Background and Purpose Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke (AIS), correlates only moderately with traditional clinical endpoints such as the modified Rankin Scale (mRS). We hypothesized that the topography of acute stroke lesions on diffusion-weighted MRI (DWI) may provide further information with regard to presenting stroke severity and long-term functional outcomes. Methods Data from a prospective stroke repository were limited to AIS subjects with MRI completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months mRS scores. Using voxel-based lesion symptom mapping techniques including age, sex and DWI lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. Results 490 subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor mRS at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), post-central gyrus, putamen, and operculum were implicated in poor mRS. More severe NIHSS involved these regions as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and pre-central gyrus. Conclusions Acute lesion topography provides important insights into anatomical correlates of admission stroke severity and post-stroke outcomes. Future models that account for infarct location in addition to DWI volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies.
Summary Introduction The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading approach to the identification of novel biological pathways for human disease. To date, GWAS have had been limited by relatively small sample sizes and yielded relatively few loci associated with ischemic stroke The National Institute of Neurological Disorders Stroke Genetics Network (NINDS-SiGN) is an international consortium that has taken a systematic approach to phenotyping and produced the largest ischemic stroke GWAS to date. Methods In order to identify genetic loci associated with ischemic stroke, we performed a two-stage genome-wide association study. The first stage consisted of 16,851 cases with state-of-the-art phenotyping and 32,473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtyped by centrally trained and certified investigators using the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identify samples genotyped on (nearly) identical arrays and of similar genetic ancestral background. Data was cleaned and imputed using dense imputation reference panels generated from whole-genome sequence data. Genome-wide testing was performed within each stratum for each available phenotype, and summary level results were combined using inverse variance-weighted fixed effects meta-analysis. The second stage consisted of in silico look-ups of 1,372 SNPs in 20,941 cases and 364,736 stroke-free controls, with cases previously subtyped using the TOAST classification system according to local standards. The two stages were then jointly analyzed in a final meta-analysis. Findings We identified a novel locus at 1p13.2 near TSPAN2 associated with large artery atherosclerosis (LAA)-related stroke (stage I OR for the G allele at rs12122341 = 1·21, p = 4.50 × 10−8; stage II OR = 1·19, p = 1·30 × 10−9). We also confirmed four loci robustly associated with ischemic stroke and reported in prior studies, including PITX2 and ZFHX3 for cardioembolic stroke, and HDAC9 for LAA stroke. The 12q24 locus near ALDH2, originally associated with all ischemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke. Other loci, including NINJ2, were not confirmed. Interpretation Our results identify a novel LAA-stroke susceptibility gene and now indicate that all loci implicated by GWAS to date are subtype specific. Follow-up studies will be necessary to determine whether the locus near TSPAN2 yields a novel therapeutic approach to stroke prevention. Given the subtype-specificity of these associations, the rich phenotyping available in SiGN is likely to prove vital for further genetic discovery in ischemic stroke. Funding National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH).
Background White matter hyperintensity (WMH), or leukoaraiosis, is a radiological finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relationship to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small vessel disease such as intracerebral hemorrhage (ICH) are associated with low levels of cholesterol. We sought to determine the relationship between hyperlipidemia (HL) and WMH severity in patients with acute ischemic stroke (AIS). Methods We analyzed two independent hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semi-automated volumetric image analysis and a semi-quantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relationship between WMH severity and study variables. Results A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (p<0.001) in both cohorts. In the multivariable analysis, after controlling for age, gender, and those significant risk factors in the univariate and age-adjusted analyses, patients with a history of HL had less severe WMH in both cohorts (p<0.01). Conclusions Results from two independent cohorts demonstrate that AIS patients with a history of HL have less severe WMH at the time of stroke. These data support the hypothesis that HL may play a relatively protective role on cerebral small vessel disease.
Objective:For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms.Methods:We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations.Results:There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10−6) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10−8; rs941898 [EVL], p = 4.0 × 10−8; rs962888 [C1QL1], p = 1.1 × 10−8; rs9515201 [COL4A2], p = 6.9 × 10−9).Conclusions:Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.
Background Elevated serum levels of brain natriuretic peptide (BNP) have been associated with cardioembolic (CE) stroke and increased post-stroke mortality. We sought to determine whether BNP levels were associated with functional outcome after ischemic stroke. Methods We measured BNP in consecutive patients aged ≥18 years admitted to our Stroke Unit between 2002–2005. BNP quintiles were used for analysis. Stroke subtypes were assigned using TOAST criteria. Outcomes were measured as 6-month modified Rankin Scale score (“good outcome” = 0–2 vs. “poor”) as well as mortality. Multivariate logistic regression was used to assess association between the quintiles of BNP and outcomes. Predictive performance of BNP as compared to clinical model alone was assessed by comparing ROC curves. Results Of 569 ischemic stroke patients, 46% were female; mean age was 67.9 ± 15 years. In age- and gender-adjusted analysis, elevated BNP was associated with lower ejection fraction (p<0.0001) and left atrial dilatation (p<0.001). In multivariate analysis, elevated BNP decreased the odds of good functional outcome (OR 0.64, 95%CI 0.41–0.98) and increased the odds of death (OR 1.75, 95%CI 1.36–2.24) in these patients. Addition of BNP to multivariate models increased their predictive performance for functional outcome (p=0.013) and mortality (p<0.03) after CE stroke. Conclusions Serum BNP levels are strongly associated with CE stroke and functional outcome at 6 months after ischemic stroke. Inclusion of BNP improved prediction of mortality in patients with CE stroke.
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