Description of sample size.
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Reitz C, Luchsinger JA, Tang M, Manly J, Mayeux R. Stroke and Memory Performance in Elderly Persons Without Dementia. Arch Neurol. 2006;63(4):571–576. doi:10.1001/archneur.63.4.571
There are conflicting data showing that stroke is associated with a higher risk of dementia and a more severe decline in persons with cognitive impairment. However, it remains unclear if cerebrovascular disease is directly related to cognitive decline in the absence of cognitive impairment or dementia.
To examine the association between stroke and changes in cognitive function over time in elderly persons without dementia at baseline.
The results of neuropsychological tests from several intervals over a 5-year period were clustered into domains of memory, abstract/visuospatial, and language in 1271 elderly persons without dementia or cognitive decline. Stroke was related to the slope of performance in each cognitive domain using generalized estimating equations.
Memory performance declined over time, while abstract/visuospatial and language performance remained stable during the study period. Stroke was associated with a more rapid decline in memory performance, while there was no association between stroke and decline in abstract/visuospatial or language performance. The association between stroke and decline in memory performance was strongest for men and for persons without an APOEε4 allele. A significant association between stroke and decline in abstract/visuospatial performance was also observed for persons without the APOEε4 allele.
A history of stroke is related to a progressive decline in memory and abstract/visuospatial performance, especially among men and those without an APOEε4 allele.
Cerebrovascular disease and dementia are among the most common diseases in aging societies. According to the World Health Organization, cerebrovascular disease is the second leading cause of mortality in Western societies and the major cause of long-term disability, leaving 30% of persons disabled.1 About 1% of people aged 65 to 69 years have dementia, and this proportion increases with age to approximately 60% for people older than 95 years.2
The role of stroke in the pathogenesis of cognitive decline remains unclear. Longitudinal population-based studies3,4 indicate that vascular risk factors, such as diabetes mellitus and hypertension, are associated with stroke, which in turn may be related to the development of vascular dementia and Alzheimer disease (AD). A relation between stroke and the risk of AD was previously reported.5 Vascular risk factors have also been associated with mild cognitive impairment,3,4 and there is evidence that cerebrovascular disease is associated with more progressive decline in persons with cognitive impairment.6,7 However, whether cerebrovascular disease is directly related to cognitive decline in the absence of cognitive impairment or dementia remains unclear.
The objective of this study was to determine if the effects of stroke result in a decline in memory and other cognitive functions in elderly persons who do not have cognitive impairment or dementia.
Participants were part of a longitudinal study of Medicare recipients, 65 years or older, residing in northern Manhattan, NY (Washington Heights, Hamilton Heights, and Inwood).8 Each participant underwent an in-person interview of general health and function at study enrollment, followed by a standard assessment, including medical history, physical and neurological examination, and a neuropsychological battery.9 Baseline data were collected from January 4, 1992, through December 24, 1994. Follow-up data were collected during evaluations at sequential intervals of approximately 18 months, performed from January 12, 1994, to November 29, 1996; January 30, 1996, to December 12, 1997; and May 15, 1997, to November 24, 1999. In this elderly population, some participants did not complete follow-up at all intervals because of refusal to participate further, relocation, or death. About half of the participants were examined at the third follow-up visit. This study was approved by the institutional review board of the Columbia-Presbyterian Medical Center, New York.
The participants selected for this study were without dementia or cognitive impairment at baseline, had complete stroke information, and completed at least 3 follow-up intervals.
Of the 2126 individuals who underwent clinical assessment at baseline, 346 were excluded because they had dementia at the initial intake examination. Information on stroke was unavailable for 83 individuals, and 426 individuals had fewer than 3 follow-up visits with a neuropsychological evaluation (Figure). Thus, the study focused on 1271 individuals without dementia or cognitive impairment at baseline, observed over a 5-year interval.
Data included medical, neurological, and neuropsychological evaluation results.9,10 All participants underwent a standardized neuropsychological test battery in either English or Spanish.9 Orientation was evaluated using parts of the modified Mini-Mental State Examination.11 Language was assessed using the Boston Naming Test,12 the Controlled Oral Word Association Test,13 category naming, and the complex ideational material and phrase repetition subtests from the Boston Diagnostic Aphasia Evaluation.12 Abstract reasoning was evaluated using the Wechsler Adult Intelligence Scale–Revised similarities subtest14 and the nonverbal identities and oddities subtest of the Mattis Dementia Rating Scale.15 Visuospatial ability was examined using the Rosen Drawing Test16 and a matching version of the Benton Visual Retention Test.17 Memory was evaluated using the multiple-choice version of the Benton Visual Retention Test17 and the 7 subtests of the Selective Reminding Test18: total recall, long-term recall, long-term storage, continuous long-term storage, words recalled on last trial, delayed recall, and delayed recognition. This neuropsychological test battery has established norms for the same community.19
Results from the neurological, psychiatric, and neuropsychological examinations were reviewed in a consensus conference composed of physicians, neurologists, neuropsychologists, and psychiatrists. Based on this review, all participants were assigned to 1 of 3 categories: normal cognitive function, cognitive impairment without dementia, or dementia. Cognitive impairment without dementia was defined as the presence of abnormal neuropsychological test results for age, sex, and education group without significant cognitive impairment and a Clinical Dementia Rating Scale score of 0.5.20 Dementia was defined as the presence of abnormalities in several cognitive domains in neuropsychiatric testing accompanied by significant functional impairment (Clinical Dementia Rating Scale score, ≥1).
Stroke was defined according to the World Health Organization criteria.21 At baseline, the presence of stroke was ascertained from an interview with participants and their informants. A positive response to any 1 of the following 8 questions was considered as suggestive of a history of stroke.
1. Have you ever had a stroke of the brain, a ministroke, stroke syndrome, or a transient ischemic attack?
2. Did a physician tell you that you had a stroke of the brain, a ministroke, stroke syndrome, or a transient ischemic attack?
3. Did you have a stroke of the brain, a ministroke, stroke syndrome, or a transient ischemic attack within the past year?
4. Have you ever had sudden paralysis (weakness) or numbness (loss of sensation) on one side of the body but not the other?
5. Have you ever suddenly lost the use of speech (not being able to talk at all) or suddenly had slurred speech (not being able to say words clearly)?
6. Have you ever had sudden loss of consciousness with severe headache, nausea, or vomiting?
7. Did the stroke or symptoms last more than 24 hours?
8. Have the stroke symptoms continued without ever going away?
Persons with stroke were confirmed through their medical records, 85% of which included results of brain imaging. The remainder were confirmed by direct examination.
APOE genotypes were determined as described by Hixson and Vernier,22 with slight modification.23 We classified persons as homozygous or heterozygous for the APOEε4 allele or as not having any APOEε4 allele.
Diabetes mellitus and hypertension were defined by self-report at baseline and at each follow-up interval or by the use of disease-specific medications. Blood pressure measurements were also considered in the definition of hypertension. Heart disease was defined as a history of myocardial infarction, congestive heart failure, or angina pectoris at any time during life. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Smoking history was assessed by self-report and categorized as never, past, and current smoking.
A factor analysis was performed using data from the entire cohort, with the 15 neuropsychological measures using a principal component analysis with Varimax rotation and Kaiser normalization.24 This analysis resulted in 3 factors: (1) a memory factor, in which the 7 subtests of the Selective Reminding Test were the main contributors; (2) an abstract/visuospatial factor, in which visuospatial tests and tests of reasoning were the main contributors; and (3) a language factor, in which language measures from the Boston Naming Test,12 Controlled Oral Word Association Test,13 and the Wechsler Adult Intelligence Scale–Revised similarities subtest14 were the main contributors. We calculated cognitive scores for each participant at each visit by adding the scores of the measures that contributed most to each factor (tests with correlations of ≥0.5). Each factor score was normally distributed.
Generalized estimating equations25 were used to examine changes in each cognitive domain over time. The dependent variables were the factor scores, and the independent variables were stroke, time (included as a continuous variable, and representing the time of follow-up of each participant), and the interaction of stroke and time. After adjusting for age and sex, subsequent models were adjusted for age, sex, education, ethnic group, APOEε4 genotype, BMI, hypertension, heart disease, diabetes mellitus, and smoking. In these full models, age, education, and BMI were included as continuous variables; ethnic group, APOEε4 genotype, and smoking, as multilevel categorical variables; and hypertension, heart disease, and diabetes mellitus, as dichotomized (not present vs present) variables.
The generalized estimating equation analysis yielded coefficient values that represent the associations between a factor score and variables included in the model. There were 3 main coefficients of interest in each model: one comparing the stroke groups (stroke yes or no) at baseline, one relating the change in cognitive scores with time, and an interaction term for stroke and time. A significant P value for the coefficient comparing stroke groups at baseline indicates a difference between 2 groups at baseline. A significant P value for the coefficient of time indicates a statistically significant change in a cognitive score over the total duration of follow-up. A significant P value for the interaction coefficient indicates a difference in the rate of change in a factor score depending on the stroke group; this is the main variable of interest for the interpretation of the analyses. All analyses were repeated after stratifying for sex and APOEε4 genotype.
The mean (SD) age of the sample was 76.2 (6.0) years; 69.6% were women; and 45.1% were Hispanic, 20.6% were white, and 33.7% were black. The mean (SD) education was 8.6 (4.6) years; 23.8% were homozygous or heterozygous for the APOEε4 allele. The mean (SD) BMI was 27.1 (5.1); 29.8% of the subjects reported having diabetes mellitus, 55.1% had hypertension, and 29.2% had heart disease. Of the subjects, 7.6% had a history of stroke. Persons with stroke at baseline had a higher prevalence of diabetes mellitus and hypertension than persons without stroke at baseline (Table 1). There were no significant differences in stroke prevalence between the sexes (P=.23) or among ethnic groups (P=.33).
In the generalized estimating equation analysis, memory declined significantly over time, while abstract/visuospatial and language performance remained stable over the study period (Table 2). A history of stroke was associated with a more rapid decline in memory performance over time. There was no relation between stroke and decline in abstract/visuospatial or language performance. There was also no relation when analyses were repeated for individual tests in the abstract/visuospatial and language domains.
All analyses were repeated, stratifying by sex and APOEε4 genotype. While in men and women and APOEε4 carriers and noncarriers, memory performance significantly declined over time, the association between stroke and decline in memory performance over time (stroke × time interaction) was stronger in men (Table 3) (P = .005 for the sex × stroke × time interaction) and in persons without an APOEε4 allele (Table 4) (P = .07 for the APOEε4 × stroke × time interaction). Persons without an APOEε4 allele also showed a significant stroke × time interaction, indicating that abstract/visuospatial function declined faster among APOEε4 noncarriers (P = .04 for the APOEε4 × stroke × time interaction). Thus, memory and abstract/visuospatial function declined at a faster rate in men or persons who lacked the APOEε4 allele with stroke compared with women or APOEε4 carriers. These associations remained unchanged after adjusting for age, education, ethnic group, BMI, hypertension, heart disease, diabetes mellitus, and smoking. There was no association between stroke and language performance.
In this study, the performance in memory, abstract/visuospatial, and language domains declined over time in individuals free of dementia or cognitive impairment at baseline. A history of stroke was associated with faster decline only in memory performance. When stratified by sex or APOEε4 genotype, stroke was associated with a faster decline in memory or abstract/visuospatial performance in men or persons lacking the APOEε4 allele.
The mechanisms by which stroke increases the risk of cognitive decline are not clear. Stroke could increase the risk of cognitive decline by destruction of brain parenchyma and atrophy, such as in the case of vascular dementia or AD associated with stroke,27,28 or by causing damage in strategic locations that lead to amnestic syndromes, such as thalamic strokes.29,30 Stroke could also increase the risk of cognitive decline by increasing the deposition of amyloid β, the key step in the pathogenesis of AD,31,32 or by a combination of these different mechanisms. It is also possible that the occurrence of stroke adds cognitive deficits in persons with subclinical AD that bring them over the diagnostic threshold, without directly affecting the deposition of amyloid β, and that stroke does not have a direct specific effect on AD.
Studies examining the role of stroke in cognitive function reported inconsistent results. The Framingham Study reported, in a nested case-control study, a doubled risk of dementia after baseline stroke,33 and a similar observation was made earlier by a longitudinal study assessing the risk of incident dementia after cerebral infarction in 971 subjects in Minnesota.34 Hospital-based cohorts with a follow-up shorter than 3 months also observed an increased risk of incident dementia after stroke35-37; and Desmond et al previously reported38 an increased risk of dementia after stroke. Others39,40 have not found an association between cerebrovascular disease and cognitive impairment or dementia.
Our results are consistent with studies5,41 showing an increased risk of AD in persons with stroke. The main cognitive domain affected in AD is memory,42,43 and it seems reasonable to postulate that if stroke is related to a higher risk of AD, it must be related to a decline in memory. Furthermore, it seems that this effect is independent of APOE genotype, which is in agreement with studies44 indicating an increased risk of AD with stroke in persons without the APOEε4 allele.
Stroke has been related to impairment in frontal executive functions.45-47 The domain in our study that better represents this construct is abstract/visuospatial performance, and we found no association between stroke and differences in this domain at baseline or with follow-up. The reasons for this negative finding may be that our cognitive battery lacked better measures of frontal executive functions, such as the Color Trails Test.48
There are several potential alternative explanations for our findings. One is chance, particularly in the context of multiple comparisons. However, this study was based on previous findings relating stroke to a higher risk of AD.5 Also, this study is consistent with other studies, as described in the previous paragraph; these facts make chance due to multiple comparisons an unlikely explanation for our findings.49 One of our findings was that stroke was related to faster cognitive decline in men. The strata for men were much smaller than for women, and only 27 men had stroke; this could also result in chance findings. These findings should be reproduced in a larger cohort. Another potential explanation is bias. For example, only subjects with preclinical AD reported stroke, while subjects who would not develop AD did not. This type of reporting bias seems unlikely, and we excluded cases of prevalent dementia or cognitive impairment that could have influenced our results. Furthermore, if having a lower level of education is related to stroke, and persons with a lower level of education are more likely to be diagnosed as having AD, then it is possible that a relation between stroke and cognitive decline could be confounded by socioeconomic status. We adjusted for years of education and ethnicity as markers of socioeconomic status to account for this possibility. However, it is possible that stroke is related to other behaviors related to poor health, which in turn may increase the risk of AD, that we could not adjust for, and we cannot eliminate the possibility of lack of control for unknown confounders as a potential explanation for our findings. Finally, a potentially major source of bias, and the main limitation of our study, is the lack of ascertainment of subclinical cerebrovascular disease in persons without stroke. We also lacked information on the location and severity of cerebrovascular disease. If subclinical stroke is associated with cognitive decline, as we hypothesized for clinical stroke, then our results are biased toward the null. Thus, our findings seem to underestimate the true relation of stroke to memory decline, and our negative findings for language and visuospatial abilities may be explained by this source of bias.
This study has several strengths. We had a comprehensive and sensitive neuropsychological battery validated for use in the communities of northern Manhattan.9 We also excluded from our analyses persons with dementia and cognitive impairment without dementia at baseline, which may have biased the analyses, and we had several evaluation time points that allowed prospective analyses.
Correspondence: Richard Mayeux, MSc, MD, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032 (email@example.com).
Accepted for Publication: December 9, 2005.
Author Contributions:Study concept and design: Reitz, Luchsinger, and Mayeux. Acquisition of data: Reitz, Luchsinger, Tang, Manly, and Mayeux. Analysis and interpretation of data: Reitz, Luchsinger, Manly, and Mayeux. Drafting of the manuscript: Reitz, Luchsinger, Tang, and Mayeux. Critical revision of the manuscript for important intellectual content: Manly and Mayeux. Statistical analysis: Reitz, Tang, and Mayeux. Obtained funding: Manly and Mayeux. Administrative, technical, and material support: Manly and Mayeux. Study supervision: Luchsinger, and Mayeux. Drs Reitz and Luchsinger contributed equally to the work.
Funding/Support: This study was supported by grants PO1 AG07232, AG07702, 1K08AG20856-01, and RR00645 from the National Institutes of Health; the Charles S. Robertson Memorial Gift for Research in Alzheimer's Disease; and the Blanchette Hooker Rockefeller Foundation.