Oral Health and Brain Health: Cause, Consequence, or Confounding?

Epidemiologic studies of the association between periodontal disease and cardiovascular disease, including stroke, had mixed findings.1 Some studies have found that serum antibodies to major periodontal pathogens are associated with coronary heart disease (CHD), suggesting that periodontal infection or the host response to periodontal infection may play a causal role in CHD.1 More recently, longitudinal studies have supported an association of periodontal disease between cognitive decline and dementia.2 The motivation for these studies has been two-fold. First, periodontal disease is known to be associated with systemic inflammation,3 which, in turn, is known to be causally associated with atherosclerotic disease.4 Second, periodontal disease is potentially modifiable in the population. The limitation of all observational epidemiologic studies is the problem of confounding by incompletely measured or unmeasured variables, such as diet, health behaviors including oral hygiene, and the host response to infection. In addition, studies oral health and either cognitive decline or dementia may suffer from reverse causality; cognitive changes may lead to lessened oral hygiene and periodontal disease.

Association Between Body Mass Index and Functional Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: Evidence of the so-called "obesity paradox," which refers to the protective effect and survival benefit of obesity in patients with spontaneous intracerebral hemorrhage (ICH), remains controversial. This study aims to determine the association between body mass index (BMI) and functional outcomes in patients with ICH and whether it is modified by race/ethnicity. METHODS: Included individuals were derived from the Ethnic/Racial Variations of Intracerebral Hemorrhage study, which prospectively recruited 1,000 non-Hispanic White, 1,000 non-Hispanic Black, and 1,000 Hispanic patients with spontaneous ICH. Only patients with available BMI were included. The primary outcome was 90-day mortality. Secondary outcomes were mortality at discharge, modified Rankin Scale (mRS), Barthel Index, and self-reported health status measures at 90 days. Associations between BMI and ICH outcomes were assessed using univariable and multivariable logistic, ordinal, and linear regression models, as appropriate. Sensitivity analyses after excluding frail patients and by patient race/ethnicity were performed. RESULTS: A total of 2,841 patients with ICH were included. The median age was 60 years (interquartile range 51-73). Most patients were overweight (n = 943; 33.2%) or obese (n = 1,032; 36.3%). After adjusting for covariates, 90-day mortality was significantly lower among overweight and obese patients than their normal weight counterparts (adjusted odds ratio [aOR] = 0.71 [0.52-0.98] and aOR = 0.70 [0.50-0.97], respectively). Compared with patients with BMI <25 kg/m2, those with BMI ≥25 kg/m2 had better 90-day mRS (aOR = 0.80 [CI 0.67-0.95]), EuroQoL Group 5-Dimension (EQ-5D) (aß = 0.05 [0.01-0.08]), and EQ-5D VAS (aß = 3.80 [0.80-6.98]) scores. These differences persisted after excluding withdrawal of care patients. There was an inverse relationship between BMI and 90-day mortality (aOR = 0.97 [0.96-0.99]). Although non-Hispanic White patients had significantly higher 90-day mortality than non-Hispanic Black and Hispanic (26.6% vs 19.5% vs 18.0%, respectively; p < 0.001), no significant interactions were found between BMI and race/ethnicity. No significant interactions between BMI and age or sex for 90-day mortality were found, whereas for 90-day mRS, there was a significant interaction with age (pinteraction = 0.004). CONCLUSION: We demonstrated that a higher BMI is associated with decreased mortality, improved functional outcomes, and better self-reported health status at 90 days, thus supporting the paradoxical role of obesity in patients with ICH. The beneficial effect of high BMI does not seem to be modified by race/ethnicity or sex, whereas age may play a significant role in patient functional outcomes.

Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage.

OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. METHODS: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.

Evidence of survival bias in the association between APOE-ϵ4 and age of ischemic stroke onset.

Large genome-wide association studies (GWAS) employing case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing age at onset (AAO) of ischemic stroke. Analyses were conducted in a Discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value < 1×10-5 in a sex-combined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for association of AAO with rs429358, an exonic variant in APOE that encodes for the APOE-ϵ4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29 years earlier stroke AOO (meta p-value = 2.48×10-11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decline in mortality among APOE-ϵ4 carriers and have no association to stroke AAO per se. Using a simulation study, we found that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a two-fold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.

Genomic risk scores and oral contraceptive-associated ischemic stroke risk: a call for collaboration.

Background: Oral contraceptives (OCs) are generally safe but vascular risk factors increase OC-associated ischemic stroke risk. We performed a case-control study to evaluate whether a genomic risk score for ischemic stroke modifies OC-associated ischemic stroke risk. Methods: The Genetics of Early-Onset Stroke study includes 332 premenopausal women (136 arterial ischemic stroke cases and 196 controls) with data on estrogen-containing OC use within 30 days before the index event (for cases) or interview (for controls). Using a previously validated genetic risk score (metaGRS) for ischemic stroke based on 19 polygenic risk scores for stroke and stroke-associated risk factors, we stratified our combined case-control sample into tertiles of genomic risk. We evaluated the association between OC use and ischemic stroke within each tertile. We tested if the association between OC use and ischemic stroke depended on the genomic risk of stroke using logistic regression with an OC use × metaGRS interaction term. These analyses were performed with and without adjustment for smoking, hypertension, diabetes, coronary heart disease, and body mass index. Results: After adjustment for vascular risk factors, the odds ratio of OC use was 3.2 (1.7-6.3) overall and increased from the lower, middle, and upper tertile of genomic risk from 1.6 (0.5-5.4) to 2.5 (0.08-8.2) to 13.7 (3.8-67.3) respectively, and a p-value for interaction of 0.001. Conclusions: Our results suggest that genomic profile may modify the OC-associated ischemic stroke risk. Larger studies are warranted to determine whether a genomic risk score could be clinically useful in reducing OC-associated ischemic stroke.

Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.

Objective: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. Methods: 95,000 base pairs spanning 1q22 , including SEMA4A, SLC25A44 and PMF1 / PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. Results: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A -promoter and PMF1 -enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. Interpretation: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22 , offering a potential new target for prevention of ICH and CSVD.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes. METHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input. RESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. DISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.

Looking for opportunities to co-enroll: The DISCOVERY study experience.

BACKGROUND: Conducting high-quality stroke trials is complex and costly. Often these trials compete for the attention of researchers and the availability of patients. Enrolling patients in more than one study concurrently has the potential to accelerate recruitment into individual studies. DISCOVERY is a multicenter, inception cohort study of cognitive impairment and dementia following ischemic or hemorrhagic stroke. At the request of site investigators, a DISCOVERY committee reviews individual studies for approval of possible concurrent co-enrollment into DISCOVERY. The purpose of this report is to summarize the characteristics and outcomes of studies reviewed by committee for possible co-enrollment. METHODS: This analysis covers studies reviewed from 07/01/2020 to 04/26/2022 by the Site Management Committee (SMC) of the DISCOVERY Recruitment and Retention Core. Characterization of each study included study type, number and length of follow-up visits, and whether there were protocol-required blood draws, brain imaging studies, or cognitive tests. Studies were scored for patient burden and scientific overlap with Discovery. The primary outcome was SMC approval to co-enroll. RESULTS: 59 studies were reviewed, and 69.5% (n = 41, 21 clinical trials; 20 observational studies) were found by the SMC to be appropriate for co-enrollment. Higher patient burden and greater scientific overlap with DISCOVERY reduced the rates of approval for co-enrollment. CONCLUSION: A large number of diverse stroke studies are being run concurrently across the DISCOVERY study network, however, about two-thirds of the studies were considered appropriate for consideration of co-enrollment. Future studies should study how co-enrollment might improve trial network efficiency.

Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics.

Background purpose: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methods: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. Results: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. Conclusion: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome.

BACKGROUND AND OBJECTIVES: To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. METHODS: MR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. RESULTS: A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location. DISCUSSION: Higher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions.

Black-white Differences in Left Ventricular Hypertrophy Rates Among Young Adults with Ischemic Stroke.

OBJECTIVES: Few studies have addressed Black-White differences in left ventricular hypertrophy (LVH) in young stroke patients without a history of hypertension. METHODS: A case-only cross-sectional analysis performed in 2019 of data from the Stroke Prevention in Young Adults Study, a population-based case-control study of ischemic stroke patients ages 15-49. The main outcomes were hypertension indicators at the time of stroke hospitalization: self-reported history of hypertension, LVH by echocardiography (Echo-LVH) and LVH by electrocardiogram (ECG-LVH). The prevalence of Echo-LVH was further determined in those with and without a history of hypertension. Adjusted odds ratios and 95% confidence intervals comparing blacks and whites were calculated by logistic regression. RESULTS: The study population included 1028 early-onset ischemic stroke patients, 48% Black cases, 54% men, median age 43 years (interquartile range, 38-46 years). Overall, the prevalence of hypertension history, Echo-LVH and ECG-LVH were 41.3%, 34.1% and 17.5%, respectively. Each of the hypertension indicators were more frequent in men than in women and in Black cases than in White cases. Black patients without a history of hypertension had higher rates of Echo-LVH than their white counterparts, 40.3% vs 27.7% (age and obesity adjusted OR 1.8; 95% CI 1.02-3.4) among men and 20.9% vs 7.6% (adjusted OR 2.7; 95% CI 1.2-6.2) among women. CONCLUSIONS: LVH was common in young patients with ischemic stroke, regardless of self-reported history of hypertension. These findings emphasize the need for earlier screening and more effective treatment of hypertension in young adults, particularly in the Black population.

Differences in Multiple Risk Factors Between Black and White Individuals With Young-Onset Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Stroke in young adults constitutes 15%-18% of all ischemic stroke cases. Black individuals have an excess risk of ischemic stroke especially in young adults. Although it is known that Black patients have a higher prevalence of hypertension and diabetes, few studies have addressed the association of concurrent multiple vascular risk factors with the excess risk of early-onset stroke among Black individuals. METHODS: A population-based case-control study of early-onset ischemic stroke, ages 15-49 years, was conducted in the Baltimore-Washington DC region between 1992 and 2007. Presence of the risk factors of obesity, hypertension, diabetes, and current smoking were obtained from both cases and controls by an in-person interview. Risk factor groups were defined as (1) 1 risk factor, (2) 2 risk factors, (3) 3 risk factors, and (4) 4 risk factors. Logistic regression analysis adjusting for age and sex was used to evaluate the association between each risk factor group and ischemic stroke compared with the reference group with no risk factors. RESULTS: The study included 1,034 cases and 1,091 controls. Of the cases, 47% were Black, 54% were men, and the mean (±SD) age was 41.0 (±6.9) years. The odds of having a stroke increased exponentially as the number of risk factors increased, 2.1, 2.6, 7.6, 16.5, all p < 0.001, for groups 1-4, respectively. When stratified by race, Black individuals were approximately 6 times more likely to have all 4 risk factors. DISCUSSION: The risk of stroke in young adults increased exponentially with the number of risk factors. Young Black patients with ischemic stroke were approximately 6 times more likely to have the co-occurrence of obesity, hypertension, diabetes, and smoking compared with their White counterparts. Targeting public health interventions to identify and improve care to Black young adults with multiple stroke risk factors may have substantial impact on lowering risk of stroke.

Risk Factors Associated With Mortality and Neurologic Disability After Intracerebral Hemorrhage in a Racially and Ethnically Diverse Cohort.

Introduction: Intracerebral hemorrhage (ICH) is the most severe subtype of stroke. Its mortality rate is high, and most survivors experience significant disability. Objective: To assess primary patient risk factors associated with mortality and neurologic disability 3 months after ICH in a large, racially and ethnically balanced cohort. Design, Setting, and Participants: This cohort study included participants from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, which prospectively recruited 1000 non-Hispanic White, 1000 non-Hispanic Black, and 1000 Hispanic patients with spontaneous ICH to study the epidemiological characteristics and genomics associated with ICH. Participants included those with uniform data collection and phenotype definitions, centralized neuroimaging review, and telephone follow-up at 3 months. Analyses were completed in November 2021. Exposures: Patient demographic and clinical characteristics as well as hospital event and imaging variables were examined, with characteristics meeting P < .20 considered candidates for a multivariate model. Elements included in the ICH score were specifically analyzed. Main Outcomes and Measures: Individual characteristics were screened for association with 3-month outcome of neurologic disability or mortality, as assessed by a modified Rankin Scale (mRS) score of 4 or greater vs 3 or less under a logistic regression model. A total of 25 characteristics were tested in the final model, which minimized the Akaike information criterion. Analyses were repeated removing individuals who had withdrawal of care. Results: A total of 2568 patients (mean [SD] age, 62.4 [14.7] years; 1069 [41.6%] women and 1499 [58.4%] men) had a 3-month outcome determination available, including death. The final logistic model had a significantly higher area under the receiver operating characteristics curve (C = 0.88) compared with ICH score alone (C = 0.76; P < .001). Among characteristics associated with neurologic disability and mortality were larger log ICH volume (OR, 2.74; 95% CI, 2.36-3.19; P < .001), older age (OR per 1-year increase, 1.04; 95% CI, 1.02-1.05; P < .001), pre-ICH mRS score (OR, 1.62; 95% CI, 1.41-1.87; P < .001), lobar location (OR, 0.22; 95% CI, 0.16-0.30; P < .001), and presence of infection (OR, 1.85; 95% CI, 1.42-2.41; P < .001). Conclusions and Relevance: The findings of this cohort study validate ICH score elements and suggest additional baseline and interim patient characteristics were associated with variation in 3-month outcome.

Sex-specific lesion pattern of functional outcomes after stroke.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults-A Worldwide Meta-analysis: The GOAL Initiative.

BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Black-White Differences in Ischemic Stroke Risk Factor Burden in Young Adults.

BACKGROUND AND PURPOSE: Although the US Black population has a higher incidence of stroke compared with the US White population, few studies have addressed Black-White differences in the contribution of vascular risk factors to the population burden of ischemic stroke in young adults. METHODS: A population-based case-control study of early-onset ischemic stroke, ages 15 to 49 years, was conducted in the Baltimore-Washington DC region between 1992 and 2007. Risk factor data was obtained by in-person interview in both cases and controls. The prevalence, odds ratio, and population-attributable risk percent (PAR%) of smoking, diabetes, and hypertension was determined among Black patients and White patients, stratified by sex. RESULTS: The study included 1044 cases and 1099 controls. Of the cases, 47% were Black patients, 54% were men, and the mean (±SD) age was 41.0 (±6.8) years. For smoking, the population-attributable risk percent were White men 19.7%, White women 32.5%, Black men 10.1%, and Black women 23.8%. For diabetes, the population-attributable risk percent were White men 10.5%, White women 7.4%, Black men 17.2%, and Black women 13.4%. For hypertension, the population-attributable risk percent were White men 17.2%, White women 19.3%, Black men 45.8%, and Black women 26.4%. CONCLUSIONS: Modifiable vascular risk factors account for a large proportion of ischemic stroke in young adults. Cigarette smoking was the strongest contributor to stroke among White patients while hypertension was the strongest contributor to stroke among Black patients. These results support early primary prevention efforts focused on smoking cessation and hypertension detection and treatment.

Cardiac Risk Factors for Stroke: A Comprehensive Mendelian Randomization Study.

BACKGROUND: Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. METHODS: We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging-derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. RESULTS: As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. CONCLUSIONS: Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.

Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10-7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples (n = 5613 cases) or UK Biobank (n = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke.

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (ß = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.