Hypertension, Executive Dysfunction, and Progression to Dementia the Canadian Study of Health and Aging

ORIGINAL CONTRIBUTION Hypertension, Executive Dysfunction, and Progression to Dementia The Canadian Study of Health and Aging

Shahram Oveisgharan, MD; Vladimir Hachinski, MD, FRCPC, DSc(Lond)

Background: Midlife hypertension has long been es- tive dysfunction and association between hypertension tablished as a risk factor for dementia, but the role of late- and cognitive deterioration. life hypertension remains unclear. Results: No difference in the rate of progression to de- Objective: To investigate the role of hypertension in cog- mentia based on the presence of hypertension was found nitive deterioration among older subjects with cogni- between subjects with memory dysfunction alone or in tive impairment, no dementia. combination with executive dysfunction. However, among subjects with executive dysfunction alone, 57.7% hav- Design: The Canadian Study of Health and Aging was con- ing hypertension progressed to dementia compared with ducted in 3 waves (1991, 1995-1996, and 2001-2002). 28.0% having normotension (P=.02). Setting: Community-based cohort study. Conclusions: Hypertension predicts progression to dementia in older subjects with executive dysfunction but Patients: We studied 990 subjects with a mean (SD) age of 83.06 (6.97) years having cognitive impairment, no not memory dysfunction. Control of hypertension could dementia who were followed up for 5 years in the Ca- prevent progression to dementia in one-third of the sub- nadian Study of Health and Aging. jects with cognitive impairment, no dementia.

Main Outcome Measures: Determination of cogni- Arch Neurol. 2010;67(2):187-192

NE IN 3 SUBJECTS REACH- degenerative process may prevent dam- ing the age of 60 years age to the central nervous system.8 If will experience stroke, hypertension has a deleterious effect on dementia, or both un- cognition, the use of antihypertensive less prevention inter- drugs at the MCI stage will have a pro- venes.O1 The worldwide prevalence of de- found effect in the prevention of demen- mentia is 24.3 million, with the addition tia among community dwellers. of 1 new case every 7 seconds.2 Subjects with vascular cognitive im- Although midlife hypertension has been pairment usually have deficits in execu- confirmed as a risk factor for the develop- tive function.9 Subjects with MCI who have ment of dementia in late life,3 there have deficits only in memory function (called been conflicting findings about the role of single-domain amnestic MCI) are more late-life hypertension.3 Some longitudinal prone to develop Alzheimer disease.9 investigations have found an association be- Because hypertension is a major risk Author Affiliations: tween late-life hypertension and the devel- factor for vascular brain diseases and vas- Department of Clinical opment of dementia,4 while others have cular cognitive impairment, we postu- Neurological Sciences, not.5,6 Such inconsistency exists even be- lated that the cognitive domain of dys- University Hospital, University tween clinical trials that evaluated antihy- function may be the crucial factor that of Western Ontario, London, pertensive treatment in older subjects.7,8 determines the association between hy- Ontario, Canada The term mild cognitive impairment pertension and cognitive deterioration. To (Drs Oveisgharan and Hachinski); and Stroke Unit, (MCI) was introduced to describe the state our knowledge, this has not been ad- Isfahan Cardiovascular between cognitive changes of aging and dressed in previous studies. Our study was 7 Research Center, Isfahan fully developed dementia. The rationale designed to investigate this association and University of Medical Sciences, to study MCI is derived from the assump- its interaction with the cognitive domain Isfahan, Iran (Dr Oveisgharan). tion that earlier intervention in a neuro- of dysfunction using data from a large

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 impairment. In CSHA-1 and CSHA-2, subjects whose scores Table 1. Clinical Diagnoses of Subjects Diagnosed on the screening test (Modified Mini-Mental State Examina- as Having Cognitive Impairment, No Dementia (CIND) tion) were less than 78 were invited for more clinical and neu- in the Canadian Study of Health and Aging (CSHA) ropsychological examinations, while in CSHA-3 this cut point was raised to 90 to include more subjects in the examinations. Diagnosis CSHA-1 CSHA-2 The Diagnostic and Statistical Manual of Mental Disorders (Fourth Delirium 10 9 Edition) criteria were used for the diagnoses in CSHA-3. Cerebral vascular, strokea 84 120 Between waves of the CSHA, some subjects died, and their General vasculara 65 43 antemortem cognitive status was estimated with a predictive Parkinson disease 10 14 algorithm using death certificate information and interviews Brain tumor 1 0 with spouses or close relatives of the decedent. These sources Multiple sclerosis 3 1 led to an overall estimation of the probability of antemortem Epilepsy 2 3 dementia.13 The details of the sampling method, screening, and Sociocultural 18 45 diagnostic criteria used by the CSHA have been published else- Social isolation 7 13 where.10,14 Blind or deaf 14 41 The present study included subjects who were diagnosed Chronic alcohol abuse 44 23 as having CIND in CSHA-1 or CSHA-2 and whose cognitive Chronic drug intoxication 28 6 impairment was not caused by neurologic or psychiatric dis- Depression 69 59 eases such as multiple sclerosis, epilepsy, or depression Other psychiatric disease 57 35 Table 1 a ( ). There were 578 such subjects in CSHA-1 and 474 Age-associated memory impairment 215 175 in CSHA-2. Sixty-two CSHA-1 subjects who were also in CSHA-2 Mental retardation 20 8 were excluded from the CSHA-1 sample and were included only Other causesa 214 72 in the CSHA-2 sample. The cognitive status of CSHA-1 sub- CIND, unknowna 064 jects and CSHA-2 subjects was determined at the 5-year follow-up in CSHA-2 and CSHA-3, respectively. For subjects who a Analyzed in the present study. died before their follow-up examination, diagnoses were coded as demented and nondemented if the probabilities of demen- population-based longitudinal study (the Canadian Study tia were at least 0.90 and less than 0.25, respectively. Fol- of Health and Aging [CSHA]).10 low-up cognitive status of 384 subjects (38.8%) was indeterminable because of uncertainty about the diagnosis, their refusal to participate further in the study, death with an antemortem METHODS probability of dementia between 0.25 and 0.90, or lack of documentation to verify cognitive status before death. Compared STUDY POPULATION with subjects having CIND and known follow-up cognitive status, these 384 subjects were similar in age, education, and preva- The CSHA was a community-based cohort study of Canadians lence of hypertension but included more male participants. The dwelling in community and institutional settings sampled from study was approved by the research ethics committee of the Uni- 36 urban and surrounding rural areas in 10 Canadian prov- versity of Western Ontario. inces. The first wave of the study, CSHA-1, started in 1991 and sampled about 9000 and 1300 older (Ն65 years) Canadians from STATISTICAL ANALYSIS community and institutional settings, respectively. Commu- nity dwellers were screened for cognitive impairment; if found, The following steps comprised the statistical methods: selec- subjects were fully evaluated by physicians and neuropsycholo- tion of neuropsychological tests, use of correspondence analy- gists to determine their cognitive status. All subjects dwelling sis to derive cognitive domains, and determination of cogni- in institutional settings were fully evaluated by physicians and tive dysfunction domains. neuropsychologists because of their high likelihood of having cognitive impairment. In addition, a random sample of com- Selection of Neuropsychological Tests munity dwellers who showed no cognitive impairment on screening were fully evaluated. Based on this process, cogni- These tests were selected from the following neuropsychologi- tion in subjects was classified as one of the following: normal; cal test battery that was administered in CSHA-1 and CSHA-2: cognitive impairment, no dementia (CIND); Alzheimer dis- Wechsler Memory Scale (information subtest),15 Buschke Cued ease; vascular dementia; other dementia; or not classified de- Recall Procedure (first, third, and delayed free and total mentia according to the Diagnostic and Statistical Manual of recall),16,17 Wechsler Adult Intelligence Scale–Revised (WAIS-R) Mental Disorders (Third Edition Revised) criteria.11 block design,18,19 WAIS-R similarities,18,19 Token Test (color nam- The second wave of the study, CSHA-2, started 5 years ing and 11 item),20 Digit Span Test,15 WAIS-R comprehen- later in 1995 to 1996 and was performed according to the sion,18,19 Rey Auditory Verbal Learning Test (first, fifth, and sixth same protocols as CSHA-1. A random sample of community trials; new list trial; and true positive and true negative recog- dwellers whose cognition was screened as normal in CSHA-1 nition trial),21-23 Verbal Fluency (the FAS Test),24 Benton Vi- and all who were evaluated by physicians and neuropsycholo- sual Retention Test,25 Verbal Fluency Animal Naming,26 and gists in CSHA-1 were examined, and their cognitive status WAIS-R digit symbol subtest.19 In CSHA-1, these tests were ad- was determined. The same diagnostic criteria (Diagnostic and ministered to 1791 subjects; 591 had 1 or more missing tests; Statistical Manual of Mental Disorders [Third Edition Revised]) in CSHA-2, these tests were administered to 1466 subjects; 369 were used, and subjects’ cognitive status was also determined had 1 or more missing tests. Missing tests were because of physi- using the Diagnostic and Statistical Manual of Mental Disorders cal disability in 37.2%, other missing factors in 33.3%, unwill- (Fourth Edition).12 ingness to perform a test in 26.8%, and misunderstanding about The third wave of the study, CSHA-3, started in 2001 to 2002 a test in 2.6%. Compared with subjects who did not miss any and followed the same protocols except that the cutoff point tests, subjects with missing tests were significantly more cog- was changed at which subjects screened positive for cognitive nitively impaired.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Use of Correspondence Analysis solute value and large difference relative to the value of to Derive Cognitive Domains correlations with other dimensions. (For example, WAIS-R comprehension was highly correlated with di- Correspondence analysis was applied to the neuropsychologi- mension 1 because it had correlation coefficients of 0.57, cal test results to derive cognitive domains. Correspondence 0.04, and 0.04 relative to dimensions 1, 2, and 3, respec- analysis is a more powerful generalization of principal compo- tively, in CSHA-1.) The sets of tests derived by correla- 27 nent analysis that can be used with continuous, categorical, tion analysis were almost the same in CSHA-1 and and count variables and explains maximum amount of vari- CSHA-2. Dimension 1 was considered the executive func- ance that can be derived by any linear method. As in principal component analysis, correspondence analysis results in fac- tion domain because of high correlations with WAIS-R tors, each of which explains a domain of variance among the comprehension, WAIS-R similarities, Verbal Fluency, and data. The first derived factor explains most of the variance, the WAIS-R digit symbol subtest (these tests had their high- second derived factor explains most of the remaining vari- est correlations with dimension 1). Dimension 2 was con- ance, and so forth until all variances are extracted into differ- sidered the memory function domain because of high cor- ent factors or domains. Usually the first 2 to 3 dimensions de- relations with Buschke Cued Recall Procedure (first, third, note meaningful factors. To assess what is measured by each and delayed free recall trials) (these tests had their high- dimension, correlations between derived dimensions and neu- est correlations with dimension 2). Dimension 3 did not ropsychological test results were calculated. Spearman rank cor- have high correlations with the tests and was removed relation coefficient was used for this purpose. from further analysis. Correspondence analysis was performed separately on CSHA-1 and CSHA-2 neuropsychological test results. Each data The mean (SD) of executive function and memory set included test results of subjects with normal cognition and function domains was determined among subjects with subjects with dementia. normal cognition separately in CSHA-1 and CSHA-2. The mean (SD) values for the executive function domain were Determination of 0.29 (0.82) in CSHA-1 and 0.26 (0.86) in CSHA-2; the Cognitive Dysfunction Domains values for the memory function domain were 0.30 (0.73) in CSHA-1 and 0.40 (0.68) in CSHA-2. The mean (SD) of each correspondence analysis–derived cognitive domain was computed by selecting subjects with nor- ASSOCIATION BETWEEN HYPERTENSION mal cognition and was performed separately in CSHA-1 and AND COGNITIVE DETERIORATION CSHA-2. A subject was considered to have dysfunction in a cognitive domain if his or her score was more than 1 SD below the Descriptive statistics of the analyzed cohort with CIND mean of the domain. are given in Table 3. About three-fourths of subjects Hypertension was defined as a diastolic blood pressure (su- had dysfunction in 1 of 2 cognitive domains. pine or sitting) of at least 90 mm Hg or a systolic blood pres- The presence of hypertension did not result in cog- sure (supine or sitting) of at least 140 mm Hg. A subject’s his- nitive deterioration across the cohort: 59.5% of subjects tory of stroke was obtained by the physicians. Pearson product moment correlation ␹2 with Yates conti- with hypertension vs 64.2% of subjects with normoten- nuity correction was used to test the association between hy- sion had developed dementia after 5 years of follow-up pertension and dementia. Logistic regression analysis was used (P=.32). However, there was a significant difference to control for the effect of age and apolipoprotein E ε 4 allele among the following 3 patterns of cognitive impair- status. ment: in subgroup 1 with cognitive impairment and ex- The analysis was performed using commercially available ecutive dysfunction alone, the presence of hypertension statistical software (SPSS, version 15; SPSS Inc, Chicago, Illi- resulted in cognitive deterioration (57.7% having hyper- nois). PϽ.05 was considered statistically significant. tension progressed to dementia vs 28.0% having normotension, P=.02), while it did not in subgroup 2 (cogni- RESULTS tive impairment and memory dysfunction alone) or subgroup 3 (cognitive impairment and both executive and memory dysfunction) (Figure). DETERMINATION OF Logistic regression analysis was performed using de- COGNITIVE DYSFUNCTION DOMAINS mentia development as the dependent variable and using hypertension, patterns of cognitive impairment (execu- Correspondence analysis was performed separately on tive dysfunction alone, memory dysfunction alone, or both CSHA-1 and CSHA-2 neuropsychological test results. In executive and memory dysfunction), and their interac- CSHA-1, the first to fifth derived dimensions explained tion as independent variables. The interaction term (but about 30%, 16%, 10%, 7%, and 5% of the variance; in not hypertension) and the patterns of cognitive impair- CSHA-2, these percentages were about 32%, 14%, 11%, ment remained significant in the model. The analysis was 7%, and 6%. The first 3 (of 24 derived dimensions) could repeated, and age, sex, and apolipoprotein E allele sta- explain more than half of the variance and were selected tus (ε 4, ε 2, or ε 3) were added to the independent vari- for further analysis. ables; there was no change in the results. Correlations of the first 3 derived dimensions To remove a possible mediating role of stroke in the (Table 2) were analyzed to determine sets of tests that effect of hypertension on cognitive deterioration among were highly correlated with each dimension. A test was subgroup 1, the rates of progression to dementia were selected to be highly correlated with a dimension if its compared between subjects without a history of stroke correlation coefficient with the dimension had high ab- having hypertension vs normotension in subgroup 1. The

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 2. Correlations Between Correspondence Analysis–Derived Dimensions and Neuropsychological Testsa

CSHA-1 Dimensionc CSHA-2

Dimensionc

Testb 123Testb 123 1 0.36d 0.43d 0.05 1 0.42d 0.33d 0.05 2 0.27d 0.002 0.006 2 0.24d 0.002 0.04 3 0.27d 0.16d 0.03 3 0.29d 0.10d 0.06 4 0.25d 0.69d 0.18d 4 0.33d 0.62d 0.21d 5 0.28d 0.74d 0.17d 5 0.36d 0.68d 0.20d 6 0.19d 0.48d 0.13d 6 0.31d 0.39d 0.17d 7 0.14d 0.49d 0.12d 7 0.26d 0.40d 0.11d 8 0.64d 0.24d 0.45d 8 0.61d 0.28d 0.42d 9 0.25d 0.76d 0.16d 9 0.36d 0.69d 0.22d 10 0.15d 0.51d 0.14d 10 0.26d 0.43d 0.15d 11 0.71d 0.03 0.05 11 0.74d 0.05 0.04 12 0.06 0.07 0.03 12 0.10d 0.04 0.009 13 0.57d 0.10d 0.005 13 0.62d 0.08d 0.03 14 0.45d 0.13d 0.05 14 0.48d 0.17d 0.04 15 0.57d 0.04 0.04 15 0.64d 0.06 0.04 16 0.39d 0.30d 0.18d 16 0.48d 0.31d 0.25d 17 0.48d 0.64d 0.27d 17 0.58d 0.53d 0.32d 18 0.36d 0.32d 0.11d 18 0.40d 0.23d 0.07 19 0.42d 0.75d 0.29d 19 0.56d 0.61d 0.35d 20 0.15d 0.26d 0.13d 20 0.27d 0.22d 0.20d 21 0.33d 0.46d 0.10d 21 0.42d 0.35d 0.13d 22 0.86d 0.12d 0.40d 22 0.89d 0.18d 0.33d 23 0.59d 0.26d 0.16d 23 0.65d 0.19d 0.10d 24 0.54d 0.30d 0.10d 24 0.66d 0.15d 0.05 25 0.87d 0.27d 0.26d 25 0.87d 0.24d 0.26d

Abbreviation: WAIS-R, Wechsler Adult Intelligence Scale–Revised. a Significant at P Յ .05. The coefficients are absolute values. b Test 1 is Wechsler Memory Scale (information subtest). Test 2 is Buschke Cued Recall Procedure (visual identification task). Test 3 is Buschke Cued Recall Procedure (object naming). Test 4 is Buschke Cued Recall Procedure (free recall trial 1). Test 5 is Buschke Cued Recall Procedure (free recall trial 3).Test6is Buschke Cued Recall Procedure (total recall trial 1). Test 7 is Buschke Cued Recall Procedure (total recall trial 3). Test 8 is WAIS-R block design. Test 9 is Buschke Cued Recall Procedure (free recall delayed trial). Test 10 is Buschke Cued Recall Procedure (total recall delayed trial). Test 11 is WAIS-R similarities. Test 12 is Token Test (color naming). Test 13 is Token Test (11 item). Test 14 is Digit Span Test. Test 15 is WAIS-R comprehension. Test 16 is Rey Auditory Verbal Learning Test (first trial). Test 17 is Rey Auditory Verbal Learning Test (fifth trial). Test 18 is Rey Auditory Verbal Learning Test (new list trial). Test 19 is Rey Auditory Verbal Learning Test (sixth trial). Test 20 is Rey Auditory Verbal Learning Test (true positive recognition trial). Test 21 is Rey Auditory Verbal Learning Test (true negative recognition trial). Test 22 is Verbal Fluency (the FAS Test). Test 23 is Benton Visual Retention Test. Test 24 is Verbal Fluency Animal Naming. Test 25 is WAIS-R digit symbol subtest. c Correspondence analysis–derived dimensions. d Significant at P Յ .01.

presence of hypertension still resulted in significant pro- cant difference in blood pressure levels 9 years before cog- gression to dementia (52.0% of subjects with hyperten- nitive assessment between subjects who developed de- sion vs 19.0% of subjects with normotension, PϽ.01). mentia and subjects who did not develop dementia. Although the 2 studies were of dissimilar design, their COMMENT contradictory results preclude conclusions about the role of hypertension in the development of dementia among The presence of hypertension did not result in cognitive older subjects. deterioration across the cohort. However, there was in- In this study, we excluded subjects with CIND whose creased progression to dementia among subjects with cognitive impairment was due to neurologic or psychi- hypertension whose cognitive impairment was associ- atric illness or chronic alcohol or substance abuse, which ated with executive dysfunction but not memory dys- may cause static encephalopathies but do not result in function. progression to dementia. By this definition, our analysis Among 4 longitudinal studies reviewed by Qiu et al,3 is comparable to investigations that have evaluated sub- only 1 found hypertension to be a risk factor for the de- jects with MCI.8 Furthermore, the rate of progression to velopment of dementia among older subjects. Accord- dementia was almost 12% a year among the present co- ing to Skoog et al,4 subjects who developed dementia later hort, the same as that reported for subjects with MCI.7 in life had significantly higher systolic and diastolic blood Few studies have evaluated the role of hypertension pressures about 10 to 15 years before cognitive assess- in progression of MCI to dementia. In a clinic-based set- ment than subjects who did not subsequently develop ting, Ravaglia et al28 followed up 165 outpatients with dementia. In contrast, Petitti et al6 reported no signifi- MCI for 3 years. The presence of hypertension had no

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 3. Descriptive Statistics of the Study Cohort 80.00 Hypertension No Yes Statistic Value P < .05 Age, mean (SD), y 83.06 (6.97) 60.00 Sex, No. Male 369 Female 621 40.00 Apolipoprotein E ε 4 allele, No./Total No. (%) 110/475 (23.2) Hypertension, No./Total No. (%) 631/953 (66.2) Pattern of cognitive impairment, No./Total No. (%) 20.00 Executive dysfunction only 165/532 (31.0) Incidence of Dementia After 5 y, % Incidence of Dementia After 5 y, Memory dysfunction only 157/532 (29.5) Both memory and executive dysfunction 79/532 (14.8) 0.00 Normal memory and executive function, 131/532 (24.6) Executive Memory Both Executive and No./Total No. (%) Dysfunction Alone Dysfunction Alone Memory Dysfunction 5-y Follow-up outcome, No./Total No. (%) Not demented 143/990 (14.4) Not Demented Demented Total Demented 201/990 (20.3) Normotensive 18 7 25 Dead, P Ն .90a 172/990 (17.4) Executive dysfunction alone Hypertensive 30 41 71 Dead, P = .25 to PϽ.90a 217/990 (21.9) a Dead, P Յ .25 90/990 (9.1) Memory Normotensive 8 23 31 Dead, lack of documentation to verify cognitive 53/990 (5.4) dysfunction alone Hypertensive 23 47 70 status before death Refusal to participate further in the study 104/990 (10.5) Both executive and Normotensive 5 11 16 Uncertainty about the diagnosis 10/990 (1.0) memory dysfunction Hypertensive 9 22 31

a P values indicate antemortem probability of dementia. Figure. Association between hypertension and cognitive deterioration among subjects with cognitive impairment, no dementia classified by their patterns of cognitive impairment. effect on progression of MCI to dementia. Similarly, hypertension was not a risk factor for the development of dementia among subjects in our study. However, Rava- is the most common risk factor, and dementia is the sec- glia et al did not include an interaction term between MCI ond most common.31 There is no preventive or thera- subtypes and hypertension in their multivariate model peutic intervention to mitigate this public health bur- of MCI conversion to dementia. den. It is assumed that cognitive decline progresses to Solfrizzi et al29 evaluated Italian patients with MCI in 1 CIND before the development of dementia. We show a community-based study and followed them up for 3 ⁄2 herein that the presence of hypertension predicts pro- years. Although the presence of hypertension did not seem gression to dementia in a subgroup of about one-third to have a detrimental effect on cognitive function, the in- of subjects with CIND. Control of hypertension in this vestigators included only patients with amnestic MCI in population could decrease by one-half the projected 50% their study. Similarly, hypertension did not accelerate cog- 5-year rate of progression to dementia.7 nitive deterioration among subjects in our study with memory dysfunction. Recently, Knopman et al30 reported a stronger asso- Accepted for Publication: October 5, 2009. ciation of stroke with nonamnestic MCI than with am- Correspondence: Vladimir Hachinski, MD, FRCPC, nestic MCI in a cross-sectional study derived from a popu- DSc(Lond), Department of Clinical Neurological Sci- lation-based cohort. It seemed plausible that the ences, University Hospital, University of Western association between hypertension and executive dys- Ontario, 339 Windermere St, Room B7-003, London, function in our study might be mediated by stroke in these ON N6A 5A5, Canada ([email protected]). subjects. However, after exclusion of subgroup 1 sub- Author Contributions: Dr Hachinski had full access to jects with a history of stroke from the analysis, hyper- all the data in the study and takes responsibility for the tension was still a significant predictor of progression to integrity of the data and the accuracy of the data analy- dementia. sis. Study concept and design: Oveisgharan. Acquisition of This study has some limitations. Our study is a sec- data: Hachinski and Oveisgharan. Analysis and interpre- ondary analysis and has the limitations of a post hoc analy- tation of data: Oveisgharan and Hachinski. Drafting of the sis. About 10% of the cohort refused further clinical ex- manuscript: Oveisgharan and Hachinski. Statistical analy- aminations, and their cognitive status was indeterminable. sis: Oveisgharan. Obtained funding: Hachinski and Oveis- About 30% of subjects died, and their antemortem cog- gharan. Study supervision: Hachinski. nitive status was estimated with a predictive algorithm Financial Disclosure: None reported. using death certificate information and interviews with Funding/Support: This work was supported by grant spouses or close relatives of the decedent. IIRG-08-91792 from the Alzheimer Association (Dr This study may have profound implications for com- Hachinski). munity dwellers with CIND. Worldwide, neurologic dis- Role of the Sponsor: The Alzheimer Association had no orders are the most frequent cause of disability- role in any part of the study or the drafting of the manu- adjusted life-years; among these, cerebrovascular disease script.

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