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Background: Frailty is a prevalent state associated with several aging-related traits and conditions. The relationship between frailty and stroke remains understudied. Here we aim to investigate whether the hospital frailty risk score (HFRS) is associated with the risk of stroke and determine whether a significant association between genetically determined frailty and stroke exists. Design: Observational study using data from All of Us research program and Mendelian Randomization analyses. Methods: Participants from All of Us with available electronic health records were selected for analysis. All of Us began national enrollment in 2018 and is expected to continue for at least 10 years. All of Us is recruiting members of groups that have traditionally been underrepresented in research. All participants provided informed consent at the time of enrollment, and the date of consent was recorded for each participant. Incident stroke was defined as stroke event happening on or after the date of consent to the All of Us study HFRS was measured with a 3-year look-back period before the date of consent for stroke risk. The HFRS was stratified into 4 categories: no-frailty (HFRS=0), low (HFRS ≥1 and Results: Two hundred fifty-three thousand two hundred twenty-six participants were at risk of stroke. In multivariable analyses, frailty status was significantly associated with risk of any (ischemic or hemorrhagic) stroke following a dose-response way: not-frail versus low HFRS (HR, 4.9 [CI, 3.5–6.8]; P P P P value for all comparisons P =0.002). Conclusions: Frailty, based on the HFRS was associated with higher risk of any stroke. Mendelian Randomization analyses confirmed this association providing evidence to support a causal relationship.

Background: Stroke is a leading cause of long-term disability. Greater rehabilitation therapy after stroke is known to improve functional outcomes. This study examined therapy doses during the first year of stroke recovery and identified factors that predict rehabilitation therapy dose. Methods: Adults with new radiologically confirmed stroke were enrolled 2 to 10 days after stroke onset at 28 acute care hospitals across the United States. Following an initial assessment during acute hospitalization, the number of physical therapy, occupational therapy, and speech therapy sessions were determined at visits occurring 3, 6, and 12 months following stroke. Negative binomial regression examined whether clinical and demographic factors were associated with therapy counts. False discovery rate was used to correct for multiple comparisons. Results: Of 763 patients enrolled during acute stroke admission, 510 were available for follow-up. Therapy counts were low overall, with most therapy delivered within the first 3 months; 35.0% of patients received no physical therapy; 48.8%, no occupational therapy, and 61.7%, no speech therapy. Discharge destination was significantly related to cumulative therapy; the percentage of patients discharged to an inpatient rehabilitation facility varied across sites, from 0% to 71%. Most demographic factors did not predict therapy dose, although Hispanic patients received a lower cumulative amount of physical therapy and occupational therapy. Acutely, the severity of clinical factors (grip strength and National Institutes of Health Stroke Scale score, as well as National Institutes of Health Stroke Scale subscores for aphasia and neglect) predicted higher subsequent therapy doses. Measures of impairment and function (Fugl-Meyer, modified Rankin Scale, and Stroke Impact Scale Activities of Daily Living) assessed 3 months after stroke also predicted subsequent cumulative therapy doses. Conclusions: Rehabilitative therapy doses during the first year poststroke are low in the United States. This is the first US-wide study to demonstrate that behavioral deficits predict therapy dose, with patients having more severe deficits receiving higher doses. Findings suggest directions for identifying groups at risk of receiving disproportionately low rehabilitation doses.

Background: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. Methods: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE—a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data. Results: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels ( P −8 ). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk ( P =2.6×10 −6 ), exceeding the Bonferroni-corrected threshold for 16 074 tests ( P −6 ). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P =0.003), with IS recurrence in the VISP trial (gene-based test, P =0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P Conclusions: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Background and ObjectivesPerihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from 2 centers, we sought to determine whether sST2 was associated with functional outcome, PHE, and the immune response following IPH.MethodsPatients with deep IPH were enrolled within 36 hours of ictus, and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as a modified Rankin Scale score of 0–3 at 90 days. Linear mixed-effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region.ResultsThe 55 included patients had a median admission Glasgow Coma Scale score of 14 (interquartile range [IQR] 9–15), an intracerebral hemorrhage (ICH) score of 1 (IQR 1–2), and a hematoma volume of 8.6 mL (IQR 3.4–13.8 mL). Receiver operating curve analysis found the sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632–0.894) and Youden optimum cut point of 61.8 ng/mL (p< 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted odds ratio 2.53, 95% CI 1.03–6.19,p= 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (β = 1.07, 95% CI 0.51–1.63,p< 0.001). High sST2 was associated with a shift toward an innate peripheral immune response (monocytes and natural killer cells; 68.6% ± 5.1% vs 47.5% ± 4.0%;p= 0.003).DiscussionOur findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify patients with IPH at highest risk for immune-mediated injury or limit injury through targeted interventions.

The evidence linking chronic kidney disease (CKD) to spontaneous intracerebral hemorrhage (ICH) is inconclusive owing to possible confounding by comorbidities that frequently coexist in patients with these 2 diseases.To determine whether there is an association between CKD and ICH risk.A 3-stage study that combined observational and genetic analyses was conducted. First, the association between CKD and ICH risk was tested in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, a multicenter case-control study in the US. All participants with available data on CKD from ERICH were included. Second, this analysis was replicated in the UK Biobank (UKB), an ongoing population study in the UK. All participants in the UKB were included in this study. Third, mendelian randomization analyses were implemented in the UKB using 27 CKD-related genetic variants to test for genetic associations. ERICH was conducted from August 1, 2010, to August 1, 2017, and observed participants for 1 year. The UKB enrolled participants between 2006 and 2010 and will continue to observe them for 30 years. Data analysis was performed from November 11, 2019, to May 10, 2022.CKD stages 1 to 5.The outcome of interest was ICH, ascertained in ERICH via expert review of neuroimages and in the UKB via a combination of self-reported data and International Statistical Classification of Diseases, Tenth Revision, codes.In the ERICH study, a total of 2914 participants with ICH and 2954 controls who had available data on CKD were evaluated (mean [SD] age, 61.6 [14.0] years; 2433 female participants [41.5%]; 3435 male participants [58.5%]); CKD was found to be independently associated with higher risk of ICH (odds ratio [OR], 1.95; 95% CI, 1.35-2.89; P .001). This association was not modified by race and ethnicity. Replication in the UKB with 1341 participants with ICH and 501 195 controls (mean [SD] age, 56.5 [8.1] years; 273 402 female participants [54.4%]; 229 134 male participants [45.6%]) confirmed this association (OR, 1.28; 95% CI, 1.01-1.62; P = .04). Mendelian randomization analyses indicated that genetically determined CKD was associated with ICH risk (OR, 1.56; 95% CI, 1.13-2.16; P = .007).In this 3-stage study that combined observational and genetic analyses among study participants enrolled in 2 large observational studies with different characteristics and study designs, CKD was consistently associated with higher risk of ICH. Mendelian randomization analyses suggest that this association was causal. Further studies are needed to identify the specific biological pathways that mediate this association.

BackgroundPatients with ischemic stroke and concomitant coronavirus 2019 (COVID-19) infection have worse outcomes than those without this infection. However, research on the impact of COVID-19 infection on outcomes following hemorrhagic stroke remains limited. We aim to study whether concomitant COVID-19 infection leads to worse outcomes in spontaneous intracerebral hemorrhage (ICH).DesignWe conducted an observational study using data from Get With The Guidelines® Stroke, an ongoing, multi-center, nationwide quality assurance registry.MethodsWe implemented a two-stage design: first, we compared outcomes of ICH patients with and without COVID-19 infection admitted during the pandemic (from March 2020 to February 2021). Second, we compared the same outcomes between ICH patients admitted before (March 2019 to February 2020) and during (March 2020 and February 2021) the pandemic. Main outcomes were poor functional outcome (defined as a modified Rankin Scale of 4 to 6 [mRS] at discharge), mortality and discharge to skilled nursing facility (SNF) or hospice.ResultsThe first stage included 60,091 COVID-19-negative and 1,326 COVID-19-positive ICH patients. In multivariable analyses, ICH patients with versus without COVID-19 infection had 68% higher odds of poor outcome (OR 1.68, 95%CI 1.41-2.01), 51% higher odds of mortality (OR 1.51, CI 1.33-1.71) and 66% higher odds of being discharged to a SNF/hospice (OR 1.66, 95%CI 1.43-1.93). The second stage included 62,743 pre-pandemic and 64,681 intra-pandemic ICH cases. In multivariable analyses, ICH patients admitted during versus before the COVID-19 pandemic had a 10% higher odds of poor outcome (OR 1.10, 95%CI 1.07-1.14), 5% higher mortality (OR 1.05, 95%CI 1.02-1.08) and no significant difference in the risk of being discharged to SNF/hospice (OR 0.93, 95%CI 0.90-0.95).ConclusionsThe pathophysiology of the COVID-19 infection and changes in healthcare delivery during the pandemic played a role in worsening outcomes in this patient population. Further research is needed to identify these factors and understand their effect on the long-term outcome.

BackgroundCardiovascular health optimization during middle age benefits brain health. The American Heart Association’s Life’s Simple 7 recently added sleep duration as a key determinant of cardiovascular health becoming the Life’s Essential 8. We tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults.MethodsWe conducted a prospective MRI neuroimaging study in middle-aged persons without stroke, dementia, or multiple sclerosis enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (ResultsWe evaluated 39,502 middle-aged persons (mean age 55, 53% female). Of these, 28,712 (72.7%) had optimal, 8,422 (21.3%) short, and 2,368 (6%) long sleep. Compared to optimal sleep, short sleep was associated with higher risk (OR 1.11; 95% CI 1.05-1.17; P0.05) of white matter hyperintensities. Short (beta=0.03, SE=0.01; P=0.004) and long sleep (beta=0.07, SE=0.02; PConclusionsAmong middle-aged adults without clinically observed neurological disease, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because the evaluated neuroimaging markers precede stroke and dementia by several years, our findings support early interventions aimed at correcting this modifiable risk factor.

ObjectiveGenome-wide association studies have identified1q22as 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 of1q22in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.Methods95,000 base pairs spanning1q22, includingSEMA4A, SLC25A44andPMF1/PMF1-BGLAPwere 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 at1q22could be causally related to ICH risk.ResultsCommon and rare variant analyses prioritized variants inSEMA4A5’-UTR andPMF1intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that1q22is 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 theSEMA4A-promoter andPMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated thatPMF1overexpression could be causally related to non-lobar ICH risk.InterpretationAltered promoter-enhancer interactions leading toPMF1overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at1q22, offering a potential new target for prevention of ICH and CSVD.

Background and ObjectivesBlood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors.MethodsWe conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke. To model the PSH, we created polygenic risk scores (PRSs) for systolic and diastolic BP using 732 genetic variants. We divided the PRSs into quintiles and used linear/logistic regression to test whether higher PSH led to higher observed BP, uncontrolled BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg), and resistant BP (uncontrolled BP despite being on ≥3 antihypertensive drugs). We conducted an independent replication using data from the Vitamin Intervention for Stroke Prevention (VISP) trial.ResultsWe analyzed 5,940 stroke survivors. When comparing stroke survivors with very low vs very high PSH, the mean systolic BP was 137 (SD 18) vs 143 (SD 20,p< 0.001), the mean diastolic BP was 81 (SD 10) vs 84 (SD 11,p< 0.001), the prevalence of uncontrolled BP was 42.8% vs 57.2% (p< 0.001), and the prevalence of resistant hypertension was 3.9% vs 11% (p< 0.001). Results remained significant using multivariable models (p< 0.001) and were replicated in the VISP study (all tests withp< 0.05).DiscussionA higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population.

ImportancePoor oral health is a modifiable risk factor that is associated with a variety of health outcomes. However, the relationship between oral and brain health is not well understood.ObjectiveTo test the hypothesis that poor oral health is associated with worse neuroimaging brain health profiles in persons without stroke or dementia.DesignWe conducted a 2-stage cross-sectional neuroimaging study using data from the UK Biobank (UKB). First, we tested for association between self-reported poor oral health and MRI neuroimaging markers of brain health. Second, we used Mendelian Randomization (MR) analyses to test for association between genetically-determined poor oral health and the same neuroimaging markers.SettingOngoing population study in the United Kingdom. The UKB enrolled participants between 2006 and 2010. Data analysis was performed from September 1, 2022, to January 10, 2023.Participants40,175 persons aged 40 to 70 enrolled between 2006 to 2010 who underwent a dedicated research brain MRI between 2012 and 2013.ExposuresDuring MRI assessment, poor oral health was defined as the presence of dentures or loose teeth. As instruments for the MR analysis, we used 116 independent DNA sequence variants known to significantly increase the composite risk of decayed, missing, or filled teeth and dentures.Main Outcomes and MeasuresAs neuroimaging markers of brain health, we assessed the volume of white matter hyperintensities (WMH), as well as aggregate measures of fractional anisotropy (FA) and mean diffusivity (MD), two metrics indicative of white matter tract disintegrity obtained through diffusion tensor imaging. These measurements were evaluated across 48 distinct brain regions, with FA and MD values for each region also considered as individual outcomes for the MR method.ResultsAmong study participants, 5,470 (14%) had poor oral health. We found that poor oral health was associated with a 9% increase in WMH volume (beta = 0.09, standard deviation (SD) = 0.014, p P< 0.001), a 10% change in the aggregate FA score (beta = 0.10, SD = 0.013, P < 0.001), and a 5% change in the aggregate MD score (beta = 0.05, SD = 0.013, P < 0.001). Genetically-determined poor oral health was associated with a 30% increase in WMH volume (beta = 0.30, SD = 0.06, P < 0.001), a 43% change in aggregate FA score (beta = 0.42, SD = 0.06, P < 0.001), and an 10% change in aggregate MD score (beta = 0.10, SD = 0.03, P = 0.01).Conclusions and RelevanceAmong middle age Britons without stroke or dementia enrolled in a large population study, poor oral health was associated with worse neuroimaging brain health profiles. Genetic analyses confirmed these associations, supporting a potential causal association. Because the neuroimaging markers evaluated in the current study are established risk factors for stroke and dementia, our results suggest that oral health may be a promising target for interventions focused on improving brain health.

Background: Patients with brain arteriovenous malformation (AVM) are at risk of intracranial hemorrhage (ICH). The epsilon 2 and 4 alleles within the APOE gene are well-described genetic risk factors for spontaneous, non-traumatic intraparenchymal hemorrhages. We tested the hypothesis that the APOE epsilon variants lead to higher risk of ICH in patients with AVMs. Methods: We conducted a two-stage (discovery and replication) genetic association study using individual-level data from the UK Biobank and the All of Us Research Program. We ascertained AVMs and ICH using validated ICD-9/10 codes. Genome-wide array genotyping was completed using the UK Biobank Axiom Array in the UK Biobank, and Illumina’s Global Diversity Array in All of Us. We used genotypic data on the APOE variants rs429358 and rs7412 to ascertain the epsilon 2 and 4 status. Within each study, we tested for association between APOE epsilon variants and ICH risk using multivariable logistic regression. Results: The discovery phase included 189 UK Biobank participants with an AVM (mean age 57 years, female sex 49%), including 37 (19.6%) that sustained an ICH. After adjusting by age, sex, and race/ethnicity, APOE epsilon 4 was associated with a higher risk of ICH (OR 4.20; 95%CI 1.99-9.25; p0.05). These results were replicated in 228 participants with AVMs enrolled in All of Us (mean age 56 years, female sex 66%), including 31 (13.6%) who sustained an ICH, where APOE epsilon 4 was associated with a higher risk of ICH (OR 2.73; 95%CI 1.05-7.22; p=0.038) whereas epsilon 2 was not (p>0.05). Conclusion: Among study participants with AVMs enrolled in two large population studies, the APOE epsilon 4 variants were associated higher risk of sustaining a brain bleed. These results point to shared pathophysiology with spontaneous intraparenchymal hemorrhages and provide support for further research focused on evaluating the role of APOE in risk stratification strategies.

Background: Patients with ischemic stroke have worse outcome if there is concomitant coronavirus 2019 (COVID-19) infection. We hypothesize that patients with intracerebral hemorrhage (ICH) during the pandemic era had worse outcomes than ICH patients during the pre-pandemic period, and that concomitant COVID-19 in ICH patients is associated with worse outcome. Methods: We analyzed data from Get With The Guidelines® Stroke. We implemented a two-stage design: first, we compared outcomes for ICH patients pre-pandemic (admitted between March 2019 and February 2020) with outcomes for ICH patients admitted during the pandemic (from March 2020 to February 2021); second, we compared outcomes of ICH patients with and without COVID-19 infection admitted during the pandemic (from March 2020 to February 2021). We used multivariable logistic regression adjusted by age, sex, race/ethnicity, and clinical covariates for in-hospital mortality and poor functional outcome using the modified Rankin Scale (mRS) at discharge (mRS >= 4) and a for length of stay (LOS). Results: The first stage included 62,743 pre-pandemic and 64,681 intra-pandemic ICH cases 64,681. ICH patients during the pandemic had worse outcomes, including higher modified rankin scale (mRS) (OR 1.10, CI 1.06-1.14) and higher mortality (OR 1.04, CI 1.01-1.07). The second stage included 60,091 COVID-19-negative and 1,326 COVID-19-positive ICH patients. Patients with concomitant COVID-19 infection had worse outcomes, including higher LOS (RR 1.32, CI 1.25-1.39), high mRS (OR 1.68, CI 1.40-2.01), and increased mortality (OR 1.50, CI 1.33-1.71). (Table). Conclusion: When comparing pre- and intra-pandemic cases of ICH, critically ill stroke patients admitted during the pandemic had worse outcomes. When comparing COVID-19 positive and negative ICH cases that happened during the pandemic, those with the infection had worse clinical outcomes. COVID-19 infection is an independent risk factor for poor outcomes in ICH.

Introduction: Ischemic Stroke survivors are at high risk of stroke recurrence. Understanding the genetic risk factors for stroke recurrence will help guide future prevention strategies. Hypothesis: Genetically-elevated LDL-cholesterol (LDL-c) negatively impact clinical trajectories after stroke, leading to higher risk of post-stroke acute vascular events. Methods: We analyzed clinical and genetic data from the Vitamin Intervention Stroke Prevention (VISP) clinical trial, which examined high-dose vitamins in stroke survivors. Genetic susceptibility to increased LDL-c was modeled through a polygenic risk score built with genetic data on 38 known genetic risk variants for LDL-cholesterol (variants influencing other lipid traits were excluded). We divided the LDL-related polygenic risk score into 0-20, 20-80, and 80-100 percentile categories labeled as low, intermediate and high genetic predisposition to high LDL. We fitted multivariable (adjusting for age, sex, vascular risk factors, and statin treatment) Cox proportional hazards and logistic regression models to test whether higher polygenic risk for elevated LDL-c was associated with observed LDL-c, ischemic stroke recurrence, and composite risk of ischemic stroke and myocardial infarction. Results: Of the 2,164 stroke survivors enrolled in VISP, 1,567 (72%) had available LDL-c and genetic data. The mean LDL in the low, intermediate and high polygenic risk categories was 114.5 (SD 2.21), 123.2 (SD 1.23), and 128.8 (SD 2.35), respectively (unadjusted p Conclusions: A higher polygenic risk for increased LDL-c is associated with worse clinical trajectories after stroke. Further research is needed to determine whether stroke survivors with an elevated genetic risk benefit from unique care pathways with additional monitoring and treatment.

Background and objective: Small, single-center studies point to biological and clinical differences in women and men who sustain a spontaneous, non-traumatic intracerebral hemorrhage (ICH). Leveraging data from four landmark studies of ICH, we investigated the impact of sex on risk factors, location, severity and outcome of ICH. Design: Individual patient data meta-analysis of four studies of ICH, including three randomized clinical trials and one multi-ethnic observational study. Setting: Academic medical centers in the United States. Patients: Patients with neuroimaging confirmed ICH. Measurements: We conducted an individual patient data meta-analysis of four landmark studies of ICH: ERICH, ATACH-II, FAST and MISTIE-III. We evaluated whether sex was associated with specific risk factor profiles, hemorrhage location (deep or lobar), neuroimaging severity (hematoma volume and expansion), and poor 90-day functional outcomes (defined as a modified Rankin scale 4 to 6). Main Results: A total of 4,812 ICH patients were evaluated (mean age 62, 60% males). Men with ICH were younger, more likely to be smokers and diabetics, and less likely to be on anticoagulants (all p Conclusions: Men with ICH are more likely to have vascular risk factors, have larger hemorrhage volumes, and have higher risk of hemorrhage expansion. They are also more likely to have a good outcome at 90 days compared to women.

Introduction: Though uncontrolled diabetes leads to recurrent cardiovascular events in stroke survivors, many don’t achieve appropriate glycemic control. We hypothesize an adverse polygenic risk profile leads to worse glycemic control and higher risk of recurrent cardiovascular events in stroke survivors. Methods: We conducted a population genetic study using data of stroke survivors enrolled in the UK Biobank and the Vitamin Intervention for Stroke Prevention (VISP) trial. In both studies, we modeled polygenic risk to diabetes through a polygenic risk score that included 462 single nucleotide polymorphisms known to associate with type 2 diabetes mellitus. Participants were stratified as low, intermediate, or high polygenic risk according to percentile values of this score (th , 20-80 th and >80 th percentile). We used multivariable linear, logistic, and Cox regression models to test for association between polygenic risk to diabetes and 1) hemoglobin A1c (HbA1c), 2) risk of treatment-resistant diabetes (HbA1c ≥7 despite pharmacological therapy), and 3) composite risk of recurrent stroke or coronary artery disease (CAD). Results: In 5,670 stroke survivors enrolled in the UK Biobank (mean age 61, 41% females), a higher polygenic risk to diabetes was associated with higher HbA1c in both participants with and without diabetes, and with higher risk of treatment-resistant diabetes (all p Conclusions: Among stroke survivors, a higher polygenic risk to diabetes is associated with worse glycemic control and higher risk of recurrent acute vascular events. Further research is needed to evaluate the portability of these results to non-white individuals and identify specific medications that may be more effective in patients with adverse genomic profiles.

Background: Mechanical thrombectomy (MT) has significantly improved clinical outcomes in acute ischemic stroke. We used single-cell RNA sequencing (scRNA-seq) to describe the landscape of human clots at single cell resolution seeking to provide greater mechanistic insight into stroke pathophysiology and to uncover an association with stroke origin. Methods: scRNA-seq was performed on 14 clots retrieved from 14 patients undergoing MT between October 2020-July 2022. We followed standard molecular biology and bioinformatics workflows for sample processing and data to characterize differences in cellular composition between clots of different stroke origin (atrial fibrillation (AF) and carotid atherosclerosis (CA)). Results: Clots revealed a significant heterogeneity of immune cells with major constituents including cells of the mononuclear phagocyte system (MPS) and neutrophils. The cellular populations most enriched in CA clots were B-cells and CD4+ T-cells. The cellular population most enriched in AF clots was red blood cells. When looking at cellular subpopulations of the MPS component, we found that CD16+ monocytes (intermediate and non-classical) were significantly more abundant than CD14+CD16- (classical) monocytes in all clots. Moreover, the proportions of CD16+ monocytes varied with stroke origin: the proportion of non-classical (CD14-CD16+) monocytes was higher in CA clots (p=0.05) whereas the proportion of intermediate monocytes (CD14+CD16+) was higher in FA clots (p=0.03). AF clots had upregulated biomarkers and pathways involved with AF or contractile dysfunction (IFI30, FABP4, PPAR, HOTAIR, ILK, Integrin). CA clots had upregulated biomarkers and pathways associated with cardiovascular diseases and atherogenesis (RNSE1, POLR2J3.1, PLTP, Sirtuin, FAK). (Figure) Conclusions: These results reveal a significant heterogeneity of immune cells and point to important differences in cellular composition associated with stroke etiology.

Introduction: Existing observational evidence indicates that blood pressure (BP) differs by race/ethnicity in the first 24 hours after spontaneous intracerebral hemorrhage (ICH). However, differences in BP across race/ethnic groups beyond this acute period remain understudied. Hypothesis: Race/ethnic differences in BP levels and variability persist after the initial 24 hours. Methods: We analyzed data from the Yale Longitudinal Study for Acute Brain Injury, an ongoing observational study that longitudinally follows adult (>18 years) patients admitted to the neurocritical care and stroke services of the Yale Health System. For this study, we included patients with ICH enrolled between January 2018 and January 2022 and abstracted from the Electronic Health Record BP measurements obtained during the first 7 days of admission. Mean systolic BP was calculated in 4-hour epochs. Blood pressure variability was calculated as the trough of systolic blood pressures. Multivariable linear regression models were used to analyze differences in systolic BP and BP variability across race/ethnic groups. Results: A total of 738 patients (mean age 68, 45% female) were included in the study, including 530 (71.8%) whites, 138 (18.7%) African Americans, and 70 (9.5%) Hispanics. African Americans had trend toward statistically higher systolic BP (beta 2.7, SE 1.49; p= 0.06) as well as higher BP variability than whites (beta 2.34, SE 1.16; p= 0.045) and Hispanics (beta -0.61, SE 1.50; p=0.68). Other factors associated with systolic BP were age (beta 0.17, SE 0.04; p Conclusions: Among patients with ICH admitted to a single health care system study of acute brain injury, Black race was associated with higher BP variability and, possibly, higher systolic BP. Given the pivotal role of BP management in the care of patients with ICH, further research is needed to understand how the observed differences could translate into race/ethnic-specific strategies to manage BP.

Introduction: White matter hyperintensity (WMH) is a neuroimaging manifestation of cerebrovascular disease that is associated with vascular risk factors and the development of cognitive impairment and stroke. Estimating atherosclerotic cardiovascular disease (ASCVD) risk is a method of measuring the extent of vascular risk for a given individual and, thus, there exists a potential link between ASCVD risk and WMH volume. Methods: We included participants in the SPRINT MIND study who underwent a research MRI with volumetric quantification of the burden of WMH in mL. We report the WMH burden by categories of 10-year ASCVD risk using the Pooled Cohort Equations CV Risk (2014 edition). The ASCVD categories include low (0-5%), borderline (5-7.49%), intermediate (7.5-19.9%), and high (>20%). We used a violin plot to show the results graphically and also report the medians and IQR. As a secondary outcome we report WMH progression, which is the difference in WMH burden between the baseline MRI and a follow-up MRI performed 48 months later. Results: We included 727 individuals, of which 22 (3.0%) were low, 46 (6.3%) were borderline, 370 (50.9%) were intermediate, and 289 (39.8%) were high ASCVD risk. The median (IQR) WMH burden was 1.6 mL (0.9-2.9) in the low, 1.7 mL (1.1-3.0) in the borderline, 2.7 mL (1.4-5.1) in the intermediate, and 4.7 mL (2.5-10.7) in the high ASCVD risk group (p Conclusions: There is a positive association between ASCVD risk and WMH volume and progression. ASCVD risk, which can be assessed through demographic and clinical variables, may be a useful predictor of the volume of WMH, which is traditionally obtained through an MRI scan.

Background and Objectives: Vascular brain injury (VBI) may contribute to imbalance and slow walk speed, but this is uncertain. We hypothesize that MRI biomarkers of VBI associate with impaired balance and slow walk speed. Methods: We performed separate, cross-sectional analyses in the Atherosclerosis Risk in Communities (ARIC) and UK Biobank (UKB) studies. Eligible participants had no prior clinical stroke and underwent a brain MRI and balance and walk speed ascertainment. MRI biomarkers of VBI analyzed were: ventricular volume, white matter hyperintensity volume (WMH), non-lacunar infarction, lacunar infarction, microhemorrhage in ARIC; ventricular volume, brain volume, WMH, fractional anisotropy (FA), mean diffusivity (MD), intra-cellular volume fraction, isotropic free water volume fraction in UKB. Quantitative biomarker levels were classified into tertiles, the unhealthiest tertile designated as the exposure. Our outcomes were poor balance and slow walk speed. We constructed multivariable logistic regression models to examine the associations between each MRI biomarker and the outcomes, adjusting for demographics and clinical history. Results: We included 1,626 ARIC participants (mean age 76.2 years; 23.4% impaired balance, 25.0% slow walk speed) and 40,098 UKB participants (mean age 55 years; 15.8% impaired balance, 2.8% slow walk speed). In ARIC, impaired balance was associated with 4 of 5 MRI measures of VBI in adjusted analysis (all p-values Conclusions: We demonstrate that MRI measures of VBI are independently associated with impaired balance and slow walk speed in two studies of community-dwelling adults with no history of clinical stroke. Consequences of VBI may extend beyond clinically apparent stroke to also include mobility.

Background: Oral health is a modifiable risk factor for stroke. However, the role of oral health in the brain health of clinically asymptomatic persons remains understudied. We hypothesize that genetically-determined poor oral health leads to worse neuroimaging brain health profiles in persons without stroke. Methods: We conducted a two-sample Mendelian Randomization (MR) study. As instruments, we used 105 genetic variants known to be associated (p-8 ) with a composite of caries, dentures and missing teeth in the GLIDE Consortium. In stroke-free participants enrolled in the UK Biobank, we tested for association between these genetic variants and white matter hyperintensity volume (natural log-transformed), fraction anisotropy and mean diffusivity. For the last two neuroimaging traits, we evaluated the first principal component of measurements obtained across 48 brain regions. Results: Our primary analysis using the inverse variance-weighted MR method indicated that genetically-increased risk of poor oral health was associated with: (1) higher burden of silent cerebrovascular disease, as represented by higher volumes of white matter hyperintensities (beta=0.24, SE=0.07 p-value=0.001), and (2) increased microstructural damage, as represented by lower fractional anisotropy (beta=-2.53, SE=0.38; p=1x10 -9 ) and higher mean diffusivity (beta=3.42, SE=0.41; p=2x10 -11 ). Sensitivity analyses identified horizontal pleiotropy in our primary results, but an outlier-corrected analysis confirmed all three initial results (all p-values Conclusion: Among persons without stroke, genetically-determined poor oral health is associated with worse neuroimaging brain health profiles. Because gene-disease associations are immune to confounding, our results indicate that this association is causal. Early treatment of poor oral health may lead to significant brain health benefits, even in persons without stroke.

Introduction: Stroke and traumatic brain injury (TBI) accounts for 70% of secondary epilepsy in the adult population. The genetic architecture of epilepsy secondary to TBI or stroke is poorly understood. Objective: We undertook a systematic review to test the association of single nucleotide polymorphisms (SNPs) with the risk of posttraumatic epilepsy (PTE) and post-stroke epilepsy (PSE). Methods: We conducted a comprehensive literature search until 5 July 2022 in PubMed, Embase, PsycINFO, Web of Science, and Google Scholar. We preregistered the protocol of this systematic review on PROSPERO (CRD42022325617). We collated the association statistics from the articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed the study quality using the Quality of Genetic Association (Q-Genie) tool. We report Odds Ratio (OR) and Hazard Ratio (HR) with a 95% confidence interval (CI), including combined OR where a meta-analysis was possible. Results: The literature search yielded 420 articles, of which 16 were included in our systematic review. Q-Genie-based assessment of the literature found that 58% of the included studies were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Twelve studies reported that 718 TBI patients (21%) suffered from PTE. Four studies reported PSE in 1192 stroke patients (50%). Eleven SNPs were associated with an increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, CD40 -1C/T, were significantly associated with an increased risk of PSE, while two SNPs, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. Only two studies tested the association of APOE E4 with PTE; no other studies validated previously reported genetic association data. Hence, the limited data precluded meta-analysis of all but one SNP, i.e., the APOE E4 allele. The meta-analysis for the association of the APOE E4 allele with PTE was non-significant (OR 1.8, CI 0.6-5.6). Conclusions: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Background: The risk of ischemic stroke mortality increases with age, but the impact of stroke severity on this relationship has not been fully examined. Methods: We included adults in the National Inpatient Sample from 2016-2019 who had a primary discharge diagnosis of ischemic stroke (I63*) and a baseline NIH Stroke Scale (NIHSS). The primary outcome was in-hospital death. The exposure of age had left skew, so we transformed it into deciles. We fit a logistic regression model adjusted for sex, race/ethnicity, diabetes, atrial fibrillation, hypertension, thrombolytic therapy, and endovascular therapy. We report the predicted probability of the primary outcome with and without NIHSS and use structural equation modeling (SEM) to estimate the proportion of age’s effect on the primary outcome that is mediated by stroke severity. Results: We included 138,637 individuals, of which 3.5% died in-hospital. The proportion of in-hospital death and an NIHSS violinplot by decile of age are seen in Figure 1, both of which had a positive linear relationship. The AUC of the multivariable model without NIHSS was 0.70 and with NIHSS was 0.86 (p Conclusions: We found that elderly individuals in the United States have more severe stroke and higher stroke mortality, but the effect of age on stroke mortality is primarily mediated by elderly individuals having more severe stroke. Additional research is needed to better understand this novel finding.

Purpose: Hematoma expansion (HE) is associated with early clinical deterioration, worse long-term outcome, and higher mortality in ICH. Identification of patients at risk of HE may allow targeted anti-expansion therapies in future trials. We aimed to train and validate a deep learning model for prediction of HE based on admission non-contrast head CT. Methods: We utilized the clinical and imaging information from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial and Yale ICH registry. All patients with spontaneous supratentorial ICH who had baseline head CT (28 were included. The HE was defined as an increase volume >33% or 6 ml. We trained a DenseNet121-based 3D convolutional neural network for prediction of HE (pipeline summarized in the Figure). Results: A total of 749 patients (610 from ATACH-2 and 183 from Yale) were randomly split (4:1) into 634 training/cross-validation (368 (58%) male, mean age of 62.8±13.1 years, median NIHSS 10, and 144 (23%) with HE); and 159 independent test set (92 (58%) male, mean age of 62.5±14.6 years, median NIHSS 12, and 36 (23%) with HE). The average of validation AUC in five-fold training/cross-validation was 0.62, with the best performing model achieving an AUC of 0.71 in validation fold. We then tested this model in the independent validation cohort isolated from training process, achieving an AUC of 0.67 in predicting HE. The attention heatmaps (Figure) confirm that deep learning model predictions were based on head CT regions containing ICH and perilesional edema. Conclusion: We could train, and independently validate a deep learning model for identification of supratentorial ICH patients at risk of impending HE. Compared to visual markers (including CTA spot sign), such model can provide an automated objective tool for future trial enrollment based on readily available non-contrast CT

Background: Evidence indicates that optimization of cardiovascular health during middle age leads to brain health benefits later in life. The AHA Life’s Simple 7, a research and public health construct capturing determinants of cardiovascular health, recently added sleep as a risk factor, becoming the Life’s Essential 8 (LE8). We hypothesize that suboptimal sleep duration worsens neuroimaging brain health profiles in middle-aged persons without stroke. Methods: We conducted a nested, cross-sectional neuroimaging analysis within the UK Biobank, a large population study conducted in the United Kingdom. We included participants without stroke/dementia who underwent a research brain MRI. We created a 6-category sleep score according to hours of sleep (best to worse): 7 to =10h; 4 to Results: Of 502,408 participants enrolled in the UKB, 39,937 (7.9%) stroke/dementia-free enrollees participated in the brain MRI study (mean age 55, 53% female). The distribution of sleep categories was: 1 (n=28,958, 72.51%), 2 (n=2060, 5.16%), 3 (n=7165, 17.94%), 4 (n=1,562, 3.91%), 5 (n=163, 0.41%) and 6 (n=29, 0.07%). In multivariable linear regression analyses, a higher (worse) sleep score was associated with larger WMH volume (beta 0.026, SE=0.0046; p Conclusion: Among middle-aged participants enrolled in the UKB, suboptimal sleep duration was significantly associated with adverse neuroimaging brain health profiles. These results emphasize the importance of sleep duration, the new component of the LE8, in determining brain health in middle-aged persons who have not developed clinically evident manifestations of poor brain health (stroke).