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Introduction: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images., Methods: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke., Result: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile., Discussion: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

White matter hyperintensities (WMHs) are well-established markers of cerebral small vessel disease, and are associated with an increased risk of stroke, dementia, and mortality. Although their prevalence increases with age, small and punctate WMHs have been reported with surprisingly high frequency even in young, neurologically asymptomatic adults. However, most automated methods to segment WMH published to date are not optimized for detecting small and sparse WMH. Here we present the SHIVA-WMH tool, a deep-learning (DL)-based automatic WMH segmentation tool that has been trained with manual segmentations of WMH in a wide range of WMH severity. We show that it is able to detect WMH with high efficiency in subjects with only small punctate WMH as well as in subjects with large WMHs (i.e., with confluency) in evaluation datasets from three distinct databases: magnetic resonance imaging-Share consisting of young university students, MICCAI 2017 WMH challenge dataset consisting of older patients from memory clinics, and UK Biobank with community-dwelling middle-aged and older adults. Across these three cohorts with a wide-ranging WMH load, our tool achieved voxel-level and individual lesion cluster-level Dice scores of 0.66 and 0.71, respectively, which were higher than for three reference tools tested: the lesion prediction algorithm implemented in the lesion segmentation toolbox (LPA: Schmidt), PGS tool, a DL-based algorithm and the current winner of the MICCAI 2017 WMH challenge (Park et al.), and HyperMapper tool (Mojiri Forooshani et al.), another DL-based method with high reported performance in subjects with mild WMH burden. Our tool is publicly and openly available to the research community to facilitate investigations of WMH across a wide range of severity in other cohorts, and to contribute to our understanding of the emergence and progression of WMH., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets., (© 2023. The Author(s).)

Aims: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia., Methods and Results: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk., Conclusion: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia., Classification of Evidence: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo., Competing Interests: Conflict of interest: The authors report no targeted funding. R.P. is funded by the Australian National Health and Medical Research Centre Australian Dementia Centre for Research Collaboration, and Neuroscience Research Australia; Y.X. is funded by NHMRC Project Grant (APP1160373); M.W. and C.S.A. are supported by Investigator Grants (APP1174120 and GNT1175861 respectively) from the National Health and Medical Research Council (NHMRC) of Australia, and together with J.C. receive funding from an NHMRC Program Grant (APP1149987); M.W. is a consultant to Amgen, Kyowa Kirin, and Freeline; J.C. has received research grants from Servier, and from the NHMRC for both PROGRESS and ADVANCE, and honoraria from Servier for speaking about them at Scientific meetings; C.S.A. has received research grants from Penumbra, Takeda, Credit, and Genesis paid to his institution., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The aim of this study was to (1) investigate the association of parental death and illness with suicidal ideation using a large sample of university students and (2) test whether associations were moderated by perceived family support., Methods: We used data from N = 15,008 French university students enrolled in the i-Share cohort (mean age, 20.5 years; 77% women). Students self-reported information on parental death, including the cause, parental illness (cardiovascular, stroke, cancer, depression/anxiety, alcohol abuse), and perceived family support during childhood/adolescence. Twelve-month suicidal ideation was self-reported and categorized into no, occasional, and frequent ideation., Results: Occasional and frequent suicidal ideation were, respectively, reported by 2692 (17.5%) and 699 (4.6%) students. After adjustment for age, gender, and parental education, we found associations between parental death and risk of occasional and frequent suicidal ideation (respectively, RR = 1.98 [1.81-2.17] and RR = 2.73 [2.30-3.24]). Parental deaths from illness, accidents, and suicides had the strongest associations. We also found associations for parental depression/anxiety (occasional, RR = 1.98 [1.81-2.17]; frequent, RR = 2.73 [2.30-3.24]), alcohol use problems (occasional, RR = 1.71 [1.5-1.94]; frequent, RR = 2.33 [1.89-2.87]), and cardiovascular diseases (occasional, RR = 1.22 [1.06-1.40]; frequent, RR = 1.83 [1.47-2.27]). For participants who experienced parental death and stroke, associations with occasional and frequent suicidal ideation (respectively) increased as perceived family support increased (Ps interaction  ≤ 0.005)., Conclusions: Students who experienced parental death and common parental illnesses were at risk of reporting suicidal ideation, especially if their family were perceived as an important source of support. As information on parental death or illness can be routinely collected during health visits, attention should be paid to students reporting such experiences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The aim of the study is to describe the use of antihypertensive and lipid-lowering drugs in post-stroke secondary prevention in France. This is a prospective cohort study based on a representative sample of the French health insurance system database. All patients aged 45 and over, hospitalized for a first stroke between 1 January 2009 and 31 December 2014 were included. For each drug class, identified using Anatomical Therapeutic Chemical (ATC) codes, patients were followed from the first drug supply after stroke until the end of study period (31 December 2017), or exit date of the database or death. Adherence was defined by the proportion of days covered and persistence by the absence of a treatment gap of more than 91 days. A total of 2674 patients were included, median age was 75.0 years (interquartile range 63.0-83.0) and 51.2% were women. For patients treated with a drug of interest after stroke, median follow-up was 4.8 years (interquartile range 3.4-6.5). Regarding antihypertensive drugs, adherence at 8 years was 84.1% and persistence was 71.0%. For lipid-lowering drugs adherence at 8 years was 68.6% and persistence was 49.4%. Adherence and persistence were lower for patients starting treatment at time of stroke (antihypertensive drugs: 70.9% for adherence and 52.6% for persistence; lipid-lowering drugs: 62.3% and 43.1%) compared to patients already treated (antihypertensive drugs: 87.2% and 75.2%; lipid-lowering drugs: 73.6% and 54.5%). In this large representative sample of patients hospitalized for a first stroke in France, post-stroke therapeutic management remains suboptimal compared to guidelines, notably regarding lipid-lowering drugs. This trend was more pronounced for newly treated patients., (© 2022 Société Française de Pharmacologie et de Thérapeutique.)

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

[Figure: see text].

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Background: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies., Methods: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks., Results: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ 2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks., Conclusions: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors., (© 2017 American Heart Association, Inc.)

Background and Purpose: White matter hyperintensity (WMH) volume and covert brain infarcts are highly prevalent in older adults and are often asymptomatic. We compared the impact of WMH volume and brain infarcts on risk of clinical stroke and dementia in older adults in the population., Methods: Participants were 1677 individuals aged ≥65 years from the 3-City Dijon study, who were free of stroke and dementia at baseline, followed-up for ≤12 years., Results: Both lesion types were comparably associated with an increased risk of stroke (adjusted hazard ratio, 1.72; 95% confidence interval, 1.24-2.40 for WMH volume and hazard ratio, 2.15; 95% confidence interval, 1.18-3.93 for brain infarcts), but only WMH volume was associated with an increased risk of dementia (hazard ratio, 1.41; 95% confidence interval, 1.09-1.83)., Conclusions: The differential impact of WMH and brain infarcts on clinical stroke and dementia suggests relatively different prognostic value of the 2 lesions. WMHs may represent a particularly pertinent magnetic resonance imaging intermediate marker that can be utilized in optimizing prevention strategies for both stroke and dementia in primary care and in trials., (© 2016 American Heart Association, Inc.)

Background and Purpose: The aim was to determine the association between antihypertensive drug class and incident stroke controlling for long-term blood pressure (BP) variability (BPV) in people aged ≥65 years., Methods: The sample included 5951 participants (median age 74 years, 60% women) taking at least 1 drug for hypertension (3727/5951) or with systolic BP >140 mm Hg or diastolic BP >90 mm Hg. Participants were evaluated for incident fatal and nonfatal stroke to 12 years follow-up. BPV was calculated with the coefficient of variation method and regressed against 9 antihypertensive drug classes (BPVreg). Hazard models were used to determine hazard ratios for incident stroke risk attributable to drug class, adjusted for BP, BPVreg, covariates, and delayed entry bias., Results: There were 273 incident strokes over a median of 9.1 years (interquartile range 6.4-10.4). Stroke risk was generally not reduced by BP-lowering drugs. Angiotensin receptor blockers (hazard ratio 1.56; 95% confidence interval 1.06-2.28; P=0.02) and β-blockers (hazard ratio 1.41; 95% confidence interval 1.03-1.92; P=0.03) were associated with an increased total stroke risk. Angiotensin receptor blockers and β-blockers were also associated with ischemic strokes after adjustment for systolic BPV. Diastolic BPV was associated with stroke risk in analyses stratified by systolic BP 140 to 160 mm Hg (per 0.10 increase in coefficient of variation, hazard ratio 1.59; 95% confidence interval 1.05-2.40; P=0.03)., Conclusions: The angiotensin receptor blocker and β-blocker drug classes were associated with incident stroke and ischemic stroke in older adults. BPV was generally not associated with incident stroke., (© 2016 American Heart Association, Inc.)

Backround: Baseline depressive symptoms have been consistently associated with the onset of cardiovascular disease (CVD)., Objectives: Since depressive symptoms vary over time in elderly persons, and to help clarify whether or not depression is an etiological factor for CVD, we quantified the association between the course of depressive symptoms and occurrence of first coronary heart disease (CHD) and stroke events in older adults., Design: A population-based prospective observational study., Setting: Participants were randomly selected from the electoral rolls of three large French cities., Participants: A total of 9,294 participants were examined at baseline between 1999 and 2001, and thereafter at repeated study visits over 10 years., Measurements: High levels of depressive symptoms (HLDS) were defined as a score≥16 on the 20-item Center for Epidemiologic Studies Depression Scale. The number of study visits with HLDS was used as a time dependent variable in Cox proportional hazard models., Results: There were 7,313 participants (36.6% males) aged 73.8±5.4 years with no history of CHD, stroke or dementia at baseline. After a median follow-up of 8.4 years (SD 2.3 years), 629 first CHD or stroke events occurred. After adjustment for sociodemographic characteristics and vascular risk factors, the risk of CHD and stroke combined increased 1.15-fold (95% CI: 1.06 to 1.25) per each additional study visit with HLDS. The results remained unchanged when accounting for the presence of disability and antidepressant intake at baseline and during follow-up., Conclusion: Elderly persons exposed to HLDS at several occasions over 10 years showed substantial increased risk of coronary heart disease and stroke events., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Objective: To determine the association between use of lipid lowering drugs (statin or fibrate) in older people with no known history of vascular events and long term risk of coronary heart disease and stroke, Design: Ongoing prospective population based cohort study recruited in 1999-2000, with five face-to-face examinations., Setting: Random sample of community dwelling population aged 65 years and over, living in three French cities (Bordeaux, Dijon, Montpellier)., Participants: 7484 men and women (63%) with mean age 73.9 years and no known history of vascular events at entry. Mean follow-up was 9.1 years., Main Outcome Measures: Adjusted hazard ratios of coronary heart disease and stroke in baseline lipid lowering drug users compared with non-users, calculated using multivariable Cox proportional hazard models adjusted for numerous potential confounding factors. Hazard ratios were estimated for use of any lipid lowering drug and for statin and fibrate separately., Results: Lipid lowering drug users were at decreased risk of stroke compared with non-users (hazard ratio 0.66, 95% confidence interval 0.49 to 0.90); hazard ratios for stroke were similar for statin (0.68, 0.45 to 1.01) and fibrate (0.66, 0.44 to 0.98). No association was found between lipid lowering drug use and coronary heart disease (hazard ratio 1.12, 0.90 to 1.40). Analyses stratified by age, sex, body mass index, hypertension, systolic blood pressure, triglyceride concentrations, and propensity score did not show any effect modification by these variables, either for stroke or for coronary heart disease., Conclusion: In a population based cohort of older people with no history of vascular events, use of statins or fibrates was associated with a 30% decrease in the incidence of stroke., (© Alpérovitch et al 2015.)

Background: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies., Methods and Results: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16)., Conclusions: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms., (© 2015 American Heart Association, Inc.)

Objective: There is ongoing controversy regarding a 'J-curve' phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke. We aimed to determine whether large treatment-related BP reductions are associated with increased risks of recurrent stroke., Design: Data are from the PROGRESS trial, where 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). There were no BP criteria for entry. BP was measured at every visit, and participant groups defined by reduction in systolic BP (SBP) from baseline were used for the analyses. Outcome was recurrent stroke., Results: During a mean follow-up of 3.9 years, 727 recurrent strokes were observed. There were clear associations between the magnitude of SBP reduction and the risk of recurrent stroke. After adjustment for cardiovascular risk factors and randomised treatment, annual incidence was 2.08%, 2.10%, 2.31% and 2.96% for participant groups defined by SBP reductions of ≥ 20, 10-19, 0-9 and <0 mm Hg, respectively (p=0.0006 for trend)., Conclusions: The present analysis provided no evidence of an increase in recurrent stroke associated with larger reductions in SBP produced by treatment among patients with cerebrovascular disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: To determine the interrelationships between baseline Mini-Mental State Examination (MMSE) score and risk of overall dementia, post-recurrent stroke dementia, and dementia without recurrent stroke among patients with a history of stroke., Methods: Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline MMSE score was available. Baseline MMSE score was divided into 4 categories: 30, 29-27, 26-24, and <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression models were used to examine the association between MMSE score and dementia., Results: Of the 6080 participants included in this analysis, 2493 had an MMSE score of 30, 1768 had a score of 29-28, 1369 had a score of 26-24, and 450 had a score of <24. Average follow-up time was 3.8 years. There were 407 cases of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing MMSE score. However, the impact of MMSE score on the risk of dementia without recurrent stroke was much stronger than the impact of MMSE score on the risk of post-recurrent stroke dementia. For those with MMSE score <24, the risk of dementia without recurrent stroke was 47.89 (95% confidence interval, 28.57-80.26), whereas the risk of post-recurrent stroke dementia was only 7.17 (95% confidence interval, 3.70-13.89). Higher MMSE scores were even less strongly associated with the risk of post-recurrent stroke dementia., Conclusions: Patients with stroke with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline.

To investigate the association between baseline depressive symptoms and first fatal and non fatal coronary heart disease (CHD) and stroke in older adults, taking antidepressants and disability into account. In the Three City Study, a community-based prospective multicentric observational study cohort, 7,308 non-institutionalized men and women aged ≥65 years with no reported history of CHD, stroke or dementia, completed the 20-item Center for Epidemiologic Studies depression scale (CESD) questionnaire. First CHD and stroke events during follow-up were adjudicated by an independent expert committee. Hazard ratios (HRs) were estimated by Cox proportional hazard model. After a median follow-up of 5.3 years, 338 subjects had suffered a first non-fatal CHD or stroke event, and 82 had died from a CHD or stroke. After adjustment for study center, baseline socio-demographic characteristics, and conventional risk factors, depressive symptoms (CESD ≥ 16) were associated with fatal events only: fatal CHD plus stroke (HR = 2.50; 95% CI 1.57-3.97), fatal CHD alone (n = 57; HR = 2.21 ; 95%CI 1.27-3.87), and fatal stroke alone (n = 25; HR = 3.27; 95% CI 1.42-7.52). These associations were even stronger in depressed subjects receiving antidepressants (HR = 4.17; 95% CI 1.84-9.46) and in depressed subjects with impaired Instrumental Activities of Daily Living (HR = 8.93; 95% CI 4.60-17.34). By contrast, there was no significant association with non fatal events (HR for non-fatal CHD or stroke = 0.94; 95% CI 0.66-1.33). In non-institutionalized elderly subjects without overt CHD, stroke or dementia, depressive symptoms were selectively and robustly associated with first fatal CHD or stroke events.

Background and Purpose: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy., Methods: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding., Results: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%-69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg)., Conclusions: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy.

Objective: We assessed whether excessive daytime sleepiness (EDS) at baseline was associated with subsequent coronary heart disease (CHD) and stroke events., Methods: The Three City Study, a French population-based multicenter prospective study, included 7,007 subjects aged ≥65 years with no personal history of CHD, stroke, or dementia, and self-rated EDS as never, rare, regular, or frequent in response to a face-to-face questionnaire. Hazard ratios (HRs) for the first episode of stroke and CHD over 6 years were estimated using a Cox proportional hazards model with age as the time scale., Results: The mean age of the cohort was 73.7 years (standard deviation, 5.37), 63% were women, and 13.3% and 4.3% reported regular and frequent EDS, respectively. After a median follow-up period of 5.1 years, 372 subjects experienced a first event, either stroke (122 subjects) or a CHD event (250 subjects). The increased risk of CHD and stroke was confined to the group with frequent EDS, and was 1.73× as much as in the group that reported never having EDS (HR, 1.73; 95% confidence interval [CI], 1.15-2.60), after adjustment for confounding and mediating factors. This association was seen in those without hypertension but not in those with hypertension at baseline (p for interaction = 0.01). Moreover, the association with frequent EDS was statistically significant for stroke (HR, 2.10; 95% CI, 1.13-3.89) but not for CHD (HR, 1.51; 95% CI, 0.87-2.61)., Interpretation: The current study suggests that frequent EDS is independently associated with future vascular events and stroke in particular in healthy community-dwelling elderly subjects., (Copyright © 2011 American Neurological Association.)

Background: stroke has been shown to follow a social gradient with incidence rising as socioeconomic status decreases., Objective: to examine the relationship between socioeconomic status and ischaemic stroke risk amongst older people., Setting: the Cities of Bordeaux, Dijon and Montpellier in France., Subjects and Methods: nine thousand and two hundred and ninety-four non-institutionalised persons aged 65 years or more followed for 6 years., Results: the distribution of cardiovascular risks factors was consistent with the classical finding of more favourable risk profiles among the advantaged socioeconomic groups. One hundred and thirty-six individuals developed a first ever ischaemic stroke (incidence rate: 3.2 per 1,000 py (person-years), 95% CI 2.7-3.8). The age- and sex-adjusted incidence of ischaemic stroke increased with increasing level of income (from 2.4 to 4.1 per 1,000 py, P = 0.04). In the multivariable analysis adjusting for cardiovascular risk factors, the higher income group displayed a 80% increased risk of ischaemic stroke compared with less wealthy participants (hazards ratio 1.77, 95% CI 1.20-2.61)., Conclusions: in this community-based sample of older individuals, a higher level of household income was associated with a higher risk of ischaemic stroke, a reversal of the social gradient usually reported in younger age groups. Selective survival is one of the potential explanations for this unexpected finding.

Objective: To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke., Design: Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010., Data Sources: Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. Selection criteria Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. Review methods and data extraction Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated., Results: Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E., Conclusion: In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.

Objectives: To examine the association between migraine and migraine aura status with risk of haemorrhagic stroke., Design: Prospective cohort study., Setting: Women's Health Study, United States., Participants: 27,860 women aged >or=45 who were free from stroke or other major disease at baseline and had provided information on self reported migraine, aura status, and lipid values., Main Outcome Measures: Time to first haemorrhagic stroke and subtypes of haemorrhagic stroke., Results: At baseline, 5130 (18%) women reported any history of migraine; of the 3612 with active migraine (migraine in the previous year), 1435 (40%) described having aura. During a mean of 13.6 years of follow-up, 85 haemorrhagic strokes were confirmed after review of medical records. Compared with women without a history of migraine, there was no increased risk of haemorrhagic stroke in those who reported any history of migraine (adjusted hazard ratio 0.98, 95% confidence interval 0.56 to 1.71, P=0.93). In contrast, risk was increased in women with active migraine with aura (2.25, 1.11 to 4.54, P=0.024). The age adjusted increased risk was stronger for intracerebral haemorrhage (2.78, 1.09 to 7.07, P=0.032) and for fatal events (3.56, 1.23 to 10.31, P=0.02). Four additional haemorrhagic stroke events were attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura had no increased risk for haemorrhagic stroke., Conclusion: Migraine with aura might, in addition to ischaemic events, also be a risk factor for haemorrhagic stroke. The relatively low number of events and attributable risk should caution against definitive conclusions and call for further confirmation of these observations.

Background: Few studies have assessed the relationship between triglycerides and the risk of hemorrhagic stroke, which contrasts the considerable number of studies about triglycerides and ischemic vascular events. We analyzed the association pattern between triglycerides and incident intracerebral hemorrhage as compared with coronary events and ischemic stroke, in a large cohort of elderly., Methods: Population-based, prospective cohort study among 8393 men and women participating in the Three-City Study, aged > or = 65 years at baseline. Fasting blood lipids, including triglycerides, were measured at baseline. Fatal and non-fatal strokes and coronary events were adjudicated and validated by scientific committees. Cox proportional hazards models were used to adjust for potential confounders., Results: During a mean follow-up of 5.0 years, 36 hemorrhagic strokes, 143 ischemic strokes, and 393 coronary events occurred. An increased level of triglycerides was associated with an increased risk of ischemic vascular events. Conversely, a low level of triglycerides (< or = 0.94 mmol/L) was associated with an increased risk of hemorrhagic stroke (adjusted hazard ratio 2.35; 95% confidence interval 1.18-4.70). The relationship with hemorrhagic stroke was mainly apparent in men, in individuals with high blood pressure, and in those with low levels of cholesterol., Conclusions: In this large cohort of elderly men and women, low triglycerides levels were associated with an increased risk of hemorrhagic stroke and a decreased risk of ischemic vascular events. The association between triglycerides and hemorrhagic stroke was particularly strong in men, in subjects with high blood pressure and in those with low cholesterol levels., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the benefits of blood pressure (BP) lowering on vascular events separately for Asian and for Western participants with particular emphasis on stroke subtypes and cardiac outcomes., Methods: This is a subsidiary analysis of Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a randomized, placebo-controlled trial that established the benefits of BP lowering in 6105 patients with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, and indapamide for those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s). Outcomes are total and cause-specific vascular outcomes., Results: The annual rates for total major vascular events were 4.2% in Asian and 5.2% in Western participants. Overall stroke rates were greater in Asian compared to Western participants with proportionally more lacunar infarctions and haemorrhagic strokes in Asians and more cardio-embolic infarctions and large artery infarctions in Western participants. Active treatment reduced BP by 10.3/4.6 mmHg in Asian, and by 8.1/3.6 mmHg in Western participants. Among Asian participants there was a 38% [95% confidence interval (CI) 23-49%] reduction in major vascular events compared to a 20% (95% CI 7-31%) reduction in Western participants (P homogeneity = 0.06). Similarly, there were higher relative risk reductions for all other outcomes among Asian participants, but this only reached statistical significance for heart failure and vascular death (P = 0.02 for each). The number needed to treat for major vascular events over 5 years was 15 (95% CI 10-26) in Asian compared to 28 (95% CI 17-94) in Western participants (P homogeneity = 0.09)., Conclusions: BP lowering reduces the risk of major vascular events, with separately significant reductions, in both Asia and the West.

Background and Purpose: White matter lesions (WMLs) have been shown to be associated with the risk of stroke in previous studies but little is known about the prediction of other vascular events. We evaluated the risk of stroke and other vascular events according to WML volume in a large population-based sample. We also studied WML volume by type (deep or periventricular) in relation to these events., Methods: The 3-City Study is a population-based prospective cohort of people aged >or=65 years followed up for, on average, 4.9 years. Among them, 1643 participants free of prevalent vascular events had quantitative measurements of WML volume at baseline using a fully automatic method. The risks of incident major vascular events according to WML volume were evaluated using Cox proportional hazards models., Results: The risk of incident stroke significantly increased with increasing baseline WML volume and was multiplied by 5 for those in the highest quartile of WML volume. Nonstroke vascular events' incidence was not associated with WML volumes, whatever their type., Conclusions: WMLs are an independent predictor of stroke in the elderly. This association is specific because WMLs are not associated with the risk of other vascular events.

Background and Purpose: External validation of the Framingham stroke risk function has been rarely performed. We assessed its predictive ability in a population-based cohort of French elderly., Methods: The sample comprised 6913 subjects from the 3C Study, aged 65 to 84 at baseline, who were followed up to 6 years. Predictive accuracy of the original Framingham stroke risk function was assessed in a 3-step procedure: comparison between the Framingham and 3C cohorts of the prevalence of selected risk factors and the associated relative risks (RR) for stroke, comparison of the predicted to the observed number of stroke events (calibration), and ability to separate high-risk from low-risk participants (discrimination). We also compared predictive performances of the original Framingham, the recalibrated Framingham, and the local stroke risk functions., Results: During follow-up, 110 incident strokes occurred. For most risk factors, RRs were comparable between the 2 cohorts, except for age in women. The original Framingham stroke risk function applied to the 3C cohort overestimated the 6-year absolute risk for stroke by a factor of 3.7 for men and 4.4 for women. However, the recalibrated Framingham and 3C functions did not show any over- or underestimation of stroke risk. The 3 stroke risk functions (original, recalibrated, and 3C) provided acceptable discrimination with areas under the ROC curve ranging from 0.67 to 0.73., Conclusions: The original Framingham stroke risk function strongly overestimated the stroke risk for 3C participants. Derived Framingham stroke score sheets should not be directly used by physicians in the French elderly population.

Background and Purpose: Excessive daytime sleepiness, one of the most frequent sleep complaints in the elderly, may affect survival, but inconsistent results have been observed in that population so far. We therefore estimated the risk of mortality for excessive daytime sleepiness (EDS) in community-dwelling elderly participating in the Three City Study., Methods: The Three City Study is a French population-based multicenter prospective study including 9294 subjects (60% women) aged >or=65 years at recruitment between 1999 to 2001. At baseline, 8269 subjects rated EDS and nocturnal sleep complaints as never, rare, regular, and frequent in response to an administered questionnaire and provided information on medication use for sleep or anxiety. Hazard ratios (HR) of EDS (regular or frequent) for mortality over 6 years were estimated by a Cox proportional hazard model., Results: At baseline, 18.7% of the study participants had regular or frequent EDS. After 6 years of follow-up, 762 subjects had died including 260 from cancer and 196 from cardiovascular disease. EDS was associated with a significant 33% increased risk of mortality (95% CI: 1.13 to 1.61) after adjustment for age, gender, study center, body mass index, previous cardiovascular disease, Mini Mental State Examination score, and cardiovascular risk factors. Further adjustment for current use of medication for sleep and for depressive symptoms slightly diminished the HRs. EDS was equally predictive of mortality in those who snored loudly and in those who did not. EDS was related to cardiovascular mortality but not to mortality attributable to cancer., Conclusions: EDS might be independently associated with total and cardiovascular mortality in community-dwelling elderly.

Background and Purpose: The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)-lowering., Methods: Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP-lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s)., Results: Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4)., Conclusions: Patients with previous vascular events are at high risk of recurrences of the same event. However, because they are also at risk of other vascular outcomes, a broad range of secondary prevention strategies is necessary for their treatment. BP-lowering is likely to be one of the most effective and generalizable strategies across a variety of major vascular events including stroke and myocardial infarction.

Background: The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease., Methods and Results: The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001)., Conclusions: These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.

Background and Purpose: Several constitutional and environmental risk factors may be involved in the occurrence of spontaneous cervical artery dissection (SCAD). This work explored the association between recent infection and SCAD in an hospital-based case-control study., Methods: Forty-seven patients with SCAD and 52 with ischemic stroke from another cause were prospectively and consecutively recruited by 2 neurology departments. A specially designed questionnaire was used to assess the history of an acute infection that could have occurred within a month before the vascular event., Results: Acute infection was more frequent in patients with SCAD (31.9%) than in control subjects (13.5%) (crude odds ratio, 3.0; 95% confidence interval, 1.1 to 8.2; P=0.032). This association was stronger in patients with multiple (odds ratio, 6.4) than single artery (odds ratio, 2.1) dissection., Conclusions: Recent infection is a risk factor and could be a trigger for SCAD.

Background and purposePeriventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.MethodsParticipants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.ResultsIn the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.ConclusionsOur study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population‐based studies using conventional T2‐weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population‐based studies with brain MRI scans. We estimated and meta‐analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13–2.68) and 1.48 (95% CI, 1.12–1.96) fold, respectively. For stroke, meta‐analyses yielded HRs of 1.59 (95% CI, 1.04–2.42) for overall arteries and 2.11 (95% CI, 1.45–3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2‐weighted brain MRI‐based brain diameter assessment in estimating the risk of dementia and stroke. [ABSTRACT FROM AUTHOR]

BackgroundThe burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.Methods and resultsWe included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).ConclusionsWe identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Background: Stroke and transient ischemic attack confer greater risk of cognitive decline and dementia. Aims: We used data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a blood pressure-lowering randomized controlled trial in stroke/transient ischemic attack. We evaluated overall and sex-specific differences in treatment effects for cognitive decline/dementia, as well as associations with vascular and stroke-specific predictors,considering death as a competing risk. Methods: Multinomial logistic regression was used to estimate overall and sex-specific odds ratios (OR) (95% confidence intervals (CI)) for treatment effects and predictors associated with the risk of cognitive decline/dementia, and the women-to-men ratio of odds ratio (RORs). Results: Over a median four years, 763 cognitive decline/dementia (30.9% women) were recorded in 5888 participants. Women had lower odds of cognitive decline/dementia than men (OR 0.78, 95%CI 0.63–0.95). Active treatment was associated with lower odds of cognitive decline/dementia (0.84, 0.72–0.98), with no evidence of sex difference. Higher education (0.96,0.94–0.98 (per year)) and baseline Mini-Mental State Examination (MMSE)) were associated with lower odds of cognitive decline/dementia (0.84,0.82–0.86 (per point higher)). Higher diastolic blood pressure (1.11,1.02–1.20 (per 10 mmHg)), low estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (1.27,1.03–1.58), and peripheral arterial disease (1.78,1.26–2.52) were associated with higher odds of cognitive decline/dementia. APOE ɛ4 was not associated with cognitive decline/dementia (1.05 (0.85–1.30)). Low eGFR was more strongly associated with cognitive decline/dementia in women than men (RORs, 1.60 (1.03–2.48)). Diabetes was more strongly associated with men than women. Conclusions: Several risk factors were associated with cognitive decline/dementia in people with prior stroke/transient ischemic attack, with notable sex differences. Long-term cognitive sequelae of stroke should be considered to strengthen joint prevention strategies for stroke, cognitive decline, and dementia. Trial Registration: This trial was not registered because enrolment began before 1 July 2005. [ABSTRACT FROM AUTHOR]