Genome-wide association study of cerebral small vessel disease reveals established and novel loci.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.

Exercise-based swallowing intervention (McNeill Dysphagia Therapy) with adjunctive NMES to treat dysphagia post-stroke: A double-blind placebo-controlled trial.

BACKGROUND: Dysphagia following stroke is prevalent; however, dysphagia treatment is often applied haphazardly and outcomes unclear. Neuromuscular electrical stimulation (NMES) has received increased attention as a treatment for post-stroke dysphagia; but application data remain conflicted. OBJECTIVE: This study investigated effectiveness and safety of an exercise-based swallowing therapy (McNeill Dysphagia Therapy: MDTP) +NMES for dysphagia rehabilitation following stroke. METHODS: Stroke patients (n = 53, x̅ age: 66 [13.2], 47.2% male) with dysphagia admitted to sub-acute rehabilitation hospital were randomised to MDTP + NMES [NMES], MDTP + sham NMES [MDTP] or usual care [UC] swallowing therapy groups. Patients were treated for 1 hour per day for 3 weeks and monitored to 3 months by a blinded evaluator. Outcomes included clinical swallowing ability, oral intake, weight, patient perception of swallow and occurrence of dysphagia-related complications. RESULTS: Post-treatment dysphagia severity and treatment response were significantly different between groups (P ≤ .0001). MDTP demonstrated greater positive change than either NMES or UC arms, including increase in oral intake (χ2  = 5, P ≤ .022) and improved functional outcome by 3 months post-stroke (RR = 1.72, 1.04-2.84). Exploratory Cox regression revealed the MDTP group conferred the greatest benefit in time to "return to pre-stroke diet" of 4.317 [95% CI: 1.08- 17.2, P< .03]. CONCLUSION: Greater benefit (eg reduction in dysphagia severity, improved oral intake and earlier return to pre-stroke diet) resulted from a programme of MDTP alone vs NMES or UC.

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: ß, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: ß, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Genetic variants in CETP increase risk of intracerebral hemorrhage.

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

Bacterial Endocarditis and Cerebrovascular Disease.

Cerebrovascular complications of endocarditis occur in 25-70% of patients with infective endocarditis. The cornerstone of treatment is early initiation of antibiotic treatment, which significantly reduces the risk of embolization after 1 week of treatment. In general, thrombolysis and anticoagulation of these patients should be avoided, while antiplatelet therapy may be considered in those with other indications. Endovascular treatment of acute septic emboli is uncertain, but a few case reports have demonstrated benefit. Other complications of infective endocarditis include intracerebral hemorrhage, which may be predicted by the presence of two or more cerebral microbleeds on gradient echo sequences. Intracranial mycotic aneurysms can often be managed with serial imaging and coiled if there is evidence of failure to reduce in size, or enlargement.

Clinical Variables Associated with Hydration Status in Acute Ischemic Stroke Patients with Dysphagia.

Acute stroke patients with dysphagia are at increased risk for poor hydration. Dysphagia management practices may directly impact hydration status. This study examined clinical factors that might impact hydration status in acute ischemic stroke patients with dysphagia. A retrospective chart review was completed on 67 ischemic stroke patients who participated in a prior study of nutrition and hydration status during acute care. Prior results indicated that patients with dysphagia demonstrated elevated BUN/Cr compared to non-dysphagia cases during acute care and that BUN/Cr increased selectively in dysphagic patients. This chart review evaluated clinical variables potentially impacting hydration status: diuretics, parenteral fluids, tube feeding, oral diet, and nonoral (NPO) status. Exposure to any variable and number of days of exposure to each variable were examined. Dysphagia cases demonstrated significantly more NPO days, tube fed days, and parenteral fluid days, but not oral fed days, or days on diuretics. BUN/Cr values at discharge were not associated with NPO days, parenteral fluid days, oral fed days, or days on diuretics. Patients on modified solid diets had significantly higher mean BUN/Cr values at discharge (27.12 vs. 17.23) as did tube fed patients (28.94 vs. 18.66). No difference was noted between these subgroups at baseline (regular diet vs. modified solids diets). Any modification of solid diets (31.11 vs. 17.23) or thickened liquids (28.50 vs. 17.81) resulted in significantly elevated BUN/Cr values at discharge. Liquid or diet modifications prescribed for acute stroke patients with dysphagia may impair hydration status in these patients.

Rare Coding Variation and Risk of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. METHODS: A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. RESULTS: No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. CONCLUSIONS: Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects.

Assessing the impact of health literacy on education retention of stroke patients.

INTRODUCTION: Inadequate health literacy is a pervasive problem with major implications for reduced health status and health disparities. Despite the role of focused education in both primary and secondary prevention of stroke, the effect of health literacy on stroke education retention has not been reported. We examined the relationship of health literacy to the retention of knowledge after recommended stroke education. METHODS: This prospective cross-sectional study was conducted at an urban safety-net hospital. Study subjects were patients older than 18 admitted to the hospital stroke unit with a diagnosis of acute ischemic stroke who were able to provide informed consent to participate (N = 100). Health literacy levels were measured by using the short form of Test of Functional Health Literacy in Adults. Patient education was provided to patients at an inpatient stroke unit by using standardized protocols, in compliance with Joint Commission specifications. The education outcomes for poststroke care education, knowledge retention, was assessed for each subject. The effect of health literacy on the Stroke Patient Education Retention scores was assessed by using univariate and multivariate analyses. RESULTS: Of the 100 participating patients, 59% had inadequate to marginal health literacy. Stroke patients who had marginal health literacy (mean score, 7.45; standard deviation [SD], 1.9) or adequate health literacy (mean score, 7.31; SD, 1.76) had statistically higher education outcome scores than those identified as having inadequate health literacy (mean score, 5.58; SD, 2.06). Results from multivariate analysis indicated that adequate health literacy was most predictive of education outcome retention. CONCLUSIONS: This study demonstrated a clear relationship between health literacy and stroke education outcomes. Studies are needed to better understand the relationship of health literacy to key educational outcomes for primary or secondary prevention of stroke and to refine stroke education for literacy levels of high-risk populations.

Endovascular Mechanical Thrombectomy for Ischemic Stroke Treatment in the Setting of Aortic Dissection: Case Report.

Introduction: Acute ischemic stroke can occur in the setting of aortic dissection. Information concerning the utility of endovascular mechanical thrombectomy as an intervention for patients with aortic dissection who are experiencing an acute stroke due to large vessel occlusion is limited to a few case reports. Case series of patients presenting with this clinical situation are needed to further investigate the potential utility of this procedure when patients with acute ischemic stroke and aortic dissection are encountered. Case Presentation: We report a patient with a chronic Stanford type A aortic dissection with dissection extension into the left common carotid artery and left internal carotid artery who had a good clinical outcome following mechanical thrombectomy for a symptomatic middle cerebral artery occlusion. We also review other cases in which endovascular mechanical thrombectomy was conducted in patients with aortic dissection and acute ischemic stroke and discuss the potential risks and benefits of carotid artery stenting in this clinical situation. Conclusion: The rate of successful arterial recanalization in patients with aortic dissection, large vessel occlusion, and acute ischemic stroke treated with mechanical thrombectomy is high. The intervention has been associated with good neurological outcomes and a low rate of procedure-related complications. Additional case series are needed to help discern if our observations are present in a broader array of patients in order to identify which patients are most likely to benefit from mechanical thrombectomy.

Burden of blood pressure-related alleles is associated with larger hematoma volume and worse outcome in intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease seems to influence not only risk of ICH but also the size of the hematoma. As the burden of high blood pressure-related alleles is associated with both hypertension-related end-organ damage and risk of ICH, we sought to determine whether this burden influences ICH baseline hematoma volume. METHODS: Prospective study in subjects of European descent with supratentorial ICH who underwent genome-wide genotyping. Forty-two single nucleotide polymorphisms associated with high blood pressure were identified from a publicly available database. A genetic risk score was constructed based on these single nucleotide polymorphisms. The score was used as the independent variable in univariate and multivariate regression models for admission ICH volume and poor clinical outcome (modified Rankin Scale, 3-6). RESULTS: A total of 323 ICH cases were enrolled in the study (135 deep and 188 lobar intracranial hematomas). The blood pressure-based genetic risk score was associated with both baseline hematoma volume and poor clinical outcome specifically in deep ICH. In multivariate regression analyses, each additional SD of the score increased mean deep ICH volume by 28% (or 2.7 mL increase; ß=0.28; SE=0.11; P=0.009) and risk of poor clinical outcome by 71% (odds ratio, 1.71; 95% confidence interval, 1.05-2.80; P=0.03). CONCLUSIONS: Increasing numbers of high blood pressure-related alleles are associated with mean baseline hematoma volume and poor clinical outcome in ICH. These findings suggest that the small vessel vasculopathy responsible for the occurrence of the hemorrhage also influences its volume.

Common variants within oxidative phosphorylation genes influence risk of ischemic stroke and intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). METHODS: This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. RESULTS: IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). CONCLUSIONS: This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences.

Heritability estimates identify a substantial genetic contribution to risk and outcome of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. METHODS: We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. RESULTS: ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOEloci and at 12% (SE, 4%) for APOE. CONCLUSIONS: Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.

Dysphagia, nutrition, and hydration in ischemic stroke patients at admission and discharge from acute care.

Dysphagia may predispose stroke patients toward undernutrition and hydration. These comorbidities increase patient risks for reduced functional outcome and short-term mortality. Despite this impact, available information on relationships among dysphagia, nutrition, and hydration status in acute stroke is limited and conflicted. This study evaluated nutrition and hydration status in ischemic stroke patients with versus without clinically significant dysphagia at admission and at discharge from acute care. Sixty-seven patients admitted to the stroke unit in a tertiary-care hospital provided data for this study. On the day of hospital admission and upon discharge or at 7 days post admission, serum biochemical measures were obtained for nutrition (prealbumin) and hydration status (BUN/Cr). Clinical evaluation for dysphagia, nutrition status, and stroke severity were completed an average of 1.4 days following hospital admission. Dysphagia was identified in 37 % of the cohort. At admission 32 % of patients demonstrated malnutrition based on prealbumin levels and 53 % demonstrated evidence of dehydration based on BUN/Cr levels. No differences in nutrition status were attributed to dysphagia. Patients with dysphagia demonstrated significantly higher BUN/Cr levels (greater dehydration) than patients without dysphagia at admission and at discharge. Dehydration at both admission and discharge was associated with dysphagia, clinical nutrition status, and stroke severity. Results of this study support prior results indicating that dysphagia is not associated with poor nutrition status during the first week post stroke. Dehydration status is associated with dysphagia during this period. The results have implications for future confirmatory research and for clinical management of dysphagia in the acute stroke period.

Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. METHODS: We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. RESULTS: No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. CONCLUSIONS: Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage.

OBJECTIVE: Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. METHODS: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. RESULTS: Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. INTERPRETATION: APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.

Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.

ObjectiveTo test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

Analysis of a physician tool for evaluating dysphagia on an inpatient stroke unit: the modified Mann Assessment of Swallowing Ability.

BACKGROUND: Although many dysphagia screening protocols have been introduced in recent years, no validated, physician-administered dysphagia screening tool exists for acute stroke that can be performed at the bedside. Based on the psychometrically validated Mann Assessment of Swallowing Ability (MASA), we developed the Modified MASA (MMASA) as a physician-administered screening tool for dysphagia in acute stroke. OBJECTIVE: The purpose of this study was to complete initial validation of this new screening tool for dysphagia in acute ischemic stroke. METHODS: Two stroke neurologists independently performed the MMASA on 150 patients with ischemic stroke. Speech-language pathologists performed the standard MASA on all patients. All examiners were blinded to the results of the other assessments. Interjudge reliability was evaluated between the neurologists. Validity between the screening tool (MMASA) and the clinical evaluation (MASA) was assessed with sensitivity/specificity and predictive value assessment. RESULTS: Interobserver agreement between the neurologists using the MMASA was good (k=0.76; SE=0.082). Based on the comprehensive clinical evaluation (MASA), 36.2% of patients demonstrated dysphagia. Screening results from the neurologists (N1 and N2) identified 38% and 36.7% prevalence of dysphagia, respectively. Sensitivity (N1: 92%, N2: 87%), specificity (N1: 86.3%, N2: 84.2%), positive predictive value (N1: 79.4%, N2: 75.8%), and negative predictive value (N1: 95.3%, N2: 92%) were high between the screen and the comprehensive clinical evaluation. CONCLUSIONS: This preliminary study suggests that the MMASA is a potentially valid and reliable physician-administered screening tool for dysphagia in acute ischemic stroke. Use of this tool may facilitate earlier identification of dysphagia in patients with stroke prompting more rapid comprehensive evaluation and intervention.

CADASIL disease, an inherited slowly progressive vascular dementia: case report with radiologic and electron microscopic findings.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease, a genetically determined arteriopathy, is a rare cause of vascular dementia. We present a case report of a 50-year-old man with migraines associated with left-sided weakness since age 34 years, a stroke at age 43 years, followed by progressive dementia. Magnetic resonance imaging revealed diffuse leukoencephalopathy with involvement of bilateral anterior temporal lobes. Skin biopsy was performed because of clinical suggestion of CADASIL and positive family history. Electron microscopy revealed granular osmophilic material deposits in dermal arterioles, diagnostic for CADASIL disease. A brief discussion of reasons for false-negative skin biopsy findings, differential diagnosis, and treatment of patients with CADASIL disease is presented.

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.

Importance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH. Design, Setting, and Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Main Outcomes and Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. Results: In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity. Conclusions and Relevance: APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.

A systematic review of outcomes in patients with staged carotid artery stenting and coronary artery bypass graft surgery.

BACKGROUND AND PURPOSE: Although current guidelines state that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) in patients with carotid stenosis, significant controversies to this recommendation still persist. Carotid artery stenting has been recently introduced as an alternative revascularization modality in high-risk patients. The aim of this study was to define, based on the published information, if carotid artery stenting is beneficial in this setting. METHODS: A search of MEDLINE and a manual search of the literature from selected articles were performed. A total of 6 studies with 277 patients reporting carotid stenting followed by staged CABG were available for this clinical outcome analysis. All were retrospective and single-center studies. RESULTS: The mean age was 69 years; 78% were males. Asymptomatic carotid stenosis was present in 76% of patients. The mean time to CABG was 32 days. The incidence of stroke and death associated with the stent procedure was 4.7%. Only 6 patients (2.2%) developed stroke associated with CABG. The overall combined 30-day event rate after CABG, including all events during carotid artery stenting, were as follows: minor stroke, 2.9%; major stroke, 3.2%; mortality, 7.6%; and combined death and any stroke, 12.3%. CONCLUSIONS: In this pooled analysis, the combined incidence of death and stroke in patients undergoing carotid artery stenting and staged CABG remains elevated. These results confirm that the presence of carotid stenosis is per se a marker of risk that might persists independent of its treatment. A systematic or randomized evaluation appears warranted.