Differential Associations of Cortical and Subcortical

Cerebral Atrophy With Retinal Vascular Signs in Patients

With Acute Stroke
Michelle L. Baker, MBBS; Jie Jin Wang, MMed, PhD; Gerald Liew, MBBS, PhD;
Peter J. Hand, MD, FRACP; Deidre A. De Silva, MRCP; Richard I. Lindley, MD, FRACP;
Paul Mitchell, MD, PhD, FRANZCO; Meng-Cheong Wong, FRCP; Elena Rochtchina, MAppStat;
Tien Y. Wong, PhD, FRANZCO; Joanna M. Wardlaw, MD, FRCR, FMedSci;
Graeme J. Hankey, MD, FRACP; the Multi-Centre Retinal Stroke Study Group

Background and PurposeThe relationship of cortical and subcortical cerebral atrophy to cerebral microvascular disease
is unclear. We aimed to assess the associations of retinal vascular signs with cortical and subcortical atrophy in patients
with acute stroke.
MethodsIn the Multi-Centre Retinal Stroke Study, 1360 patients with acute stroke admitted to 2 Australian and 1
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Singaporean tertiary hospital during 2005 to 2007 underwent neuroimaging and retinal photography. Cortical and
subcortical cerebral atrophy were graded based on standard CT scans. A masked assessment of retinal photographs
identified focal retinal vascular signs, including retinopathy and retinal arteriolar wall signs (ie, focal arteriolar
narrowing, arteriovenous nicking, arteriolar wall light reflex) and measured quantitative signs (retinal arteriolar and
venular caliber).
ResultsAfter adjusting for age, gender, study site, hypertension, hypercholesterolemia, diabetes, and smoking status,
none of the retinal vascular signs assessed were associated with cortical atrophy, whereas retinopathy (OR, 1.9; CI, 1.2
to 3.0) and enhanced arteriolar light reflex (OR, 2.0; CI, 1.2 to 3.2) were significantly associated with subcortical
atrophy.
ConclusionOur finding that certain retinal vascular signs are associated with subcortical but not cortical atrophy,
suggests a differential pathophysiology between these 2 cerebral atrophy subtypes and a potential role for small vessel
disease underlying subcortical cerebral atrophy. (Stroke. 2010;41:2143-2150.)
Key Words: blood brain barrier cerebral atrophy cortical atrophy retinal vascular signs subcortical atrophy

P athological processes underlying cerebral atrophy may

vary by location and pattern of atrophy.1 Atrophy of the
cerebral cortex, termed cortical atrophy, reflects loss of nerve
cells in the cortical gray matter and is associated with
Alzheimer disease2 but can also occur in drug and alcohol
toxicity.3 In contrast, atrophy of the cerebral subcortical white
and gray matter, termed subcortical atrophy, reflecting loss of
nerve cells in the basal ganglia or fibers in the deep white
matter, has received relatively little attention in the literature.
An association with age-related cerebral small vessel disease
was found in 1 study,4 but it can occur due to other processes
such as inflammatory demyelination (ie, multiple sclerosis).5
Many patients demonstrate both cortical and subcortical
atrophy, perhaps due to a combination of multiple patholo-
gies, including Alzheimer disease and cerebrovascular dis-
ease.6 The predominant underlying vasculopathy is consid-
ered to be arteriosclerosis7 because epidemiological studies
have reported associations of cerebral atrophy (including
cortical and/or subcortical atrophy) with risk factors for
arteriosclerosis such as hypertension,8,9 cigarette smoking8,10
and diabetes,8,11,12 although few histopathologic studies have
confirmed this. In addition, epidemiological studies do not

Received June 22, 2010; accepted July 30, 2010.

From the Centre for Eye Research Australia (M.L.B., J.J.W., T.Y.W.), University of Melbourne, Melbourne, Australia; the Centre for Vision Research
(J.J.W., G.L., P.M., E.R.), Westmead Millennium Institute, University of Sydney, Sydney, Australia; the Department of Neurology (P.J.H.), Royal
Melbourne Hospital, University of Melbourne, Melbourne, Australia; Singapore General Hospital Campus (D.D.S.), National Neuroscience Institute,
Singapore; the Discipline of Medicine (R.I.L.), Sydney Medical SchoolWestern, Westmead Hospital, University of Sydney, Sydney, Australia; the
National Medical Research Council (M.-C.W.), Singapore; Singapore Eye Research Institute (T.Y.W.), National University of Singapore, Singapore; the
SINAPSE Collaboration (J.M.W.), Department of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh, UK; and Royal
Perth Hospital (G.J.H.), University of Western Australia, Western Australia, Australia.
Full list of collaborators of the Multi-Centre Retinal Stroke Study Group is shown in Lindley et al.17
Correspondence to Jie Jin Wang, MMed, PhD, Centre for Vision Research, Westmead Millennium Institute, University of Sydney C24, Westmead
Hospital, NSW 2145 Australia. E-mail jiejin_wang@wmi.usyd.edu.au
2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.594317

2143
 2144 Stroke October 2010
have detailed MRI phenotypic assessment so that differences
between cortical and subcortical cerebral atrophy cannot be
fully investigated in population-based studies.
Small vessel disease in the brain has been increasingly
recognized to be one of the most prevalent neurological
disorders and is also associated with aging.13 Recent studies
using the retinal circulation as a surrogate for cerebral
microcirculation have documented associations between vas-
cular signs in the retina and various brain pathologies.14,15
The Atherosclerosis Risk and Communities (ARIC) study of
1684 healthy middle-aged persons suggested that participants
with cortical and subcortical atrophy were more likely to have
retinopathy than those without cerebral atrophy.16 However,
whether similar associations are present in acute stroke cases
with cortical and subcortical atrophy is unclear. Other retinal
microvascular signs such as focal retinal arteriolar narrowing,
arteriovenous nicking, and arteriolar wall light reflex have not
been assessed for their specific associations with cerebral
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atrophy. In this study, we aimed to examine whether differ-
ential patterns of associations are present for retinal vascular
signs in cortical compared with subcortical cerebral atrophy
in patients with acute stroke.
Materials and Methods
Study Population
The Multi-Centre Retina & Stroke (MCRS) Study is a prospective
hospital-based cross-sectional study. The study population, study
design, and methods of the MCRS are described in detail else-
where.17 In brief, 1565 participants, aged 19 to 94 years, were
prospectively recruited from stroke units at Westmead Hospital,
Sydney (n280), Royal Melbourne Hospital, Melbourne (n562),
and Singapore General Hospital (n723) within 7 days of acute
stroke (first or recurrent events) during 2005 to 2007. Participating
patients underwent an interview with standardized questionnaires,
neurological examination, neuroimaging, and retinal photography.
Written informed consent was obtained from patients or their next of
kin. The MCRS was approved by the Human Research Ethics
committees of the respective hospitals. In the present study, we
included 1360 acute stroke cases after excluding 43 cases classified
as stroke mimic, 93 as transient ischemic attack, and 69 with
ungradable images.
Assessment of Acute Stroke
A final consensus diagnosis of acute stroke definite, probable, or
possiblewas made for each patient by a panel of stroke experts
with access to the clinical information and neuroimaging findings.
We included all definite, probable, or possible stroke cases in this
report. All patients had CT brain scanning, and a large subset also
had MRI scanning.17 The finding of a hyperdense intraparenchymal
or intraventricular lesion on CT (that was not determined to be
calcium) led to a diagnosis of intracranial hemorrhage (lobar or deep
intracranial hemorrhage differentiated by location); hemorrhagic
transformation of an infarct was coded as a cerebral infarct; and
intracranial hemorrhage due to secondary causes such as trauma,
neoplasm, or arteriovenous malformation was excluded. The ische-
mic stroke subtypes were classified into 5 core etiologic groupings:
large vessel atherosclerosis; small vessel (lacunar); cardioembolic
infarction; stroke of other etiology; and stroke of undetermined
etiology or competing causes determined from a pragmatic modifi-
cation of the Trial of Org 10172 in Acute Stroke Treatment
classification (Appendix, copied from the methodology article of this
study17) as adopted by the Greater Metropolitan Clinical Taskforce
for Stroke in New South Wales, Australia.18
Patients only proceeded to MRI according to their attending
clinician. In general, patients with large vessel disease had demon-
strated large artery stenosis. Lacunar stroke was defined on CT brain
scan as a small rounded lesion with lower attenuation than normal
brain but with higher attenuation than cerebrospinal fluid in the
subcortical white matter, basal ganglia, pons, or brain stem and no
greater than 20 mm diameter. On MR brain scan, this was defined as
an area of increased signal on T2-weighted and fluid-attenuated
inversion recovery images with respect to normal brain but not of
cerebrospinal fluid signal with no hemosiderin in the lesion (to
suggest primary hemorrhage) on gradient echo and a maximum
permitted diameter of 20 mm. Lacunar infarction on MRI-positive
diffusion-weighted imaging was defined as high signal diffusion-
weighted imaging with reduced signal on the apparent diffusion
coefficient map with or without a corresponding lesion present on
structural MRI. Cardioembolic infarction was defined to include
atrial fibrillation, intracardiac thrombus or tumor, rheumatic mitral
stenosis, prosthetic valves, endocarditis, sick sinus syndrome, left
ventricular aneurysm or akinesia after acute myocardial infarction,
acute (3 months) myocardial infarction, and cardiomyopathy in the
absence of another etiology. In this report, we used 2 major ischemic
stroke subtypes, lacunar in 1 group and all other remaining ischemic
strokes in a second group, termed nonlacunar infarction.
White matter lesions were defined as bilateral or patchy subcor-
tical hypodensities not discernible as a clearcut infarct on CT or as
hyperintensities on T2-weighted and fluid-attenuated inversion re-
covery MRI images. However, they were not as hyperintense as
cerebrospinal fluid on T2-weighted and not cerebrospinal fluid
intensity on fluid-attenuated inversion recovery to distinguish them
from lacunes (if 3 mm in diameter) and enlarged perivascular
spaces (if 3 mm diameter).
Assessment of Cortical and Subcortical
Cerebral Atrophy
Cortical and subcortical atrophy were graded on CT (as well as MRI
in a subset [40%] of patients) by stroke physicians masked to
patients retinal image grading according to a set of CT reference
standards19 based on a standardized atrophy classification system
devised to visually rate global cerebral atrophy and to distinguish
superficial cortical from deep white matter subcortical atrophy. This
was initially based on experience with the Wahlund atrophy scale20
but was extended to differentiate superficial from deep atrophy and
for use with CT and MR images. This approach was recently
validated in a range of older aged persons.21 Kappa value for the
intragrader reproducibility between CT and MRI in our study sample
was 0.68.
Retinal Photography and Grading
The retinal photography procedures used in this study are described
elsewhere.17 Briefly, up to 6 retinal photographs of each eye were
taken, following diabetic retinopathy study fields 1 to 6,22 using a
nonmydriatic digital camera (Canon D60; Canon, Tokyo, Japan),
usually after pharmacological pupil dilatation.
Focal retinal signs, including retinopathy lesions (microaneu-
rysms, cotton wool spots, retinal hemorrhages, and hard exudates)
were graded as either present or absent. Retinal arteriolar wall signs
were graded as absent, mild, or severe for focal arteriolar narrowing,
arteriovenous nicking, and enhanced arteriolar light reflex. The
grading was performed by comparison with a standard set of images
for various retinal microvascular signs, as previously described.23,24
All lesions detected were adjudicated by a senior researcher (J.J.W.),
and cases that had pathologies other than retinal vascular wall signs
were further adjudicated by a retinal specialist (P.M.).
Quantitative retinal vessel signs were graded at the Centre for Eye
Research Australia, which included estimates of retinal arteriolar and
venular caliber, using a semiautomated computer-assistant method.
The Parr-Hubbard-Knudtson formula25 was used to summarize the
average luminal caliber of retinal arterioles and venules and is
represented as the central retinal arteriolar equivalent and central
retinal venular equivalent. Graders were masked to clinical diag-
noses. Intraclass correlation coefficients for the intra- and intergrader
reproducibility were 0.97 to 0.98 for arteriolar caliber and 0.94 to
 Baker et al Cerebral Atrophy and Retinal Vascular Signs 2145

Table 1. Participant Characteristics and Vascular Risk Factor Profiles for Cortical Atrophy, Subcortical Atrophy, and Both
Atrophy Subtypes
Cerebral Atrophy

None Cortical Subcortical Both Subtypes

(N589) (N203) P* (N144) P* (N424) P*
Age, years 59.3 (12.2) 68.6 (12) 0.0001 67.8 (11) 0.0001 73.7 (10) 0.0001
Men, % 60.9 60.1 0.83 69.4 0.06 59.7 0.68
White, % 34.2 55.1 0.0001 39.2 0.26 52.5 0.0001
Chinese, % 48.8 31.5 0.0001 46.2 0.57 35.6 0.0001
Hypertension, % 62.4 67.5 0.20 63.9 0.74 72.9 0.0005
Diabetes mellitus, % 32.0 28.1 0.30 38.9 0.11 30.0 0.49
Hypercholesterolemia, % 39.7 42.6 0.47 46.5 0.13 41.6 0.54
Systolic blood pressure, mm Hg 158 (28) 159 (28) 0.46 159 (29) 0.51 161 (26) 0.07
Diastolic blood pressure, mm Hg 83 (16) 81 (14) 0.11 84 (14) 0.58 81 (16) 0.02
Current smoker, % 31.2 25.9 0.16 18.3 0.002 20.3 0.0001
Past smoker, % 19.5 24.4 0.14 32.4 0.009 31.9 0.0001
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Angina, % 3.3 6.9 0.02 7.6 0.02 7.3 0.003

Myocardial infarction, % 5.8 9.4 0.07 9.0 0.16 12.0 0.004
CABG, % 8.4 8.4 0.97 12.5 0.12 12.3 0.04
Atrial fibrillation, % 6.5 12.9 0.004 20.1 0.0001 18.2 0.0001
Peripheral vascular disease, % 4.4 6.0 0.38 7.7 0.11 7.8 0.03
Previous stroke, % 11.9 17.0 0.07 23.6 0.0003 27.8 0.0001
Previous TIA, % 7.5 9.9 0.28 10.5 0.24 11.1 0.05
Family history of stroke, % 20.7 19.4 0.69 18.3 0.52 15.4 0.03
Dementia, % 0.5 4.0 0.0003 4.9 0.0001 5.2 0.0001
Cancer, % 4.4 5.0 0.76 4.9 0.8 8.8 0.005
NIHSS score 3.5 (3.8) 3.1 (3.4) 0.21 3.7 (3.5) 0.68 3.3 (3.6) 0.39
Antiplatelet, % 35.6 41.7 0.17 40.3 0.35 48.6 0.0003
*P value for comparison with no cerebral atrophy.
Data in cells are means with SDs in parentheses.
CABG indicates coronary artery bypass grafting; TIA, transient ischemic attack; NIHSS, National Institutes of Health Stroke Scale.

0.98 for venular caliber. Retinal arteriolar narrowing was defined as
the lowest quintile of central retinal arteriolar equivalent and retinal
venular widening defined as the highest quintile of central retinal
venular equivalent.
Vascular Risk Factors
Patients underwent an extensive assessment of atherosclerotic dis-
eases and vascular risk factors during their admission.17 In brief,
hypertension was diagnosed according to a self- reported history or
the use of antihypertensive medication. Diabetes was diagnosed as a
fasting glucose 7.0 mmol/L or a self-reported history of diabetes,
which included use of oral hypoglycemic agents or insulin. Coronary
heart disease and myocardial infarction were ascertained by an
adjudication process involving medical history, physical examina-
tion, and laboratory criteria, including an electrocardiogram.
Statistical Methods
Logistic regression models were constructed to assess the associa-
tions of various retinal vascular signs (independent variables) with
cortical, subcortical atrophy, or both (dependent variables) compared
with patients with acute stroke without any cerebral atrophy. Models
were adjusted for age, gender, study site, hypertension, hypercho-
lesterolemia, diabetes, and cigarette smoking status. Forty patients
were assessed as having dementia. Supplemental analyses were
performed after excluding these 40 patients. Subgroup analyses were
also performed stratified by the presence of hypertension, diabetes
and the 2 major ischemic stroke types (lacunar and nonlacunar
infarction). Relatively small numbers in other acute stroke subtypes
did not permit analyses to be conducted for each of these. ORs and
95% CIs are reported.
Results
Cerebral atrophy was present in 771 of 1360 patients with
acute stroke (56.7%), of whom 203 (26.3%) had isolated
cortical atrophy, 144 (18.7%) had isolated subcortical atro-
phy, and 424 (55.0%) had both atrophy subtypes. Patient
characteristics and vascular risk factor profiles or those with
cortical atrophy, subcortical atrophy, both subtypes, or no
cerebral atrophy (n589) are shown in Table 1. Patients with
either or both cerebral atrophy types were significantly older,
more likely to give a history of previous stroke, angina, or
myocardial infarction, and to copresent with either dementia
or atrial fibrillation. Among patients with cortical atrophy,
50% were white and approximately one third were Chinese.
Among patients with subcortical atrophy, 39% and 46% were
white and Chinese, respectively. In addition, patients with
subcortical atrophy were more likely to have smoked in the
past but were less likely to be current smokers. Patients with
both atrophy subtypes were more likely than patients without
cerebral atrophy to have dementia or a history of cancer
(Table 1).
 2146 Stroke October 2010

Table 2. Acute Stroke Subtypes and Cerebrovascular Lesions by Cortical, Subcortical Atrophy, and Both Atrophy Subtypes
Cerebral Atrophy

None Cortical Subcortical Both Subtypes

(N589) (N203) P* (N144) P* (N424) P*
TOAST classification
Large artery 38.2 41.8 0.38 39.5 0.78 41.0 0.38
Cardioembolic 12.9 20.6 0.01 22.5 0.006 19.2 0.008
Lacunar 35.8 27.0 0.03 29.5 0.17 28.4 0.02
Other etiology 3.5 1.1 0.08 1.6 0.25 1.3 0.03
Undetermined etiology or competing causes 9.6 9.5 0.98 7.0 0.35 10.1 0.79
Intracerebral hemorrhage
Deep ICH 4.8 3.0 0.27 6.3 0.47 1.7 0.008
Lobar ICH 1.9 2.0 0.93 3.5 0.24 1.0 0.23
White matter lesions 30.2 39.4 0.02 59.0 0.0001 71.7 0.0001
Data presented in cells are proportions.
*P value for comparison with no cerebral atrophy.
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TOAST indicates Trial of Org 10172 in Acute Stroke Treatment; ICH, intracranial hemorrhage.

The frequencies of acute stroke subtypes (defined using
the modified Trial of Org 10172 in Acute Stroke Treatment
criteria) and other cerebrovascular diseases in patients with
either isolated cortical or subcortical atrophy, both atrophy
subtypes, or those with no cerebral atrophy are shown in
Table 2. Compared with patients without cerebral atrophy,
those with atrophy (either cortical or subcortical or both
subtypes) were more likely to have an ischemic stroke of
cardioembolic etiology plus white matter lesions. Patients
with isolated cortical atrophy were less likely to have
lacunar infarction, whereas the majority (60% to 70%) of
patients with either isolated subcortical atrophy or with
both atrophy subtypes were more likely to have white
matter lesions (Table 2).
Compared with patients with acute stroke without cerebral
atrophy, those with isolated cortical atrophy were not signif-
icantly more likely to have retinal vascular signs. However,
patients with isolated subcortical atrophy or with both atro-
phy subtypes were significantly more likely to have retinop-
athy lesions (OR, 1.9; CI, 1.2 to 3.0) or enhanced arteriolar

Table 3. Association of Retinal Vascular Signs With Cortical, Subcortical Atrophy, or Both Atrophy Subtypes
Cerebral Atrophy

Subcortical Atrophy Only Cortical Atrophy Only Both Atrophy Types

Retinal Sign No. (%) OR* (95% CI) No. (%) OR* (95% CI) No. (%) OR* (95% CI)
Focal arteriolar narrowing
Absent 112 (10.5) 1.0 174 (16.3) 1.0 296 (27.6) 1.0
Present 14 (8.5) 0.8 (0.41.6) 20 (12.2) 0.7 (0.41.3) 72 (43.9) 1.5 (0.92.4)
Arteriovenous nicking
Absent 89 (9.4) 1.0 150 (15.9) 1.0 270 (28.6) 1.0
Present 34 (12.3) 1.4 (0.92.3) 45 (16.3) 1.0 (0.61.5) 89 (32.3) 1.1 (0.71.6)
Enhanced light reflex
Absent 83 (9.1) 1.0 147 (16.1) 1.0 265 (29.0) 1.0
Present 40 (13.1) 2.0 (1.23.2) 44 (14.4) 1.3 (0.82.0) 97 (31.7) 1.9 (1.32.8)
Retinopathy
Absent 77 (8.8) 1.0 145 (16.6) 1.0 265 (30.3) 1.0
Present 61 (13.9) 1.9 (1.23.0) 55 (12.5) 0.9 (0.61.3) 138 (31.4) 1.6 (1.12.3)
Retinal arteriolar narrowing
Absent 110 (10.6) 1.0 162 (15.7) 1.0 309 (29.9) 1.0
Present 26 (9.8) 1.0 (0.61.7) 32 (12.0) 0.9 (0.51.5) 91 (34.2) 1.3 (0.92.0)
Retinal venular widening
Absent 105 (10.1) 1.0 160 (15.4) 1.0 333 (32.1) 1.0
Present 31 (11.7) 1.3 (0.82.2) 34 (12.9) 0.9 (0.61.5) 67 (25.4) 1.3 (0.82.0)
*Odds ratios adjusted for age, gender, study site, hypertension, hypercholesterolemia, diabetes, smoking status.
 Baker et al Cerebral Atrophy and Retinal Vascular Signs 2147

Table 4. Association of Retinal Vascular Signs With Cortical, Subcortical Atrophy, or Both Atrophy Types in Persons
With Hypertension
Cerebral Atrophy

Subcortical Atrophy Only Cortical Atrophy Only Both Atrophy Subtypes

Retinal Sign No. (%) OR* (95% CI) No. (%) OR* (95% CI) No. (%) OR* (95% CI)
Focal arteriolar narrowing
Absent 74 (10.5) 1.0 119 (17.0) 1.0 212 (30.2) 1.0
Present 10 (8.6) 0.8 (0.41.8) 11 (9.5) 0.6 (0.31.2) 53 (45.7) 1.5 (0.82.5)
Arteriovenous nicking
Absent 57 (9.3) 1.0 100 (16.3) 1.0 189 (30.8) 1.0
Present 24 (12.2) 1.8 (0.93.2) 32 (16.3) 1.2 (0.72.0) 70 (35.7) 1.4 (0.92.3)
Enhanced light reflex
Absent 50 (8.6) 1.0 95 (16.4) 1.0 189 (32.6) 1.0
Present 32 (13.9) 2.5 (1.44.3) 32 (13.9) 1.5 (0.92.5) 74 (32.2) 2.1 (1.33.4)
Retinopathy
Absent 42 (7.7) 1.0 97 (17.9) 1.0 178 (32.8) 1.0
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Present 47 (14.3) 2.6 (1.54.6) 38 (11.6) 0.8 (0.51.3) 114 (34.7) 2.1 (1.33.2)
Retinal arteriolar narrowing
Absent 73 (10.7) 1.0 113 (16.6) 1.0 222 (32.6) 1.0
Present 17 (9.4) 1.2 (0.62.3) 16 (8.8) 0.6 (0.31.2) 68 (37.6) 1.3 (0.82.2)
Retinal venular widening
Absent 67 (9.7) 1.0 108 (15.6) 1.0 246 (35.5) 1.0
Present 23 (13.6) 1.5 (0.82.7) 21 (12.4) 0.8 (0.41.4) 44 (26.0) 1.1 (0.71.9)
*Odds ratios adjusted for age, gender, study site, hypercholesterolemia, diabetes, smoking status.

light reflex (OR, 2.0; CI, 1.2 to 3.2) after adjusting for age,
gender, study site, hypertension, hypercholesterolemia, dia-
betes and smoking status (Table 3). These associations were
similar across 3 ethnic groups (whites, Chinese, others, data
not shown). After excluding the 40 patients classified as
having dementia, the association of retinopathy (OR, 1.9;
95% CI, 1.2 to 3.0) or enhanced arteriolar light reflex (OR,
1.9; 85% CI, 1.2 to 3.0) with subcortical atrophy remained.
In subgroup analyses stratified by hypertension, adjusting
for the same variables (except for hypertension), as those in
the model in Table 3, the associations of subcortical atrophy
with retinopathy or enhanced arteriolar light reflex were only
evident in patients with a history of hypertension (OR, 2.6;
95% CI, 1.5 to 4.6 for retinopathy and OR, 2.5; 95% CI, 1.4
to 4.3 for enhanced arteriolar light reflex; Table 4), but not in
patients without hypertension (OR, 1.1; 95% CI, 0.5 to 2.6
and OR, 0.9; 95% CI, 0.4 to 2.4 for these 2 retinal lesions,
respectively).
In analyses stratified by the presence of diabetes, adjusting
for the same covariables (except for diabetes) as those in the
model in Table 3, the associations were similar in the 2
subgroups but were significant only in the group without
diabetes (OR, 1.9; 95% CI, 1.0 to 3.4 for retinopathy and OR,
2.0; 95% CI, 1.1 to 3.8 for enhanced arteriolar light reflex;
Table 5) and were nonsignificant in patients with diabetes
(OR, 1.8; 95% CI, 0.9 to 3.7 for retinopathy and OR, 1.9;
95% CI, 0.9 to 3.9 for enhanced arteriolar light reflex). In
addition to these associations, patients without diabetes, with
isolated subcortical atrophy, were also more likely to have
retinal venular widening (Table 5).
In analyses stratified by lacunar (N395 cases) and non-
lacunar infarction (N860 cases), adjusting for the same
covariables as those in the model in Table 3, the associations
of retinopathy (OR, 2.4; 95% CI, 1.4 to 4.3) and enhanced
arteriolar light reflex (OR, 2.4; 95% CI, 1.3 to 4.6) with
subcortical atrophy were evident in only patients with non-
lacunar infarction, but not in those with lacunar infarction
(OR, 1.2; 95% CI, 0.5 to 3.0 and OR, 1.5; 95% CI, 0.5 to 3.7
for the 2 retinal lesions, respectively). In the lacunar infarc-
tion subgroup, subcortical atrophy was significantly associ-
ated with retinal venular widening (OR, 2.8; 95% CI, 1.2 to
6.6). This association was not evident in patients with
nonlacunar infarction (OR, 0.7; 95% CI, 0.3 to 1.5).
Discussion
In this study that includes 1300 patients recruited after an
acute stroke event, we documented associations with 2 retinal
vascular signs (retinopathy and enhanced arteriolar wall light
reflex) and subcortical cerebral atrophy. However, we did not
identify any retinal vascular signs that were associated with
cortical atrophy. These observed associations of the retinal
vascular signs with subcortical atrophy remained after ex-
cluding patients with dementia. In stratified analyses, the
associations were evident only in patients with hypertension.
This could be due to a greater prevalence of pathology, for
example, small vessel disease, in patients with hypertension.
Our findings support the concept that cortical and subcortical
cerebral atrophy may have a differential pathophysiology and
that subcortical atrophy is related to cerebral small vessel
disease or microvasculopathy.
 2148 Stroke October 2010

Table 5. Association of Retinal Vascular Signs With Cortical, Subcortical Atrophy, or Both Atrophy Types in Persons
Without Diabetes
Cerebral Atrophy

Subcortical Atrophy Only Cortical Atrophy Only Both Atrophy Types

Retinal Sign No. (%) OR* (95% CI) No. (%) OR* (95% CI) No. (%) OR* (95% CI)
Focal arteriolar narrowing
Absent 66 (8.9) 1.0 128 (17.3) 1.0 204 (27.6) 1.0
Present 12 (10.0) 1.5 (0.73.3) 15 (12.5) 0.9 (0.41.8) 57 (47.5) 2.3 (1.34.0)
Arteriovenous nicking
Absent 53 (8.3) 1.0 108 (16.8) 1.0 186 (29.0) 1.0
Present 23 (11.4) 1.4 (0.72.5) 34 (16.8) 1.0 (0.61.6) 68 (33.7) 1.2 (0.71.8)
Enhanced light reflex
Absent 55 (8.3) 1.0 107 (16.1) 1.0 196 (29.6) 1.0
Present 21 (11.9) 2.0 (1.13.8) 32 (18.1) 1.6 (0.92.7) 59 (33.3) 1.9 (1.23.2)
Retinopathy
Absent 58 (8.2) 1.0 112 (15.9) 1.0 220 (31.3) 1.0
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Present 25 (12.3) 1.9 (1.03.4) 33 (16.3) 1.1 (0.71.9) 67 (33.0) 1.4 (0.82.2)
Retinal arteriolar narrowing
Absent 70 (9.7) 1.0 119 (16.6) 1.0 222 (30.9) 1.0
Present 14 (7.7) 1.0 (0.52.1) 24 (13.3) 1.2 (0.72.2) 62 (34.3) 1.4 (0.82.3)
Retinal venular widening
Absent 64 (8.7) 1.0 117 (15.8) 1.0 242 (32.7) 1.0
Present 20 (12.5) 1.9 (1.03.8) 26 (16.3) 1.3 (0.72.3) 42 (26.3) 1.4 (0.82.5)
*Odds ratios adjusted for age, gender, study site, hypertension, hypercholesterolemia, smoking status.

Our findings are consistent with the previous ARIC study
report,16 which examined a generally healthy population-
based sample and found that retinopathy lesions were asso-
ciated with cortical and subcortical atrophy, independent of
age, gender, race, blood pressure, cigarette smoking, common
carotid artery intima-media thickness, and other vascular risk
factors.16
Small vessel disease in the brain is now recognized as a
common neurological disorder, particularly in aged persons.13
Although our findings provide support for the concept that
small vessel disease in the brain (using the surrogate of
retinopathy and enhanced light reflex in the retina) plays a
role in subcortical atrophy,26 the precise sequence of events
leading to cerebral small vessel disease is not clear. Pathol-
ogists have proposed at least 5 distinct entities that can cause
damage to small-caliber vessels in the brain: (1) an intrinsic
arteriolar wall abnormality termed lipohyalinosis (a destruc-
tive wall lesion containing mural foam cells and fibrinoid
necrosis in some acute lesions)27; (2) a concentric thickening
of the hyaline wall seen termed hyaline arteriosclerosis,
commonly in old age; (3) amyloid angiopathy (caused by
neuron-derived -amyloid infiltration into the endothelial
wall)28; (4) insidious endothelial (blood brain barrier) dys-
function29; and (5) other rare causes.30
Retinopathy is less frequent in the general population (7%
to 11%)15 compared with patients with acute stroke (preva-
lence ranged from 33.4% in nonlacunar cerebral infarction to
39.8% in intracerebral hemorrhage). The retinopathy preva-
lence was particularly high in patients with acute stroke with
subcortical atrophy (44.2%), whereas there was no significant
difference in prevalence between cortical atrophy (27.5%)
patients and those without cerebral atrophy (32.2%). Possible
disruption of the blood brain barrier in the cerebral micro-
circulation, analogous to the disruption of bloodretina bar-
rier, is suggested by the presence of retinopathy lesions31 and
could be a distinct pathological feature in the development of
subcortical atrophy. The most frequent retinopathy lesions are
microaneurysms and retinal hemorrhages.32,33 Disruption of
the blood brain barrier could result in a leakage of serum
components (ie, plasmin or other proteases, environmental
toxins carried in the blood, infectious agents, altered electro-
lyte levels) into the brain through small vessel walls, resulting
in perivascular edema and thus cerebral matter injury.34
Our data showed different frequencies of a number of
important and interesting vascular factors in persons with
cortical, subcortical and diffuse (both cortical and subcorti-
cal) atrophy (Table 1). As expected, our study confirmed an
association between dementia and cerebral atrophy (preva-
lence of dementia was 4.0% among patients with cortical
atrophy, 4.9% in those with subcortical atrophy, 5.2% in
those with both, and only 0.5% in those with none; Table 1).
Our study findings suggest additional pathophysiological
mechanisms in support of recent concepts of vascular demen-
tia and that the pathogenesis of Alzheimer dementia extends
beyond aging to include oxidative and inflammatory damages
to the brain and its microvasculature.35,36 Some other differ-
ences such as a history of cancer are likely due to the older
age of patients with cerebral atrophy, because adjustment for
age eliminated this association (data no shown).
 Baker et al
Finally, the significance of wider retinal venular caliber in
patients with subcortical atrophy and without diabetes is
unclear, but it is consistent with previous associations of
wider retinal venular caliber with generalized small vessel
disease such as the presence of white matter lesions,37,38
increased risk of stroke,39,40 cerebral hypoxia, reduced small
vessel arteriolar compliance, endothelial dysfunction, hyper-
glycemia, inflammation, 41,42 and dilatory effects of
-amyloid deposition on vascular tone.43
The strengths and weaknesses of the MCRS have been
detailed elsewhere.44 Our assessments of cerebral atrophy
from MRI, and retinal signs from photographs, were made by
observers masked to the other assessments and to clinical
details. For cerebral atrophy, the rating was masked in the
sense that those grading the brain imaging made these ratings
from the neuroimaging data rather than from their clinical
assessment of patients, and they were blind to the retinal
analyses. Although some atrophy signs could be affected by
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a very large infarct, this would not substantially affect any
association with retinal vascular signs. The retinal signs
were assessed from photographs by masked graders, who
had no access to any clinical information about the patients or
about their MRI assessments.
A number of important limitations of this study may have
influenced our study findings. First, there is a possibility of
misclassification of cerebral atrophy cases because variation
in brain morphology between individuals increases signifi-
cantly with increasing age, resulting in a wider range of
normal images at extremes of age.21 We did not adjust for
peak brain volume, a surrogate for intracranial volume, or
evaluate associations by specific regions of atrophy, but used
global ratings of cortical and subcortical atrophy.45 However,
these visual scales automatically adjust for overall head size
because the eye adjusts for how much the brain has shrunk
relative to the skull. Some investigators have suggested that
the temporal and occipital regions are more vulnerable than
other regions to the effects of vascular disease.9 Second, there
are currently limited methods for grading cerebral atrophy,
and the method we used, although reliable, is simple and
therefore effective for use in large-scale studies. Cortical and
subcortical atrophy were graded on CT (using a set of 3 CT
brain templates for cortical and subcortical atrophy, respec-
tively) and on MRI in a subset (using the same CT brain
templates where we selected the nearest likeness as seen on
MRI), and this method has been validated for MR and CT
interchangeably. We used only dichotomous definitions
for the presence or absence of cortical and subcortical
atrophy and avoided using quantitative estimation for
severity. Third, our study has insufficient power to assess
differences in the associations of retinopathy lesion sub-
types with cerebral atrophy across most acute stroke
subtypes. Finally, longitudinal data are needed to deter-
mine whether retinal microvascular signs and subcortical
atrophy occur concurrently.
Conclusion
Patients with acute stroke with cortical and subcortical
atrophy differ in their prevalence of presenting retinal vascu-
lar signs. Cortical atrophy was not associated with any retinal
Cerebral Atrophy and Retinal Vascular Signs 2149
vascular signs, whereas subcortical atrophy was associated
with retinopathy, indicating bloodretina barrier breakdown.
These data support the concept of a distinct microvasculopa-
thy or small vessel disease underlying subcortical atrophy.
Appendix
Trial of Org 10172 in Acute Stroke
Treatment Classification
(1) Large artery atherosclerosis: atherosclerosis with stenosis:
50% narrowing or occlusion of the relevant extracranial or
intracranial large artery in the absence of another etiology.
Atherosclerosis without stenosis: 50% diameter narrowing
in the absence of another etiology in patients with 2 of the
following risk factors: current smoking, age 50 years,
hypertension, diabetes, high cholesterol.
(2) Cardioembolism: atrial fibrillation, intracardiac thrombus or
tumor, rheumatic mitral stenosis, prosthetic valves, endocar-
ditis, sick sinus syndrome, left ventricular aneurysm or
akinesia after acute myocardial infarction, acute (3 months)
myocardial infarction, cardiomyopathyin the absence of
another etiology.
(3) Small artery: lacunar syndrome and normal CT/MRI or
relevant lesion 1.5 cm and absence source embolism and
50% stenosis.
(4) Stroke of other determined etiology: arterial dissection, fibro-
muscular dysplasia, arteriovenous malformation, vasculitis,
venous sinus thrombosis, hypercoagulable states, migrainous
ischemia.
(5) Stroke of undetermined etiology: none of the previously
mentioned causes could be determined. Two or more potential
causes of infarction.
Sources of Funding
Funded by the Australian National Health and Medical Research
Council (ID 352337) and the Singapore National Medical Research
Council (grant number 2004/073). J.J.W. was funded by a National
Health & Medical Research Council Senior Research Fellowship
(2005-2014). R.I.L. was supported by an infrastructure grant from
NSW Health.
Disclosures
None.
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 Differential Associations of Cortical and Subcortical Cerebral Atrophy With Retinal
Vascular Signs in Patients With Acute Stroke
Michelle L. Baker, Jie Jin Wang, Gerald Liew, Peter J. Hand, Deidre A. De Silva, Richard I.
Lindley, Paul Mitchell, Meng-Cheong Wong, Elena Rochtchina, Tien Y. Wong, Joanna M.
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Stroke. 2010;41:2143-2150; originally published online September 2, 2010;

doi: 10.1161/STROKEAHA.110.594317
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2010 American Heart Association, Inc. All rights reserved.
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