STROKE is the third leading cause of death in the United

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1 Journal of Gerontology: MEDICAL SCIENCES 2003, Vol. 58A, No. 6, Copyright 2003 by The Gerontological Society of America Cognitive Function and Incidence of Stroke in Older Mexican Americans Glenn V. Ostir, 1,2,3 Mukaila A. Raji, 1,3 Kenneth J. Ottenbacher, 1,2,3 Kyriakos S. Markides, 2,3 and James S. Goodwin 1,2,3 Departments of 1 Internal Medicine and 2 Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas. 3 Sealy Center on Aging, University of Texas Medical Branch, Galveston, Texas. Background. Given the high prevalence of cognitive impairment in older Mexican Americans and limited longitudinal research examining cognitive function in this ethnic group, we conducted a study examining whether cognitive impairment is a risk factor for new onset of stroke among older Mexican Americans. Methods. We performed a prospective cohort study of 2682 Mexican Americans aged 65 years and older living in the southwestern United States. For subjects with no prior history of stroke and who completed the Mini-Mental State Examination (MMSE) at baseline, stroke incidence was assessed after 2, 5, and 7 years of follow-up. Results. In Cox proportional regression models, MMSE score at baseline predicted risk of incident stroke over a 7-year follow-up period. For the unadjusted model, subjects with an MMSE score of 21 or higher were half as likely to report stroke at follow-up (hazard ratio [HR], 0.49; 95% confidence interval [CI], ; p,.001) compared with those with a score of less than 21. We found similar results after controlling for relevant risk factors for stroke including age, gender, smoking status, education, body mass index, diabetes, heart attack, systolic blood pressure, and depressive symptoms (HR, 0.54; 95% CI, ; p 5.001). Additionally, each 1-point increase in MMSE score was associated with a 5% reduction in risk (HR, 0.95; 95% CI, ; p 5.01). Conclusions. Increasing MMSE score is associated with a decreasing incidence of stroke in older Mexican Americans. This study highlights the need for a more aggressive focus on identifying and addressing cognitive decline in the Mexican American population. STROKE is the third leading cause of death in the United States after heart disease and cancer (1). The yearly incidence of first-ever stroke is approximately 500,000, with an additional 100,000 individuals experiencing a recurrent stroke (1). For those aged 55 years and older, stroke risk doubles in each successive decade, with men at a greater risk than women (1). Although stroke is associated with poor health outcomes including vascular dementia and Alzheimer disease (2 8), recent studies have also demonstrated an association between poor cognitive function and increased stroke risk (9 13). Ferrucci and colleagues (9), using data from 3 communities of the Established Population for Epidemiologic Studies of the Elderly (EPESE), reported a twofold increased risk of stroke in older white and black subjects with poor cognitive function, compared with those with good cognitive function over a 3-year period. The prevalence of cognitive impairment in the Mexican American population is known to be high (14,15), and information regarding risk factors for stroke in this population is limited. Black and colleagues (16), in a cross-sectional analysis of older Mexican Americans, found an association between cognitive function and stroke. However, little is known about the relationship between prestroke cognitive function and risk of stroke. Given the high prevalence of cognitive impairment in the Hispanic population, the economic impact of poor cognitive function in the elderly, and the lack of longitudinal research examining cognitive function in this ethnic group, we conducted a study examining whether poor cognitive function was associated with incident stroke in a large-area probability sample of Mexican American older adults. METHODS Sample Data are from the Hispanic Established Population for the Epidemiologic Study of the Elderly (H-EPESE). The H- EPESE is an ongoing, community-based study funded by the National Institute on Aging of 3050 Mexican American subjects aged 65 and older (17). The sample was designed to be generalizable to approximately 85% of older Mexican Americans living in 5 southwestern states including Texas, California, Colorado, Arizona, and New Mexico (17). A full description of the rationale, methods, and subject characteristics can be found elsewhere (17). The response rate at the baseline interview ( ) was 83%, with 2873 subjects (94.2%) interviewed in person and 177 (5.8%) interviewed by proxy. Measures Cognitive function. The Mini-Mental State Examination (MMSE) is a 30-item measurement instrument used to assess cognitive function. It is among the most frequently 531

2 532 OSTIR ET AL. Table 1. Selected Baseline Characteristics by MMSE Score MMSE Score,21 >21 Baseline Characteristic No. (%) No. (%) Chi-Square p Value Age, years (47.3) 1628 (71.2) (37.4) 559 (24.5) >85 59 (14.9) 99 (4.3),.001 Sex Men 159 (40.2) 954 (41.7) Women 237 (59.9) 1332 (58.3).56 Education, years (92.7) 1607 (70.9) (6.3) 410 (18.1) >12 4 (1.0) 251 (11.0),.001 BMI, kg/m 2,22 64 (17.3) 203 (9.1) (55.1) 1337 (59.9) > (27.6) 693 (31.0),.001 Current smoker No 214 (54.2) 1362 (59.7) Yes 181 (45.8) 919 (40.3).04 Myocardial infarction No 361 (91.2) 2118 (92.7) Yes 35 (8.8) 168 (7.4).30 Diabetes No 288 (75.8) 1664 (77.5) Yes 92 (24.2) 484 (22.5).47 Systolic blood pressure, mm Hg, (56.8) 1383 (62.8) > (43.3) 821 (37.3).03 Depressive symptoms, CES-D score, (68.6) 1764 (77.7) > (31.4) 505 (22.3),.001 Note: All subjects were stroke free at baseline assessment. MMSE 5 Mini- Mental State Examination; BMI 5 body mass index; CES-D 5 Center for Epidemiological Studies-Depression. used cognitive screening measures in studies of older adults (18). The English and Spanish versions of the MMSE were adopted from the Diagnostic Interview Schedule and have been used in prior community surveys (19). Scores have a potential range of 0 to 30, with lower scores indicating poorer cognitive ability. We analyzed MMSE scores both as a continuous variable (range, 0 30) and as a dichotomized variable (,21 vs >21) (20). Stroke. Stroke was assessed over a 7-year follow-up period for subjects who were initially stroke free at the baseline assessment. At baseline subjects were asked, Did a doctor ever tell you that you had a stroke? At the followup interviews, subjects were asked, Since the last interview, did a doctor tell you that you had a stroke? At the 2-, 5-, and 7-year follow-up interviews, 129, 66, and 43 first-time strokes were reported, respectively. If a study participant was deceased at a follow-up interview, information was collected from the responding family member regarding cause of death. Vital status was confirmed by a mortality search of the Social Security Administration Death Master File. A total of 71 subjects died as a direct result of the stroke. Covariates. The baseline sociodemographic variables recorded included age, sex, marital status, education, body mass index (BMI), depressive symptoms, and selected medical conditions. Education was categorized as years of formal education: 0 to 6, 7 to 11, and 12 or more years. BMI was categorized as less than 22, 22 to 29.9, and at least 30 kg/m 2. Depressive symptomatology was measured by the Center for Epidemiological Studies-Depression (CES-D) scale. The scale is widely used in older population settings and consists of 20 items in which subjects are asked whether they have experienced certain feelings or symptoms in the past week (21). Response items are scored on a 4-point scale (0 3), with an overall range of 0 to 60, where higher scores indicate increased depressive symptomatology. For the analysis, individuals with a score of 16 or more were classified as having high levels of depressive symptomatology (21). For selected health conditions, subjects were asked if they ever had a physician diagnosis of heart attack or diabetes mellitus. Blood pressure was measured twice using a standard mercury sphygmomanometer with appropriate cuff size after the subject had remained seated for at least 5 minutes, according to the standard protocol used in the Hypertension Detection and Follow-up Program (22). Blood pressure was categorized as a mean systolic pressure of less than 140 mm Hg and 140 mm Hg or higher. Statistical Analyses We examined sociodemographic variables for all subjects stratified by an MMSE categorical score (,21 and >21) using contingency tables. Chi-square analyses were used to test for differences between low cognition (MMSE score,21) and high cognition (MMSE score >21) at the baseline assessment interview. An age-adjusted hazard function using the actuarial method estimated the difference between the influence of low cognition and high cognition on the risk of stroke over 7-years of follow-up. Cox proportional hazard models were used to estimate hazard ratios (HRs) of stroke over 7-years by MMSE status at baseline interview, adjusting for relevant risk factors. We computed 2 Cox proportional hazard models. The first model examined the bivariate relationship between MMSE score (,21 vs >21) at baseline and new-onset stroke (present vs absent) at the 3 follow-up assessment interviews. The second model examined the relationship between MMSE score (,21 vs >21) at baseline and new-onset stroke at the 3 follow-up assessment interviews, adjusting for age, smoking status, BMI, education, depressive symptoms, and medical conditions including heart attack, hypertension, and diabetes mellitus. We also examined continuous MMSE score at baseline and new-onset stroke at the follow-up assessment interviews with adjustments made for age, smoking status, BMI, education, depressive symptoms, and medical conditions including heart attack, hypertension, and diabetes mellitus. All analyses used the SAS software package (SAS Institute Inc., Cary, NC). RESULTS Table 1 presents baseline sociodemographic characteristics and medical conditions by MMSE score category (,21 vs >21). Subjects with MMSE scores of less than

3 COGNITION AND INCIDENT STROKE 533 Figure 1. Hazard function of Mini-Mental State Examination score and estimated risk of stroke at follow-up. 21 were more likely to be older, to have a BMI of less than 22 kg/m 2, to be a current smoker, to be less educated, to have a CES-D score of 16 or higher, and to have a systolic blood pressure of 140 mm Hg or higher. There were no significant differences in the prevalence of heart attack or diabetes mellitus by MMSE score category. Figure 1 presents an age-adjusted estimated risk of stroke at follow-up by high cognitive function (MMSE score >21) and low cognitive function (MMSE score,21) at baseline. The figure suggests that subjects with low cognitive function at baseline assessment were at a significantly increased risk of stroke at follow-up ( p,.001) compared with those with high cognitive function. Figure 2 shows the relationship between cognitive function (MMSE score,21 vs >21) and incident stroke among those with and without known risk factors (hypertension and diabetes mellitus). As expected, subjects with hypertension and diabetes mellitus had higher rates of stroke than subjects without these medical conditions, irrespective of their baseline cognitive status. Additionally, subjects with hypertension and diabetes mellitus with a low MMSE score (,21) were significantly more likely to have a stroke when compared with diabetic and hypertensive subjects who had a high MMSE score (>21). Table 2 presents 2 Cox proportional hazard models predicting incidence of stroke over the 7-year follow-up as a function of baseline MMSE categorical score. The unadjusted HR for incident stroke for subjects who scored 21 or higher on the MMSE was 0.49 (95% confidence interval [CI], ; p,.001). Adjusted HRs suggested that those with an MMSE score of 21 or higher had a 46% reduction in the risk of incident stroke (HR, 0.54; 95% CI ; p,.001). Using the MMSE score as a continuous variable, and adjusting for factors listed in Table 2, each 1-point increase in MMSE score was associated with a 5% reduction in the risk of stroke over a period of 7 years (HR, 0.95; 95% CI, ; p 5.01). DISCUSSION In this study, we examined the association between cognitive function and new onset of stroke for older Mexican American subjects with no prior history of stroke at the baseline assessment. Our findings indicate a significant association between cognitive function and incident stroke, after controlling for potential risk factors including Figure 2. The relation of Mini-Mental State Examination score with stroke incidence according to hypertension (p for trend,.001) and diabetes ( p for trend,.001) status. Hypertension was defined as a measured systolic blood pressure of 140 mm Hg or higher. age, education, sex, and medical conditions (heart attack, diabetes, and hypertension). Over a 7-year follow-up period, subjects with good cognitive function (MMSE score >21 vs,21) at baseline were approximately half as likely to report a stroke in the unadjusted model, with similar results found in the fully adjusted model. Additionally, when MMSE scores were analyzed as a continuous variable in the fully adjusted model, each unit increase was associated with a 5% reduction in incidence of stroke. To our knowledge, this is the first longitudinal study addressing this relationship in older Mexican American subjects. Our findings are important for at least 2 reasons. First, until recently, cognitive impairment among nondemented subjects was not considered to be a prognostic indicator of stroke in older adults. Second, the race variable has demonstrated a significant association with the expression and course of cerebrovascular diseases in the elderly (23 25). For example, data from the Northern Manhattan Stroke Study (25) show that Hispanic and black individuals have almost twice the risk of incident stroke compared with white individuals. There are several hypotheses about how cognitive impairment may increase stroke risk. First, cognitive impairment might represent a clinically silent phase of a pathologic process that ultimately leads to overt stroke. Several studies support this hypothesis (26 31). Among nondemented subjects with no known history of stroke, several studies have shown significant associations between poor cognition and presence of asymptomatic brain infarcts and other

4 534 OSTIR ET AL. Table 2. Cox Proportional Hazard Models Assessing Incidence of Stroke Over a 7-Year Follow-up by MMSE Score and Other Covariates (N ) Stroke Risk, Unadjusted Model Stroke Risk, Fully Adjusted Model HR (95% CI) p Value HR (95% CI) p Value MMSE (>21 vs,21) 0.49 ( ), ( ).001 Age (continuous) 1.05 ( ),.001 Women (vs men) 1.01 ( ).99 Education, years ( ) ( ).84 > Current smoker 1.21 ( ).21 BMI, kg/m 2, ( ) > ( ).94 Diabetes 1.84 ( ),.001 Myocardial infarction 2.52 ( ),.001 Systolic BP.13 >140 mm Hg 1.26 ( ) Depressive symptoms (continuous) 1.01 ( ).18 Note: MMSE 5 Mini-Mental State Examination; HR 5 hazard ratio; CI 5 confidence interval; BP 5 blood pressure. All subjects were stroke free at the baseline assessment. stroke risk factors (26 29). In the Caerphilly cohort studies, Elwood and colleagues (26) found a significant association between the presence of cardiac or peripheral vascular disease and a reduction in cognitive function. Results from the Cardiovascular Health Study (27) demonstrated that the presence of subclinical brain infarcts on magnetic resonance images was associated with low MMSE score after adjusting for age, education, and sex. Second, it is possible that an unrecognized pathology is associated with an increased risk for both poor cognition and stroke, such that cognitive deficits might manifest much earlier before clinically evident stroke. Elevated plasma homocysteine levels, for example, are associated with poor cognitive function and incident stroke (28 32). A third possibility is that cognitive impairment may simply be a marker for unhealthy lifestyles, poor access to medical care, or suboptimal management of stroke risk factors, leading indirectly to an increased risk of stroke. Gregg and colleagues (33), using data from the Study of Osteoporotic Fractures Research Group, showed that older women with diabetes had lower baseline scores on tests of cognitive function compared with older women without diabetes after adjusting for relevant sociodemographic factors and health status. There are some limitations to this study. First, the occurrence of stroke was obtained only by self-report. However, Horner and colleagues (34) found good agreement between a subject s self-reported stroke and stroke verified by the Veterans Health Administration hospital discharge database. The study found self-report of stroke among older subjects from the North Carolina EPESE had a sensitivity of 86% and a specificity of 100%, with a positive predictive value of 100%. Additionally, any underreporting of stroke among subjects with cognitive impairment would tend to make our results more conservative. A second limitation is the use of MMSE as a measure of cognitive performance. The MMSE is primarily a clinical tool designed to screen for possible cognitive impairment in subjects. Although the MMSE has been used extensively in large community-based surveys as a measure of cognitive function, formal neuropsychological testing gives the most accurate assessment of cognitive functioning. A third limitation is that we did not have access to hospital records, imaging studies, or autopsy information to confirm the presence, type, location, and severity of stroke. Despite these limitations, our study has several strengths, including its large community-based sample of older Mexican Americans, its prospective design, 7 years of follow-up, and use of pre-event cognitive measures. In conclusion, our findings suggest that older cognitively impaired Mexican Americans might be at risk for future stroke. Measures aimed at early recognition and treatment of modifiable vascular risk factors targeted to this population might reduce rates of stroke and subsequent disability. This study highlights the need for a more aggressive focus on identifying and addressing cognitive decline in the Mexican American population. Appropriate studies aimed at early intervention of cognitive decline in this population and other older populations might lower the incidence of stroke and subsequent disability and institutionalization. ACKNOWLEDGMENTS This research was supported by National Institute on Aging grant AG-10939, and AHRQ grant HS Glenn V. Ostir is supported by a fellowship grant from the Canadian Institutes of Health Research (CIHR). Mukaila Raji is supported by the Bureau of Health Professions Geriatric Academic Career Award 1 K01 HP The contents and conclusions of this article are those of the authors and do not necessarily reflect the official position of the funding agency or the institutions they are affiliated with. Address correspondence to Glenn V. Ostir, PhD, Sealy Center on Aging, the University of Texas Medical Branch, Galveston, TX gostir@utmb.edu. 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