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At the Framingham Heart Study under separate research grant funding from the National Institute of Aging, NIH, we are gathering brain structure and cognitive information on the Framingham Offspring, creating one of the largest known data sets to assess changes in brain structure associated with normative ageing and cognitive decline. Subject recruitment, data collection, data management and statistical analysis require a collaborative integrated effort on the part of the Framingham project team. Here we describe this effort, as well as the various brain structure and cognitive function parameters we are now collecting. We are currently performing analyses of data collected through 2002, and we discuss the statistical issues arising relating brain structure parameters to cognitive function.

The magnitude of disability among elderly stroke survivors is substantial. There have been few community-based estimates of the contribution gender and older age make to stroke-related disability and outcome. Using the original Framingham Study cohort, we documented gender-specific neurological deficits and disability differences in stroke survivors at six months post-stroke. Logistic regression analyses were performed to estimate odds ratios, comparing men and women, and adjusting for age, and age and stroke subtype. Age and gender-matched controls were then compared to distinguish stroke-related disability from disability associated with general aging. Results showed that almost half (43%) of all elderly stroke survivors in the cohort had moderate to severe neurological deficits. In the crude analyses, women were more dependent in ADLs (33.9% vs 15.6%), less likely to walk unassisted (40.3% vs 17.8%), and living in nursing homes (34.9 % vs 13.3%). After adjusting for age and stroke subtype, it was older age that accounted for the severity of disability. When compared to age and gender-matched controls, stroke cases were significantly more disabled in all domains studied. In this elderly cohort, more women experienced initial strokes and were more disabled at 6 months post-stroke than men. However, older age at stroke onset, not gender or stroke subtype, was associated with greater disability. Health care providers need to understand that strokes occur later in life for women and that because of age, women are at greater risk for disability and institutionalization.

Atrial fibrillation (AF) is characterized by structural remodeling and atrial systolic failure. It is unclear if atrial filling abnormalities precede the onset of AF. We evaluated 942 Framingham Study subjects (587 women; mean age 75 years) who underwent Doppler echocardiographic evaluation at a routine examination and who did not have a history of AF. We used multivariable Cox regression models (stratified by gender and prevalent cardiovascular disease) to examine the relations of Doppler transmitral flow indexes (ratio of the velocity-time integrals of the early [E] and late [A] diastolic filling waves [VTI E/A], a correlate of atrial conduit function; E-wave deceleration time; the atrial filling fraction, an index of atrial systolic function; and peak A wave velocity) to the incidence of AF. At follow-up (mean 7 years), 85 subjects (41 women) developed AF. In models adjusting for established risk factors for AF (including left atrial size) at baseline, and for heart failure and myocardial infarction on follow-up, a 1 SD increment in VTI E/A was associated with a 28% increase in risk of AF (hazards ratio 1.28, 95% confidence interval 1.02 to 1.59). A 1 SD decrease in the atrial filling fraction was associated with a 28% higher risk of AF (hazards ratio 1.28, 95% confidence interval 0.98 to 1.67). There was a U-shaped relation between peak A-wave velocity and risk of AF. Thus, in our elderly community-based sample, increased VTI E/A and a low atrial filling fraction were markers of increased risk of AF, suggesting that altered atrial filling may antedate AF.

OBJECTIVE: To determine the independent effects of obesity and hypertension on cognitive functioning. METHODS: Using a prospective design, male (n=551) and female (n=872) participants of the Framingham Heart Study were classified by presence or absence of obesity and hypertension based on data collected over an 18-y surveillance period. All subjects were free from dementia, stroke, and clinically diagnosed cardiovascular disease up to the time of cognitive testing. Statistical models were adjusted for age, education, occupation, cigarette smoking, alcohol consumption, total cholesterol, and a diagnosis of type II diabetes. Body mass index status (nonobese or obese) and blood pressure status (normotensive or hypertensive) were then related to cognitive performance (learning, memory, executive functioning, and abstract reasoning) on tests administered 4–6 y later. RESULTS: Adverse effects of obesity and hypertension on cognitive performance were observed for men only. Obese and hypertensive men performed more poorly than men classified as either obese or hypertensive, and the best performance was observed in nonobese, normotensive men. CONCLUSIONS: The adverse effects of obesity and hypertension in men are independent and cumulative with respect to cognitive deficit.

Background and Purpose— Carotid intima-media thickness (IMT) is a quantitative measure of subclinical atherosclerosis that is predictive of subsequent myocardial infarction and stroke. There is controversy regarding the proportion of variability in IMT explained by genetic factors. Thus, it is uncertain whether carotid IMT is a heritable trait that can be used in genetic studies. Methods— From 1996 to 1998, we measured carotid IMT in 906 men (mean age, 56.7 years) and 980 women (mean age, 57.4 years) from 586 extended families (1630 sib pairs) in the Framingham Offspring cohort. B-mode carotid ultrasonography was used to define mean and maximum IMT of the common carotid artery (CCA) and internal carotid artery (ICA). Correlation coefficients were calculated in pairs of siblings. Variance component methods were used to estimate heritability with crude, age- and sex-adjusted, and multivariable-adjusted normalized deviates. Results— Multivariable-adjusted correlation coefficients for mean CCA and ICA IMT were 0.16 and 0.16, respectively. Crude, age- and sex-adjusted, and multivariable-adjusted heritabilities were 0.67, 0.44, and 0.38 for the mean CCA IMT (all P P Conclusions— These data suggest that a substantial proportion of the variability in carotid IMT is explained by genetic factors. Further studies of genetic linkage and candidate gene association are warranted to identify specific genetic variants predisposing to subclinical atherosclerosis and stroke.

BACKGROUND/STUDY CONTEXT: The number of individuals who reach extreme age is quickly increasing. Much of the current literature focuses on impaired cognition in extreme age, and debate continues regarding what constitutes "normal" cognition in extreme age. This study aimed to provide oldest-old normative data and to compare cognitive performances of cognitively intact elderly individuals from the Framingham Heart Study.A total of 1302 individuals aged 65+ years from the Framingham Heart Study were separated into 5-year age bands and compared on cognitive tests. Multivariate linear regression analyses were conducted, adjusting for gender, the Wide Range Achievement Test-Third Edition (WRAT-III) Reading score, and cohort. Analyses also included comparisons between 418 individuals aged 80+ and 884 individuals aged 65-79, and comparisons within oldest-old age bands.Normative data for all participants are presented. Significant differences were found on most tests between age groups in the overall analysis between young-old and oldest-old, and analysis of oldest-old age bands also revealed select significant differences (all ps.05).As aging increases, significant cognitive differences and increased variability in performances are evident. These results support the use of age-appropriate normative data for oldest-old individuals.

Objectives We sought to determine whether seropositivity to Helicobacter pylori , Chlamydia pneumoniae , and cytomegalovirus (CMV) is an independent predictor of incident cardiovascular disease. Background Recent reports have suggested that infections may contribute to risk of cardiovascular disease. However, prospective studies of these associations in a free-living population are lacking. Methods We measured serum H. pylori IgG, C. pneumoniae IgG and IgA, and CMV IgG levels in Framingham Heart Study cohort participants. Blood samples were drawn during the 16th biennial examination cycle (1979 to 1982) from 1,187 participants free of cardiovascular disease (mean age 69 years) and stored at −20°C. A pooled primary end point of myocardial infarction, atherothrombotic stroke, and coronary heart disease deaths was studied in relation to serology. Using a Cox model, hazard ratios (HR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender, and established risk factors. Results Seropositivity to H. pylori IgG, C. pneumoniae IgG, C. pneumoniae IgA, and CMV IgG was 60%, 45%, 11%, and 69%, respectively. During 10 years of follow-up, incident cardiovascular disease occurred in 199 participants (16.8%). In age- and gender-adjusted models, H. pylori IgG (HR 1.09, 95% CI 0.81 to 1.46), C. pneumoniae IgG (HR 0.91, 95% CI 0.68 to 1.20), C. pneumoniae IgA (HR 0.65, 95% CI 0.39 to 1.07), and CMV IgG (HR 0.84, 95% CI 0.62 to 1.12) were not associated with incident cardiovascular disease. These associations were further attenuated after adjustment for risk factors including body mass index, total and high-density lipoprotein cholesterol, diabetes mellitus, smoking, and hypertension. These estimates did not change for the individual components of cardiovascular disease, and seropositivity to more than one organism did not alter these risk estimates substantially. Conclusions In this elderly cohort, chronic H. pylori , C. pneumoniae , and CMV infections, as evidenced by seropositivity, were not associated with increased risk for cardiovascular disease. Additional studies are needed to determine the relations of chronic infections to cardiovascular disease risk in younger persons.

Objective— The objective of this study was to examine the relationship between C-reactive protein (CRP) and carotid atherosclerosis. Background— Levels of CRP, a nonspecific marker of inflammation, predict risk for cardiovascular events. However, the association between CRP and direct measures of atherosclerosis is not well established. Methods and Results— Subjects (n=3173, 52% women, mean age 55) in the offspring cohort of the Framingham Heart Study received a CRP measurement and then underwent carotid ultrasonography 4 years later. Carotid stenosis (≥25%) was present in 24% of men and 14% of women. Age-adjusted odds ratios for carotid stenosis were 1.62 (95%CI 1.12 to 2.36) for men and 3.90 (CI 2.44 to 6.44) for women in the fourth quartile of CRP compared with those in the lowest quartile. After further adjustment for traditional cardiovascular disease risk factors, the odds ratio remained significant for women (2.97, CI 1.72 to 5.25) but not for men. Similarly, after multivariable adjustment, women in the fourth CRP quartile had a higher mean internal carotid intima-media thickness than those in the lowest CRP quartile ( P ≤0.001). There was no association between common carotid intima-media thickness and CRP. Conclusions— There is a graded association between CRP and carotid atherosclerosis in women but not in men. The significance of this difference between sexes merits further investigation.

The objective was to identify, in primary prevention, patients whose “required risk reduction” (ReqRR) is greater than the “achievable risk reduction” (ARR) that cholesterol-lowering or antihypertensive medication could provide. Individualized estimates of 10-year coronary heart disease or stroke risk were derived for 66 hypercholesterolemic (HC) and 64 hypertensive (HT) patients without symptomatic cardiovascular disease. These estimates were used in trade-off tasks identifying each individual’s ReqRR. Then individual ARRs were estimated (in HC patients by assuming total cholesterol/high density lipoprotein ratio reductions to 5.0; in HT patients by assuming systolic blood pressure reductions to 120 mmHg). 12 (18%) HC and 12 (19%) HT subjects would refuse medication regardless of the risk reduction offered. Of the remaining patients, 15/54 (28%; 95% C.I.: 16-40%) HC and 19/52 (37%; 95% C.I.: 24-51%) HT subjects were “over-requirers,” in that their ReqRR/ARR ratio was 1.5. There may be a notable proportion of patients whose ReqRR is considerably greater than what is achievable, implying that decision aids may help individuals clarify preferences about accepting/refusing medication for the primary prevention of cardiovascular disease.

Background and Purpose — Stroke is a major cause of death in the United States. The association between alcohol consumption and ischemic stroke (IS) remains controversial. Methods — We used data collected on participants in the Framingham Study to assess the association between total alcohol intake and type of alcoholic beverage and development of IS, overall and according to age. Results — A total of 196 men and 245 women developed IS during three 10-year follow-up periods. In the categories of never drinkers, drinkers of 0.1 to 11, 12 to 23, and ≥24 g/d of ethanol (a “typical drink” is ≈12 g of ethanol), and former drinkers of 0.1 to 11 and ≥12 g/d, crude incidence rates of IS were 6.5, 5.9, 4.9, 5.0, 6.7, and 17.8 cases per 1000 person-years, respectively, for men and 5.9, 4.1, 4.1, 4.3, 8.3, and 7.1, respectively, for women. Overall, compared with never drinkers in a multivariate Cox regression, current alcohol consumption was not related significantly to IS in either sex. Former drinking of ≥12 g/d of alcohol was associated with a 2.4 times higher risk of IS among men but not among women. When stratified by age, alcohol intake was associated with lower risk of IS among subjects aged 60 to 69 years. In beverage-specific analysis, only wine consumption was related to a decreased risk of IS. Conclusions — Our data showed no significant association between total alcohol and IS overall but showed a protective effect of alcohol among subjects aged 60 to 69 years.

In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies.A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6.Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled.An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

Background: Long-term exposure to ambient air pollution is associated with lower cognitive function in elderly people, but whether it is related to structural changes in the brain is not clear. We ...

Overall MCI 2.30 (1.28-4.11) 0.005 2.92 (1.50-5.66) 0.002 3.14 (1.69-5.82) 0.0003 MCI single domain amnestic 1.05 (0.37-3.00) 0.92 1.49 (0.36-6.22) 0.58 0.94 (0.23-3.89) 0.93 MCI multi-domain amnestic 4.79 (2.00-11.5) 0.0005 6.07(1.42-26.0) 0.02 11.4 (3.79-34.5)

Objective: To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages. Methods: Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE e4, plasma homocysteine, waist-hip ratio, and physical activity. Results: Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p Conclusion: Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.

Aims Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD). Methods and results In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32–2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08–3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42–1.53; P = 0.51) of subclinical CVD ( P interaction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure. Conclusion Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.

Background and Purpose— Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. Methods— The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case–control study of ischemic stroke. Results— In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P =2.3×10 −6 ; ischemic stroke: Δjoint area under the curve=0.021, P =3.7×10 −7 ), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index ( P −4 ). Conclusions— The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Background: Inflammatory cascades are believed to be involved in pathogenesis of small vessel disease and atherothrombosis. We related a comprehensive panel of inflammatory biomarkers to risk of incident ischemic stroke (IS) in a community-dwelling sample Methods: Stroke-free Framingham Offspring attending exam cycle 7 (1998-2001) had multiple serum inflammatory biomarkers measured. Fourteen biomarkers representing various components of the inflammatory cascade, including systemic inflammation (C-reactive protein [CRP], interleukin-6, monocyte chemotactic protein 1, tumor necrosis factor-α, tumor necrosis factor receptor 2 [TNFr2], osteoprotegerin and fibrinogen), vascular inflammation (intercellular adhesion molecule-1, CD40 ligand, P-selectin, lipoprotein-associated phospholipase A2 mass and activity, total homocysteine [tHcy] and vascular endothelial growth factor [VEGF]) and oxidative stress (myeloperoxidase) were selected. Cox proportional hazard models were used to relate individual biomarkers to risk of incident IS. Model A included age and sex. Model B additionally adjusted for systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation. Hazard ratios (HR) are presented as per 1 SD increment. Results: In 3224 participants (age: 61±9 years, 54% women), 98 experienced incident IS (mean follow-up of 9.8 [±2.2] years). In Model A, log-CRP (HR: 1.28 [95%CI 1.04-1.56]), log-TNFR2 (HR: 1.33 [95%CI 1.09-1.63]), tHcy (HR: 1.32 [95%CI 1.11-1.58]) and VEGF (HR: 1.25 [95%CI 1.07-1.46]) were associated with risk of incident IS. All associations, except for CRP, remained significant in Model B {log-TNFR2 (1.24 [1.02-1.51]), tHcy (1.20 [1.01-1.43]), VEGF (1.21 [1.04-1.42]) and CRP (1.13 [0.92-1.40])}. Addition of these 4 biomarkers to the clinical Framingham Stroke Risk Profile score improved stroke risk prediction (net reclassification improvement: 0.34; p Conclusions: Higher levels of four biomarkers: CRP, tHcy, TNFR2 and VEGF increased risk of incident ischemic stroke. Further research is required to confirm their utility in improving stroke risk prediction, and explore their role as potential therapeutic targets.

Stroke is a major cause of morbidity and mortality. Risk factors for stroke have been determined through prospective epidemiologic study. Control of risk factors has been demonstrated to reduce stroke incidence, either through controlled trials or inferred from observational studies. In the past few years, new approaches to the treatment of established risk factors have been discovered. These include aggressive control of hypertension in diabetes patients, prevention of type 2 diabetes through lifestyle modification, carotid endarterectomy for moderate symptomatic carotid stenosis, encouragement of a high level of physical activity, and control of abdominal obesity and elevated body mass index. In addition, new strategies for stroke prevention have been identified, including encouragement of a diet high in fruits, vegetables, whole grains, and omega-3 fatty acids, the use of vitamins B12, B6, and folic acid in hyperhomocysteinemia, and moderate alcohol consumption. Clinical trial data support the use of hydroxy-methyl-coenzyme A inhibitors in patients with coronary artery disease, and ramipril in high-risk patients with coronary artery disease and diabetes, for the primary prevention of stroke. New risk factors for stroke are being investigated, including the role of chronic inflammation and infection, and these may provide future strategies for stroke prevention.

Stroke ranks as the third leading cause of death in the United States. It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million stroke survivors.1 2 The economic burden of stroke was estimated by the American Heart Association to be $51 billion (direct and indirect costs) in 1999.3 Despite the advent of treatment of selected patients with acute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies, the best approach to reducing the burden of stroke remains prevention.4 5 High-risk or stroke-prone individuals can be identified and targeted for specific interventions.6 This is important because epidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and a possible increase in stroke incidence.7 8 The Stroke Council of the American Heart Association formed an ad hoc writing group to provide a clear and concise overview of the evidence regarding various established and potential stroke risk factors. The writing group was chosen based on expertise in specific subject areas, and it used literature review, reference to previously published guidelines, and expert opinion to summarize existing evidence and formulate recommendations (Table 1⇓). View this table: Table 1. Levels of Evidence and Grading of Recommendations As given in Tables 2 through 4⇓⇓⇓, risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented, less well documented).5 The tables give the estimated prevalence, population attributable risk, relative risk, and risk reduction with treatment for each factor when known. Population attributable risk reflects the proportion of ischemic strokes in the population that can be attributed to a particular risk factor and is given by the formula 100×[prevalence(relative risk−1)/prevalence(relative risk−1)+1]). …

Background and Purpose— This guideline provides an overview of the evidence on various established and potential stroke risk factors and provides recommendations for the reduction of stroke risk. M...

The incidence of disease is estimated in medical and public health applications using various different techniques presented in the statistical and epidemiologic literature. Many of these methods have not yet made their way to popular statistical software packages and their application requires custom programming. We present a macro written in the SAS macro language that produces several estimates of disease incidence for use in the analysis of prospective cohort data. The development of the Practical Incidence Estimators (PIE) Macro was motivated by research in Alzheimer's Disease (AD) in the Framingham Study in which the development of AD has been prospectively assessed over an observation period of 24 years. The PIE Macro produces crude and age-specific incidence rates, overall and stratified by the levels of a grouping variable. In addition, it produces age-adjusted rates using direct standardization to the combined group. The user specifies the width of the age groups and the number of levels of the grouping variable. The PIE macro produces estimates of future risk for user-defined time periods and the remaining lifetime risk conditional on survival event-free to user-specified ages. This allows the user to investigate the impact of increasing age on the estimate of remaining lifetime risk of disease. In each case, the macro provides estimates based on traditional unadjusted cumulative incidence, and on cumulative incidence adjusted for the competing risk of death. These estimates and their respective standard errors, are provided in table form and in an output data set for graphing. The macro is designed for use with survival age as the time variable, and with age at entry into the study as the left-truncation variable; however, calendar time can be substituted for the survival time variable and the left-truncation variable can simply be set to zero. We illustrate the use of the PIE macro using Alzheimer's Disease incidence data collected in the Framingham Study.

The ankle-brachial index (ABI) is widely used in the clinical diagnosis of peripheral arterial disease. The contributions of genetic and environmental influences to normal and abnormal ABI values are unknown. In this study, the authors used available data on 94 monozygotic pairs and 90 dizygotic pairs of elderly, White, male twins examined in 1995-1997 to investigate the contributions of genetic and environmental influences to normative ABI values. Within-twin-pair correlations for normative ABI values were statistically significant, and the correlation in monozygotic twin pairs was significantly greater than that in dizygotic pairs. Structural equation modeling of the variance-covariance matrices of monozygotic and dizygotic twins indicated that 48% of the observed variability in ABI values could be attributed to additive genetic effects. In contrast, concordance rates for low ABI values (ABI< or =0.9) for both monozygotic and dizygotic twins were significantly greater than would be expected by chance alone, but within-pair monozygotic similarity was not significantly greater than dizygotic similarity. A matched-cotwin analysis in 21 pairs that were discordant for low ABI values found that twins with low ABI values were physically less active and more likely to be persistent smokers than their normal-control brothers. These findings reinforce the role of individual health practices (e.g., physical activity, smoking) in the manifestation of peripheral arterial disease among subjects matched for age, genetics, and early shared environment.

Cognitive decline and poor physical function are risk factors for disability in old age and may occur more often in subjects with the apolipoprotein E epsilon4 (ApoE-epsilon4) allele. The objective of this study was to investigate the joint effect of ApoE-epsilon4 and structural changes detected on MRI brain scans on cognitive decline and lower-extremity function.Brain MRI (1.5 T), neuropsychological tests, and lower-extremity physical function tests were administered to World War II male veteran twins ages 69 to 80. Quantification of MRI scans used a previously published algorithm to segment brain images into total cerebral brain (TCB), cerebrospinal fluid (CSF), and white-matter hyperintensity (WMH) volumes. A short battery of physical performance tests was used to assess lower-extremity function. Ten-year changes in performance on the Mini-Mental State Exam (MMSE), the Benton Visual Retention Test (BVRT), and the Digit Symbol Substitution (DSS) test were used to assess cognitive decline.For the sample as a whole, the comparison of subjects by median split of total cerebral brain volume found that those with brain volumes below the median performed worse on tests of gait and balance (p.01) and experienced greater cognitive decline on the MMSE and BVRT cognitive test batteries (both p.01). In addition, subjects with WMH volumes above the median had poor performance on the standing balance tasks and experienced greater decline on the DSS test (p.01). Stratified analyses revealed that the joint effect of radiological findings and the ApoE-epsilon4 allele on cognitive decline and lower-extremity function was often greater than that expected from the separate effects combined.We conclude that radiological findings in conjunction with ApoE-epsilon4 may single out a group at higher risk for dementia. We speculate that the observed interaction effect may be due to increased susceptibility to brain injury or impaired repair mechanisms in subjects with ApoE-epsilon4.

Genetically informative longitudinal data on self-reported symptoms of depression allow for an investigation of the causes of stability and change in depression symptoms throughout adult life. In this report, the authors investigated the relative contribution of genetic and environmental influences to symptoms of depression in 83 monozygotic and 84 dizygotic male twin pairs from the National Heart, Lung, and Blood Institute (NHLBI) Twin Study. Participants first completed the Center for Epidemiologic Studies-Depression (CES-D) scale in 1985-1986 and again during 1995-1997. Mean age of twins at baseline was 63 years, range 59 to 70. From cross-sectional genetic analyses we estimated the heritability of CES-D to be 25% (95% confidence interval [CI], 11%-39%) at baseline and 55% (95% CI, 40%-71%) at follow-up. Fitting longitudinal genetic models to the two-wave data, we found that stability of symptoms over the 10-year follow-up was due primarily to continuity of genetic influences.

White-matter hyperintensities (WMHI) are frequently associated with cerebrovascular risk factors in the elderly, particularly hypertension, and have been interpreted as a subclinical form of ischemic brain damage. WMHI, clinical stroke and blood pressures show significant genetic influences. The objective of this study was to determine whether a relationship exists between family history of stroke and/or hypertension in first degree relatives and WMHI in the elderly. WMHI and stroke (CVA) volumes were quantified from brain MRI performed on 414 white, male twins born between 1917 and 1927 (average age 72.3 ± 2.9 years). WMHI, adjusted for age and head size, was significantly correlated with the family history score (r = 0.21, p < 0.001). Dividing the family history scores into quintiles revealed significant differences in WMHI by quintile mean (p < 0.05). Subjects in the highest quintile of family history score had the highest mean WMHI. Recalculation of the family history score, by only counting relatives reported to have had a clinical stroke as a positive event, revealed a nonsignificant correlation with WMHI, but the correlation of the family history score with MRI CVA volume was significant (p < 0.05). Stepwise multivariate analysis including ApoE status, current smoking status, smoking packyear history, Doppler ankle/arm blood pressure ratios, current and long term hypertensive status and current systolic and diastolic pressures indicated that the stroke/hypertension family history score was the single best predictor (p < 0.01) of WMHI volumes. Family history was not an independent predictor of CVA volume.

Tests of balance, gait, and endurance were administered to 95 monozygotic (MZ) and 92 dizygotic (DZ), white male twins aged 68 to 79 years who had been born in the United States. Within-twin-pair correlations were calculated for each individual task and for an overall summary performance score. These were subjected to structural equation modeling to determine the contributions of genetic and environmental influences to individual differences in performance scores. MZ intraclass correlations were significant and greater than DZ correlations for the 8-foot walk and the repeated chair stands task, but not for the standing balance task. The heritability of the lower-extremity summary score was 57%, of which 39% was due to additive genetic effects and 18% due to nonadditive effects. In addition, we found that genetic influences contributed primarily to twin similarity in the poorest quartile of performance, whereas shared environmental influences contributed to twin similarity in the best quartile. Language: en

Diabetes and peripheral artery disease (PAD) are acknowledged hallmarks of development of atherosclerotic cardiovascular disease (CVD). The prognostic implications of physical indicators of PAD, compared with and in conjunction with glucose intolerance based on population based data, are not well documented.The influence of carotid and femoral bruits and nonpalpable pedal pulses, with and without glucose intolerance, on development of coronary disease (CHD), congestive heart failure (CHF), and stroke (CVA) was investigated in a cohort of 1672 men and 2264 women ages 47 to 99 years participating in the Framingham Study. Cross-sectional pooling yielded 29,063 2-year person-examination units based on the sample of whom 440 men and 484 women had glucose intolerance develop. Over the 26 years of follow-up, 210 men and 199 women had 1 or more of the specified CVD events. Logistic regression analysis was used to estimate age-adjusted odds ratios comparing incidence of CVD events in subjects with glucose intolerance, signs of PAD, or both conditions with those with neither condition. Glucose intolerance was associated with a 2-fold excess occurrence of physical signs of PAD (P.01 ). Femoral and carotid bruits were generally associated with greater increased risk of CHD, CHF, and CVA than was glucose intolerance alone. Particularly in women, the concomitant presence of bruits augmented the CVD risk of glucose intolerance. Nonpalpable pedal pulses were a stronger risk factor for CVD end points than glucose intolerance; particularly in men and in both sexes, those with both conditions were at substantially greater risk of CVD events than those with either alone.Physical findings of PAD appear to signify a compromised arterial circulation to the heart and brain as well as the limbs in persons with glucose intolerance. Persons with the combination are candidates at high risk for CHD, CHF, and CVA.

Background —Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors. Methods and Results —We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survival. In secondary multivariate analyses, in subjects free of valvular heart disease and preexisting cardiovascular disease, AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes. Conclusions —In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The decreased survival seen with AF was present in men and women and across a wide range of ages.

Background and Purpose —Questionnaires to elicit symptoms of transient ischemic attacks (TIAs) may detect late-life transient visual symptoms similar to the visual aura of migraine, often without headache. We determined the frequency, characteristics, and stroke outcome of these symptoms in the Framingham Study. Methods —During 1971–1989, at biennial examinations, 2110 subjects of the Framingham cohort were systematically queried about the occurrence of sudden visual symptoms. Results —Visual migrainous symptoms were reported by 1.23% (26/2110) of subjects (1.33% of women and 1.08% of men). In 65% of subjects the episodes were stereotyped, and they began after age 50 years in 77%. Mean±SD age at onset of the episodes was 56.2±18.7 years. In 58% of subjects the episodes were never accompanied by headaches, and 42% had no headache history. The number of episodes ranged from 1 to 500 and was 10 or more in 69% of subjects. The episodes lasted 15 to 60 minutes in 50% of subjects. Sixty-five percent of the subjects were examined by a study neurologist, and only 19% of them met the criteria of the International Headache Society. Twelve percent of subjects sustained a stroke after the onset of migrainous visual symptoms: a subarachnoid hemorrhage 1 year later, an atherothrombotic brain stem infarct 3 years later, and a cardioembolic stroke 27 years later. In contrast, of 87 subjects with TIAs in the same cohort, 33% developed a stroke ( P =0.030), two thirds within 6 months of TIA onset. Conclusions —Late-life-onset transient visual phenomena similar to the visual aura of migraine are not rare and often occur in the absence of headache. These symptoms appear not to be associated with an increased risk of stroke, and invasive diagnostic procedures or therapeutic measures are generally not indicated.

Background and Purpose —White matter hyperintensities (WMHs), as detected by MRI, are common among the elderly and are frequently interpreted as representing a subclinical form of ischemic brain damage. We used volumetric MR techniques to investigate the contribution of genes and the environment to measures of brain morphology in a sample of community dwelling elderly male twins. Methods —Brain MR (1.5 T) scans were obtained from 74 monozygotic (MZ) and 71 dizygotic (DZ), white, male, World War II veteran twins born in the United States and age 68 to 79 when scanned. MR quantification used a previously published semiautomated segmentation algorithm to segment brain images into total brain, cerebrospinal fluid (CSF), and WMH volumes. Twin pair covariances were computed for each measure, and structural equation genetic models were fitted to these data. Results —Total cranial, brain parenchyma, CSF, and WMH volumes were highly correlated in MZ pairs, and correlations in MZ pairs were significantly greater than those in DZ pairs. Structural equation modeling indicated heritabilities of 91%, 92%, and 73%, respectively, for total cranial, brain parenchyma, and WMH volumes. Correction for age and head size reduced the heritability of brain parenchyma to 62% (95% confidence interval, 56% to 68%) and the heritability of WMH volume to 71% (95% confidence interval, 66% to 76%). Proband concordance rates for large amounts of WMH were 61% in MZ pairs and 38% in DZ pairs, compared with a prevalence of 15% in the entire sample. Conclusions —This study is the first to quantify the relative contribution of genetic and individual environmental influences to measures of brain morphology in the elderly.

Background and Purpose —The causes and characteristics of cognitive decline after stroke are poorly defined, because most studies have relied on the diagnosis of dementia after stroke, without measurement of prestroke cognitive function. Methods —The Mini-Mental State Examination (MMSE) was used to assess the cognitive performance of 74 subjects from the Framingham Study cohort who had suffered a stroke during a 13-year period. We compared their poststroke cognitive performance with the prestroke MMSE scores collected during their biennial examinations, and their prestroke/poststroke changes in MMSE score were then compared with those of 74 control subjects matched for age and sex. Cases and controls underwent testing for symptoms of depression using the Center for Epidemiologic Studies of Depression (CES-D) scale, and these findings were correlated with their cognitive performance. Changes in cognitive performance in the cases were correlated with the CT-documented characteristics of the stroke. Results —The cases had a significantly lower mean±SE MMSE score at prestroke baseline (27.28±0.34) than did the control subjects (28.08±0.21), a difference that became more pronounced (23.57±0.92 versus 28.31±0.25; P Conclusions —Stroke is followed by a significant decline in cognitive performance when prestroke and poststroke measurements are compared. Although depression is more frequent in the stroke patients, their intellectual decline appears to be independent from the presence of depression.

Background and Purpose —We examined the 20-or-more-year survival and functional levels of 148 stroke survivors and 148 age- and sex-matched control subjects from the Framingham Study Cohort, whom we originally studied in 1972–1974 to ascertain the survival and disability status of stroke survivors compared with that of controls. Methods —This long-term evaluation was done with use of data from the 1993–1995 Framingham Study Cohort Examination 23 on the 10 stroke survivors and 20 control subjects still living to identify and compare the host characteristics and functional status of each group. The survival curves for both stroke survivors and controls were derived from the ongoing Framingham Study database. Results —Twenty-plus-year stroke survivors experienced a greater mortality than age- and sex-matched controls (92.5% and 81%, respectively). The slopes of the two survival curves were essentially the same. Functional status (eg, walking and independence in activities of daily living) of stroke survivors, however, compared very favorably with that of the control subjects. Stroke survivors were more likely to be female and to have a number of comorbidities, including elevated blood pressures, greater use of medications, less use of alcohol, and less depressive symptomology. Conclusions —In the Framingham cohort, 20-plus-year stroke survivors showed greater mortality than age- and sex-matched control subjects; functionally, however, the groups were very similar and in general quite independent.

Background\ud \ud Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.\ud \ud Methods and Results\ud \ud We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).\ud \ud Conclusion\ud \ud Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

Background Plasma amyloid-β (Aβ) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date. Methods A total of 2189 dementia-free, Framingham Study participants aged >60 years (mean age, 72 ± 8 years; 56% women) had plasma Aβ 1-42 and Aβ 1-40 measured and were followed prospectively (mean, 7.6 ± 3.0 years) for dementia/AD. Results Increased plasma Aβ 1-42 levels were associated with lower risk of dementia (Aβ 1-42 : hazard ratio [HR] = 0.80 [0.71‒0.90], P 1-42 -to-Aβ 1-40 ratio: HR = 0.86 [0.76‒0.98], P = .027) and AD (Aβ 1-42 : HR = 0.79 [0.69‒0.90], P 1-42 -to-Aβ 1-40 ratio: HR = 0.83 [0.72‒0.96], P = .012). Conclusion Our results suggest that lower plasma Aβ levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma Aβ levels as a biomarker for risk of developing clinical AD and dementia.

The American Heart Association Prevention Conference IV, “Prevention and Rehabilitation of Stroke,” was held May 1-2, 1996, in Tucson, Ariz. The report of the conference presents the state of knowledge on stroke epidemiology, etiologic basis, treatment, and rehabilitation. The conference report in its entirety is published in the July 1, 1997, issue of Stroke . This executive summary appears in the July 15, 1997, issue of Circulation . Reprints of the executive summary and full text are available from the American Heart Association. Stroke results from either ischemia, due to arterial occlusion or stenosis, or hemorrhage, due to leakage or rupture of an artery. Differentiation cannot be reliably made from the history or clinical examination alone. Most—but not all—strokes have a sudden or rapid onset. Differential diagnosis of sudden change in focal neurological status includes seizures or postepileptic paralysis, hemorrhage into a tumor (itself a form of stroke), and migraine. Neuroimaging helps to differentiate between these and the cause of short-lived symptoms (transient ischemic attack [TIA]) usually due to ischemia but possibly due to new-onset infarction or hemorrhage. More precise classification of stroke into a pathogenic subtype evades the best clinical skills. ### Ischemic Stroke Mechanism Embolism to the brain. Embolism to the brain may be arterial or cardiac in origin. Commonly recognized cardiac sources include atrial fibrillation (AF), sinoatrial disorder, recent acute myocardial infarction (AMI), marantic or subacute bacterial endocarditis, cardiac tumors, and valvular disorders, both native and artificial. Myocardial infarction. Stroke is an important complication in patients with AMI, occurring in 1% to 3% of all infarctions and in 2% to 6% of patients with anterior wall infarctions. Atrial fibrillation . Pooling of blood in the dysfunctional atrium leads to clots and emboli. AF increases risk of thromboembolism up to 18 times. Risk of stroke in patients with AF can be reduced …

Normative data are presented for a neuropsychological test battery (Kaplan-Albert) consisting of subtests from the original Wechsler Adult Intelligence and Memory Scales and the Benton and Hamsher Aphasia Examination. Analyses were based on archival data resulting from administration (1976-1978) of the battery to community residents participating in the Framingham Heart Study, a prospective, longitudinal study of cardiovascular risk factors. Using 3 age groups (55-64, 65-74, and 75-88 years) and 4 education levels (5-8, 9-11, 12, > 12 years), individuals were stratified by age, gender, and education. Multiple linear regression analysis was used to relate main effects (age, education, and gender) and interactions of these effects to 9 test scores and to 2 composite scores identified by factor analysis. The oldest participants who had the fewest years of formal education had the lowest performance levels, with lower levels of performance for men than women in this least educated elderly cohort.

Allthough progress is being made in treatment of acute ischemic stroke to reduce the size of the cerebral infarct and thereby lessen the severity of the neurologic deficit, it seems likely that prevention holds the key to reducing death and disability from stroke. Prevention requires the major stroke precursors to be identified, these include risk factors; increasing blood pressure level, diabetes, cigarette smoking, low levels of physical activity, increased fibrinogen level; positive family history of stroke, extremes of alcohol consumption; left ventricular enlargement either left ventricular hypertrophy by ECG (or preferably left ventricular mass by echocardiography), as well as predisposing diseases; coronary heart disease, cardiac failure, and atrial fibrillation. Other cardiac abnormalities, increased left atrial size and mitral annular calcification have also been implicated. High total cholesterol or low HDL-cholesterol has not been consistently related to ischemic stroke, while low levels of total cholesterol have been related to intracerebral hemorrhage.Clinical trials have provided evidence that reducing blood pressure, systolic as well as diastolic, reduces stroke incidence and that warfarin anti-coagulation prevents stroke in atrial fibrillation. Recent trials of rigid control of blood sugar in insulin dependent diabetics suggest that vascular complications may also be prevented by improved management. Observational data strongly support cessation of cigarette smoking and promotion of moderate physical activity as a means of significant stroke reduction. Recent trials of HMG CoA reductase inhibitors for cholesterol reduction have disclosed a striking reduction in cardiovascular events including stroke perhaps via an effect of these drugs on plaque rupture, lesion activation and endothelial dysfunction. Elevated plasma homocysteine levels, amenable to reduction with vitamins particularly folic acid, have also recently been implicated.Identification of persons at increased risk, accounting for the cumulative effect of multiple risk factor abnormalities, is key to stroke prevention. A Framingham stroke risk profile identifies those at high risk and provides each individual's conditional probability of stroke. These high risk individuals can thus be alerted so effective preventive measures may be instituted.

Atrial fibrillation (AF) in the presence of mitral stenosis, a consequence of rheumatic heart disease, was long recognized as the basis for cerebral infarction. Although it had long been acknowledged that atrial stasis resulting from mitral stenosis, often in the presence of AF, predisposed to thrombus formation, investigators questioned whether the AF played a role in the occurrence of systemic embolism, including stroke. As examples, in 1951, the esteemed Boston cardiologists Harris and Levine concluded, “…one wonders whether AF has much importance in influencing thrombus formation in mitral stenosis.”1 In his memoirs, Fisher2 recounts the events in 1949 soon after his arrival as a graduate fellow in neuropathology at the Boston City Hospital. He stated > One day, three months after I’d arrived, I had the opportunity to examine the cerebral arteries before slicing three brains that had large hemorrhagic infarcts. The basal vessels were empty of thrombus … People were signing out these cases as cerebral artery thrombosis—but pathologically there was no thrombus. Afterward, I looked up the records on these three cases and they had all been in AF and the general autopsy had shown infarcts in the spleen and kidneys. I speculated that they might be cases of embolism from the heart. The hemorrhagic change was from reperfusion of blocked vessels. This experience led Fisher to conclude AF was indeed frequently associated with stroke attributed to cerebral thrombosis, and the hemorrhagic infarction in such cases was related to lysis of cerebral emboli and reperfusion of the infarct. At about the same time, beginning in 1946, Wright and Foley3 at the New York Hospital-Cornell Medical Center showed that anticoagulation could prevent strokes originating from fibrillating atria in patients with mitral stenosis. This work was later extended to those with nonvalvular AF and was discussed by Wright …

Background and Purpose— Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer disease (AD) risk. Methods— A cognitive battery was administered to 1679 dementia and stroke-free Framingham offspring (age, >55 years; mean, 65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD ≤10 years of follow-up. As a secondary analysis, we explored these associations in The Framingham Heart Study original cohort (mean age, 67.5±7.3 and 84.8±3.3 years at the cognitive assessment and MRI examination, respectively). Results— A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored 20 percentile) white matter hyperintensity volume had a higher risk of stroke (HR, 1.97; 95% CI, 1.03–3.77 and HR, 2.74; 95% CI, 1.51–5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the offspring and original cohorts (HR, 4.41; 95% CI, 2.00–9.72 and HR, 2.37; 95% CI, 1.12–5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imaging markers. Conclusions— Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.

INTRODUCTION Novel error scores and traditional indices of executive function (EF) were related to cardiovascular risk factors measured 10 to 15 years earlier. METHODS From 1991 to 1995, the Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was ascertained in 1755 Framingham Offspring participants (54% women, mean age=54±9 y). Participants were administered EF tests, which included: FAS and Animals Fluency tests, Trail Making Test B (TrB), and Digit Span-Backwards (DS-B), from 2005 to 2009. Linear and logistic regression were used to relate the FSRP and its components to both error responses and traditional scores. RESULTS Consistent with previous findings, the FSRP and the individual components, diabetes and sex, were associated with several traditional measures of EF. Of interest were relationships between the FSRP score and TrB Total Errors (P=0.04), DS-B% Total Errors (P=0.02) and DS-B Capacity Score (P=0.03), and prevalent CVD related to making FAS Perseverations in the 75th percentile (P=0.03). By comparison, FSRP and CVD were not related to the traditional DS-B or FAS scores. In addition, age was associated with higher Animals % Total Errors and % Perseverations among ApoE4+ individuals and with higher TrB Total Errors among ApoE4- individuals. CONCLUSIONS For those middle-aged and healthy, including those who are ApoE4+, cardiovascular risk factors are related to impairments in EF as ascertained by novel errors and traditional measures.

Background Individuals with a high risk of stroke are also more prone to cognitive impairment perhaps because of concomitant vascular risk factors. In addition, clinical stroke increases the risk of subsequent dementia. Nevertheless, the relationship between clinical stroke and subsequent cognitive function in initially nondemented individuals remains less clear as most prior studies examined case series without controls. Aims To specify among nondemented individuals the cognitive domains affected by clinical stroke, independently of vascular risk factors and prestroke cognition. Methods One hundred thirty-two Framingham study participants (mean age = 77 ± 9 years, 54% women) with prospectively validated initial strokes, as well as age- and gender-matched controls, underwent identical cognitive evaluations ∼six-months after the stroke. Linear regression models were used to assess the differences in cognitive scores between stroke cases and controls adjusting for prestroke cognitive function as assessed by Mini-Mental State Examination scores, and with and without adjustment for vascular risk factors. Results Adjusting for prestroke cognition and vascular risk factors, persons with stroke had poorer cognitive function in the domains of immediate recall of logical and visual memories (β = −1·27 ± 0·60, P = 0·035; β = −1·03 ± 0·47, P = 0·028, respectively), verbal learning (paired associate test; β = −1·31 ± 0·57, P = 0·023), language (Boston naming test; β = −0·27 ± 0·08, P = 0·002), executive function (digit span backward; β = −0·53 ± 0·21, P = 0·015), and visuospatial and motor skills (block design; β = −3·02 ± 1·06, P = 0·005). Conclusions Clinical stroke is associated with subsequent poorer performance in multiple cognitive domains. This association cannot be entirely explained by the individual's cognitive function prior to stroke or by concomitant vascular risk factor levels.