Guido J. Falcone

Predicting Hematoma Expansion After Primary Intracerebral Hemorrhage

IMPORTANCE Many clinical trials focus on restricting hematoma expansion following acute intracerebral hemorrhage (ICH), but selecting those patients at highest risk of hematoma expansion is challenging. OBJECTIVE To develop a prediction score for hematoma expansion in patients with primary ICH. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study at 2 urban academic medical centers among patients having primary ICH with available baseline and follow-up computed tomography for volumetric analysis (817 patients in the development cohort and 195 patients in the independent validation cohort). MAIN OUTCOMES AND MEASURES Hematoma expansion was assessed using semiautomated software and was defined as more than 6 mL or 33% growth. Covariates were tested for association with hematoma expansion using univariate and multivariable logistic regression. A 9-point prediction score was derived based on the regression estimates and was subsequently tested in the independent validation cohort. RESULTS Hematoma expansion occurred in 156 patients (19.1%). In multivariable analysis, predictors of expansion were as follows: warfarin sodium use, the computed tomography angiography spot sign, and shorter time to computed tomography (≤ 6 vs >6 hours) (P < .001 for all), as well as baseline ICH volume (<30 [reference], 30-60 [P = .03], and >60 [P = .005] mL). The incidence of hematoma expansion steadily increased with higher scores. In the independent validation cohort (n = 195), our prediction score performed well and showed strong association with hematoma expansion (odds ratio, 4.59; P < .001 for a high vs low score). The C statistics for the score were 0.72 for the development cohort and 0.77 for the independent validation cohort. CONCLUSIONS AND RELEVANCE A 9-point prediction score for hematoma expansion was developed and independently validated. The results open a path for individualized treatment and trial design in ICH aimed at patients at highest risk of hematoma expansion with maximum potential for therapeutic benefit.

Premorbid body mass index and risk of amyotrophic lateral sclerosis.

Abstract Our objective was to determine if amyotrophic lateral sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier. At baseline 537,968 females and 562,942 males in five ongoing cohorts reported height, current weight and weight at age 18/21 years. During 14–28 years of follow-up, 1153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random-effects models. Results showed that lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95% CI 14% 27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR = 0.76 (95% CI 0.62–0.93)) and obese (RR = 0.73 (95% CI 0.55–0.96)). Among never smokers the association persisted: RR = 0.75 (95% CI 0.65–0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of males and females had a healthy BMI at age 18/21 years, 15% of males and 8% of females were overweight or obese; there was no association with ALS although numbers with an unhealthy weight were small. In conclusion, these findings support an association between lower premorbid BMI and ALS.

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Current concepts and clinical applications of stroke genetics

Driven by innovative technologies, novel analytical methods, and collaborations unimaginable not long ago, our understanding of the role of genetic variation in stroke has advanced substantially in recent years. However, a vast amount of data have accumulated quickly, and increasingly complex methodologies used in studies make keeping up to date on relevant findings difficult. In addition to well known, highly penetrant rare mutations that cause mendelian disorders related to stroke, several common genetic variants have been associated with common stroke subtypes, some of which also affect disease severity and clinical outcome. Furthermore, common genetic variations in biological pathways that have an important role in the pathophysiology of cerebrovascular diseases-such as blood pressure and oxidative phosphorylation-have been implicated in stroke. Clinical and translational applications of these and future discoveries in stroke genetics include identification of novel targets for treatment and development of personalised approaches to stroke prevention and management.

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.

Predictors of Hematoma Volume in Deep and Lobar Supratentorial Intracerebral Hemorrhage

IMPORTANCE Hematoma volume is the strongest predictor of outcome in intracerebral hemorrhage (ICH). Despite known differences in the underlying biology between deep and lobar ICHs, limited data are available on location specificity of factors reported to affect hematoma volume. OBJECTIVE To evaluate whether determinants of ICH volume differ by topography, we sought to estimate location-specific effects for potential predictors of this radiological outcome. DESIGN Prospective cohort study. SETTING Academic medical center. PARTICIPANTS A total of 744 supratentorial primary ICH patients (388 deep and 356 lobar) aged older than 18 years admitted between January 1, 2000, and December 31, 2010. MAIN OUTCOMES AND MEASURES Intracerebral hemorrhage volume measured from the computed tomography scan obtained on presentation to the emergency department. Linear regression analysis, stratified by ICH location, was implemented to identify determinants of log-transformed ICH volume. RESULTS Median ICH volume was larger in lobar hemorrhages (39 mL; interquartile range, 16-75 mL) than in deep hemorrhages (13 mL; interquartile range, 5-40 mL; P < .001). In multivariable linear regression, independent predictors of deep ICH volume were intensity of anticoagulation (β = 0.32; standard error [SE] = 0.08; P < .001; test for trend across 4 categories of the international normalized ratio), history of coronary artery disease (β = 0.33; SE = 0.17; P = .05), male sex (β = 0.28; SE = 0.14; P = .05), and age (β = -0.02; SE = 0.01; P = .001). Independent predictors of lobar ICH volume were intensity of anticoagulation (β = 0.14; SE = 0.06; P = .02) and antiplatelet treatment (β = 0.27; SE = 0.13; P = .03). CONCLUSIONS AND RELEVANCE Predictors of hematoma volume only partially overlap between deep and lobar ICHs. These findings suggest that the mechanisms that determine the extent of bleeding differ for deep and lobar ICHs. Further studies are needed to characterize the specific biological pathways that underlie the observed associations.

Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration.

Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease

Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14–1.46, p = 0.00003; r2 > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03–1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01–1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non–small vessel disease cerebrovascular phenotypes. Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

Interrelationship of superficial siderosis and microbleeds in cerebral amyloid angiopathy.

Objective: We sought to explore the mechanisms leading to cerebral amyloid angiopathy (CAA)-related cortical superficial siderosis (cSS) by examining its neuroimaging and genetic association with cerebral microbleeds (CMBs). Methods: MRI scans of 84 subjects with probable or definite CAA participating in a longitudinal research study were graded for cSS presence and severity (focal, restricted to ≤3 sulci vs disseminated, ≥4 sulci), and CMB count. APOE ε variants were directly genotyped. We performed cross-sectional analysis comparing CMB counts and APOE ε2 and ε4 allele frequency between subjects with no, focal, or disseminated cSS. Results: cSS was present in 48% (n = 40) of the population. APOE ε2 was overrepresented among participants with focal (odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7–29.3, p = 0.008) and disseminated (OR 11.5, 95% CI 2.8–46.2, p = 0.001) cSS relative to individuals without cSS. CMB counts decreased with increasing severity of cSS (median: 41, 38, and 15 for no cSS, focal cSS, and disseminated cSS, respectively, p = 0.09). The highest CMB count tertile was associated with APOE ε4 (OR 3.0, 95% CI 1.4–6.6, p = 0.006) relative to the lowest tertile. Conclusions: Among individuals with advanced CAA, cSS tends to occur in individuals with relatively lower CMB counts and with a distinct pattern of APOE genotypes. These results suggest that CAA-related cSS and CMBs may arise from distinct vasculopathic mechanisms.

Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: Pooled results from 5 cohort studies

Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited.