Genetic Variation and Stroke Recovery: The STRONG Study.

BACKGROUND: Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes. METHODS: For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG. RESULTS: The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P=1×10-5). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (P<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (P=3.2×10-5). CONCLUSIONS: This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.

Deep learning survival model predicts outcome after intracerebral hemorrhage from initial CT scan.

BACKGROUND: Predicting functional impairment after intracerebral hemorrhage (ICH) provides valuable information for planning of patient care and rehabilitation strategies. Current prognostic tools are limited in making long term predictions and require multiple expert-defined inputs and interpretation that make their clinical implementation challenging. This study aimed to predict long term functional impairment of ICH patients from admission non-contrast CT scans, leveraging deep learning models in a survival analysis framework. METHODS: We used the admission non-contrast CT scans from 882 patients from the Massachusetts General Hospital ICH Study for training, hyperparameter optimization, and model selection, and 146 patients from the Yale New Haven ICH Study for external validation of a deep learning model predicting functional outcome. Disability (modified Rankin scale [mRS] > 2), severe disability (mRS > 4), and dependent living status were assessed via telephone interviews after 6, 12, and 24 months. The prediction methods were evaluated by the c-index and compared with ICH score and FUNC score. RESULTS: Using non-contrast CT, our deep learning model achieved higher prediction accuracy of post-ICH dependent living, disability, and severe disability by 6, 12, and 24 months (c-index 0.742 [95% CI -0.700 to 0.778], 0.712 [95% CI -0.674 to 0.752], 0.779 [95% CI -0.733 to 0.832] respectively) compared with the ICH score (c-index 0.673 [95% CI -0.662 to 0.688], 0.647 [95% CI -0.637 to 0.661] and 0.697 [95% CI -0.675 to 0.717]) and FUNC score (c-index 0.701 [95% CI- 0.698 to 0.723], 0.668 [95% CI -0.657 to 0.680] and 0.727 [95% CI -0.708 to 0.753]). In the external independent Yale-ICH cohort, similar performance metrics were obtained for disability and severe disability (c-index 0.725 [95% CI -0.673 to 0.781] and 0.747 [95% CI -0.676 to 0.807], respectively). Similar AUC of predicting each outcome at 6 months, 1 and 2 years after ICH was achieved compared with ICH score and FUNC score. CONCLUSION: We developed a generalizable deep learning model to predict onset of dependent living and disability after ICH, which could help to guide treatment decisions, advise relatives in the acute setting, optimize rehabilitation strategies, and anticipate long-term care needs.

Educational attainment, severity and short-term prognosis of intracerebral haemorrhage.

Background: Educational attainment is a critical social determinant of health that impacts the risk and severity of incident ischaemic stroke, but less is known of its impact on intracerebral haemorrhage (ICH). The objective of this study is to determine whether educational attainment is associated with ICH severity and short-term prognosis. Methods: Subjects were enrolled in a prospectively ascertained cohort with primary ICH from 1994 to 2020 at Massachusetts General Hospital. Educational attainment, medical history of ICH risk factors, ICH volume and ICH score were obtained on admission. The primary outcomes were ICH volume and the ICH score. Results: Of 2539 eligible patients eligible, the median age of the sample was 74 (IQR 64-82) and 2159 (85%) had high school-only education. 1655 (65%) presented with an ICH volume less than or equal to 30 mL and 1744 (69%) presented with an ICH score less than 3. In multivariable logistic regression analyses controlling for age, income, employment history and prestroke diagnoses of hypertension and coronary artery disease, patients with high school-only education were more likely to have an ICH volume greater than 30 mL compared with college diplomates (OR 1.58, 95% CI 1.24 to 2.08) and more likely to have an ICH score of 3 or greater compared with college diplomates (OR 2.37, 95% CI 1.77 to 3.19). Discussion: Prestroke educational attainment is independently associated with ICH severity and short-term prognosis, with lower educational attainment associated with larger ICH volumes and higher ICH scores. Future studies should examine how educational attainment impacts exposure to traditional clinical risk factors.

Nutrition markers and discharge outcome in deep and lobar intracerebral hemorrhage.

INTRODUCTION: Malnutrition is common in stroke patients and has been associated with poor functional outcomes and increased mortality after stroke. Previous research on nutrition status and post-intracerebral hemorrhage (ICH) outcomes, however, is limited and conflicting. PATIENTS AND METHODS: Monocenter study of patients with spontaneous deep or lobar ICH from a longitudinal cohort enrolling consecutive patients between 1994 and 2022. Nutrition status was assessed using admission body mass index (BMI), albumin, total bilirubin, cholesterol, c-reactive protein, hemoglobin a1c, high-density lipoprotein, hemoglobin, low-density lipoprotein, mean corpuscular volume, alanine transaminase, and triglycerides. Main outcome was favorable discharge outcome (mRS 0-2). Multivariable logistic regression was conducted with adjustment for baseline differences. RESULTS: Among 2170 patients, 1152 had deep and 1018 had lobar ICH. Overweight BMI was associated with higher odds of favorable discharge outcome in all (aOR = 3.01, 95% CI 1.59-5.69, p = 0.001) and lobar (aOR = 3.26, 95% CI 1.32-8.08, p = 0.011) ICH after adjustment for baseline differences. This association did not reach statistical significance in deep (aOR = 2.77, 95% CI 0.99-7.72, p = 0.052) ICH. No lab values were associated with functional outcome in all, deep, or lobar ICH after adjustment. DISCUSSION AND CONCLUSION: Overweight BMI was associated with favorable discharge status after ICH. These findings could inform future studies to determine whether overweight BMI has a protective effect in ICH patients.

Hypertension control after intracerebral hemorrhage among varying small vessel disease etiologies.

INTRODUCTION: Intracerebral hemorrhage (ICH) is attributable to cerebral small vessel disease (cSVD), which includes cerebral amyloid angiopathy (CAA) and hypertensive-cSVD (HTN-cSVD). HTN-cSVD includes patients with strictly deep ICH/microbleeds and mixed location ICH/microbleeds, the latter representing a more severe form of HTN-cSVD. We test the hypothesis that more severe forms of HTN-cSVD are related to worse hypertension control in long-term follow-up after ICH. METHODS: From consecutive non-traumatic ICH patients admitted to a tertiary care center, we classified the ICH as CAA, strictly deep ICH/microbleeds, and mixed-location ICH/microbleeds. CSVD burden was quantified using a validated MRI-based score (range: 0-6 points). We created a multivariable (linear mixed effects) model adjusting for age, sex, race, year of inclusion, hypertension, and antihypertensive medication usage to investigate the association of average systolic blood pressure (SBP) during follow-up with cSVD etiology/severity. RESULTS: 796 ICH survivors were followed for a median of 48.8 months (IQR 41.5-60.4). CAA-related ICH survivors (n = 373) displayed a lower median SBP (138 mmHg, IQR 133-142 mmHg) compared to those of strictly deep ICH (n = 222, 141 mmHg, IQR 136-143 mmHg, p = 0.04), and mixed location ICH/microbleeds (n = 201, 142 mmHg, IQR 135-144 mmHg, p = 0.02). In the multivariable analysis, mixed location ICH/microbleeds (effect: + 3.8 mmHg, SE: 1.3 mmHg, p = 0.01) and increasing cSVD severity (+ 1.8 mmHg per score point, SE: 0.8 mmHg, p = 0.03) were associated with higher SBP in follow-up. CONCLUSION: CSVD severity and subtype predicts long-term hypertension control in ICH patients.

Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Study.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.

Treating Hypertension: Important for Heart Health, Fundamental for Brain Health.

The Brain Health crisis stands as one of humankind's most pressing threats, with age-related noncommunicable brain diseases, particularly stroke, and dementia, affecting hundreds of millions annually and jeopardizing the economic well-being of populations worldwide. Epidemiological studies indicate that ≈40% of dementia and 60% of stroke cases are attributable to modifiable risk factors. In this Comments and Opinions article, we underscore the pivotal role of blood pressure (BP) control in reducing suffering, enhancing economic well-being, and promoting healthy longevity for populations worldwide. Emphasizing that BP control is crucial for both brain and heart health, it advocates for heightened awareness, positioning hypertension as a primary focus for preventing dementia and stroke with potential global impact. Despite its significance, BP control encounters global challenges, with proportions of the population maintaining adequately controlled hypertension ranging from 23% to 90%. The World Health Organization estimated that 46% of the 1.28 billion people with hypertension are unaware of their elevated BP. Given the notable disparities in BP management, addressing BP management also contributes to combating significant health inequalities. The next time you are faced with a patient anxious about the prospect of experiencing a fate similar to a parent with dementia or a sister with a stroke, we suggest a straightforward answer for health care providers: start ensuring BP control. BP is a matter of brain health, and it is a matter of our economic future.

Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Predicting post-stroke cognitive impairment using electronic health record data.

BACKGROUND: Secondary prevention interventions to reduce post-stroke cognitive impairment (PSCI) can be aided by the early identification of high-risk individuals who would benefit from risk factor modification. AIMS: To develop and evaluate a predictive model to identify patients at increased risk of PSCI over 5 years using data easily accessible from electronic health records. METHODS: Cohort study that included primary care patients from two academic medical centers. Patients were aged 45 years or older, without prior stroke or prevalent cognitive impairment, with primary care visits and an incident ischemic stroke between 2003 and 2016 (development/internal validation cohort) or 2010 and 2022 (external validation cohort). Predictors of PSCI were ascertained from the electronic health record. The outcome was incident dementia/cognitive impairment within 5 years and beginning 3 months following stroke, ascertained using International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes. For model variable selection, we considered potential predictors of PSCI and constructed 400 bootstrap samples with two-thirds of the model derivation sample. We ran 10-fold cross-validated Cox proportional hazards models using a least absolute shrinkage and selection operator (LASSO) penalty. Variables selected in >25% of samples were included. RESULTS: The analysis included 332 incident diagnoses of PSCI in the development cohort (n = 3741), and 161 and 128 incident diagnoses in the internal (n = 1925) and external (n = 2237) validation cohorts, respectively. The C-statistic for predicting PSCI was 0.731 (95% confidence interval (CI): 0.694-0.768) in the internal validation cohort, and 0.724 (95% CI: 0.681-0.766) in the external validation cohort. A risk score based on the beta coefficients of predictors from the development cohort stratified patients into low (0-7 points), intermediate (8-11 points), and high (12-23 points) risk groups. The hazard ratios (HRs) for incident PSCI were significantly different by risk categories in internal (high, HR: 6.2, 95% CI: 4.1-9.3; Intermediate, HR: 2.7, 95% CI: 1.8-4.1) and external (high, HR: 6.1, 95% CI: 3.9-9.6; Intermediate, HR: 2.8, 95% CI: 1.9-4.3) validation cohorts. CONCLUSION: Five-year risk of PSCI can be accurately predicted using routinely collected data. Model output can be used to risk stratify and identify individuals at increased risk for PSCI for preventive efforts. DATA ACCESS STATEMENT: Mass General Brigham data contain protected health information and cannot be shared publicly. The data processing scripts used to perform analyses will be made available to interested researchers upon reasonable request to the corresponding author.

Predicting post-stroke cognitive impairment using electronic health record data.

Importance: Secondary prevention interventions to reduce post-stroke cognitive impairment (PSCI) can be aided by the early identification of high-risk individuals who would benefit from risk factor modification. Objective: To develop and evaluate a predictive model to identify patients at increased risk of PSCI over 5 years using data easily accessible from electronic health records. Design: Cohort study with patients enrolled between 2003-2016 with follow-up through 2022. Setting: Primary care practices affiliated with two academic medical centers. Participants: Individuals 45 years or older, without prior stroke or prevalent cognitive impairment, with primary care visits and an incident ischemic stroke between 2003-2016 (development/internal validation cohort) or 2010-2022 (external validation cohort). Exposures: Predictors of PSCI were ascertained from the electronic health record. Main Outcome: The outcome was incident dementia/cognitive impairment within 5 years and beginning 3 months following stroke, ascertained using ICD-9/10 codes. For model variable selection, we considered potential predictors of PSCI and constructed 400 bootstrap samples with two-thirds of the model derivation sample. We ran 10-fold cross-validated Cox proportional hazards models using a least absolute shrinkage and selection operator (LASSO) penalty. Variables selected in >25% of samples were included. Results: The analysis included 332 incident diagnoses of PSCI in the development cohort (n=3,741), and 161 and 128 incident diagnoses in the internal (n=1,925) and external (n=2,237) validation cohorts. The c-statistic for predicting PSCI was 0.731 (95% CI: 0.694-0.768) in the internal validation cohort, and 0.724 (95% CI: 0.681-0.766) in the external validation cohort. A risk score based on the beta coefficients of predictors from the development cohort stratified patients into low (0-7 points), intermediate (8-11 points), and high (12-35 points) risk groups. The hazard ratios for incident PSCI were significantly different by risk categories in internal (High, HR: 6.2, 95% CI 4.1-9.3; Intermediate, HR 2.7, 95% CI: 1.8-4.1) and external (High, HR: 6.1, 95% CI: 3.9-9.6; Intermediate, HR 2.8, 95% CI: 1.9-4.3) validation cohorts. Conclusions and Relevance: Five-year risk of PSCI can be accurately predicted using routinely collected data. Model output can be used to risk stratify and identify individuals at increased risk for PSCI for preventive efforts.

Assessing Risk of Health Outcomes From Brain Activity in Sleep: A Retrospective Cohort Study.

Background and Objectives: Patterns of electrical activity in the brain (EEG) during sleep are sensitive to various health conditions even at subclinical stages. The objective of this study was to estimate sleep EEG-predicted incidence of future neurologic, cardiovascular, psychiatric, and mortality outcomes. Methods: This is a retrospective cohort study with 2 data sets. The Massachusetts General Hospital (MGH) sleep data set is a clinic-based cohort, used for model development. The Sleep Heart Health Study (SHHS) is a community-based cohort, used as the external validation cohort. Exposure is good, average, or poor sleep defined by quartiles of sleep EEG-predicted risk. The outcomes include ischemic stroke, intracranial hemorrhage, mild cognitive impairment, dementia, atrial fibrillation, myocardial infarction, type 2 diabetes, hypertension, bipolar disorder, depression, and mortality. Diagnoses were based on diagnosis codes, brain imaging reports, medications, cognitive scores, and hospital records. We used the Cox survival model with death as the competing risk. Results: There were 8673 participants from MGH and 5650 from SHHS. For all outcomes, the model-predicted 10-year risk was within the 95% confidence interval of the ground truth, indicating good prediction performance. When comparing participants with poor, average, and good sleep, except for atrial fibrillation, all other 10-year risk ratios were significant. The model-predicted 10-year risk ratio closely matched the observed event rate in the external validation cohort. Discussion: The incidence of health outcomes can be predicted by brain activity during sleep. The findings strengthen the concept of sleep as an accessible biological window into unfavorable brain and general health outcomes.

Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

BACKGROUND: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. AIMS: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. METHODS: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. RESULTS: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). CONCLUSION: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. DATA ACCESS STATEMENT: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.

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

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

Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis.

BACKGROUND: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. METHODS: Leveraging data from 522 681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6R (IL-6 receptor) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization, we assessed its effects on 3281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3301). Using mediation Mendelian randomization, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. RESULTS: We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 (C-X-C motif chemokine ligand 10) were associated with risk of coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease, with up to 67% of the effects of genetically downregulated IL-6 signaling on these end points mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. CONCLUSIONS: Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ-inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in 3 vascular compartments and, as such, could serve as a promising drug target for atheroprotection.

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.

Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations.

This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.

Brain health scores to predict neurological outcomes from electronic health records.

BACKGROUND: Preserving brain health is a critical priority in primary care, yet screening for these risk factors in face-to-face primary care visits is challenging to scale to large populations. We aimed to develop automated brain health risk scores calculated from data in the electronic health record (EHR) enabling population-wide brain health screening in advance of patient care visits. METHODS: This retrospective cohort study included patients with visits to an outpatient neurology clinic at Massachusetts General Hospital, between January 2010 and March 2021. Survival analysis with an 11-year follow-up period was performed to predict the risk of intracranial hemorrhage, ischemic stroke, depression, death and composite outcome of dementia, Alzheimer's disease, and mild cognitive impairment. Variables included age, sex, vital signs, laboratory values, employment status and social covariates pertaining to marital, tobacco and alcohol status. Random sampling was performed to create a training (70%) set for hyperparameter tuning in internal 5-fold cross validation and an external hold-out testing (30%) set of patients, both stratified by age. Risk ratios for high and low risk groups were evaluated in the hold-out test set, using 1000 bootstrapping iterations to calculate 95% confidence intervals (CI). RESULTS: The cohort comprised 17,040 patients with an average age of 49 ± 15.6 years; majority were males (57 %), White (78 %) and non-Hispanic (80 %). The low and high groups average risk ratios [95 % CI] were: intracranial hemorrhage 0.46 [0.45-0.48] and 2.07 [1.95-2.20], ischemic stroke 0.57 [0.57-0.59] and 1.64 [1.52-1.69], depression 0.68 [0.39-0.74] and 1.29 [0.78-1.38], composite of dementia 0.27 [0.26-0.28] and 3.52 [3.18-3.81] and death 0.24 [0.24-0.24] and 3.96 [3.91-4.00]. CONCLUSIONS: Simple risk scores derived from routinely collected EHR accurately quantify the risk of developing common neurologic and psychiatric diseases. These scores can be computed automatically, prior to medical care visits, and may thus be useful for large-scale brain health screening.

Genetic and Nongenetic Components of Stroke Family History: A Population Study of Adopted and Nonadopted Individuals.

Background Genetic and nongenetic factors account for the association of family history with disease risk. Comparing adopted and nonadopted individuals provides an opportunity to disentangle those factors. Methods and Results We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495 640 UK Biobank participants (mean age, 56.5 years; 55% women) stratified by childhood adoption status (5747 adoptees). We estimated hazard ratios (HRs) per affected family member, and for polygenic risk scores in Cox models adjusted for baseline age and sex. A total of 12 518 strokes and 23 923 MIs occurred over a 13-year follow-up. In nonadoptees, family history of stroke and heart disease was associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR, 1.16 [95% CI, 1.12-1.19]) and family history of heart disease for incident MI (HR, 1.48 [95% CI, 1.45-1.50]). In adoptees, family history of stroke associated with incident stroke (HR, 1.41 [95% CI, 1.06-1.86]), but family history of heart disease was not associated with incident MI (P>0.5). Polygenic risk scores showed strong disease-specific associations in both groups. In nonadoptees, the stroke polygenic risk score mediated 6% risk between family history of stroke and incident stroke, and the MI polygenic risk score mediated 13% risk between family history of heart disease and incident MI. Conclusions Family history of stroke and heart disease increases risk for their respective conditions. Family history of stroke contains substantial potentially modifiable nongenetic risk, indicating a need for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

The ABCD-GENE score influences vascular event rates in both users of clopidogrel and aspirin, as well as non-users of either drug in a population-based cohort study.

Background and Objectives: Clopidogrel is an antiplatelet used in both primary and secondary prevention of cardiovascular diseases. It is a prodrug, requiring CYP2C19 for its metabolism to the active metabolite. The ABCD-GENE score, combining clinical attributes (age, body mass index, chronic kidney disease, diabetes mellitus), with genetic information (presence of 1 or 2 loss of function (LOF) alleles in the CYP2C19 gene) has been shown to identify patients with higher risk of recurrent cardiovascular events in high-risk populations undergoing percutaneous coronary intervention. We aimed to determine if the ABCD-GENE score or LOF alleles were associated with an increased risk of vascular events among clopidogrel users in a general population. Methods: We conducted a population based cohort study with UK Biobank's primary care prescription records to identify clopidogrel users. ABCD-GENE scores were calculated with closest available data from the first date of clopidogrel prescription. The number of LOF alleles present, and the clinical component ABCD, were separate exposures. The outcome of interest was a composite endpoint of vascular events comprised of myocardial infarction, ischemic stroke, and death due to either of these. We performed Cox proportional hazards models with clopidogrel as a time varying exposure to predict hazards of these outcomes. In order to determine the drug specificity of these exposures, the analyses were repeated in aspirin users, and in non-users of either aspirin or clopidogrel. Results: Among 11,248 clopidogrel users, 3,365 (30%) developed a vascular event over a mean follow-up of 5.95±3.94 years. ABCD-GENE score ≥10 was associated with an increased risk of vascular events (HR 1.13, 95% CI 1.03-1.23). In aspirin users, and in non-users of either aspirin or clopidogrel, the ABCD-GENE score was also associated with increased risk of vascular events. In clopidogrel users, aspirin users, and non-users of either drug, the ABCD score was associated with increased risk of vascular events. The presence of two CYP2C19 LOF alleles was associated with an increased risk of vascular events in aspirin and non-users but not in clopidogrel users. Discussion: In this population-based cohort study, the ABCD-GENE score was associated with an increased risk of vascular events in clopidogrel users, aspirin users, and in non-users of either drug. The clinical component, ABCD was also associated with an increased risk of vascular events in all three groups. This suggests that the ABCD-GENE score is not specific to clopidogrel users in identifying persons at high risk of vascular events in a general sample with low baseline CYP2C19 LOF allele frequency.