Incidence of Dementia After Ischemic Stroke

Results of a Longitudinal Study

David W. Desmond, PhD; Joan T. Moroney, MD, MRCPI; Mary Sano, PhD; Yaakov Stern, PhD

Background and Purpose—A number of cross-sectional epidemiological studies have reported that one fourth of elderly
patients meet criteria for dementia 3 months after ischemic stroke, but few longitudinal studies of the incidence of
dementia after stroke have been performed. We conducted the present study to investigate the incidence and clinical
predictors of dementia after ischemic stroke.
Methods—We administered neurological, neuropsychological, and functional assessments annually to 334 ischemic stroke
patients (age, 70.4⫾7.5 years) and 241 stroke-free control subjects (age, 70.6⫾6.5 years), all of whom were
nondemented in baseline examinations. We diagnosed incident dementia using modified Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition criteria requiring deficits in memory and ⱖ2 additional cognitive
domains, as well as functional impairment.
Results—The crude incidence rate of dementia was 8.49 cases per 100 person-years in the stroke cohort and 1.37 cases per
100 person-years in the control cohort. A Cox proportional-hazards analysis found that the relative risk (RR) of incident
dementia associated with stroke was 3.83 (95% CI, 2.14 to 6.84), adjusting for demographic variables and baseline
Mini-Mental State Examination score. Within the stroke cohort, intercurrent medical illnesses associated with cerebral
hypoxia or ischemia were independently related to incident dementia (RR, 4.40; 95% CI, 2.20 to 8.85), adjusting for
recurrent stroke, demographic variables, and baseline Mini-Mental State Examination score.
Conclusions—The risk of incident dementia is high among patients with ischemic stroke, particularly in association with
intercurrent medical illnesses that might cause cerebral hypoxia or ischemia, suggesting that cerebral hypoperfusion may
serve as a basis for some cases of dementia after stroke. (Stroke. 2002;33:2254-2262.)
Key Words: Alzheimer disease 䡲 cerebrovascular disorders 䡲 dementia 䡲 dementia, vascular 䡲 stroke
Downloaded from http://ahajournals.org by on October 16, 2019

A number of cross-sectional epidemiological studies have

suggested that ischemic stroke is a potent risk factor for
dementia.1–3 In our own work,3 we diagnosed dementia in one
fourth of a large cohort of elderly patients 3 months after
ischemic stroke. The clinical determinants of dementia in-
cluded features of the presenting stroke such as its size and
location, vascular risk factors such as diabetes mellitus and
prior stroke, and host characteristics such as older age.
Because of the increased frequency of adverse outcomes
among patients with stroke and dementia,4 which results in
early patient attrition and the underestimation of the true
frequency of dementia after stroke in prevalence surveys,5
however, studies of the incidence of dementia would be likely
to provide a more accurate estimate of the magnitude of the
association between ischemic stroke and dementia.6 Such
studies could also permit the recognition of risk factors for
incident dementia, which might be responsive to targeted
interventions to slow or arrest the course of cognitive decline,
but few such studies have been performed.
See Editorial Comment, page 2261
We conducted the present study to investigate the frequency and
clinical determinants of incident dementia after ischemic stroke.
Following our previous report on this topic,7 we recruited a second
stroke cohort and extended the length of follow-up of the stroke and
control cohorts that we had recruited previously. We administered
comprehensive annual assessments to all subjects who were found
to be free of dementia in baseline assessments in an effort to answer
2 specific questions. First, what is the risk of incident dementia
associated with ischemic stroke? Second, consistent with studies
that have suggested that cerebral hypoperfusion may serve as a basis
for vascular dementia,8,9 what role do intercurrent medical illnesses
associated with cerebral hypoxia or ischemia play as determinants
of incident dementia after ischemic stroke?
Methods
Subjects
As part of a longitudinal study of stroke and dementia,3 we recruited
585 subjects among patients consecutively admitted to Columbia-

Received November 16, 2001; final revision received March 7, 2002; accepted May 13, 2002.
From the Departments of Neurology and Pathology, SUNY Downstate Medical Center, Brooklyn, NY (D.W.D.); Department of Clinical
Neurosciences, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland (J.T.M.); and Departments of Neurology and Psychiatry and
the Gertrude H. Sergievsky Center, Columbia University, College of Physicians and Surgeons, New York, NY (M.S., Y.S.).
Correspondence to Dr David W. Desmond, SUNY Downstate Medical Center, 450 Clarkson Ave, Box 25, Brooklyn, NY 11203. E-mail
dwdesmond@usa.net
© 2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000028235.91778.95

2254
 Desmond et al
Presbyterian Medical Center for ischemic stroke. We recruited 297
of those patients from 1988 to 1990 and the remaining 288 patients
from 1994 to 1997; those 2 recruitment phases corresponded to 2
funding cycles. Eligibility requirements included age ⱖ60 years and
a diagnosis of ischemic stroke within the previous 30 days confirmed
by brain imaging (relevant infarct or normal). Patients were excluded
when certain clinical features precluded reliable assessment of
cognitive function, including a Boston Diagnostic Aphasia Exami-
nation10 severity rating ⬍3 (lower scores represent greater severi-
ties), persistent impairment of consciousness, or a primary language
other than English or Spanish. Additional exclusion criteria included
the presence of a concomitant neurological disorder potentially
affecting cognitive function (eg, Parkinson’s disease) or a severe
comorbid medical illness (eg, terminal cancer) that would preclude
follow-up throughout the course of this longitudinal study. Using
neuropsychological and functional assessments performed 3 months
after stroke and modified criteria from the Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition (DSM-III-R),11
all of which are described in detail below, we diagnosed dementia in
119 of the 453 ischemic stroke patients available for examination.3
The remaining 334 nondemented patients (age, 70.4⫾7.5 years;
education, 10.7⫾4.9 years) constitute the incidence patient cohort
for this study. Regarding race and ethnicity, 126 of the 334 stroke
patients were black (37.7%), 98 patients were Hispanic (29.3%), 104
patients were white (31.2%), and 6 patients (1.8%) were of other
race/ethnicity. Regarding sex, 167 of the 334 stroke patients (50.0%)
were women.
We also recruited a control cohort of 249 subjects who were ⱖ60
years of age and who were free of any history of stroke or evidence
of stroke in neurological examination. Most of the control cohort was
randomly selected from the surrounding community from a Medicare
list (53.0%); the remaining subjects were spouses of stroke patients
also enrolled in our study (17.3%) or neighborhood volunteers who
came to our attention through advertisements or referrals by friends
(29.7%). As a group, control subjects were matched to the stroke
Downloaded from http://ahajournals.org by on October 16, 2019
cohort by age. In baseline examinations, 8 of those 249 subjects were
found to be demented, and the remaining 241 subjects (age,
70.6⫾6.5 years; education, 12.4⫾4.5 years) constitute the incidence
control cohort for this study. Regarding race and ethnicity, 77 of the
241 control subjects were black (32.0%), 36 subjects were Hispanic
(14.9%), and 128 subjects were white (53.1%). Regarding sex, 159
of the 241 control subjects (66.0%) were women.
This study was approved by the Institutional Review Board of
Columbia-Presbyterian Medical Center, and all subjects provided
informed consent.
Assessment Procedures and Follow-Up
Seven to 10 days after stroke onset, neurologists specializing in
stroke administered a structured neurological examination and doc-
umented any history of stroke, transient ischemic attack, or exposure
to risk factors for cerebrovascular disease on the basis of a review of
medical records and a structured interview administered to all
patients and knowledgeable informants. A comprehensive medical
history was also recorded. Patients were classified by infarct location
and stroke syndrome using modified methods of the Stroke Data
Bank12 on the basis of a review of clinical features and brain imaging
performed immediately after stroke.
We performed our baseline comprehensive assessment of the
stroke cohort 3 months after stroke. We then examined all subjects
annually on the basis of the date of stroke onset for patients and the
date of the baseline examination for control subjects using the same
assessment protocol. During the baseline assessment and all annual
examinations, all subjects were administered a comprehensive bat-
tery of neuropsychological tests developed for use in epidemiologi-
cal studies of dementia,13 which is described in detail elsewhere,3
with testing performed in either English or Spanish, whichever was
spoken in the subject’s home; the Mini-Mental State Examination
(MMSE),14 which was not part of our dementia diagnosis paradigm;
the Barthel Index,15 which taps the physical aspects of activities of
daily living; and the Structured Interview Guide for the Hamilton
Depression Rating Scale (SIGH-D),16 with depression defined as an
Incidence of Dementia After Ischemic Stroke 2255
SIGH-D total score ⬎11 with the acknowledgment of depressed
mood. Knowledgeable informants were administered the Blessed
Functional Activity Scale (BFAS),17 which taps the cognitive aspects
of activities of daily living. Neurologists specializing in stroke
administered a structured neurological examination and documented
any recurrent strokes and intercurrent illnesses that may have
occurred. Stroke patients were also rated on the Stroke Data Bank
Stroke Severity Scale.12
To maximize follow-up rates, we visited subjects’ homes or
healthcare facilities if they were unable or unwilling to be examined
in our clinic, and we did not consider subjects to be “refusals” for a
particular interval until at least 4 attempts had been made to contact
and examine them. When in-person examinations were not possible,
we obtained information by telephone to ascertain vital status and the
occurrence of major clinical events.
Diagnosis of Hypoxic-Ischemic Disorders
Consistent with our previous work,7 intercurrent illnesses and
hospitalizations were reviewed to identify all disorders that could
result in cerebral hypoxia or ischemia, including cardiopulmonary
arrest, cardiac arrhythmias, congestive heart failure, myocardial
infarction, syncope, seizures, sepsis, pneumonia, respiratory failure,
drug overdose, burns, hypotension with general anesthesia, profound
hypoglycemia, hanging, and strangulation. Some of those disorders
were not present in our sample (eg, strangulation), and others were
always associated with patient death (eg, cardiopulmonary arrest).
We did not rely on specific diagnostic criteria for each hypoxic-is-
chemic (HI) disorder but instead relied on the clinical judgment of
the treating physician. Exact dates for all HI disorders were recorded
when available; otherwise, the date of occurrence was assigned to the
midpoint of the corresponding follow-up interval. For those patients
who experienced ⬎1 HI disorder, we used the date of the event
closest to that of the next scheduled follow-up examination. The
diagnosis of HI disorders was performed by researchers blinded to
incident dementia status.
Dementia Diagnosis
Dementia was diagnosed using criteria modified from the DSM-III-
R.11 We required deficits in memory and ⱖ2 additional cognitive
domains as determined in the neuropsychological evaluation, as well
as functional impairment not solely related to physical disability
documented with the BFAS. When patients were aphasic, we
required that they exhibit evidence of nonverbal memory impair-
ment. We defined impairment within any cognitive domain as any
neuropsychological test score within that domain falling below a
predetermined cutoff that was selected in a pilot study. We consider
those cutoffs to be conservative.
We used this same paradigm to diagnose incident dementia at
every interval. We did not require a specific decrement in perfor-
mance for that diagnosis. Instead, we required only performance
falling below our cutoff scores combined with functional impairment
documented with the BFAS. These procedures were intended to
maximize consistency and reliability in diagnosis over time.
Statistical Analyses
We calculated survival time from the date of the baseline examina-
tion. The date of onset of new dementia was defined as the date of
the examination during which a subject’s performance first met
diagnostic criteria for that disorder. For patients who never met
criteria for incident dementia, the date of censoring was considered
to be the date of the final completed annual examination. Reasons for
censoring included death, subject dropout or loss to follow-up, or the
end of formal study follow-up on May 31, 1999. The crude incidence
rate of new dementia, stratified by stroke status, was calculated using
life-table methods. To compute the relative risk (RR) of incident
dementia associated with stroke versus control status, we performed
Cox proportional-hazards analyses, first unadjusted and then ad-
justed for demographic variables and baseline MMSE score, which
served to represent the severity of cognitive impairment 3 months
after stroke for patients and at baseline for control subjects.
 2256 Stroke September 2002

We then investigated the clinical predictors of incident dementia

within our stroke cohort. We performed log-rank tests to investigate
the location and severity of the presenting stroke, vascular risk
factors, and demographic variables as potential predictors. We also
performed unadjusted Cox proportional-hazards analyses to investi-
gate the risk associated with HI disorders and recurrent stroke, which
were entered as time-dependent covariates. HI disorders and recur-
rent stroke were eligible for inclusion in our analyses only if they
occurred between the baseline examination and either the date of
diagnosis of incident dementia or the date of censoring. We then
performed Cox proportional-hazards analyses to determine whether
any of the variables found to be related to incident dementia in the
univariate analyses (P⬍0.10) would be independently related to the
incidence of dementia.

Results
Incidence of Dementia in the Stroke and
Control Cohorts
In the stroke cohort, 290 of the 334 patients (86.8%) had ⱖ1
follow-ups, 184 patients (55.1%) had ⱖ2 follow-ups, and 125
patients (37.4%) had ⱖ3 follow-ups. Death occurred in 63
patients, and 17 patients were lost to follow-up. Overall,
members of the stroke cohort completed a median of 64.6%
of all possible follow-up visits before a diagnosis of incident
dementia, death, or the formal end of follow-up. The median
follow-up was 21.1 months, with a maximum follow-up of
120.0 months. It is important to note that a proportion of our
second stroke cohort was never eligible for second- or
third-year follow-up examinations because of the restricted
interval between their baseline examinations and the formal
end of follow-up. New dementia was diagnosed in 72 stroke
Downloaded from http://ahajournals.org by on October 16, 2019
Kaplan-Meier analysis showing cumulative proportion of sub-
jects surviving free of dementia stratified by stroke status during
follow-up of up to 120 months. Numbers of subjects remaining
active at the end of each interval for the stroke group (bottom
line) and control group (top line) were 211 and 206 at year 1,
144 and 195 at year 2, 92 and 170 at year 3, 60 and 150 at year
4, 48 and 125 at year 5, 40 and 112 at year 6, 30 and 97 at
year 7, 20 and 74 at year 8, and 7 and 21 at year 9,
respectively.
95% CI, 1.85 to 6.87) and 9 to 12 years (RR, 1.61; 95% CI,
0.84 to 3.07) versus ⱖ13 years, black race (RR, 1.56; 95% CI,
0.90 to 2.72) and Hispanic ethnicity (RR, 1.21; 95% CI, 0.63
to 2.31) versus white race, and female sex (RR, 1.08; 95% CI,

patients (21.6%) during 848.1 person-years of follow-up, 0.68 to 1.70). As shown in Table 1 (model 1), when a baseline
yielding a crude incidence rate of 8.49 cases per 100 MMSE score ⬍24, which was not part of our dementia
person-years. diagnosis paradigm, was added to that model, the RR asso-
In the control cohort, 209 of the 241 subjects (86.7%) had ciated with stroke status was 3.83 (95% CI, 2.14 to 6.84),
ⱖ1 follow-ups, 196 subjects (81.3%) had ⱖ2 follow-ups, and adjusting for age ⱖ80 years (RR, 5.88; 95% CI, 3.22 to
164 subjects (68.0%) had ⱖ3 follow-ups. Death occurred in 10.76) and age 70 to 79 years (RR, 2.15; 95% CI, 1.27 to
35 control subjects, and 16 subjects were lost to follow-up.
Overall, members of the control cohort completed a median TABLE 1. Primary Cox Proportional-Hazards Models of the
of 62.5% of all possible follow-up visits before a diagnosis of Predictors of Incident Dementia
incident dementia, death, or the formal end of follow-up. The
RR (95% CI)
median follow-up was 62.2 months, with a maximum
follow-up of 119.9 months. New dementia was diagnosed in Model 1,
17 control subjects (7.0%) during 1243.7 person-years of Stroke and Model 2,
follow-up, yielding a crude incidence rate of 1.37 cases per Variable Control Cohorts Stroke Cohort
100 person-years. A log-rank test determined that the survival Stroke vs control status 3.83 (2.14–6.84) 䡠䡠䡠
curves of the stroke and control cohorts, which are shown in Age (vs 60–69 y), y
the Figure, were significantly different (P⬍0.0001). ⱖ80 5.88 (3.22–10.76) 4.17 (2.03–8.56)
An unadjusted Cox proportional-hazards analysis found 70–79 2.15 (1.27–3.62) 1.95 (1.08–3.52)
that stroke status was a significant predictor of incident
Education (vs ⱖ13 y), y
dementia (RR, 6.12; 95% CI, 3.57 to 10.50). That RR
0–8 2.69 (1.34–5.38) 2.02 (0.88–4.64)
suggests that patients with ischemic stroke are at a 6-fold-
increased risk of dementia during long-term follow-up, 9–12 1.49 (0.76–2.92) 1.53 (0.70–3.35)
whereas the CI suggests that there is a 95% probability that Race/ethnicity (vs white)
the risk of dementia is increased by at least 4-fold and Black 1.72 (0.98–3.02) 1.28 (0.67–2.44)
possibly by as much as 10-fold among those patients. When Hispanic 1.47 (0.76–2.84) 1.34 (0.64–2.81)
demographic variables were added to that model, the RR Sex (female) 0.93 (0.58–1.49) 0.89 (0.51–1.54)
associated with stroke status was 5.20 (95% CI, 2.97 to 9.12), MMSE total score⬍24 3.11 (1.90–5.09) 3.45 (2.02–5.88)
adjusting for age ⱖ80 years (RR, 6.30; 95% CI, 3.50 to
Recurrent stroke 䡠䡠䡠 2.71 (1.44–5.10)
11.33) and age 70 to 79 years (RR, 2.70; 95% CI, 1.62 to
HI disorders 䡠䡠䡠 4.40 (2.20–8.85)
4.48) versus age 60 to 69, education of 0 to 8 years (RR, 3.57;
 Desmond et al Incidence of Dementia After Ischemic Stroke 2257

TABLE 2. Demographic Variables, Vascular Risk Factors, and TABLE 3. Index Stroke Characteristics and Recurrent Stroke
HI Disorders by Incident Dementia Status in the Stroke Cohort by Incident Dementia Status in the Stroke Cohort
Incident Dementia, n (%) Incident Dementia, n (%)

Variable Yes (n⫽72) No (n⫽262) P Variable Yes (n⫽72) No (n⫽262) P

Age, y Stroke syndrome
ⱖ80 15 (20.8) 27 (10.3) ⬍0.001 Major dominant hemispheral 8 (11.1) 12 (4.6) 0.323
70–79 30 (41.7) 85 (32.4) Major nondominant hemispheral 6 (8.3) 17 (6.5)
60–69 27 (37.5) 150 (57.3) Minor dominant hemispheral 9 (12.5) 39 (14.9)
Education, y Minor nondominant hemispheral 8 (11.1) 30 (11.5)
0–8 31 (43.1) 75 (28.6) 0.010 Lacunar/deep hemispheral 28 (38.9) 103 (39.3)
9–12 30 (41.7) 104 (39.7) Brainstem/cerebellar 13 (18.1) 61 (23.3)
ⱖ13 11 (15.3) 83 (31.7) Stroke location
Race/ethnicity Left hemisphere 22 (30.6) 80 (30.7) 0.344
Black 33 (46.5) 93 (36.2) 0.515 Right hemisphere 30 (41.7) 91 (34.9)
Hispanic 20 (28.2) 78 (30.4) Brainstem/cerebellum 20 (27.8) 90 (34.5)
White 18 (25.4) 86 (33.5) Vascular territory
Sex (female) 47 (65.3) 120 (45.8) 0.050 ICA 2 (2.8) 11 (4.2) 0.558
Hypertension 52 (72.2) 194 (74.0) 0.758 ACA 3 (4.2) 5 (1.9)
Diabetes mellitus 25 (34.7) 82 (31.3) 0.286 MCA 36 (50.0) 124 (47.3)
Myocardial infarction 16 (22.2) 41 (15.6) 0.117 PCA 10 (13.9) 34 (13.0)
Angina 16 (22.2) 54 (20.8) 0.662 Vertebrobasilar 21 (29.2) 88 (33.6)
Atrial fibrillation 12 (16.7) 34 (13.1) 0.200 Stroke mechanism
Congestive heart failure 7 (9.9) 24 (9.2) 0.626 Large-artery atherosclerosis 12 (16.7) 48 (18.3) 0.463
Hypercholesterolemia 13 (18.1) 67 (25.9) 0.485 Cardiac embolism 16 (22.2) 52 (19.8)
Consistent cigarette use 42 (58.3) 159 (61.6) 0.624 Lacunar 26 (36.1) 100 (38.2)
Downloaded from http://ahajournals.org by on October 16, 2019

Consistent alcohol use 32 (45.1) 137 (53.1)
Prior stroke 20 (27.8) 52 (19.8)
Prior transient ischemic attack 10 (14.3) 47 (18.1)
HI disorders 13 (18.1) 26 (9.9)
Significance levels are based on log-rank tests for all variables except HI
disorders, which was entered into an unadjusted Cox proportional-hazards
analysis as a time-dependent covariate.
3.62) versus age 60 to 69 years, education of 0 to 8 years (RR,
2.69; 95% CI, 1.34 to 5.38) and 9 to 12 years (RR, 1.49; 95%
CI, 0.76 to 2.92) versus ⱖ13 years, black race (RR, 1.72; 95%
CI, 0.98 to 3.02) and Hispanic ethnicity (RR, 1.47; 95% CI,
0.76 to 2.84) versus white race, female sex (RR, 0.93; 95%
CI, 0.58 to 1.49), and an MMSE score ⬍24 (RR, 3.11; 95%
CI, 1.90 to 5.09). The results of this analysis were essentially
unchanged after further adjustment for vascular risk factors
such as hypertension, diabetes mellitus, and cardiac disease.
Risk Factors for Incident Dementia in the
Stroke Cohort
Demographic variables, vascular risk factors, and the occur-
rence of HI disorders by incident dementia status in the stroke
cohort are shown in Table 2. Index stroke characteristics and
recurrent stroke by incident dementia status are shown in
Table 3. Log-rank tests demonstrated that patients with
incident dementia were older, had received fewer years of
education, tended to be female, and more often met our
operationalized criteria for depression than patients who did
not develop incident dementia. Because of the numerous
categories included in the stroke syndrome variable, we also
0.332 Unknown/other cause 18 (25.0) 62 (23.7)
0.217 Depression 9 (13.8) 13 (5.1) 0.086
0.429 (SIGH-D total score ⬎11
with depressed mood)
⬍0.001
Recurrent stroke 17 (23.6) 22 (8.4) ⬍0.001
ICA indicates internal carotid artery; ACA, anterior cerebral artery; MCA,
middle cerebral artery; and PCA, posterior cerebral artery. Significance levels
are based on log-rank tests for all variables except recurrent stroke, which was
entered into an unadjusted Cox proportional-hazards analysis as a time-
dependent covariate.
examined a variable representing a major hemispheral stroke
syndrome versus all other stroke syndromes, and that variable
was significantly related to incident dementia status by a
log-rank test (P⫽0.032). Dichotomous recodings of the
vascular territory and stroke mechanism variables were not
related. Unadjusted Cox proportional-hazards analyses, with
HI disorders and recurrent stroke entered as time-dependent
covariates, demonstrated that each of those variables was
significantly associated with incident dementia.
An unadjusted Cox proportional-hazards analysis deter-
mined that the RR of incident dementia associated with HI
disorders, which was entered as a time-dependent covariate,
was 3.20 (95% CI, 1.66 to 6.14). That RR suggests that stroke
patients with HI disorders are at a 3-fold-increased risk of
dementia during long-term follow-up, whereas the CI sug-
gests that there is a 95% probability that the risk of dementia
is increased by at least 2-fold and possibly by as much as
6-fold among those patients. Adding demographic variables
to that model showed that the risk of incident dementia
 2258 Stroke September 2002
remained elevated in association with HI disorders (RR, 4.70;
95% CI, 2.37 to 9.35), with adjustment for age ⱖ80 years
(RR, 4.66; 95% CI, 2.36 to 9.22) and age 70 to 79 years (RR,
2.68; 95% CI, 1.52 to 4.74) versus age 60 to 69 years,
education of 0 to 8 years (RR, 3.06; 95% CI, 1.43 to 6.58) and
9 to 12 years (RR, 1.68; 95% CI, 0.80 to 3.50) versus ⱖ13
years, black race (RR, 1.45; 95% CI, 0.78 to 2.71) and
Hispanic ethnicity (RR, 1.21; 95% CI, 0.59 to 2.49) versus
white race, and female sex (RR, 1.19; 95% CI, 0.71 to 1.99).
Finally, as shown in Table 1 (model 2), our primary Cox
proportional-hazards analysis demonstrated that the risk of
incident dementia was elevated in association with HI disor-
ders (RR, 4.40; 95% CI, 2.20 to 8.85), while adjusting for
recurrent stroke (RR, 2.71; 95% CI, 1.44 to 5.10), age ⱖ80
(RR, 4.17; 95% CI, 2.03 to 8.56) and age 70 to 79 (RR⫽1.95;
95% CI, 1.08 to 3.52) versus age 60 to 69, education of 0 to
8 years (RR, 2.02; 95% CI, 0.88 to 4.64) and 9 to 12 years
(RR, 1.53; 95% CI, 0.70 to 3.35) versus ⱖ13 years, black race
(RR, 1.28; 95% CI, 0.67 to 2.44) and Hispanic ethnicity (RR,
1.34; 95% CI, 0.64 to 2.81) versus white race, female sex
(RR, 0.89; 95% CI, 0.51 to 1.54), and an MMSE score ⬍24
(RR, 3.45; 95% CI, 2.02 to 5.88). Depression and a major
hemispheral stroke syndrome were not significantly related to
incident dementia status and were excluded from this multi-
variate model.
Within the group of 39 stroke patients who had experi-
enced intercurrent HI disorders, 27 patients experienced
cardiac HI disorders (myocardial infarction in 1 incident and
10 nonincident patients, congestive heart failure in 2 incident
Downloaded from http://ahajournals.org by on October 16, 2019
and 6 nonincident patients, atrial fibrillation or other arrhyth-
mias in 2 incident and 3 nonincident patients, and syncope in
1 incident and 2 nonincident patients), and 12 patients
experienced noncardiac HI disorders (pneumonia in 4 inci-
dent and 1 nonincident patients, seizures in 3 incident and 2
nonincident patients, and sepsis in 2 nonincident patients).
Although the cell sizes are relatively small, noncardiac HI
disorders, particularly pneumonia and seizures, were associ-
ated with a significantly higher frequency of incident demen-
tia (58.3%) than cardiac HI disorders (22.2%; P⫽0.027 by
␹2). The results of that analysis were unchanged after adjust-
ment for age.
Discussion
We found that the risk of incident dementia was increased
4-fold among ischemic stroke patients who were initially
nondemented relative to clinically stroke-free elderly control
subjects after adjustment for demographic factors and base-
line level of cognitive function. Among stroke patients, the
risk of incident dementia was elevated in association with
intercurrent illnesses that might cause cerebral hypoxia or
ischemia after adjustment for those same variables and
recurrent stroke, suggesting that cerebral hypoperfusion may
serve as a basis for some cases of dementia after stroke.
Although the cell sizes were relatively small, noncardiac HI
disorders, particularly pneumonia and seizures, were associ-
ated with a significantly higher frequency of incident demen-
tia than cardiac HI disorders. In addition to the risk factors
that we identified in this study, it is also likely that a
proportion of our cohort was affected by concomitant Alz-
heimer’s disease, which may have served as the primary basis
for their cognitive decline, and certain patients whose base-
line neuropsychological test scores were slightly higher than
our operationalized cutoffs may have crossed over those
cutoffs without exhibiting clinically meaningful decline,
causing them to be identified as incident cases of dementia
when they might have been more accurately characterized as
prevalent cases.
The findings of the few previous longitudinal studies that
have been performed based on hospitalized stroke series are
consistent with our own in suggesting that the risk of incident
dementia associated with stroke is high. Tatemichi et al18
reported that the incidence of dementia was 6.7% among
patients 60 to 64 years of age and 26.5% among patients ⱖ85
years of age after 1 year of follow-up in a sample of 610
patients who were initially nondemented after stroke, but they
did not report an overall frequency of incident dementia.
Bornstein et al19 reported that 56 of 175 patients who were
initially nondemented after stroke (32.0%) developed inci-
dent dementia during 5 years of follow-up after first ischemic
stroke. Hénon et al20 examined a cohort of 169 patients who
had been nondemented before stroke onset and reported that
the cumulative proportion of patients with incident dementia
was 21.3% after 3 years of follow-up. The onset of new
dementia occurred immediately after the index stroke in most
cases, however, and only 7% of patients who were nonde-
mented 6 months after that index stroke developed incident
dementia during the remainder of the 3 years of follow-up. In
2 studies based on patients presenting with a lacunar infarc-
tion as their first stroke, Loeb et al21 found that 25 of 108
patients (23.2%) developed incident dementia during an
average of 4 years of follow-up, and Samuelsson et al22 found
that 4 (4.9%) and 8 (9.9%) of 81 patients developed incident
dementia after 1 and 3 years of follow-up, respectively.
In population-based studies of stroke and incident demen-
tia, Kokmen et al23 reviewed the medical records of a sample
of 971 patients who were free of dementia before first stroke.
The cumulative incidence of dementia, which includes prev-
alent cases with an onset immediately after stroke, was 7% at
1 year, 10% (ie, an additional 3% of new cases) at 3 years,
15% (ie, a further 5% of new cases) at 5 years, and 23% (ie,
a further 8% of new cases) at 10 years. Zhu et al24 studied
1301 initially nondemented subjects ⱖ75 years of age, 7.1%
of whom had a history of stroke, and diagnosed incident
dementia in 224 subjects (17.2%) after 3 years of follow-up.
The RR of incident dementia associated with prior stroke was
1.7 (95% CI, 1.1 to 2.6) after adjustment for potential
confounders, and prior stroke was particularly potent when it
had occurred within the preceding 3 years. In addition, the
RR of incident dementia associated with incident stroke, or a
first stroke occurring during follow-up, was 2.4 (95% CI, 1.6
to 3.5). Our study and certain of the studies cited earlier have
similarly recognized the importance of recurrent stroke oc-
curring during the study period,21,23 and the central role of
recurrent stroke as a risk factor for incident dementia has
received a great deal of attention in studies of cerebral
autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL).25,26
 Desmond et al
Although numerous studies have focused on the clinical
consequences of catastrophic HI events, particularly cardio-
pulmonary arrest,27,28 and some studies have reported an
association between HI events and memory disorders,29,30
only a few studies have investigated the association between
HI disorders and dementia. Using a sample of 133 patients
with vascular dementia, Sulkava and Erkinjuntti8 identified 6
patients (4.5%) who exhibited the acute onset of dementia in
temporal association with cardiac arrhythmias and systemic
arterial hypotension that were judged to be responsible for
cerebral hypoperfusion. Similarly, Skoog et al31 found that
4.1% of 147 elderly (85 years of age) patients with dementia
had cerebral hypoperfusion as the primary cause of their
dementia syndrome. In the study described above, Hénon et
al20 found that 13.9% of 36 stroke patients experienced
intercurrent HI disorders before the onset of incident demen-
tia, but it should also be noted that 12.0% of the 133 patients
who did not develop incident dementia also experienced
those disorders. In the Cardiovascular Health Study,32 ortho-
static hypotension was significantly associated with white-
matter lesions on MRI of the brain, and those lesions were
associated with poorer performance on a mental status test.
Cooper and Mungas33 compared 502 patients with vascular
dementia with 810 patients with Alzheimer’s disease and
found that patients with vascular dementia more frequently
had a history of general anesthesia than patients with Alzhei-
mer’s disease, whereas those groups did not differ with regard
to a family history of dementia or a history of head injury.
Finally, Brun9 found that 28.8% of patients with vascular
Downloaded from http://ahajournals.org by on October 16, 2019
dementia had neuropathological evidence of cerebral hypo-
perfusion, with either selective incomplete infarction of the
cerebral white matter or borderzone infarction.
In addition to those variables that were significantly related
to incident dementia in our study, including HI disorders,
recurrent stroke, and older age, it is also worthwhile to review
selected variables that were not related. First, qualitative
brain imaging variables, including the location of the index
stroke, were not associated with incident dementia, and other
studies have reported similar findings.21,23 Although our
previous work suggests that certain of those variables were
likely to have been related to deficits in baseline cognitive
function, which were represented by the baseline MMSE
score in our primary Cox proportional-hazards analysis, the
effects of those lesions would typically have been static or
slightly remitting rather than progressive. Second, similar to
the findings of other studies,19,21 vascular risk factors were
not related to incident dementia in our stroke cohort, but it is
likely that certain of them may have elevated the risk of
recurrent stroke and thus indirectly contributed to the inci-
dence of dementia. To the extent that more effective man-
agement of vascular risk factors might reduce the risk of
recurrent stroke, such an intervention might also reduce the
risk of incident dementia. Third, like virtually all dementia
studies, we recognized the importance of older age as a risk
factor, but education and other demographic variables were
unrelated to incident dementia in our primary Cox
proportional-hazards analysis. Our failure to recognize an
association between education and incident dementia sug-
gests that the “cognitive reserve” hypothesis that has received
Incidence of Dementia After Ischemic Stroke 2259
a great deal of attention in studies of Alzheimer’s disease34
may be of less importance in studies of dementia after stroke.
Our study has certain limitations. First, although most of
our control cohort was randomly selected from the surround-
ing community from a Medicare list, the remaining subjects
were spouses of stroke patients also enrolled in our study or
neighborhood volunteers who came to our attention through
advertisements or referrals by friends. Given that our methods
may have been biased toward the recruitment of healthier
control subjects, we may have slightly overestimated the
magnitude of the risk of incident dementia associated with
ischemic stroke. Second, we did not have neuropathological
confirmation of the dementia subtype in our patients. Thus,
we were unable to characterize the importance of concomi-
tant Alzheimer’s disease as a risk factor for incident dementia
after stroke. In our Cox proportional-hazards analyses, how-
ever, we found that older age was associated with a signifi-
cantly elevated risk of incident dementia, and it is likely that
that variable can be considered a crude surrogate for Alzhei-
mer’s disease. Third, although we focused on the qualitative
features of the index stroke as predictors of incident demen-
tia, certain quantitative brain imaging measures (eg, the
volume or number of clinically “silent” cerebral infarctions,
severity of diffuse white matter disease, severity of atrophy),
standardized imaging of symptomatic and clinically “si-
lent”35,36 recurrent stroke, and the findings of state-of-the-art
brain imaging techniques (eg, diffusion tensor imaging to
assess the integrity of subcortical pathways) might have been
relevant to incident dementia. Fourth, we did not examine the
contribution of genetic factors. It is becoming clear that
genetic factors are important in vascular dementia, whether as
risk markers such as the apolipoprotein E ⑀4 allele37 or as
primary independent risk factors such as Notch3 mutations in
CADASIL,38,39 and these and other genetic factors warrant
further study. Fifth, the results of studies such as ours are
influenced by the paradigm selected for use in the diagnosis
of dementia. To the extent that our use of an alternative
diagnostic method might have caused us to identify a larger
or smaller number of prevalent cases of dementia, the group
of patients who would have been found to be nondemented at
baseline and thus at risk of incident dementia would have
differed from those on whom this study is based, potentially
affecting our estimate of the incidence rate and the risk
factors that we identified. In previous work,4 however, we
found that the diagnostic method used in this study had
greater predictive validity with regard to the adverse out-
comes of recurrent stroke and death than less restrictive
paradigms based on neuropsychological testing or a reliance
on the MMSE or clinical judgment, suggesting that our
approach was reasonable. Sixth, we performed our follow-up
examinations annually; we may have obtained more precise
information regarding the timing of the onset of dementia if
we had examined patients more frequently and over shorter
intervals. Such an approach would have reduced our ability to
recruit and assess such a large cohort of patients, however,
and more frequent visits might have caused reduced compli-
ance with follow-up assessments.
 2260 Stroke September 2002
Acknowledgments
This work was supported by grants R01-NS26179, P01-AG07232,
K07-AG00959, and K08-NS02051 from the National Institutes of
Health. We would like to acknowledge the staff of the Stroke and
Aging Research Project for their assistance with data collection.
References
1. Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M. Dementia three months
after stroke: baseline frequency and effect of different definitions of
dementia in the Helsinki Stroke Aging Memory Study (SAM) cohort.
Stroke. 1997;28:785–792.
2. Barba R, Martínez-Espinosa S, Rodríguez-García E, Pondal M, Vivancos
J, Del Ser T. Poststroke dementia: clinical features and risk factors.
Stroke. 2000;31:1494 –1501.
3. Desmond DW, Moroney JT, Paik MC, Sano M, Mohr JP, Aboumatar S,
Tseng CL, Chan S, Williams JBW, Remien RH, Hauser WA, Stern Y.
Frequency and clinical determinants of dementia after ischemic stroke.
Neurology. 2000;54:1124 –1131.
4. Desmond DW, Moroney JT, Bagiella E, Sano M, Stern Y. Dementia as
a predictor of adverse outcomes following stroke: an evaluation of diag-
nostic methods. Stroke. 1998;29:69 –74.
5. Desmond DW, Bagiella E, Moroney JT, Stern Y. The effect of patient
attrition on estimates of the frequency of dementia following stroke. Arch
Neurol. 1998;55:390 –394.
6. Kelsey JL, Thompson WD, Evans AS. Methods in Observational Epide-
miology. New York, NY: Oxford University Press; 1986.
7. Moroney JT, Bagiella E, Desmond DW, Paik MC, Stern Y, Tatemichi
TK. Risk factors for incident dementia after stroke: role of hypoxic and
ischemic disorders. Stroke. 1996;27:1283–1289.
8. Sulkava R, Erkinjuntti T. Vascular dementia due to cardiac arrhythmias
and systemic hypotension. Acta Neurol Scand. 1987;76:123–128.
9. Brun A. Pathology and pathophysiology of cerebrovascular dementia:
Downloaded from http://ahajournals.org by on October 16, 2019
pure subgroups of obstructive and hypoperfusive etiology. Dementia.
1994;5:145–147.
10. Goodglass H, Kaplan E. The Assessment of Aphasia and Related Dis-
orders. 2nd ed. Philadelphia, Pa: Lea & Febiger; 1983.
11. American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders. 3rd ed, revised. Washington, DC: American Psy-
chiatric Association; 1987.
12. Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB. The Stroke Data
Bank: design, methods, and baseline characteristics. Stroke. 1988;19:
547–554.
13. Stern Y, Andrews H, Pittman J, Sano M, Tatemichi T, Lantigua R,
Mayeux R. Diagnosis of dementia in a heterogeneous population: devel-
opment of a neuropsychological paradigm-based diagnosis of dementia
and quantified correction for the effects of education. Arch Neurol.
1992;49:453– 460.
14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical
method for grading the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12:189 –198.
15. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md
Med J. 1965;14:61– 65.
16. Williams JBW. A structured interview guide for the Hamilton Depression
Rating Scale. Arch Gen Psychiatry. 1988;45:742–747.
17. Blessed G, Tomlinson BE, Roth M. The association between quantitative
measures of dementia and of senile change in the cerebral grey matter of
elderly subjects. Br J Psychiatry. 1968;114:797– 811.
18. Tatemichi TK, Foulkes MA, Mohr JP, Hewitt JR, Hier DB, Price TR,
Wolf PA. Dementia in stroke survivors in the Stroke Data Bank cohort:
prevalence, incidence, risk factors, and computed tomographic findings.
Stroke. 1990;21:858 – 866.
19. Bornstein NM, Gur AY, Treves TA, Reider-Groswasser I, Aronovich BD,
Klimovitzky SS, Varssano D, Korczyn AD. Do silent brain infarctions
predict the development of dementia after first ischemic stroke? Stroke.
1996;27:904 –905.
20. Hénon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Post-
stroke dementia: incidence and relationship to prestroke cognitive
decline. Neurology. 2001;57:1216 –1222.
21. Loeb C, Gandolfo C, Croce R, Conti M. Dementia associated with
lacunar infarction. Stroke. 1992;23:1225–1229.
22. Samuelsson M, Söderfeldt B, Olsson GB. Functional outcome in patients
with lacunar infarction. Stroke. 1996;27:842– 846.
23. Kokmen E, Whisnant JP, O’Fallon WM, Chu CP, Beard CM. Dementia
after ischemic stroke: a population-based study in Rochester, Minnesota
(1960 –1984). Neurology. 1996;46:154 –159.
24. Zhu L, Fratiglioni L, Guo Z, Basun H, Corder EH, Winblad B, Viitanen
M. Incidence of dementia in relation to stroke and the apolipoprotein E ⑀4
allele in the very old: findings from a population-based longitudinal
study. Stroke. 2000;31:53– 60.
25. Dichgans M, Mayer M, Uttner I, Brüning R, Müller-Höcker J, Rungger
G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of
CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731–739.
26. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The
natural history of CADASIL: a pooled analysis of previously published
cases. Stroke. 1999;30:1230 –1233.
27. Dougherty JH, Rawlinson DG, Levy DE, Plum F. Hypoxic-ischemic
brain injury and the vegetative state: clinical and neuropathologic corre-
lation. Neurology. 1981;31:991–997.
28. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F.
Predicting outcome from hypoxic-ischemic coma. JAMA. 1985;253:
1420 –1426.
29. Volpe BT, Hirst W. The characterization of an amnesic syndrome fol-
lowing hypoxic ischemic injury. Arch Neurol. 1983;40:436 – 440.
30. Alexander MP. Specific semantic memory loss after hypoxic-ischemic
injury. Neurology. 1997;48:165–173.
31. Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A. A
population-based study of dementia in 85-year-olds. N Engl J Med.
1993;328:153–158.
32. Longstreth WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis
CA, Enright PL, O’Leary D, Fried L. Clinical correlates of white matter
findings on cranial magnetic resonance imaging of 3301 elderly people:
the Cardiovascular Health Study. Stroke. 1996;27:1274 –1282.
33. Cooper J, Mungas D. Risk factor and behavioural differences between
vascular and Alzheimer’s dementias: the pathway to end-stage disease. J
Geriatr Psychiatry Neurol. 1993;6:29 –33.
34. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R.
Influence of education and occupation on the incidence of Alzheimer’s
disease. JAMA. 1994;271:1004 –1010.
35. Meyer JS, Muramatsu K, Mortel KF, Obara K, Shirai T. Prospective CT
confirms differences between vascular and Alzheimer’s dementia. Stroke.
1995;26:735–742.
36. Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K,
Ohmori S, Nomiyama K, Kawano H, Ueda K, Sueishi K, Tsuneyoshi M,
Fujishima M. Incidence and risk factors of vascular dementia and Alz-
heimer’s disease in a defined elderly Japanese population: the Hisayama
Study. Neurology. 1995;45:1161–1168.
37. Slooter AJC, Tang MX, van Duijn CM, Stern Y, Ott A, Bell K, Breteler
MMB, Van Broeckhoven C, Tatemichi TK, Tycko B, Hofman A, Mayeux
R. Apolipoprotein E ⑀4 and the risk of dementia with stroke: a
population-based investigation. JAMA. 1997;277:818 – 821.
38. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P,
Alamowitch S, Domenga V, Cécillion M, Maréchal E, Maciazek J,
Vayssière C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach
JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a
hereditary adult-onset condition causing stroke and dementia. Nature.
1996;383:707–710.
39. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Shungu DC,
Naini AB, Mohr JP. CADASIL in a North American family: clinical,
pathologic, and radiologic findings. Neurology. 1998;51:844 – 849.
 Desmond et al
Editorial Comment
Dementia After Stroke: High Incidence and Intriguing Associations
Around 25% of patients with cerebrovascular disease meet
operationalized criteria for dementia 3 months after a stroke,1
and a greater number have cognitive impairment short of
dementia.2 Compared with individuals without ischemic brain
disease, patients who are cognitively intact 3 months after a
stroke have a 6- to 9-fold greater risk of developing dementia
in the following year,3,4 and whereas the increased risk is
greatest in the first 12 months,4 it is still present several years
later. The relationship between acute stroke and prevalent and
incident dementia has been studied in several hospitalized
cohorts; the first one was assembled between 1988 and 1990
by Thomas Tatemichi and his colleagues.3 In this issue of
Stroke, Desmond et al present combined longitudinal
follow-up data of that cohort and a second group of patients
assembled using identical methodologies between 1994 and
1997 at Columbia University.5 Subjects enrolled into the
study include 334 stroke patients who were not demented 3
months after the cerebrovascular event and 241 stroke-free
controls who either were selected from Medicare lists or were
family or community volunteers. Median follow-up was 21.1
months, but a few patients were still in the study after 9 years.
The crude incidence rate of dementia (defined according to
Downloaded from http://ahajournals.org by on October 16, 2019
Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition criteria using a comprehensive neuro-
psychological and clinical evaluation) in the stroke group was
8.49 cases per 100 person-years while among the controls it
was 1.37 cases per 100 person-years. Although its magnitude
may be overestimated because many of the controls were
volunteers and not a random sample of the population from
which the cases were recruited, the relative risk for incident
dementia among patients with stroke was 4.4 (95% CI 2.20 to
8.85). The incidence and relative risk figures are similar to
those reported by this and other groups3 and highlight the
magnitude of the problem.
Why do patients with stroke have such a high risk of
developing dementia? Traditional concepts of vascular
dementia postulate that cognitive decline in patients with
cerebrovascular disease can result from the stroke alone
when a large volume of brain is affected by infarcts and
hemorrhages overcoming the brain’s reserve or compen-
satory mechanisms, and that strategic lesions can lead to
intellectual decline when specific cortical or subcortical
areas important for cognition and their connections are
damaged. However, recent epidemiological and neuro-
pathological studies have suggested that many patients
with stroke develop dementia through the interaction of
neurodegenerative and vascular insults to the brain that by
themselves may not produce dementia yet in association
hasten the decline of the intellect, blurring the sharp
dichotomy between Alzheimer’s and vascular dementia.
Some patients with dementia after stroke have a progres-
sive course suggestive of a degenerative disorder,4 and
Incidence of Dementia After Ischemic Stroke 2261
given the high prevalence of cerebrovascular pathology
and Alzheimer’s disease in the elderly, it is likely that most
have overlapping pathological processes.6 Patients who at
autopsy have coexistent Alzheimer-type changes and ce-
rebral infarcts have more severe cognitive impairment (and
a higher prevalence of dementia) during life than patients
with isolated senile plaques and neurofibrillary tangles.7
Traditional cerebrovascular risk factors have been linked
to Alzheimer’s disease.8 Further studies must address
whether this interaction is responsible for the increased
risk of dementia in hospitalized stroke cohorts.
Among Desmond and colleagues’ stroke patients, the risk
of dementia was elevated in those who had a loosely defined
group of intercurrent illnesses that can produce hypoxia. This
finding is intriguing given that cerebral hypoperfusion can
lead to cognitive impairment9 and in animal models it
enhances amyloid ␤ precursor protein mRNA expression and
cleavage of that protein.10 In addition, some conditions
considered hypoxic-ischemic in the present study, such as
atrial fibrillation, have been identified as risk factors for
Alzheimer’s disease. However, the association described by
Desmond et al, while previously reported by that group11 and
others,12 does not establish causality. The category of
hypoxic-ischemic disorders used in the study is too broad; it
includes conditions that produce transient (seizures and syn-
cope) and prolonged (heart failure, myocardial infarction)
hypoxia, and it encompasses conditions that do not necessar-
ily produce similar alterations in brain oxygenation. The
association, however, warrants further studies with precise
measures of cerebral blood flow to understand the pathophys-
iologic processes that lead to dementia in stroke patients. A
greater understanding will result in new prophylactic
interventions.
If the interaction of vascular and neurodegenerative pro-
cesses is the cause of dementia in patients with stoke, the
therapeutic implications are enormous. In recent years, rigor-
ous clinical trials have demonstrated the value of statin agents
and inhibitors of angiotensin-converting enzyme in addition
to antithrombotic drugs and surgery for the prevention of
stroke and Alzheimer’s disease. We can expect that their use
will lead to fewer cases of dementia. Conversely, if vascular
and neurodegenerative processes indeed interact to produce
dementia in a substantial number of cases, it makes sense to
treat patients with stroke with acetylcholinesterase inhibitors
in an effort to slow the neurodegenerative process. However,
there is scant evidence that vascular preventive strategies lead
to preserved cognitive function after a stroke. To test this
hypothesis, future clinical stroke trials—acute and preven-
tive—must incorporate cognitive evaluations as primary out-
come measures. This, of course, opens up exciting new
possibilities.
 2262 Stroke September 2002
José G. Merino, MD, MPhil, Guest Editor
Department of Neurology
Comprehensive Stroke Program
University of Florida Health Sciences Center
Jacksonville, Florida
References
1. Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M. Dementia three months
after stroke: baseline frequency and effect of different definitions of
dementia in the Helsinki Stroke Aging Memory Study (SAM) cohort.
Stroke. 1997;28:785–792.
2. Tatemichi TK, Desmond DW, Stern Y, Paik M, Sano M, Bagiella E.
Cognitive impairment after stroke: frequency, patterns, and relationship
to functional activity. J Neurol Neurosurg Psychiatry. 1994;57:202–207.
3. Tatemichi TK, Paik M, Bagiella E, Desmond DW, Stern Y, Sano M,
Hauser WA, Mayeux R. Risk of dementia after stroke in a hospitalized
cohort: results of a longitudinal study. Neurology. 1994;44:1885–1891.
4. Kokmen E, Whisnant JP, O’Fallon WM, Chu CP, Beard CM. Dementia
after ischemic stroke: a population-based study in Rochester, Minnesota
(1960 –1984). Neurology. 1996;19:154 –159.
Downloaded from http://ahajournals.org by on October 16, 2019
5. Desmond DW, Moroney JT, Sano M, Stern Y. The incidence of dementia
after ischemic stroke: results of a longitudinal study. Stroke 2002;33:(this
issue).
6. Neuropathology Group of the Medical Research Council Cognitive
Function and Ageing Study. Pathological correlates of late-onset
dementia in a multicentre, community-based population in England and
Wales. Lancet. 2001;357:169 –175.
7. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA,
Markesbery WR. Brain infarction and the clinical expression of Alzhei-
mer disease: the Nun Study. JAMA. 1997;277:813– 817.
8. Breteler MMB. Vascular risk factors for Alzheimer’s disease: an epide-
miologic perspective. Neurobiol Aging. 2000;21:153–160.
9. Meyer JS, Rauch G, Rauch RA, Haque A. Risk factors for cerebral
hypoperfusion, mild cognitive impairment, and dementia. Neurobiol
Aging. 2000;21:161–169.
10. Shi J, Yang SH, Stubley L, Day AL, Simpkins JW. Hypoperfusion
induces overexpression of ␤-amyloid precursor protein mRNA in a focal
ischemic rodent model. Brain Res. 2000;853:1– 4.
11. Moroney JT, Bagiella E, Desmond DW, Paik MC, Stern Y, Tatemichi
TK. Risk factors for incident dementia after stroke: role of hypoxic and
ischemic disorders. Stroke. 1996;27:1283–1289.
12. Hénon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Post-
stroke dementia: incidence and relationship to prestroke cognitive
decline. Neurology. 2001;57:1216 –1222.