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BackgroundIn the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.Methods and ResultsIn the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.ConclusionThe CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi‐Ethnic Study of Atherosclerosis, 967 participants completed 14‐day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.

ObjectiveTo test the hypothesis that silent myocardial infarction (MI) is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.MethodsThe Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989 to 1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: nonlacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.ResultsAmong 4,224 participants, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.03–2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53–119) and long term (HR, 1.60; 95% CI, 1.04–2.44). In secondary analyses, the association between silent MI and stroke was limited to nonlacunar ischemic stroke (HR, 2.40; 95% CI, 1.36–4.22).ConclusionIn a community-based sample, we found an association between silent MI and ischemic stroke.

Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.To evaluate whether DSI is associated with incident dementia in older adults.This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05).In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

Background and aims Prevalent valvular calcification (VC) is associated with stroke but little is known about associations of VC progression with stroke. Methods Progression (interval increase >0 Agatston units/year) of aortic valvular calcification (AVC) and mitral annular calcification (MAC) was assessed by two cardiac CTs over a median of 2.4 years. We determined the risk of adjudicated total and ischemic stroke using Cox regression adjusted for cardiovascular disease (CVD) risk factors. Results We studied 5,539 MESA participants free of baseline CVD and atrial fibrillation. Baseline mean±SD age was 62±10 years; 53% were women; 83% had no progression of VC; 15%, progression at one site (AVC or MAC), and 3%, progression at both sites. Over a median of 12 years, 211 total and 167 ischemic strokes occurred. The number of sites with VC progression (range 0-2) was not associated with total and ischemic stroke (all p>0.05). We found MAC progression to be associated with increased risk of total stroke [adjusted hazard ratio (95% CI) 1.59 (1.11, 2.28)] and ischemic stroke [1.64 (1.10, 2.45)]. Results remained significant after further adjustment for baseline coronary artery calcification. After excluding participants with interim atrial fibrillation and coronary heart disease, findings were no longer statistically significant in fully-adjusted models. There was no interaction by age, sex, or race/ethnicity. There was no association with AVC progression and stroke. Conclusions Progression of MAC but not AVC over 2.4 years is associated with increased risk of total and ischemic stroke.

ObjectiveTo test the hypothesis that orthostatic hypotension (OH) might cause cerebral hypoperfusion and injury, we examined the longitudinal relationship between OH or orthostatic symptoms and incident neurologic outcomes in a community population of older adults.MethodsCardiovascular Health Study participants (≥65 years) without dementia or stroke had blood pressure (BP) measured after lying down for 20 minutes and after standing 3 for minutes. Participants reported dizziness immediately upon standing and any dizziness in the past 2 weeks. OH was defined as a drop in standing systolic/diastolic BP ≥20/≥10 mm Hg. We determined the association between OH or dizziness with (1) MRI brain findings (ventricular size, white matter hyperintensities, brain infarcts) using linear or logistic regression, (2) cognitive function (baseline and over time) using generalized estimating equations, and (3) prospective adjudicated events (dementia, stroke, death) using Cox models. Models were adjusted for demographic characteristics and OH risk factors. We used multiple imputation to account for missing OH or dizziness (n = 534).ResultsPrior to imputation, there were 5,007 participants (mean age 72.7 ± 5.5 years, 57.6% women, 10.9% Black, 16% with OH). OH was modestly associated with death (hazard ratio [HR] 1.11; 95% confidence interval 1.02–1.20), but not MRI findings, cognition, dementia, or stroke. In contrast, dizziness upon standing was associated with lower baseline cognition (β = −1.20; −1.94 to −0.47), incident dementia (HR 1.32; 1.04–1.62), incident stroke (HR 1.22; 1.06–1.41), and death (HR 1.13; 1.06–1.21). Similarly, dizziness over the past 2 weeks was associated with higher white matter grade (β = 0.16; 0.03–0.30), brain infarcts (OR 1.31; 1.06–1.63), lower baseline cognition (β = −1.18; −2.01 to −0.34), and death (HR 1.13; 1.04–1.22).ConclusionsDizziness was more consistently associated with neurologic outcomes than OH 3 minutes after standing. Delayed OH assessments may miss pathologic information related to cerebral injury.

Recent evidence indicates that our understanding of the relationship between cardiac function and ischemic stroke remains incomplete. The Cardiovascular Health Study enrolled community-dwelling adults ≥ 65 years old. We included participants with speckle-tracking data from digitized baseline study echocardiograms. Exposures were left atrial reservoir strain (primary), left ventricular longitudinal strain, left ventricular early diastolic strain rate, septal e’ velocity, and lateral e’ velocity. The primary outcome was incident ischemic stroke. Cox proportional hazards models were adjusted for demographics, image quality, and risk factors including left ventricular ejection fraction and incident atrial fibrillation. Among 4,000 participants in our analysis, lower (worse) left atrial reservoir strain was associated with incident ischemic stroke (HR per SD absolute decrease, 1.14; 95% CI 1.04–25). All secondary exposure variables were significantly associated with the outcome. Left atrial reservoir strain was associated with cardioembolic stroke (HR per SD absolute decrease, 1.42; 95% CI 1.21–1.67) and cardioembolic stroke related to incident atrial fibrillation (HR per SD absolute decrease, 1.60; 1.32–1.95). Myocardial dysfunction that can ultimately lead to stroke may be identifiable at an early stage. This highlights opportunities to identify cerebrovascular risk earlier and improve stroke prevention via therapies for early myocardial dysfunction.

Background and Purpose— Serum cholesterol variability, independent of mean, has been associated with stroke, white matter hyperintensities on cranial magnetic resonance imaging (MRI), and other cardiovascular events. We sought to assess the relationship between total serum cholesterol (TC) variability and cranial MRI findings of subclinical or covert vascular brain injury in a longitudinal, population-based cohort study of older adults. Methods— In the Cardiovascular Health Study, we assessed associations between intraindividual TC mean, trend, and variability over ≈5 years with covert brain infarction (CBI) and white matter grade (WMG) on cranial MRI. Mean TC was calculated for each study participant from 4 annual TC measurements between 2 MRI scans. TC trend was calculated as the slope of the linear regression of the TC measurements, and TC variability was calculated as the SD of the residuals from the linear regression. We evaluated the association of intraindividual TC variability with incident CBI and worsening WMG between 2 MRI scans in primary analyses and with prevalent CBI number and WMG on the follow-up MRI scan in secondary analyses. Results— Among participants who were eligible for the study and free of clinical stroke before the follow-up MRI, 17.9% of 1098 had incident CBI, and 27.8% of 1351 had worsening WMG on the follow-up MRI. Mean, trend, and variability of TC were not associated with these outcomes. TC variability, independent of mean and trend, was significantly associated with the number of CBI (β=0.009 [95% CI, 0.003–0.016] P =0.004; N=1604) and was associated with WMG (β, 0.009 [95% CI, −0.0002 to 0.019] P =0.055; N=1602) on the follow-up MRI. Conclusions— Among older adults, TC variability was not associated with incident CBI or worsening WMG but was associated with the number of prevalent CBI on cranial MRI. More work is needed to validate and to clarify the mechanisms underlying such associations.

Objective Valid neuropsychological assessment is critical to the accurate diagnosis and effective treatment of diverse populations. American Indians and Alaska Natives experience substantial health disparities relative to the general U.S. Population Given the dearth of studies on neuropsychological health in this population, we aimed to characterize neuropsychological performance among older American Indians with respect to age, sex, education, income, and language use. Method From 2010 to 2014, we recruited 818 American Indians aged 60 and older from the Cerebrovascular Disease and Its Consequences in American Indians Study, who comprised all of the surviving members of a cardiovascular study (Strong Heart Study). This cohort from 11 tribes resided on or near their home reservations in three geographic regions (Northern Plains, Southern Plains, and Southwest). Using a cross-sectional design investigating potential vascular brain injury, we administered a brief, targeted neuropsychological and motor function assessments. Results Higher scores on neuropsychological tests were associated with younger age, female sex, more education, higher income, and less Native American language use. Similar associations were found for the motor tests, although men had higher scores on both motor function tests. After accounting for other sociocultural and health factors, age, sex, education, income, and Native American language use all had significant associations to the test scores. Conclusions Our findings may be used to guide research and inform clinical practice. The development of future normative studies for older American Indians will be more culturally appropriate when sociocultural factors are included. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.

Importance Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown. Objective To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction. Design, Setting, and Participants An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020. Exposure Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria. Main Outcomes and Measures The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications. Results Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1). Conclusions and Relevance This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

Background Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n‐6 and n‐3], and trans fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996–1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow‐up of 11.7 years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P =0.0328) and dihomo‐γ‐linolenic acid (20:3n‐6) was positively associated with CHD mortality (HR, 1.34; 95% CI, 1.02–1.76; P =0.0351). Elaidic acid (18:1n‐7 t ) was positively associated with incident nonfatal MI (HR, 1.46; 95% CI, 1.01–2.12; P =0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo‐γ‐linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.

Key Points Question Is sickle cell trait associated with increased risk of myocardial infarction and coronary heart disease among African American individuals? Findings In this cohort study of 23 197 African American individuals in 5 cardiovascular epidemiologic studies, sickle cell trait was not associated with increased risk of myocardial infarction or coronary heart disease among African American individuals. Meaning In this study, sickle cell trait was not associated with increased risk of fatal and nonfatal myocardial infarction or coronary heart disease, suggesting that these disorders may not be associated with sickle cell trait–related sudden death., Importance The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women’s Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait–related sudden death in this population., This cohort study evaluates whether African American individuals with sickle cell trait have a higher incidence of myocardial infarction or composite coronary heart disease outcomes compared with those without sickle cell trait.

Cardiac magnetic resonance imaging (MRI) has revealed fibrosis in embolic stroke of undetermined source (ESUS) patients comparable to levels seen in atrial fibrillation (AFib). We used computational modeling to understand the absence of arrhythmia in ESUS despite the presence of putatively pro-arrhythmic fibrosis. MRI-based atrial models were reconstructed for 45 ESUS and 45 AFib patients. The fibrotic substrate’s arrhythmogenic capacity in each patient was assessed computationally. Reentrant drivers were induced in 24/45 (53%) ESUS and 22/45 (49%) AFib models. Inducible models had more fibrosis (16.7 ± 5.45%) than non-inducible models (11.07 ± 3.61%; p, eLife digest The heart usually beats with a regular rhythm to pump the blood that carries oxygen and nutrients to different organs. Sometimes, alterations in the heart’s rhythm known as arrhythmias can occur. Atrial fibrillation, also called AFib, is a type of arrhythmia in which the heart beats rapidly and irregularly, causing abnormal blood-flow that can lead to the formation of blood clots. If one of these blood clots travels to the brain, it can block a blood vessel, causing a stroke. However, many strokes occur without any evidence of AFib. One subset of strokes that are not associated with AFib are embolic strokes of undetermined source (ESUS), which account for 25% of all strokes. By definition ESUS and AFib do not occur together, but both are associated with similar elevated levels of disease-related remodeling (i.e., fibrosis) in the heart tissue, which appears when the heart is injured. Fibrosis impairs the heart’s normal electrical activity. Bifulco et al. wanted to determine whether there is some fundamental difference in fibrosis between people with AFib and those who have had an ESUS event. To do this, they used a computational approach to model the geometries and patterns of fibrosis of the hearts of 45 ESUS patients and 45 patients with AFib, essentially producing a virtual version of each patient’s heart. Bifulco et al. then applied a virtual pace-maker (working in overdrive mode) to each heart model to determine whether electrical inputs that can lead to AFib had different effects on ESUS and AFib patients. The results showed that the electrical inputs had similar effects in all of the heart models. This led Bifulco et al. to conclude that ESUS and AFib patients have indistinguishable patterns of fibrosis. The key difference is that ESUS patients are missing the trigger to initiate the fibrillation process – if atrial fibrosis is the proverbial tinderbox, these triggers are the spark needed to ignite a fire. Further research, including confirmation of Bifulco et al.’s findings in live patients, will be needed to confirm the hypothesis that ESUS patients lack AFib primarily due to an absence of triggers. If this is indeed the case, these findings may make it easier to identify ESUS patients at higher risk for AFib or further strokes. Additionally, a better understanding of fibrosis as a link between stroke and AFib will help clinicians provide better, more personalized treatments, for example guiding whether a patient should take blood thinners or undergo more rigorous cardiac monitoring.

Background: Clinical stroke is prevalent in American Indians, but the lifestyle risk factors for vascular brain injury have not been well-studied in this population. The purpose of this study was to correlate brain magnetic resonance imaging (MRI) findings with obesity, alcohol use, and smoking behaviors in elderly American Indians from the Strong Heart Study. Methods: Cranial MRI scans (n = 789) were analyzed for dichotomous measures of infarcts, hemorrhages, white matter hyperintensities (WMH), and cerebral atrophy and continuous measures of total brain, WMH, and hippocampal volume. Poisson regression was used to estimate prevalence ratios, and linear regression was used to estimate measures of association for continuous outcomes. Models were adjusted for the risk factors of interest as well as age, sex, study site, income, education, hypertension, diabetes, and low-density lipoprotein cholesterol. Results: Smoking was associated with increased hippocampal atrophy (p = 0.002) and increased prevalence of sulcal widening (p < 0.001). Relative to nonsmokers, smokers with more than 25 pack-years of smoking had a 27% (95% CI 7–47%) increased prevalence of high-grade sulci, p = 0.005. Body mass index was inversely associated with prevalence of nonlacunar infarcts and sulcal widening (all p = 0.004). Alcohol use was not significantly associated with any of the measured MRI findings. Conclusions: This study found similar associations between smoking and vascular brain injury among American Indians, as seen in other populations. In particular, these findings support the role of smoking as a key correlate for cerebral atrophy.

ObjectiveTo determine the association left atrial diameter (LAD) and vascular brain injury on brain MRI.MethodsWe analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort of community-dwelling adults ≥65 years old. LAD was measured from 2-dimensional transthoracic echocardiograms. Among CHS participants who underwent brain MRI, we examined associations of LAD with brain infarcts and leukoaraiosis. Primary outcomes (number for analysis) were prevalent infarcts (2,327) and degree of leukoaraiosis on initial MRI (2,315). Secondary outcomes were prevalent nonlacunar infarcts (2,327), incident infarcts (939), incident nonlacunar infarcts (1,185), and degree of leukoaraiosis on follow-up MRI adjusted for initial MRI (1,158). Relative risk (RR) and linear regression models were adjusted for demographics, vascular risk factors, and potential confounders.ResultsMean age of the 2,335 participants with initial brain MRI was 72.0 ± 4.8 years; 38.7% were men; and 29.0% participants had prevalent infarcts. In multivariable, fully adjusted models, LAD was associated with prevalent infarcts (RR 1.20, 95% confidence interval [CI] 1.08–1.34) and prevalent nonlacunar infarcts (RR 1.28, 95% CI 1.06–1.54) but not with leukoaraiosis (−0.08, 95% CI −0.17 to 0.07), incident infarcts (RR 1.00, 95% CI 0.78–1.29), nonlacunar infarcts (RR 0.98, 95% CI 0.67–1.42), or worsening leukoaraiosis (−0.04, 95% CI −0.10 to 0.02).ConclusionLAD is independently associated with prevalent brain infarcts, particularly nonlacunar infarcts, but not leukoaraiosis. Larger studies are needed to determine associations with incident infarct risk and whether this risk in patients with left atrial enlargement can be reduced with anticoagulant agents.

Background and Purpose— Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke. Methods— The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V 1 , left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors. Results— Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V 1 (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001–1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03–1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67–2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84–1.10). Conclusions— In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease.

Objective— In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings. Approach and Results— In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15% and worsening white matter grade in 27%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95% confidence interval, 1.12–1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95% confidence interval, 1.24–1.69). These findings persisted in secondary and sensitivity analyses. Conclusions— Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ.

ObjectiveTo test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.MethodsOur samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.ResultsWe studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03–1.23; p = 0.01) following adjustments for age, sex, APOE ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.ConclusionsCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

Objective:American Indians experience substantial health disparities relative to the US population, including vascular brain aging. Poorer cognitive test performance has been associated with cranial magnetic resonance imaging findings in aging community populations, but no study has investigated these associations in elderly American Indians.Methods:We examined 786 American Indians aged 64 years and older from the Cerebrovascular Disease and its Consequences in American Indians study (2010–2013). Cranial magnetic resonance images were scored for cortical and subcortical infarcts, hemorrhages, severity of white matter disease, sulcal widening, ventricle enlargement, and volumetric estimates for white matter hyperintensities (WMHs), hippocampus, and brain. Participants completed demographic, medical history, and neuropsychological assessments including testing for general cognitive functioning, verbal learning and memory, processing speed, phonemic fluency, and executive function.Results:Processing speed was independently associated with the presence of any infarcts, white matter disease, and hippocampal and brain volumes, independent of socioeconomic, language, education, and clinical factors. Other significant associations included general cognitive functioning with hippocampal volume. Nonsignificant, marginal associations included general cognition with WMH and brain volume; verbal memory with hippocampal volume; verbal fluency and executive function with brain volume; and processing speed with ventricle enlargement.Conclusions:Brain-cognition associations found in this study of elderly American Indians are similar to those found in other racial/ethnic populations, with processing speed comprising an especially strong correlate of cerebrovascular disease. These findings may assist future efforts to define opportunities for disease prevention, to conduct research on diagnostic and normative standards, and to guide clinical evaluation of this underserved and overburdened population.

Background American Indians ( AIs ) have high stroke morbidity and mortality. We compared stroke incidence and mortality in AI s, blacks, and whites. Methods and Results Pooled data from 2 cardiovascular disease cohort studies included 3182 AI s from the SHS (Strong Heart Study), aged 45 to 74 years at baseline (1988–1990) and 3765 blacks and 10 413 whites from the ARIC (Atherosclerosis Risk in Communities) Study, aged 45 to 64 years at baseline (1987–1989). Stroke surveillance was based on self‐report, hospital records, and death certificates. We estimated hazard ratios for incident stroke (ischemic and hemorrhagic combined) through 2008, stratified by sex and birth‐year tertile, and relative risk for poststroke mortality. Incident strokes numbered 282 for AI s, 416 for blacks, and 613 for whites. For women and men, stroke incidence among AI s was similar to or lower than blacks and higher than whites. Covariate adjustment resulted in lower hazard ratios for most comparisons, but results for these models were not always statistically significant. After covariate adjustment, AI women and men had higher 30‐day poststroke mortality than blacks (relative risk=2.1 [95% CI=1.0, 3.2] and 2.2 [95% CI=1.3, 3.1], respectively), and whites (relative risk=1.6 [95% CI=0.8, 2.5] and 1.7 [95% CI=1.1, 2.4]), and higher 1‐year mortality (relative risk range=1.3–1.5 for all comparisons). Conclusions Stroke incidence in AI s was lower than for blacks and higher than for whites; differences were larger for blacks and smaller for whites after covariate adjustment. Poststroke mortality was higher in AI s than blacks and whites.

Background and Purpose— Continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea may improve stroke recovery, but adherence is poor. We assessed the effectiveness of an intensive CPAP adherence program during and after inpatient stroke rehabilitation on 3-month adherence and stroke recovery. Methods— In a single-arm study, 90 stroke rehabilitation patients were enrolled into an intensive CPAP adherence program. CPAP was continued after a run-in among qualifying patients with evidence of obstructive sleep apnea. The primary outcome was CPAP adherence, defined as ≥4 hours of use on ≥70% of days, over 3 months. Results— A total of 62 patients qualified for continued CPAP and 52 of these were willing to continue CPAP after discharge from rehabilitation. At 3 months, the average daily CPAP use was 4.7 hours (SD 2.6), and 32/52 (62%) patients were adherent. Factors significantly associated with adherence included more severe stroke, aphasia, and white race. Compared with nonadherent patients, adherent patients experienced greater improvements in the cognitive component of the Functional Independence Measure ( P =0.02) and in the National Institutes of Health Stroke Scale ( P =0.03). Conclusions— This intensive CPAP adherence program initiated during stroke rehabilitation can lead to CPAP adherence in the majority of patients with evidence of obstructive sleep apnea, including those with more severe stroke and aphasia, and may promote recovery. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02809430.

Background and Purpose— Depression is associated with stroke, but the effects of changes in depressive symptoms on stroke risk are not well understood. This study examined whether depressive symptom changes across 2 successive annual assessments were associated with incident stroke the following year. Methods— We used visit data from 4319 participants of the Cardiovascular Health Study who were stroke free at baseline to examine whether changes in depressive symptoms classified across 2 consecutive annual assessments predicted incident first stroke during the subsequent year. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression scale (high versus low at ≥10). Survival models were inverse probability weighted to adjust for demographics, health behaviors, medical conditions, past depressive symptoms, censoring, and survival. Results— During follow-up, 334 strokes occurred. Relative to stable low scores of depressive symptoms, improved depression symptoms were associated with almost no excess risk of stroke (adjusted hazards ratio, 1.02; 95% confidence interval, 0.66–1.58). New-onset symptoms were nonsignificantly associated with elevated stroke risk (adjusted hazards ratio, 1.44; 95% confidence interval, 0.97–2.14), whereas persistently high depressive symptoms were associated with elevated adjusted hazard of all-cause stroke (adjusted hazards ratio, 1.65; 95% confidence interval, 1.06–2.56). No evidence for effect modification by race, age, or sex was found. Conclusions— Persistently high symptoms of depression predicted elevated hazard of stroke. Participants with improved depressive symptoms had no elevation in stroke risk. Such findings suggest that strategies to reduce depressive symptoms may ameliorate stroke risk.

ObjectiveTo examine the hypothesis that atrial fibrosis and associated atrial cardiopathy may be in the causal pathway of cardioembolic stroke independently of atrial fibrillation (AF) by comparing atrial fibrosis burden between patients with embolic stroke of undetermined source (ESUS), patients with AF, and healthy controls.MethodsWe used late-gadolinium-enhancement MRI to compare atrial fibrosis in 10 patients with ESUS against 10 controls (no stroke, no AF) and 10 patients with AF. Fibrosis was compared between groups, controlling for stroke risk factors.ResultsMean age was 51 ± 15 years, and 43% of participants were female. Patients with ESUS had more atrial fibrosis than controls (16.8 ± 5.7% vs 10.6 ± 5.7%, p = 0.019) and similar fibrosis compared to patients with AF (17.8 ± 4.8%, p = 0.65). Odds ratios of ESUS per quartile of fibrosis were 3.22 (95% CI [CI] 1.11–9.32, p = 0.031, unadjusted) and 3.17 (95% CI 1.05–9.52, p = 0.041, CHA2DVASc score adjusted). Patients with >12% fibrosis had a higher percentage of ESUS (77.8% vs 27.3%, p = 0.02), and patients with >20% fibrosis had the highest proportion of ESUS (4 of 5).ConclusionsPatients with ESUS exhibit similar atrial fibrosis compared to patients with AF and more fibrosis than healthy controls. Fibrosis is associated with ESUS after controlling for stroke risk factors, supporting the hypothesis that fibrosis is in the causal pathway of cardioembolic stroke independently of AF. Prospective studies are needed to assess the role of anticoagulation in primary and secondary stroke prevention in patients with high atrial fibrosis.

Importance African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear. Objective To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans. Design, Setting, and Participants This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women’s Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017. Interventions or Exposures Participants’ SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation. Main Outcomes and Measures Incident ischemic stroke. Results This meta-analysis included 19 464 African American individuals (1520 with SCT, 17 944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35;P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar. Conclusions and Relevance Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.

Background Changes in social networks are rarely examined before and after various diseases because of insufficient data. CHS (The Cardiovascular Health Study) offers an opportunity to compare social network trajectories surrounding well‐adjudicated myocardial infarction ( MI ) or stroke events. We tested the hypothesis that social networks will be stable after MI and decrease after stroke. Methods and Results We examined trajectories of the Lubben Social Network Scale score ( LSNS , range 0–50) before and after vascular events over 11 years. The LSNS assesses engagement in family networks, friends’ networks, and social supports. We used a linear mixed model with repeated measures and fixed effects to compare the change in social network score before and after events in 395 people with MI and 382 with ischemic stroke. Over a mean of 12.4 years of follow‐up for MI and 11.1 years for stroke, we examined an average of 4 social network scores for each participant. We controlled for sociodemographics, baseline cognitive function, and comorbidities. The participants’ mean age was 73.5, 51% were women, and 88% were non‐Hispanic white. After MI , the social network trajectory remained stable compared with the baseline trajectory (−0.06 points per year, adjusted P =0.2356). After stroke, the social network trajectory declined compared with the baseline trajectory (−0.14 points per year, adjusted P =0.0364). Conclusions Social networks remained stable after MI and declined after stroke. This small and persistent decline after adjustment for potential confounders is notable because it deviates from stable network trajectories found in CHS participants and is specific to stroke.

Background: Clinical stroke is prevalent in American Indians, but the risk factors for cerebrovascular pathology have not been well-studied in this population. The purpose of this study was to correlate abnormalities on brain magnetic resonance imaging (MRI) with clinical risk factors in a cohort of elderly American Indians. Methods: Brain MRI scans from 789 participants of the Strong Heart Study were analyzed for infarcts, hemorrhage, white matter disease, and measures of cerebral atrophy including ventricular and sulcal grade and total brain volume. Clinical risk factors included measures of hypertension, diabetes, and high levels of low-density lipoprotein (LDL) cholesterol. Regression models adjusted for potential confounders were used to estimate associations between risk factors and brain MRI outcomes. Results: ­Hypertension was associated with the presence of infarcts (p = 0.001), ventricle enlargement (p = 0.01), and increased white matter hyperintensity volume (p = 0.01). Diabetes was associated with increased prevalence of cerebral atrophy (p < 0.001), ventricular enlargement (p = 0.001), and sulcal widening (p = 0.001). High LDL was not significantly associated with any of the measured cranial imaging outcomes. Conclusions: This study found risk factors for cerebrovascular disease in American Indians similar to those seen in other populations and provides additional evidence for the important roles of hypertension and diabetes in promoting cerebral infarcts and brain atrophy, respectively.

Prolongation of the QT interval is associated with an increased risk of atrial fibri llation (AF) and stroke. The purpose of this analysis was to determine if AF explains the association between prolonged QT and stroke. A total of 6305 participants (mean age 62 ± 10 years; 54 % women; 38 % whites; 27 % blacks; 23 % Hispanics; 12 % Chinese–Americans) from the Multi-Ethnic Study of Atherosclerosis (MESA) were included in this analysis. A linear scale was used to compute heart rate-adjusted QT (QTa). Prolonged QTa was defined as ≥460 ms in women and ≥450 ms in men. Incident AF cases were identified using hospital discharge records and Medicare claims data. Vascular neurologists adjudicated stroke events by medical record review. Cox regression was used to examine the association between prolonged QTa and stroke with and without AF. A total of 216 (3.4 %) of study participants had prolonged QTa. Over a median follow-up of 8.5 years, 280 (4.4 %) participants developed AF and 128 (2.0 %) participants developed stroke. In a multivariable Cox regression analysis adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, prolonged QTa was associated with an increased risk of AF (HR = 1.7, 95 % CI 1.1, 2.6) and stroke (HR = 2.3, 95 % CI 1.3, 4.1). When AF was included as a time-dependent covariate, the association between prolonged QTa and stroke was not substantively altered (HR = 2.4, 95 % CI 1.3, 4.3). The increased risk of stroke in those with prolonged QT potentially is not explained by documented AF. Further research is needed to determine if subclinical AF explains the association between the QT interval and stroke.

Background: To describe adjudication of transient ischemic attack (TIA) and stroke in an observational study. Methods: We detail the process used to adjudicate TIA and stroke in the Multi-Ethnic Study of Atherosclerosis (MESA), a large longitudinal cohort study. Two of three vascular neurologists adjudicated each event using specific protocols. We examined the initial agreement, effect of imaging on diagnosis of TIA versus ischemic stroke, and effect of strict and less strict criteria on the number of ischemic stroke subtypes classified as undetermined. Results: Of 573 adjudicated events over 13.5 years of follow-up, 95 (16.5%) had TIA and 269 (47.0%) had stroke: 211 (78.4%) ischemic, 43 (16.0%) hemorrhagic, and 15 (5.6%) other. Disagreements occurred on 16% of initial adjudication of events. Using results from imaging, the number with TIA decreased by 8.6% and with ischemic stroke increased by 4.1%. Using less strict criteria to classify ischemic stroke subtypes reduced the number classified as undetermined, from 137 to 59, and numbers classified as cardioembolic and small vessel doubled. Conclusions: We hope that this work will motivate and facilitate investigators to use MESA data to investigate issues concerning TIA and stroke and will inform investigators seeking to adjudicate TIA and stroke in other studies.

Background and aims The volume and density of coronary artery calcium (CAC) both independently predict cardiovascular disease (CVD) beyond standard risk factors, with CAC density inversely associated with incident CVD after accounting for CAC volume. We tested the hypothesis that ascending thoracic aorta calcium (ATAC) volume and density predict incident CVD events independently of CAC. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of participants without clinical CVD at baseline. ATAC and CAC were measured from baseline cardiac computed tomography (CT). Cox regression models were used to estimate the associations of ATAC volume and density with incident coronary heart disease (CHD) events and CVD events, after adjustment for standard CVD risk factors and CAC volume and density. Results Among 6811 participants, 234 (3.4%) had prevalent ATAC and 3395 (49.8%) had prevalent CAC. Over 10.3 years, 355 CHD and 562 CVD events occurred. One-standard deviation higher ATAC density was associated with a lower risk of CHD (HR 0.48 [95% CI 0.29–0.79], p 0.01) and CVD (HR 0.56 [0.37–0.84], p 0.01) after full adjustment. ATAC volume was not associated with outcomes after full adjustment. Conclusions ATAC was uncommon in a cohort free of clinical CVD at baseline. However, ATAC density was inversely associated with incident CHD and CVD after adjustment for CVD risk factors and CAC volume and density.

Background and Purpose— This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults. Methods— Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years. Results— One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all P for trend ≤0.02) but not for trait anger ( P >0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16–2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11–2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29–3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor–adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables. Conclusions— Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors.

Background and purpose— Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke. Methods— We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression. Results— Among 29 595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280 549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m 2 were 1.30 (95% confidence interval, 1.01–1.68) and 0.92 (0.47–1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27–2.07) for ischemic and 2.57 (1.37–4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke ( P =0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure. Conclusions— Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.

HDL-associated paraoxonase-1 (PON1) is an enzyme whose activity is associated with cerebrovascular disease. Common PON1 genetic variants have not been consistently associated with cerebrovascular disease. Rare coding variation that likely alters PON1 enzyme function may be more strongly associated with stroke. The National Heart, Lung, and Blood Institute Exome Sequencing Project sequenced the coding regions (exomes) of the genome for heart, lung, and blood-related phenotypes (including ischemic stroke). In this sample of 4,204 unrelated participants, 496 had verified, noncardioembolic ischemic stroke. After filtering, 28 nonsynonymous PON1 variants were identified. Analysis with the sequence kernel association test, adjusted for covariates, identified significant associations between PON1 variants and ischemic stroke (P = 3.01 × 10(-3)). Stratified analyses demonstrated a stronger association of PON1 variants with ischemic stroke in African ancestry (AA) participants (P = 5.03 × 10(-3)). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of PON1Val109Ile (overall P = 7.88 × 10(-3); AA P = 6.52 × 10(-4)), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identified in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted.

SummaryObjective Ischaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men. Design Cohort study. Participants Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010. Measurements Adjudicated ischaemic stroke. Results Among 1032 men (mean age 76, range 66–97), followed for a median of 10 years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P = 0·006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75 ng/dl, with greater risk of stroke at DHT levels above 75 ng/dl or below 50 ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0·77 (95% CI, 0·61, 0·98) per standard deviation in analyses adjusted for stroke risk factors. Conclusions Dihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

Background Acute kidney injury (AKI) is common and is associated with poor clinical outcomes. Information about the incidence of AKI and its effect on stroke outcomes is limited. Methods Data were analyzed from a registry of subjects with ischemic stroke and intracerebral hemorrhage (ICH) hospitalized at a single academic medical center. Admission creatinine was considered to be the baseline. AKI was defined as a creatinine increase during hospitalization of 0.3 mg/dL or a percentage increase of at least 50% from baseline. Multivariate logistic regression models were created for both stroke types, with hospital mortality as the outcome. Covariates included gender, race, age, admission creatinine, National Institutes of Health Stroke Scale score at admission, the performance of a contrast-enhanced computed tomographic scan of the head and neck, and medical comorbidities. Results There were 528 cases of ischemic stroke with 70 deaths (13%), and 829 cases of ICH with 268 deaths (32%). The mean age was 64 years; 56% of patients were men and 71% were white. AKI complicated 14% of ischemic stroke and 21% of ICH hospitalizations. In multivariate analysis stratified by stroke type, AKI was associated with increased hospital mortality from ischemic stroke (odds ratio [OR] 3.08; 95% confidence interval [CI] 1.49-6.35) but not ICH (OR 0.82; 95% CI 0.50-1.35), except for those surviving at least 2 days (OR 2.11; 95% CI 1.18-3.77). Conclusions AKI occurs frequently after stroke and is associated with increased hospital mortality. Additional studies are needed to establish if the association is causal and if measures to prevent AKI would result in decreased mortality.

Objectives:To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).Methods:We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.Results:High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types

Objective The risk of seizures after malignant middle cerebral artery (MCA) infarction with decompressive hemicraniectomy (DHC) is uncertain. Also unknown is how this complication influences survivors’ recovery and quality of life. Methods We retrospectively reviewed medical charts of all patients admitted to Harborview Medical Center between 1 January 2002 and 31 June 2011 for space-occupying MCA ischaemic stroke and who underwent DHC. Survivors and their surrogates were invited to participate in a telephone or in-person interview. Results Fifty-five patients were followed for a median of 311 days (IQR 134–727). Twenty-seven patients (49%) had seizures, 25 (45%) developed epilepsy and 21 (38%) achieved moderate disability or better (modified Rankin Scale score ≤3) by 1 year after stroke onset. The only factor significantly associated with seizure occurrence was male gender. Median time from stroke to first seizure was 222 days, with a cluster of first seizures within weeks after cranioplasty; only two of the first seizures occurred right around the time of stroke onset. Follow-up time was significantly longer for patients with seizures (605 days, IQR 297–882) than for those without (221 days, IQR 104–335). Of the 20 patients interviewed, 12 achieved moderate disability or better, 15 experienced a seizure with 6 indicating the seizure was a major drawback. Regardless, all 20 would have chosen DHC again. Conclusions In this case series, patients were at high risk of developing seizures after malignant MCA stroke with DHC, especially after cranioplasty. Assuming these findings are replicated, means should be sought to reduce the occurrence of this complication.

Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant's 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21).Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.

Background: The Cerebrovascular Disease and its Consequences in American Indians study conducted cranial MRI examination of surviving participants of the Strong Heart Study, a longitudinal cohort of elderly American Indians. Methods: Of the 1,033 recruited participants, some were unable to complete the MRI (n = 22), some scans were unusable due to participant motion or technical errors (n = 13), and one community withdrew consent after data collection (n = 209), leaving 789 interpretable MRI scan images. Six image sequences were obtained in contiguous slices on 1.5T scanners. Neuroradiologists graded white matter hyperintensities (WMH), sulci, and ventricles on a 0- to 9-point scale, and recorded the presence of infarcts and hemorrhages. Intracranial, brain, hippocampal, and WMH volumes were estimated by automated image processing. Results: The median scores for graded measures were 2 (WMH) and 3 (sulci, ventricles). About one-third of participants had lacunar (20%) or other infarcts (13%); few had hemorrhages (5.7%). Findings of cortical atrophy were also prevalent. Statistical analyses indicated significant associations between older age and findings of vascular injury and atrophy; male gender was associated with findings of cortical atrophy. Conclusions: Vascular brain injury is the likely explanation in this elderly American Indian population for brain infarcts, hemorrhages, WMH grade, and WMH volume. Although vascular brain injury may play a role in other findings, independent degenerative other disease processes may underlie abnormal sulcal widening, ventricular enlargement, hippocampal volume, and total brain volume. Further examination of risk factors and outcomes with these findings may expand the understanding of neurological conditions in this understudied population.

Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6). Interpretation: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394.

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Introduction Whether co-occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co-occurring Lewy body disease (LBD) or vascular brain injury (VBI). Methods Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center. Results Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only ( P = .06) and slightly slower for ADNP + VBI ( P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD ( P = .002) and VBI ( P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP. Discussion The impact of co-occurring pathologies on progression may depend on severity of ADNP.

Background and Purpose— Hepatocyte growth factor (HGF) is positively associated with ischemic and hemorrhagic stroke risk factors. However, understanding the relation between HGF and stroke is in its infancy. Therefore, we sought to examine the association of circulating HGF with incident stroke using data from the MESA (Multi-Ethnic Study of Atherosclerosis). We hypothesized that circulating HGF would be positively associated with an increased risk of stroke. Methods— Participants aged 45 to 84 years (n=6711) had HGF measured between 2000 and 2002 and were followed for incident stroke through 2013 (n=233). Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for incident stroke. A secondary analysis stratified results by adjudicated stroke type (n=183 ischemic; n=39 hemorrhagic; n=11 other). Results— After adjustment for potential confounding variables, risk of stroke was 17% higher with each standard deviation increase in HGF (hazard ratio, 1.17; 95% confidence interval, 1.03–1.34). This association was mainly driven by ischemic stroke and did not change on exclusion of cardioembolic strokes, although the number of excluded cases was small. The few hemorrhagic and other types of stroke were not associated with HGF. Conclusions— Circulating HGF was positively associated with the incidence of stroke in a diverse, population-based cohort of men and women from the United States. Our findings support the hypothesis that circulating HGF is a marker of endothelial damage and suggest that HGF may have utility as a prognostic marker of stroke risk.

Background Recent studies have failed to establish a causal relationship between high‐density lipoprotein cholesterol levels ( HDL ‐C) and cardiovascular disease ( CVD ), shifting focus to other HDL measures. We previously reported that smaller/denser HDL levels are protective against cerebrovascular disease. This study sought to determine which of small+medium HDL particle concentration ( HDL ‐P) or large HDL ‐P was more strongly associated with carotid intima‐media thickening ( cIMT ) in an ethnically diverse cohort. Methods and Results In cross‐sectional analyses of participants from the Multi Ethnic Study of Atherosclerosis ( MESA ), we evaluated the associations of nuclear magnetic resonance spectroscopy–measured small+medium versus large HDL ‐P with cIMT measured in the common and internal carotid arteries, through linear regression. After adjustment for CVD confounders, low‐density lipoprotein cholesterol ( LDL ‐C), HDL ‐C, and small+medium HDL ‐P remained significantly and inversely associated with common (coefficient=−1.46 μm; P =0.00037; n=6512) and internal cIMT (coefficient=−3.82 μm; P =0.0051; n=6418) after Bonferroni correction for 4 independent tests (threshold for significance=0.0125; α=0.05/4). Large HDL ‐P was significantly and inversely associated with both cIMT outcomes before HDL ‐C adjustment; however, after adjustment for HDL ‐C, the association of large HDL ‐P with both common (coefficient=1.55 μm; P =0.30; n=6512) and internal cIMT (coefficient=4.84 μm; P =0.33; n=6418) was attenuated. In a separate sample of 126 men, small/medium HDL ‐P was more strongly correlated with paraoxonase 1 activity ( r p =0.32; P =0.00023) as compared to both total HDL ‐P ( r p =0.27; P =0.0024) and large HDL ‐P ( r p =0.02; P =0.41) measures. Conclusions Small+medium HDL ‐P is significantly and inversely correlated with cIMT measurements. Correlation of small+medium HDL ‐P with cardioprotective paraoxonase 1 activity may reflect a functional aspect of HDL responsible for this finding.

Background and Purpose— Whether consideration of carotid intima-media thickness (cIMT) and carotid plaque would improve risk prediction of ischemic stroke in persons with atrial fibrillation (AF) is unknown. The purpose of this study was to assess the improvement in risk prediction of stroke by adding cIMT and carotid plaque to the CHA 2 DS 2 -VASc (variables age, heart failure, hypertension, diabetes mellitus, myocardial infarction, and peripheral arterial disease) score. Methods— We included participants from the Atherosclerosis Risk in Communities (ARIC) study (mean age, 63 years) who developed AF within 5 years after carotid measurement, were not on warfarin, and had no prior stroke at AF diagnosis. AF was ascertained from study ECGs and diagnosis codes, and stroke was physician adjudicated. Multivariable Cox models were used to assess association between carotid indices and ischemic stroke. Improvement in 10-year risk prediction of stroke was assessed by the C -statistic, net reclassification improvement, and relative integrated discrimination improvement. Results— There were 81 (11.2%) stroke events that occurred among 724 participants with AF during a mean follow-up of 8.5 years. Increased cIMT and presence of carotid plaque were significantly associated with increased stroke risk. The addition of cIMT+plaque to the CHA 2 DS 2 -VASc score marginally increased the C -statistic (95% confidence interval) from 0.685 (0.623−0.747) to 0.698 (0.638−0.759). The net reclassification improvement and integrated discrimination improvement for cIMT+plaque were 0.091 (95% confidence interval, 0.012−0.170) and 0.101 (95% confidence interval, 0.002−0.226), respectively. Conclusions— Increased cIMT and presence of carotid plaque are associated with increased risk of ischemic stroke in individuals with AF. Furthermore, they may improve risk prediction of stroke, over and above the CHA 2 DS 2 -VASc score.

Background and Purpose— Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset Methods— The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P −6 and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results— One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P =9.5×10 −9 ). The associated locus is in an intergenic region between TCF7L2 and HABP2 . In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII–activating protease levels, a product of HABP2 . Conclusions— HABP2 , which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions.To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated.Population-based inception cohort study.Enrollees in Group Health, an integrated health care system, aged 30-84 with newly diagnosed AF in 2001-2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385).Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6-36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs).Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5-24.9 kg/m(2)), BMI levels of 25.0-29.9 (overweight), 30.0-34.9 (obese 1), 35.0-39.9 (obese 2), and ≥ 40.0 kg/m(2) (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF.For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.

Background: Viet Nam is experiencing a health transition from infectious to chronic disease. Data on cardiovascular diseases, including strokes, are limited. Methods: Data were randomly collected from six communities in Da Nang, Viet Nam, on participant demographics, medical history, blood pressure, anthropometrics and health behavior using World Health Organization (WHO) guidelines. Stroke symptoms were collected by self-report with the standardized Questionnaire for Verifying Stroke Free Status. Multivariate logistic regression was used to identify factors associated with the presence of stroke symptoms. Results: One thousand six hundred and twenty one adults were examined with a mean age of 52.0 years (±12.5 years), of which 56.1% were women. 27.3% of the participants were found to have hypertension, 26.2% used tobacco, and 16.1% were overweight. More than two-thirds of the participants with hypertension were unaware of their condition. Almost one fourth of the participants were identified by the questionnaire as previously experiencing at least one stroke symptom. Age, rural residence, and education were associated with the presence of stroke symptoms. Models adjusted for demographics found hypertension, high cholesterol, reported severe chest pain, former smoking, and being overweight to be associated with a higher prevalence of stroke symptoms. Conclusions: The high frequency of stroke symptoms in Da Nang calls for further evaluation and interventions to reduce hypertension and other risk factors for chronic disease in Viet Nam and other health transition countries.

To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.After adjustment for other IPH risk factors, the hazard ratios (95% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or ≥3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83-4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10 -8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10 -11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10 -12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10 -3 for 6q22 and 1.2 × 10 -3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. © 2012 Nature America, Inc. All rights reserved.