Advances in Stroke

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

See related article, pages 825–832. With a swiftly moving, highly technical field, it helps to have a reliable guide. In this issue of Stroke, Lanktree et al1 provide a timely overview of genomic analysis applied to stroke.1 Readers find a clear and concise synopsis of single-nucleotide polymorphisms, copy number variations, listings of the strengths and limitations of genome-wide association studies (GWAS), and a distillation of the findings from GWAS performed in 6 cohorts (5 of which were ischemic stroke cohorts). The review also covers a topic not usually found in clinical reviews, namely techniques to visually display quantitative information. Excellence in statistical graphics should, among other things, avoid distorting what the data have to say, present many numbers in a small space, and make large data sets coherent.2 The Manhattan and quantile–quantile plots are excellent examples of statistical graphics that have become invaluable for interpreting GWAS results. Along with visualization comes interpretation of data in the context of GWAS. Clinical investigators are well aware of the problem of multiple testing from such settings as interim and subgroup analyses in clinical trials, which can lead to wildly spurious conclusions, such as concluding that aspirin only helped individuals of certain astrological signs in the second International Study of Infarct Survival.3 GWAS simply escalates the problem of multiple testing by orders of magnitude. Because single-nucleotide polymorphism-based GWAS test hundreds of thousands …

Causes of death in both ischemic stroke (IS) and hemorrhagic stroke (HS) subtypes are not comprehensively studied. Between 2008 and 2011, we enrolled 11 215 first-ever stroke patients from the Stroke Registry of Chang-Gung Healthcare System and linked these data to the national death registry. The main causes of death in each stroke subtype were assessed. Patients with HS had higher overall mortality than IS (32.0% vs 18.1%, P < .001). In IS subtypes, large-artery atherosclerosis plus cardioembolism had the worst mortality (40.7%, P < .001). Stroke was the leading cause of death in both IS and HS within the first year. Stroke remained the major cause of death in HS, but cancer was the leading cause of death in IS after the first year. After excluding the patients with previous cancer history, cancer was still an important cause of death in IS and HS, particularly in the IS subtypes of small vessel occlusion, stroke of undetermined etiology, and transient ischemic attack.

Background: Family history (FHx) of stroke is perceived to be an important risk factor for ischaemic stroke. However, there are several intermediate phenotypes that are often involved in the aetiology of ischaemic stroke and that have a substantial genetic component themselves. We studied FHx of ischaemic heart disease (IHD), hypertension (HTN) and diabetes mellitus (DM) as risk factors for ischaemic stroke. Methods: We performed a systematic review of case-control and cohort studies reporting on FHx_IHD, FHx_HTN or FHx_DM as risk factors for stroke using bibliographic databases, and by hand searching reference lists and journals. Odds ratios of FHx as a risk factor for stroke were calculated within individual studies. We included unpublished data from two Oxfordshire population-based studies to assess effects on subtypes of ischaemic stroke. Results: We identified 54 studies that investigated the odds of stroke conferred by a positive FHx, 24 of which reported data on FHx of one or more intermediate phenotypes in addition to FHx of stroke. Most studies reported an increased frequency of FHx_IHD and FHx_HTN in stroke patients versus controls. The association was significant in 6 out of 14 studies for FHx_IHD and 4 out of 11 studies for FHx_HTN. In contrast, FHx_DM was not associated with stroke. FHx_IHD was particularly associated with large vessel strokes (OR 1.72, CI 1.3–2.2, p = 0.00004). Conclusions: FHx_IHD and FHx_HTN are both risk factors for stroke. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN and large vessel atherosclerosis. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly.

Chinese have a higher stroke incidence and a different distribution of ischemic stroke (IS) subtypes as compared with Caucasians. Herein we aimed to investigate the prevalence and associations of major risk factors in IS and its subtypes in Chinese patients. From 2006 to 2011, we included 4953 acute IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry (mean age 68 years; male 59%). For each risk factor, we accessed the proportion in all IS patients, and calculated odds ratios for each main IS subtype versus other subtypes. Multiple logistic regression models were used to adjust for confounders, and to examine the associations of risk factors with IS subtypes. Compared with other ischemic subtypes, large artery atherosclerotic and lacunar strokes were associated with hypertension, diabetes, and hyperlipidaemia, while cardioembolic strokes were associated with ischemic heart disease. Furthermore, the associations with hypertension and diabetes became stronger in lacunar strokes after adjusting for confounders, but not in other ischemic subtypes. Here we report the variable effects of risk factors on different IS subtypes in Chinese patients in Taiwan. Our findings could help shed light on different mechanisms of IS subtypes and provide targets to make more effective strategies for IS prevention.

Background: The Stroke Genetics Network (SiGN) funded by the NINDS aims to identify genetic risk factors in ischemic stroke using whole-genome association studies (GWAS). High quality phenotyping is crucial to successful application of GWAS. As a heterogenous disorder, stroke poses specific challenges. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is a broadly used, but its validity is challenged especially when performed by multiple investigators with differing interpretations of the system. The Causative Classification System for Ischemic Stroke (CCS) system is a new, web-based, and computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner ( ccs.mgh.harvard.edu ) to generate subtypes. Methods: In planning the SiGN proposal, a sample of 20 coded charts were collected from a subset of participating studies to assess feasibility of central adjudication and comparability to study-specific TOAST. Two central adjudicators reviewed all records and generated TOAST and CCS subtypes. These were compared to study-specific TOAST subtype and the CCS phenotype generated for SiGN by local trained adjudicators. CCS data is now available for 7134 included cases using both a 5 and a 7 category system as defined in the table . Results: All 4 phenotypes were available for 115 ischemic stroke cases from 6 studies in SiGN. Basic demographics were 54% women, 63% white, and median age between 65-74. Table 1 provides the agreement between the various subtypes. Table 2 describes the types of disagreement. Conclusions: Central adjudication with only two adjudicators and curated medical records yielded more consistent subtyping independent of phenotyping system. The agreement for TOAST was higher than published rates by independent groups (∼0.50). In contrast, the agreement for CCS was lower than previously published (0.85-0.95). Site adjudicators' familiarity with TOAST and inexperience with CCS may contribute. Although CCS is an automated algorithm and has a number of user friendly features, our findings suggest that formal training and certification process before starting to use CCS may be worthwhile to achieve optimal benefit from the system.

Backround: It is very important to know and detect various stroke symptoms because stroke is an emergency condition. Lack of knowledge about stroke symptoms leads to delay on stroke treatment. Objective: The aim of this study is to compare clinical symptoms and risk factors between ischemic and hemorrhagic stroke. Methods: This study was a case control study. The subjects in this study were ischemic and hemorrhagic stroke patients. Subject data were recorded in electronic stroke registry at Bethesda Hospital, Yogyakarta. Results: The most common clinical symptoms in both groups were limb weakness (76.4% vs 71.4%), whereas the rarest was face drooping (2% vs 3.6%). Hypertension was the most common risk factor in both group (48% vs 71.4%), whereas atrial fibrillation was the rarest. This study did not find the specific correlation between any clinical symptoms to ischemic stroke incidence, however, decrease a level of consciousness was significant to hemorrhagic stroke incidence (OR: 2.738, 95% CI: 1.503-4.990, p: 0.001). Previous stroke (OR: 2.413, 95% CI: 1.314-4.433, p: 0.005) and dyslipidemia (OR: 4.862, 95% CI: 2.613-9.045, p: 0.000) were significant increasing risk of ischemic stroke. Hypertension was only the significant increasing risk of hemorrhagic stroke (OR: 3.680, 95% CI: 2.086-6.492, p: 0.000). Conclusion: Decrease level of consciousness has a significant correlation to hemorrhagic stroke incidence, but there is no specific symptom correlate to ischemic stroke incidence. Previous stroke and dyslipidemia are significant risk factors for ischemic stroke, whereas hypertension is the only significant risk factor for hemorrhagic stroke.

The Scandinavian Candesartan Acute Stroke Trial (SCAST) found no benefits of blood pressure-lowering treatment with candesartan in acute stroke. We have investigated whether the effect of treatment is different in different subtypes of ischemic stroke. SCAST was a randomized- and placebo-controlled trial of candesartan in 2029 patients presenting within 30 hours of ischemic or hemorrhagic stroke and systolic blood pressure ≥140 mm Hg. Ischemic stroke subtype was categorized by the Oxfordshire Community Stroke Project classification. There were 2 primary effect variables: the composite vascular end point of vascular death, myocardial infarction, or stroke during the first 6 months and functional outcome at 6 months. A total of 1733 patients with ischemic stroke were included: total anterior circulation infarcts in 129, partial anterior in 850, posterior in 236, and lacunar in 510 patients. For functional outcome there was a significant trend toward a better effect of candesartan in patients with larger infarcts (total anterior circulation or partial anterior circulation) than in patients with smaller infarcts (lacunar infarction; P=0.02). For the composite vascular end point, there were no differences in treatment effect. The results suggest that the effect of blood pressure-lowering treatment with candesartan may differ according to different types of acute ischemic stroke, but this needs to be confirmed in future trials. http://www.clinicaltrials.gov. Unique identifier: NCT00120003.

Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P<0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P<0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Background Although chronic kidney disease is recognized as an independent risk factor for cerebrovascular disease, its association with hemorrhagic and ischemic stroke remains controversial. Methods A retrospective cohort study conducted using the National Health Insurance Service-National Sample Cohort, which is representative of the entire Korean population. Overall, 196,005 Korean who were not diagnosed with ischemic and hemorrhagic stroke before 2009 were included from 2009 to 2013. The eGFR was divided into six categories (≥90, 75–89, 60–74, 45–59, 30–44, &amp;lt;30 mL/min/1.73 m2). The Kaplan-Meier plot was illustrated to compare the cumulative incidence of ischemic stroke and hemorrhagic stroke. Cox proportional hazard model was used to estimate the hazard ratio (HR) of eGFR for risk of ischemic and hemorrhagic stroke. Results During an average of 4.36 years follow-up period, 2,236 and 668 people were diagnosed with newly ischemic stroke and hemorrhagic stroke, respectively. Among people with eGFR&amp;gt;90 mL/min/1.73 m2, age and sex adjusted incidence rate for ischemic stroke was 452.3 per 100,000 person-years, whereas the adjusted incidence rate for ischemic stroke among people eGFR with 30-44 and 45 mL/min/1.73m2 was 833.5 and 617.7 per 100,000 person-years, respectively. After adjusting for multiple covariates, the adjusted HR for ischemic stroke increased with decreasing eGFR (p for trend=0.005). However, there was no significant dose-response relationship between eGFR and risk of hemorrhagic stroke. Conclusions Reduced glomerular filtration rate less than 45 mL/min/1.73 m2 was associated with an increased risk of ischemic stroke but not hemorrhagic stroke. Key messages Reduction in kidney function had inverse dose-response relationship with the risk of ischemic stroke, but not with the hemorrhagic stroke. Especially, the risk of ischemic stroke was markedly increased from estimated glomerular filtration rate &amp;lt; 45 mL/min/1.73 m2.

Background and objectivesPrior evidence suggests that atrial fibrillation detected after stroke (AFDAS) is distinct from known atrial fibrillation (KAF), with particular clinical characteristics and impacts on outcomes in ischaemic stroke....

Dietary Intake of α-Linolenic Acid Is Not Appreciably Associated with Risk of Ischemic Stroke among Middle-Aged Danish Men and Women

To establish whether subtypes of ischemic stroke aggregate within ischemic stroke-affected sibling pairs more than expected by chance alone. This retrospective family study was based on a pooled analysis of two cohorts of male and female adult sibling pairs with symptomatic ischemic stroke. One hospital-based cohort of 404 individuals (first proband seen August 30, 1999) was recruited from the United States and Canada, and another population-based cohort of 198 individuals (first proband seen April 17, 1997) was recruited from Umeå, Sweden. Subtype diagnoses were based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Agreement for subtype diagnoses within families was poor (mean +/- asymptotic SE kappa = 0.17 +/- 0.04). Occurrence of one ischemic stroke subtype in a proband was not associated with a greater likelihood of that subtype being the qualifying stroke subtype in the sibling. Comparable levels of agreement were seen when restricting the analysis to same-sex sibling pairs (kappa = 0.22 +/- 0.05) to sibling pairs in which the proband's stroke occurred before the age of 65 years (kappa = 0.16 +/- 0.05) or to pairs in which the proband's stroke occurred at or after the age of 65 years (kappa = 0.19 +/- 0.05). The subtype of ischemic stroke in a proband was a poor determinant of the subtype of ischemic stroke in the respective sibling. This suggests that many genetic risk factors for ischemic stroke may not be specific for one subtype.

Scalable privacy-preserving data sharing methodology for genome-wide association studies