parietal lobe
Left cuneus

18

88

18

3.08

0.001

243

Left precuneus

31

17

71

24

3.06

0.001

155

Right precuneus

19

39

70

42

3.01

0.001

60

Left superior occipital gyrus

19

30

80

25

3.04

0.001

109

Right lingual gyrus

18

13

73

3.65

0.001

464

19

25

67

3.13

0.001

134

Note : Talairach coordinates represent peak-value voxel location based on the atlas of Talairach.17 Maximum Z is the maximum Z
score of the cluster demonstrating significant difference in gray matter volume between groups.

The nature of these relationships suggests that as thalamic

integrity is affected, cognitive performance suffers.
The wide spectrum of affected cognitive domains reflects
the multimodal nature of thalamic relays throughout the
brain. Rather than finding isolated thalamic volume cognitive relationships, relationships to multiple cognitive behaviors with frontal lobe function and temporal lobe function
were noted. This suggests that thalamic damage after ischemic stroke may lead to deficits in multiple cognitive domains,
which might ultimately manifest in a diagnosis of dementia.
The specific relationship between VBM-derived thalamic
gray matter volume and cognitive impairment in ischemic
stroke has not been previously reported to our knowledge.
Prior studies have investigated cortical gray matter volume
and have found it to be predictive of the presence of cognitive
impairment7 as well as the rate of cognitive decline.8 These

studies, however, did not investigate subcortical gray matter

volumes.
One previous study investigated whole brain gray matter
volume in patients with ischemic stroke in the acute and
chronic phases of stroke.34 Although cognitive function was
not assessed, this study did note a shrinkage in brain tissue
from acute to chronic phases. This shrinkage was present in
the area of radiologically identified lesions, contralateral
homologous regions, and in the striatum and thalamus. The
shrinkage in the striatum and thalamus was not related to
lesion size and was suggested to be independent of the
ischemic event.
Additional evidence of thalamic involvement in cognitive
impairment after stroke is found in studies of patients with
concomitant Alzheimer disease. Patients with neuropathologically confirmed Alzheimer disease were likely to have

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Stebbins et al

Gray Matter Atrophy in Ischemic Stroke

791

Figure. Regions of significant decreased

gray matter volume in patients with ischemic stroke with impaired performance in
one or more cognitive domains compared
with patients with ischemic stroke with no
cognitive impairment. Differences in volume values were corrected for group differences in age, educational level, presence of left-sided strokes, total brain
volume, and total stroke lesion volumes in
an analysis of covariance model. Voxels
evidencing significant decrease in the
cognitive impairment group are displayed
on representative coronal sections (number represents the y plane of Talairach
coordinates17) of an average T1-weighted
brain image created from the sample
scans. The color scale indicates the magnitude of T values with lowest appearing
in dark red and the highest in bright yellow/white. The left side of the images represents the left side of the brain.

greater cognitive impairment in the presence of infarcts in the

thalamus, basal ganglia, and deep white matter.35 Even in
patients without significant neuropathological evidence of
Alzheimer disease, the presence of thalamic lacunes was
associated with lower cognitive function during life.36 Thalamic involvement in cognitive function is also found in
patients with cerebral autosomal-dominant arteriopathy with
subcortical infarcts and leukoencephalopathy. Diffusion tensor imaging studies have found evidence of decreased white
and gray matter integrity in the thalamus in patients with
cerebral autosomal-dominant arteriopathy with subcortical
infarcts and leukoencephalopathy with and without dementia.3739 In these studies, measures of thalamic integrity

correlated with cognitive performance measures of general

mental status,37 general IQ,38 and executive function.38,39 The
abnormalities in gray and white matter integrity appeared to
be unrelated to frank infarctions, but rather, reflected secondary degeneration due to disruption of distant tissue.
Our finding of decreased thalamic gray matter volume in
the patients with stroke with impaired cognitive function
compared with patients with stroke without cognitive impairment after controlling for differences in age, educational
level, presence of left-sided strokes, total brain volume, or the
volume of ischemic lesions suggests that the damage to
thalamic tissue was not due to primary stroke effects, but
rather may be secondary to degenerative processes. Given the

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792

Stroke

March 2008

central role of the thalamus as a gateway to the cerebral

hemispheres, damage to widely dispersed cortical regions
might well result in secondary atrophy to this structure.
Regardless of the cause, decreased thalamic gray matter
volume was related to cognitive status as measures by a wide
spectrum of cognitive function measures and provided information that significantly improved a classification model of
cognitive impairment based on demographic variables,
stroke-related data, and cognitive domain performance alone.
The application of VBM methodologies to ischemic stroke
cases could be problematic.40 Infarcted tissue misclassification during the segmentation process could falsely contribute
to gray matter, white matter, or cerebrospinal fluid compartments. In the present study, however, we used a costfunction
technique11 that removes the infarcted tissue from the classification of tissue type and determination of normalization
parameters. By removing these lesions from the VBM determination of segmentation and normalization parameters, the
tissue classification and image warping are unaffected. An
additional concern with any VBM study is the accuracy of the
normalization process. Voxel-based morphometry methodologies depend on warping native images into a common space.
Such warping techniques may be associated with decreasing
accuracy as the algorithm proceeds from central to peripheral
structures.41 Although such an effect may be present in our
results, we do identify many structural differences in the
periphery between patients with stroke with and without
cognitive impairment, suggesting a minimal effect. Additionally, our findings of significant gray matter volume differences in patients with stoke with at least one impaired
cognitive domain do not necessarily demonstrate a casual
relationship between loss of thalamic volume and development of cognitive impairment. A longitudinal design would
be more adept at demonstrating such a casual relationship.
These results are based on a single sample of patients with
ischemic stroke with and without cognitive impairment. The
sample is drawn from a large tertiary university hospital, not
all persons who were approached participated, and although
persons diagnosed with Alzheimer disease before their stroke
were excluded from participation, we cannot rule out the
presence of Alzheimer disease pathology or other sources of
prestroke cognitive decline in our sample. In addition, we
excluded a small number of patients with temporal lobe
stroke. This may have lowered the possibility that we might
have identified medial temporal lobe structures involved in
the group classification. For these reasons, these findings
need to be replicated in an independent sample of patients
with stroke. Still, the results suggest that thalamic damage,
apart from frank thalamic infarction, is a contributing factor
in the development of cognitive impairment after ischemic
stroke.

Source of Funding
This study was supported by National Institute on Aging grant R01
AG17934 (PI:PBG 2000 2003; DN 20032005).

Disclosures
None.

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Gray Matter Atrophy in Patients With Ischemic Stroke With Cognitive Impairment
Glenn T. Stebbins, David L. Nyenhuis, Changsheng Wang, Jennifer L. Cox, Sally Freels,
Katherine Bangen, Leyla deToledo-Morrell, Kumar Sripathirathan, Michael Moseley, David A.
Turner, John D.E. Gabrieli and Philip B. Gorelick
Stroke. 2008;39:785-793; originally published online February 7, 2008;
doi: 10.1161/STROKEAHA.107.507392
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2008 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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