The predictive validity of a Brain Care Score for dementia and stroke: data from the UK Biobank cohort.

Introduction: The 21-point Brain Care Score (BCS) was developed through a modified Delphi process in partnership with practitioners and patients to promote behavior changes and lifestyle choices in order to sustainably reduce the risk of dementia and stroke. We aimed to assess the associations of the BCS with risk of incident dementia and stroke. Methods: The BCS was derived from the United Kingdom Biobank (UKB) baseline evaluation for participants aged 40-69 years, recruited between 2006-2010. Associations of BCS and risk of subsequent incident dementia and stroke were estimated using Cox proportional hazard regressions, adjusted for sex assigned at birth and stratified by age groups at baseline. Results: The BCS (median: 12; IQR:11-14) was derived for 398,990 UKB participants (mean age: 57; females: 54%). There were 5,354 incident cases of dementia and 7,259 incident cases of stroke recorded during a median follow-up of 12.5 years. A five-point higher BCS at baseline was associated with a 59% (95%CI: 40-72%) lower risk of dementia among participants aged <50. Among those aged 50-59, the figure was 32% (95%CI: 20-42%) and 8% (95%CI: 2-14%) for those aged >59 years. A five-point higher BCS was associated with a 48% (95%CI: 39-56%) lower risk of stroke among participants aged <50, 52% (95%CI, 47-56%) among those aged 50-59, and 33% (95%CI, 29-37%) among those aged >59. Discussion: The BCS has clinically relevant and statistically significant associations with risk of dementia and stroke in approximately 0.4 million UK people. Future research includes investigating the feasibility, adaptability and implementation of the BCS for patients and providers worldwide.

Genetic considerations in cerebral small vessel diseases.

Cerebral small vessel disease (CSVD) encompasses a broad clinical spectrum united by pathology of the small vessels of the brain. CSVD is commonly identified using brain magnetic resonance imaging with well characterized markers including covert infarcts, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds. The pathophysiology of CSVD is complex involving genetic determinants, environmental factors, and their interactions. While the role of vascular risk factors in CSVD is well known and its management is pivotal in mitigating the clinical effects, recent research has identified novel genetic factors involved in CSVD. Delineating genetic determinants can promote the understanding of the disease and suggest effective treatments and preventive measures of CSVD at the individual level. Here we review CSVD focusing on recent advances in the genetics of CSVD. The knowledge gained has advanced understanding of the pathophysiology of CSVD, offered promising early results that may improve subtype identification of small vessel strokes, has led to additional identification of mendelian forms of small vessel strokes, and is getting closer to influencing clinical care through pharmacogenetic studies.

Pleiotropy analysis between lobar intracerebral hemorrhage and CSF ß-amyloid highlights new and established associations.

BACKGROUND AND AIMS: Combining biologically related traits in genome-wide association studies (GWAS) increases the power for genetic discovery. Given the established relationship between lobar intracerebral hemorrhage (ICH) and cerebral amyloid angiopathy (CAA), and between the latter and levels of cerebrospinal fluid amyloid-ß 42 (CSF-Aß42), we leveraged genetic predisposition for lower CSF-Aß42 levels as a proxy phenotype for CAA to identify new genes associated with lobar ICH. METHODS: We used publicly available GWAS data for CSF-Aß42 levels (n = 3146) and for lobar ICH (n = 2094). First, we evaluated the association between lobar ICH risk and CSF-Aß42 in lobar ICH patients using a polygenic risk score (PRS) for CSF-Aß42. Next, we conducted multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aß42. MTAG results were further tested using Expression Quantitative Trait Locus and Differential Gene Expression Analyses. RESULTS: CSF-Aß42 PRS was associated with lobar ICH risk (p = 0.04). MTAG analysis identified a novel association within CDH9 (rs1007589; minor allele frequency = 0.09; MTAG p = 5.4 × 10-8; lobar ICH odds ratio = 1.4 and p = 2.4 × 10-3; CSF-Aß42 ß = -0.03 and p = 4.5 × 10-6). rs1007589 was significantly associated with the expression levels of CDH9 in temporal and occipital cortices, regions known to preferentially accumulate microhemorrhages in CAA. CONCLUSION: Our pleiotropy analysis suggested a variant possibly implicated with lobar ICH driven by amyloid-related mechanisms in CDH9 and associated with differential expression in brain regions characteristically affected by CAA. CDH9 is one subtype of the cadherin superfamily, which regulates intercellular adhesion, is involved in blood-brain barrier integrity, and is elevated in Alzheimer's disease patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.

Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project.

BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1. CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

Interactions Between Kidney Function and Cerebrovascular Disease: Vessel Pathology That Fires Together Wires Together.

The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.

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.

Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence.

OBJECTIVE: Black and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk. METHODS: We analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk. RESULTS: We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD (p = 0.011) and HTNA burden (p = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all p < 0.05). CONCLUSIONS: We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.

BACKGROUND: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. METHODS: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. FINDINGS: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. INTERPRETATION: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-ß signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. FUNDING: British Heart Foundation.

Longitudinal changes in MoCA performances in patients with mild cognitive impairment and small vessel disease. Results from the VMCI-Tuscany Study.

Objectives: The Montreal Cognitive Assessment (MoCA) is a cognitive screening test largely employed in vascular cognitive impairment, but there are no data about MoCA longitudinal changes in patients with cerebral small vessel disease (SVD). We aimed to describe changes in MoCA performance in patients with mild cognitive impairment (MCI) and SVD during a 2-year follow-up, and to evaluate their association with transition to major neurocognitive disorder (NCD). Materials and Methods: Within the prospective observational VMCI-Tuscany Study, patients with MCI and SVD underwent a comprehensive clinical, neuropsychological, and functional evaluation at baseline, and after 1 and 2 years. Results: Among the 138 patients (mean age 74.4 ± 6.9 years; males: 57%) who completed the study follow-up, 44 (32%) received a major NCD diagnosis. Baseline MoCA scores (mean±SD) were lower in major NCD patients (20.5 ± 5) than in reverter/stable MCI (22.2 ± 4.3), and the difference approached the statistical threshold of significance (p=.051). The total cohort presented a decrease in MoCA score (mean±SD) of -1.3 ± 4.2 points (-2.6 ± 4.7 in major NCD patients, -0.7 ± 3.9 in reverter/stable MCI). A multivariate logistic model on the predictors of transition from MCI to major NCD, showed MoCA approaching the statistical significance (OR=1.09, 95% CI=1.00-1.19, p=.049). Discussion: In our sample of MCI patients with SVD, longitudinal changes in MoCA performances were consistent with an expected more pronounced deterioration in patients who received a diagnosis of major NCD. MoCA sensitivity to change and predictive utility need to be further explored in VCI studies based on larger samples and longer follow-up periods.

Genetic overlap and causal inferences between kidney function and cerebrovascular disease.

OBJECTIVE: Leveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes. METHODS: We used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization. RESULTS: A PRS for lower eGFR was associated with higher large artery stroke (LAS) risk (p = 1 × 10-4). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38-3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12-4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH. CONCLUSIONS: Impaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease.

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.

Association Between Perihematomal Perfusion and Intracerebral Hemorrhage Outcome.

BACKGROUND: The prognostic impact of perihematomal hypoperfusion in patients with acute intracerebral hemorrhage (ICH) remains unclear. We tested the hypothesis that perihematomal hypoperfusion predicts poor ICH outcome and explored whether hematoma growth (HG) is the pathophysiological mechanism behind this association. METHODS: A prospectively collected single-center cohort of consecutive ICH patients undergoing computed tomography perfusion on admission was analyzed. Cerebral blood flow (pCBF) was measured in the manually outlined perihematomal low-density area. pCBF was categorized into normal (40-55 mL/100 g/min), low (< 40 mL/100 g/min), and high (> 55 mL/100 g/min). HG was calculated as total volume increase from baseline to follow-up CT. A modified Rankin scale > 2 at three months was the outcome of interest. The association between cerebral perfusion and outcome was investigated with logistic regression, and potential mediators of this relationship were explored with mediation analysis. RESULTS: A total of 155 subjects were included, of whom 55 (35.5%) had poor outcome. The rates of normal pCBF, low pCBF, and high pCBF were 17.4%, 68.4%, and 14.2%, respectively. After adjustment for confounders and keeping subjects with normal pCBF as reference, the risk of poor outcome was increased in patients with pCBF < 40 mL/100 g/min (odds ratio 6.11, 95% confidence interval 1.09-34.35, p = 0.040). HG was inversely correlated with pCBF (R = -0.292, p < 0.001) and mediated part of the association between pCBF and outcome (proportion mediated: 82%, p = 0.014). CONCLUSION: Reduced pCBF is associated with poor ICH outcome in patients with mild-moderate severity. HG appears a plausible biological mediator but does not fully account for this association, and other mechanisms might be involved.

Mendelian Randomization Study of Obesity and Cerebrovascular Disease.

OBJECTIVE: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. METHODS: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. RESULTS: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (ß = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose. INTERPRETATION: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524.

Adversity exposure during sensitive periods predicts accelerated epigenetic aging in children.

OBJECTIVES: Exposure to adversity has been linked to accelerated biological aging, which in turn has been shown to predict numerous physical and mental health problems. In recent years, measures of DNA methylation-based epigenetic age--known as "epigenetic clocks"--have been used to estimate accelerated epigenetic aging. Although a small number of studies have found an effect of adversity exposure on epigenetic age in children, none have investigated if there are "sensitive periods" when adversity is most impactful. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 973), we tested the prospective association between repeated measures of childhood exposure to seven types of adversity on epigenetic age assessed at age 7.5 using the Horvath and Hannum epigenetic clocks. With a Least Angle Regression variable selection procedure, we evaluated potential sensitive period effects. RESULTS: We found that exposure to abuse, financial hardship, or neighborhood disadvantage during sensitive periods in early and middle childhood best explained variability in the deviation of Hannum-based epigenetic age from chronological age, even after considering the role of adversity accumulation and recency. Secondary sex-stratified analyses identified particularly strong sensitive period effects. These effects were undetected in analyses comparing children "exposed" versus "unexposed" to adversity. We did not identify any associations between adversity and epigenetic age using the Horvath epigenetic clock. CONCLUSIONS: Our results suggest that adversity may alter methylation processes in ways that either directly or indirectly perturb normal cellular aging and that these effects may be heightened during specific life stages.

Associations of Radiographic Cerebral Small Vessel Disease with Acute Intracerebral Hemorrhage Volume, Hematoma Expansion, and Intraventricular Hemorrhage.

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH). METHODS: CSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of leukoaraiosis and cerebral atrophy using visual rating scales. The associations of leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing. RESULTS: A total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0-25.3) mL. IVH was detected in 971 patients (38%). Neither leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (ß (95% Confidence Interval [CI]) - 0.30[- 0.46, - 0.14], - 0.33[- 0.49, - 0.17], - 0.40[- 0.60, - 0.20], and - 0.54[- 0.76, - 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance. CONCLUSIONS: Leukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.

Influence of Genetic Variation in PDE3A on Endothelial Function and Stroke.

We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9-12 years of age; ß[SE], 0.38 [0.070]; P=3.8×10-8) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02-1.06]; P=5.2×10-6). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24-27 years; ß[SE], 0.47 [0.23]; P=0.047) but not in older adults (ß[SE], -0.012 [0.13]; P=0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.

Impact of Cerebral Small Vessel Disease on Functional Recovery After Intracerebral Hemorrhage.

Background and Purpose- In this study, we aim to investigate the association of computed tomography-based markers of cerebral small vessel disease with functional outcome and recovery after intracerebral hemorrhage. Methods- Computed tomographic scans of patients in the ERICH study (Ethnic and Racial Variations of Intracerebral Hemorrhage) were evaluated for the extent of leukoaraiosis and cerebral atrophy using visual rating scales. Poor functional outcome was defined as a modified Rankin Scale (mRS) of ≥3. Multivariable logistic and linear regression models were used to explore the associations of cerebral small vessel disease imaging markers with poor functional outcome at discharge and, as a measure of recovery, change in mRS from discharge to 90 days poststroke. Results- After excluding in-hospital deaths, data from 2344 patients, 583 (24.9%) with good functional outcome (mRS of 0-2) at discharge and 1761 (75.1%) with poor functional outcome (mRS of 3-5) at discharge, were included. Increasing extent of leukoaraiosis (P for trend, 0.01) and only severe (grade 4) global atrophy (odds ratio, 2.02; 95% CI, 1.22-3.39, P=0.007) were independently associated with poor functional outcome at discharge. Mean (SD) mRS change from discharge to 90-day follow-up was 0.57 (1.18). Increasing extent of leukoaraiosis (P for trend, 0.002) and severe global atrophy (ß [SE], -0.23 [0.115]; P=0.045) were independently associated with less improvement in mRS from discharge to 90 days poststroke. Conclusions- In intracerebral hemorrhage survivors, the extent of cerebral small vessel disease at the time of intracerebral hemorrhage is associated with poor functional outcome at hospital discharge and impaired functional recovery from discharge to 90 days poststroke.