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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.

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.

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.

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.

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.

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.

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).

Background: The interaction between social determinants of health and genetic risk factors in causing acute ischemic stroke (AIS) is poorly understood. We hypothesize that community deprivation, a geographic metric that captures several social determinants of health, modifies the effect of genetic variation on risk of AIS. Methods: We analyzed data from All of Us , a large population study that aims to enroll one million Americans. We ascertained AIS cases using Observational Medical Outcomes Partnership codes. We evaluated community deprivation using the deprivation index, an aggregate variable derived from six metrics of the American Community Survey that was divided into tertiles. We modeled the polygenic contribution to AIS through a polygenic risk score that included 530 known genetic risk variants for cardiometabolic risk factors. We used multivariable logistic regression to model AIS risk as a function of community deprivation and polygenic risk, using product terms to test for interaction. Results: Out of 372,397 participants currently enrolled in All of Us , 147,492 had available genetic and deprivation index data, including 3,201 (2.2%) strokes. Both community deprivation and the polygenic risk score were independently associated with AIS risk (both p0.05). Conclusion: Among study participants enrolled in All of Us, those living in areas of low community deprivation were more susceptible to the effects of polygenic variation. We speculate that in areas with high deprivation, several social determinants of health known to lead to higher risk of AIS dilute the contribution of genetic risk factors.

Background: Cerebral amyloid angiopathy (CAA) is a condition characterized by amyloid deposition in the brain’s blood vessels. CAA is a common cause of spontaneous intracerebral hemorrhage (ICH) in older patients. Although other types of intracranial hemorrhages can occur in conjunction with CAA-related ICH, it is unknown whether CAA is a risk factor for other types of intracranial hemorrhage in the absence of ICH. Hypothesis: CAA is an independent risk factor for isolated non-traumatic subdural hemorrhage (SDH). Methods: We conducted a 2-stage (discovery and replication) observational study that retrospectively analyzed data from the UK Biobank (discovery phase) and the All of Us (replication phase) study. We included participants over 55 years of age to meet the age threshold for the modified Boston Criteria. The exposure was a diagnosis of CAA and the outcome was non-traumatic SDH, both identified using ICD-9 and ICD-10 codes. We used survival analyses with log-rank tests and multivariable Cox proportional hazards models adjusted for demographic characteristics and vascular risk factors. Results: The discovery phase included 283,452 UK Biobank participants comprising 123 CAA cases and 504 SDH cases. SDH subsequently occurred in 2.4% of participants with CAA versus 0.2% of those without CAA. In a multivariable Cox model, CAA was associated with a significantly increased risk of SDH (hazard ratio [HR], 7.3; 95% CI, 2.3-22.7). This finding was replicated among 168,370 study participants in All of US, where 66 had CAA and 443 had a SDH (HR, 11.66; 95% CI, 5.2-26.2). Conclusion: In two large heterogeneous cohorts conducted in different countries, CAA was independently associated with a higher risk of isolated non-traumatic SDH. Further research is needed to further determine causality and identify biological pathways that may mediate this association.

Background: Social determinants of health are emerging as a key group of risk factors for cerebrovascular disease. Carotid artery stenosis (CAS) is an important risk factor for ischemic stroke. We hypothesize that community deprivation, an exposure that captures several social determinants for health, leads to significant disparities in healthcare access in patients with known CAS. Methods: We conducted a cross-sectional study within the All of Us Research Program, a prospective population study that aims to enroll 1 million Americans. We included study participants with CAS, as defined by validated ICD-9/10 codes. We evaluated access to healthcare using 5 metrics included in the Health Care Access and Utilization Survey (Table 1). We evaluated community deprivation using the Deprivation Index, a novel compound metric developed by the American Community Survey. We tested for association between tertiles of the Deprivation Index (labeled low, intermediate and high community deprivation) and health care access using multivariable models adjusting for potential confounders. Results: Of 333,845 participants enrolled in All of Us, we identified 2,465 (0.74%) participants with CAS (mean age 69, 53% female). Of these, 259 (10.5%) could not afford prescription medication, 132 (5.4%) could not afford specialist care, 144 (5.8) skipped medications, 109 (4.4%) could not afford follow up care and 97 (3.9%) could not afford mental health care. In unadjusted analysis, higher community deprivation was associated with a higher prevalence of all 5 evaluated indicators of poor access to health. In multivariable analysis adjusted for potential confounder variables, difficulty affording prescription medication, specialist care and follow up care remained statistically significant (Table 1). Conclusion: Among persons with CAS enrolled in All of Us, community deprivation was associated with a lower likelihood of accessing and utilizing important healthcare services.

Background: Social determinants of health are emerging as a key group of risk factors for cerebrovascular disease. Carotid artery stenosis (CAS) is an important risk factor for ischemic stroke. We hypothesize that community deprivation, an exposure that captures several social determinants for health, leads to significant disparities in healthcare access in patients with known CAS. Methods: We conducted a cross-sectional study within the All of Us Research Program, a prospective population study that aims to enroll 1 million Americans. We included study participants with CAS, as defined by validated ICD-9/10 codes. We evaluated access to healthcare using 5 metrics included in the Health Care Access and Utilization Survey (Table 1). We evaluated community deprivation using the Deprivation Index, a novel compound metric developed by the American Community Survey. We tested for association between tertiles of the Deprivation Index (labeled low, intermediate and high community deprivation) and health care access using multivariable models adjusting for potential confounders. Results: Of 333,845 participants enrolled in All of Us, we identified 2,465 (0.74%) participants with CAS (mean age 69, 53% female). Of these, 259 (10.5%) could not afford prescription medication, 132 (5.4%) could not afford specialist care, 144 (5.8) skipped medications, 109 (4.4%) could not afford to follow up care and 97 (3.9%) could not afford mental health care. In unadjusted analysis, higher community deprivation was associated with a higher prevalence of all 5 evaluated indicators of poor access to health. In multivariable analysis adjusted for potential confounder variables, difficulty affording prescription medication, specialist care and follow up care remained statistically significant (Table 1). Conclusion: Among persons with CAS enrolled in All of Us, community deprivation was associated with a lower likelihood of accessing and utilizing important healthcare services.

Introduction: Neighborhood disadvantage is associated with various health factors. Given the mounting evidence linking social determinants to risk of, and outcomes after, spontaneous intracerebral hemorrhage (ICH), we tested the hypothesis that higher neighborhood disadvantage leads to poorer outcomes following ICH. Methods: We conducted a nested study within an ongoing longitudinal study that prospectively follows patients with acute brain injury admitted to Connecticut’s largest healthcare system. The nested study included ICH survivors and evaluated neighborhood deprivation using the Area Deprivation Index, a publicly available metric that uses 9-digit zip codes to rank neighborhoods’ socioeconomic disadvantage based on factors such as income, employment, and education. Patients were given a tertile designation according to the Area Deprivation Index: low, intermediate, and high deprivation. Functional outcome was evaluated through the 6-month post-ICH Modified Rankin Scale, dichotomized as 0-3 (good outcome) and 4-6 (poor outcome). We used chi-square tests and multivariable logistic regression for unadjusted and adjusted association analyses, respectively. Results: Out of 687 ICH patients enrolled from 2018 to 2022, 518 (mean age 67, 47.5 % female, 19% Black, 8% Hispanic) had 9-digit zip code and outcomes data. The unadjusted risk of poor outcome was 40%, 55%, and 61% for patients living in neighborhoods with low, intermediate, and high disadvantage (unadjusted p=0.02). This association was confirmed in multivariable analyses adjusting for potential confounders: compared to patients living in low-disadvantage neighborhoods, those living in neighborhoods with intermediate and high disadvantage had 66% (OR 1.66, 95% CI 0.82-3.40) and 2.5 times (OR 2.44, 95% CI 1.17-5.19) higher risk of poor outcomes (test-for-trend p=0.01). Conclusion: Among ICH survivors enrolled in a prospective study of acute brain injury, increased neighborhood disadvantage was associated with a higher risk of poor outcomes. Our results validate the Area Deprivation Index as a useful tool to assess the numerous social determinants of health. Additionally, our findings highlight the negative role of these social determinants in patients' recoveries.

BackgroundMounting evidence indicates that hypertension leads to higher risk of cognitive decline and dementia. Hypertension is a highly heritable trait and a higher polygenic susceptibility to hypertension (PSH) is known to be associated with higher risk of dementia. We tested the hypothesis that a higher PSH leads to worse cognitive performance in middle-aged persons without dementia.MethodsWe conducted a nested, cross-sectional, genetic study within the UK Biobank, a large population study that enrolled middle-aged Britons. Study participants with a history of dementia or stroke were excluded. We categorized participants as having low (≤20th percentile), intermediate (>20th and th percentile), or high (≥80th percentile) PSH according to results of 2 polygenic risk scores for systolic and diastolic blood pressure (BP), generated with genomic data on 732 genetic risk variants for these traits. Cognitive performance was evaluated via 5 simple tests: Pairs Memory, Reaction Time, Numeric Memory, Prospective Memory and Fluid Intelligence. A general cognitive ability score was calculated as the first principal component of a principal component analysis that included the results of these 5 tests. Primary analyses focused on Europeans and secondary analyses included all race/ethnic groups.ResultsOut of 409,551 study participants of European ancestry with available genomic data, 42,080 (10.3%) completed all 5 tests. Multivariable regression models using systolic BP-related genetic variants indicated that, compared to study participants with low PSH, those with intermediate and high PSH had reductions of 3.9% (beta -0.039, SE 0.012) and 6.6% (beta - 0.066, SE 0.014), respectively, in their general cognitive ability score (test for trend p ConclusionsAmong non-demented, community-dwelling, middle-aged Britons, a higher PSH is associated with worse cognitive performance. These findings suggest the genetic predisposition to hypertension influence brain health in persons who have not yet developed dementia.

Background and objectivesWe aimed to investigate the white matter (WM) microstructural/cytostructural disintegrity patterns related to higher systolic blood pressure (SBP), and whether they mediate SBP effects on cognitive performance in middle-aged adults.MethodsUsing the UK Biobank study of community-dwelling volunteers aged 40–69 years, we included participants without a history of stroke, dementia, demyelinating disease or traumatic brain injury. We investigated the association of SBP with MRI diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (a measure of neurite density), isotropic (free) water volume fraction (ISOVF) and orientation dispersion across WM tracts. Then, we determined whether WM diffusion metrics mediated the effects of SBP on cognitive function.ResultsWe analysed 31 363 participants—mean age of 63.8 years (SD: 7.7), and 16 523 (53%) females. Higher SBP was associated with lower FA and neurite density, but higher MD and ISOVF. Among different WM tracts, diffusion metrics of the internal capsule anterior limb, external capsule, superior and posterior corona radiata were most affected by higher SBP. Among seven cognitive metrics, SBP levels were only associated with ‘fluid intelligence’ (adjusted pDiscussionAmong asymptomatic adults, higher SBP is associated with pervasive WM microstructure disintegrity, partially due to reduced neuronal count, which appears to mediate SBP adverse effects on fluid intelligence. Diffusion metrics of select WM tracts, which are most reflective of SBP-related parenchymal damage and cognitive impairment, may serve as imaging biomarkers to assess treatment response in antihypertensive trials.

The American Heart Association (AHA) Life's Simple 7 (LS7) score captures 7 biological and lifestyle factors associated with promoting cardiovascular health.To test whether healthier LS7 profiles are associated with significant brain health benefits in persons without stroke or dementia, and to evaluate whether genomic information can recapitulate the observed LS7.This genetic association study was a nested neuroimaging study within the UK Biobank, a large population-based cohort study in the United Kingdom. Between March 2006 and October 2010, the UK Biobank enrolled 502 480 community-dwelling persons aged 40 to 69 years at recruitment. This study focused on a subset of 35 914 participants without stroke or dementia who completed research brain magnetic resonance imaging (MRI) and had available genome-wide data. All analyses were conducted between March 2021 and March 2022.The LS7 (blood pressure, low-density lipoprotein cholesterol, hemoglobin A1c, smoking, exercise, diet, and body mass index) profiles were ascertained clinically and genomically. Independent genetic variants known to influence each of the traits included in the LS7 were assessed. The total LS7 score ranges from 0 (worst) to 14 (best) and was categorized as poor (≤4), average (4 to 9) and optimal (9).The outcomes of interest were 2 neuroimaging markers of brain health: white matter hyperintensity (WMH) volume and brain volume (BV).The final analytical sample included 35 914 participants (mean [SD] age 64.1 [7.6] years; 18 830 [52.4%] women). For WMH, compared with persons with poor observed LS7 profiles, those with average profiles had 16% (β = -0.18; SE, 0.03; P .001) lower mean volume and those with optimal profiles had 39% (β = -0.39; SE, 0.03; P .001) lower mean volume. Similar results were obtained using the genomic LS7 for WMH (average LS7 profile: β = -0.06; SE, 0.014; P .001; optimal LS7 profile: β = -0.08; SE, 0.018; P .001). For BV, compared with persons with poor observed LS7 profiles, those with average LS7 profiles had 0.55% (β = 0.09; SE, 0.02; P .001) higher volume, and those with optimal LS7 profiles had 1.9% (β = 0.14; SE, 0.02; P .001) higher volume. The genomic LS7 profiles were not associated with BV.These findings suggest that healthier LS7 profiles were associated with better profiles of 2 neuroimaging markers of brain health in persons without stroke or dementia, indicating that cardiovascular health optimization was associated with improved brain health in asymptomatic persons. Genomic information appropriately recapitulated 1 of these associations, confirming the feasibility of modeling the LS7 genomically and pointing to an important role of genetic predisposition in the observed association among cardiometabolic and lifestyle factors and brain health.

Background: While chronological age is defined by time, biological age (also known as phenotypic age) is defined by biological variables that summarize the status of key physiological processes. Mounting evidence indicates that biological age is a crucial determinant of longevity and other aging-related traits. We hypothesize that biological age influences clinically-evident and asymptomatic cerebrovascular disease. Methods: We analyzed data from the UK Biobank (discovery) and All of Us (replication) studies. We ascertained ischemic and hemorrhagic stroke using questionnaires and EHR data. In the UK Biobank we also evaluated MRI-defined white matter hyperintensity (WMH) volume and brain volume (BV). We estimated biological age using PhenoAge, a validated tool that integrates information on albumin, creatinine, glucose, C reactive protein, lymphocyte percentage, mean corpuscular volume, red blood cell distribution width, alkaline phosphatase and white blood cell count. Biological age was divided into tertiles and entered in multivariate Cox and linear regression models adjusting for chronological age and vascular risk factors. Results: The discovery phase included 416,415 UK Biobank participants. Compared to the biologically youngest tertile, the risk of stroke was 17% (HR 1.17, 95%CI 1.04-1.32) and 61% (HR 1.61, 95%CI 1.40-1.86) higher in tertiles 2 and 3 of biological age, respectively (test-for-trend p Conclusion: Biological age is a significant contributor to clinically evident and silent cerebrovascular disease. Combined interventions targeting the biological processes that determine biological age could result in important synergistic effects for primary and secondary prevention. Further research is needed to determine the role of biological age in stroke outcome and recurrence.

Introduction: Lung cancer has been linked to increased risk of thromboembolic events, including stroke. However, a causal relationship between lung cancer and ischemic stroke (IS) has yet to be established. Methods: We conducted a two-stage study using observational and genetic data from the UK Biobank, a large cohort study that enrolled over 500,000 Britons aged 40-69. We included participants of European descent. In Stage I, we used logistic regression to test the association between self-reported / ICD-defined lung cancer and risk of IS. In Stage II, we constructed a polygenic risk score (PRS) using 31 independent genetic variants known to associate with lung cancer, fitted logistic regression to assess the relationship between this PRS and risk of IS, and implemented the inverse variance weighted method of Mendelian randomization (MR). We tested for horizontal pleiotropy using the MR-Egger and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) approaches. Results: Out of 409,629 participants of European descent enrolled in the UK Biobank, there were 5,060 IS cases (mean age, 61.6 [standard deviation 6.5]; female sex, 1813 [35.8%]). The prevalence of lung cancer was 1.9% (n=94) and 0.5% (n=1,961) among persons with and without IS, respectively (unadjusted p Conclusions: Genetically determined lung cancer is associated with increased risk of ischemic stroke. These findings provide evidence for a causal link between lung cancer and ischemic stroke. Further studies are needed to identify the biological pathways that mediate this link.

Background: The AHA Life’s Simple 7 (LS7) promote cardiovascular health. We hypothesized that a better LS7 profile translates into significant brain health benefits in persons without stroke or dementia. We also evaluated whether genomic information can effectively recapitulate the observed LS7. Methods: We conducted a nested study within the UK Biobank, restricting analysis to stroke- and dementia-free participants with brain MRI and genomic data. We ascertained the LS7 (blood pressure, LDL cholesterol, HbA1c, smoking, exercise, diet and BMI) clinically and genomically. For the latter, we used genetic variants known to influence each trait. The total LS7 score ranges from 0 (poor) to 14 (optimal), and was categorized as poor (≤4), average (49). We tested for association between observed/genomic LS7 and two neuroimaging markers of brain health: white matter hyperintensities (WMH) volume and brain volume. Results: We analyzed 35,914 participants. For WMH, compared to persons with poor observed LS7, those with average and optimal had 18% (beta -0.17; se=0.02; p0.05). Blood pressure and HbA1c were the most powerful contributors to WMH and brain volume, respectively (Figure). Conclusions: Better LS7 profiles are associated with better profiles of 2 brain health-related neuroimaging markers in persons without stroke/dementia. Genomic information appropriately recapitulated one of these associations. These results emphasize the beneficial role of cardiovascular health optimization in persons without stroke/dementia and point to genomic data as potentially useful to identify high risk individuals.