Caroline Jackson

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10−11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Are Lacunar Strokes Really Different? A Systematic Review of Differences in Risk Factor Profiles Between Lacunar and Nonlacunar Infarcts

Background and Purpose— Differences in risk factors between lacunar and nonlacunar infarcts might support a distinct arterial pathological process underlying lacunar infarction. Methods— We did a systematic review of studies comparing risk factors in patients with lacunar versus nonlacunar infarction. For each risk factor, we calculated study-specific and pooled relative risks (RRs) for lacunar versus nonlacunar infarction. Results— A total of 16 of 28 studies included risk factors in their ischemic stroke subtype definitions. Hypertension and diabetes appeared commoner among patients with lacunar versus nonlacunar infarction. However, analyses confined to studies using risk factor–free ischemic subtype definitions found only a marginal excess of hypertension with lacunar versus nonlacunar infarction (RR, 1.11; 95% CI, 1.04 to 1.19) and no difference for diabetes (RR, 0.95; 95% CI, 0.83 to 1.09). Atrial fibrillation and carotid stenosis were associated more with nonlacunar than lacunar infarction but less so when only studies using risk factor–free classifications were considered. Otherwise, there was no evidence of differences in risk factor profiles. Conclusions— Risk factor–free ischemic stroke subtype classification methods should be used for comparing risk factor profiles between lacunar and nonlacunar subtypes.

Improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale (BOMBS)

Background and Purpose— If the diagnostic and prognostic significance of brain microbleeds (BMBs) are to be investigated and used for these purposes in clinical practice, observer variation in BMB assessment must be minimized. Methods— Two doctors used a pilot rating scale to describe the number and distribution of BMBs (round, low-signal lesions, <10 mm diameter on gradient echo MRI) among 264 adults with stroke or TIA. They were blinded to clinical data and their counterpart’s ratings. Disagreements were adjudicated by a third observer, who informed the development of a new Brain Observer MicroBleed Scale (BOMBS), which was tested in a separate cohort of 156 adults with stroke. Results— In the pilot study, agreement about the presence of ≥1 BMB in any location was moderate (&kgr;=0.44; 95% CI, 0.32-0.56), but agreement was worse in lobar locations (&kgr;=0.44; 95% CI, 0.30-0.58) than in deep (&kgr;=0.62; 95% CI, 0.48-0.76) or posterior fossa locations (&kgr;=0.66; 95% CI, 0.47-0.84). Using BOMBS, agreement about the presence of ≥1 BMB improved in any location (&kgr;=0.68; 95% CI, 0.49-0.86) and in lobar locations (&kgr;=0.78; 95% CI, 0.60-0.97). Conclusion— Interrater reliability concerning the presence of BMBs was moderate to good, and could be improved with the use of the BOMBS rating scale, which takes into account the main sources of interrater disagreement identified by our pilot scale.

Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6

In a prospective cohort study of patient outcomes following stroke, William Whiteley and colleagues find that markers of inflammatory response are associated with poor outcomes. However, addition of these markers to existing prognostic models does not improve outcome prediction.

Genetic Heritability of Ischemic Stroke and the Contribution of Previously Reported Candidate Gene and Genomewide Associations

Background and Purpose— The contribution of genetics to stroke risk, and whether this differs for different stroke subtypes, remains uncertain. Genomewide complex trait analysis allows heritability to be assessed from genomewide association study (GWAS) data. Previous candidate gene studies have identified many associations with stoke but whether these are important requires replication in large independent data sets. GWAS data sets provide a powerful resource to perform replication studies. Methods— We applied genomewide complex trait analysis to a GWAS data set of 3752 ischemic strokes and 5972 controls and determined heritability for all ischemic stroke and the most common subtypes: large-vessel disease, small-vessel disease, and cardioembolic stroke. By systematic review we identified previous candidate gene and GWAS associations with stroke and previous GWAS associations with related cardiovascular phenotypes (myocardial infarction, atrial fibrillation, and carotid intima-media thickness). Fifty associations were identified. Results— For all ischemic stroke, heritability was 37.9%. Heritability varied markedly by stroke subtype being 40.3% for large-vessel disease and 32.6% for cardioembolic but lower for small-vessel disease (16.1%). No previously reported candidate gene was significant after rigorous correction for multiple testing. In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease (P=2.63e−6), PITX2 in cardioembolic stroke (P=4.78e−8), and ZFHX3 in cardioembolic stroke (P=5.50e−7). Conclusions— There is substantial heritability for ischemic stroke, but this varies for different stroke subtypes. Previous candidate gene associations contribute little to this heritability, but GWAS studies in related cardiovascular phenotypes are identifying robust associations. The heritability data, and data from GWAS, suggest detecting additional associations will depend on careful stroke subtyping.

Enlarged perivascular spaces and cerebral small vessel disease

Background and aims Enlarged perivascular spaces (also known as Virchow-Robin spaces) on T2-weighted brain magnetic resonance imaging are common, but their etiology, and specificity to small vessel as opposed to general cerebrovascular disease or ageing, is unclear. We tested the association between enlarged perivascular spaces and ischemic stroke subtype, other markers of small vessel disease, and common vascular risk factors. Methods We prospectively recruited patients with acute stroke, diagnosed and subtyped by a stroke physician using clinical features and brain magnetic resonance imaging. A neuroradiologist rated basal ganglia and centrum semiovale enlarged perivascular spaces on a five-point scale, white matter lesions, recent and old infarcts, and cerebral atrophy. We assessed associations between basal ganglia-, centrum semiovale- and total (combined basal ganglia and centrum semiovale) enlarged perivascular spaces, stroke subtype, white matter lesions, atrophy, and vascular risk factors. Results Among 298 patients (mean age 68 years), after adjusting for vascular risk factors and white matter lesions, basal ganglia-enlarged perivascular spaces were associated with increasing age (P = 0·001), centrum semiovale-enlarged perivascular spaces (P < 0·001), cerebral atrophy (P = 0·03), and lacunar stroke subtype (P = 0·04). Centrum semiovale- enlarged perivascular spaces were associated mainly with basal ganglia-enlarged perivascular spaces. Total enlarged perivascular spaces were associated with increasing age (P = 0·01), deep white matter lesions (P = 0·005), and previous stroke (P = 0·006). Conclusions Enlarged perivascular spaces are associated with age, lacunar stroke subtype and white matter lesions and should be considered as another magnetic resonance imaging marker of cerebral small vessel disease. Further evaluation of enlarged perivascular spaces in studies of ageing, stroke, and dementia is needed to determine their pathophysiological importance.

Differing Risk Factor Profiles of Ischemic Stroke Subtypes: Evidence for a Distinct Lacunar Arteriopathy?

Background and Purpose— Differences in risk factor profiles between lacunar and other ischemic stroke subtypes may provide evidence for a distinct lacunar arteriopathy, but existing studies have limitations. We overcame these by pooling individual data on 2875 patients with first-ever ischemic stroke from 5 collaborating prospective stroke registers that used similar, unbiased methods to define risk factors and classify stroke subtypes. Methods— We compared risk factors between lacunar and nonlacunar ischemic strokes, altering the comparison groups in sensitivity analyses, and incorporated these data into a meta-analysis of published studies. Results— Unadjusted and adjusted analyses gave similar results. We found a lower prevalence of cardioembolic source (adjusted odds ratio, 0.33; 95% CI, 0.24 to 0.46), ipsilateral carotid stenosis (odds ratio, 0.21; 95% CI, 0.14 to 0.30), and ischemic heart disease (odds ratio, 0.75; 95% CI, 0.58 to 0.97) in lacunar compared with nonlacunar patients but no difference for hypertension, diabetes, or any other risk factor studied. Results were robust to sensitivity analyses and largely confirmed in our meta-analysis. Conclusions— Hypertension and diabetes appear equally common in lacunar and nonlacunar ischemic stroke, but lacunar stroke is less likely to be caused by embolism from the heart or proximal arteries, and the lower prevalence of ischemic heart disease in lacunar stroke provides additional support for a nonatherosclerotic arteriopathy causing many lacunar ischemic strokes. Our findings have implications for how clinicians classify ischemic stroke subtypes and highlight the need for additional research into the specific causes of and treatments for lacunar stroke.

Counting Cavitating Lacunes Underestimates the Burden of Lacunar Infarction

Background and Purpose— On brain imaging, lacunes, or cerebrospinal fluid–containing cavities, are common and are often counted in epidemiological studies as old lacunar infarcts. The proportion of symptomatic lacunar infarcts that progress to lacunes is unknown. Noncavitating lacunar infarcts may continue to resemble white matter lesions. Methods— We identified patients with acute lacunar stroke, with or without an acute lacunar infarct on computed tomography or MRI, who had follow-up imaging. A neuroradiologist classified lacunar infarcts progressing to definite or possible cavities on follow-up imaging. We tested associations between cavitation and patient-related, stroke-related, and imaging-related features, including other features of small vessel disease. Results— Among 90 patients (mean age 67 years), any cavitation was present on follow-up imaging in 25 (28%), and definite cavitation in 18 (20%). Definite cavitation was associated with increasing time to follow-up imaging (median 228 days, range 54 to 1722, versus no cavitation 72 days, range 6 to 1440; P=0.0003) and deep cerebral atrophy (P=0.03) but not with age, stroke severity, larger initial infarct size, or other features of small vessel disease. Hypertension and diabetes were negatively associated with cavitation (P=0.01 and 0.02, respectively). Conclusions— Definite cavitation occurs in one fifth of symptomatic lacunar ischemic strokes, implying that most continue to resemble white matter lesions. Epidemiology and pathophysiology studies of lacunar stroke, which have only counted lacunes as lacunar infarcts, may have substantially underestimated by as much as 5 times the true burden of lacunar stroke disease.

Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents

Background: Age at natural menopause (ANM) is considered a marker of biological ageing and is increasingly recognized as a sentinel for chronic disease risk in later life. Socioeconomic position (SEP) and lifestyle factors are thought to be associated with ANM. Methods: We performed a systematic review and meta-analyses to determine the overall mean ANM, and the effect of SEP and lifestyle factors on ANM by calculating the weighted mean difference (WMD) and pooling adjusted hazard ratios. We explored heterogeneity using meta-regression and also included unpublished findings from the Australian Longitudinal Study on Women’s Health. Results: We identified 46 studies across 24 countries. Mean ANM was 48.8 years [95% confidence interval (CI): 48.3, 49.2], with between-study heterogeneity partly explained by geographical region. ANM was lowest among African, Latin American, Asian and Middle Eastern countries and highest in Europe and Australia, followed by the USA. Education was associated with later ANM (WMD middle vs low education 0.30, 95% CI: 0.10, 0.51; high vs low education 0.64, 95% CI 0.26, 1.02). A similar dose-response relationship was also observed for occupation. Smoking was associated with a 1-year reduction of ANM (WMD: -0.91, 95% CI: –1.34, –0.48). Being overweight and moderate/high physical activity were modestly associated with later ANM, but findings were less conclusive. Conclusions: ANM varies across populations, partly due to differences across geographical regions. SEP and some lifestyle factors are associated with ANM, but further research is needed to examine the impact of the associations between risk factors and ANM on future health outcomes.

Interventions to prevent substance use and risky sexual behaviour in young people: a systematic review.

AIMS To identify and assess the effectiveness of experimental studies of interventions that report on multiple risk behaviour outcomes in young people. METHODS A systematic review was performed to identify experimental studies of interventions to reduce risk behaviour in adolescents or young adults and that reported on both any substance (alcohol, tobacco and illicit drug) use and sexual risk behaviour outcomes. Two authors reviewed studies independently identified through a comprehensive search strategy and assessed the quality of included studies. The report was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS From 1129 papers, 18 experimental studies met our inclusion criteria, 13 of which were assigned a strong or moderate quality rating. The substantial heterogeneity between studies precluded the pooling of results to give summary estimates. Intervention effects were mixed, with most programmes having a significant effect on some outcomes, but not others. The most promising interventions addressed multiple domains (individual and peer, family, school and community) of risk and protective factors for risk behaviour. Programmes that addressed just one domain were generally less effective in preventing multiple risk behaviour. CONCLUSIONS There is some, albeit limited, evidence that programmes to reduce multiple risk behaviours in school children can be effective, the most promising programmes being those that address multiple domains of influence on risk behaviour. Intervening in the mid-childhood school years may have an impact on later risk behaviour, but further research is needed to determine the effectiveness of this approach.