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Background and Objectives: The 21-point Brain Care Score (BCS) is an index that ranks behaviors and clinical measurements with the aim of encouraging lifestyle adjustments to lower the incidence of age-related brain disease, including stroke, late-life depression (LLD), and dementia. A higher BCS at baseline is associated with a lower risk of these outcomes. We aimed to investigate whether the associations between BCS and stroke, LLD, and dementia risks are independent of genetic predisposition for these conditions and quantify the effect of healthy lifestyle across genetic risk distributions for these outcomes., Methods: Using the UK Biobank (UKB) prospective cohort study, we computed baseline BCSs and polygenic scores to estimate genetic predisposition for stroke and LLD and APOE ε allele status to stratify dementia risk. As for outcomes again in UKB, we measured incidence of stroke, LLD, and dementia. We used multivariate Cox proportional hazard models to assess associations between BCS, genetic predisposition, and these outcomes. We also conducted stratified and interaction analyses to estimate the incidence of these outcomes across quartiles of genetic risk and BCS., Results: We included 368,340 UKB participants (median age 58 years (interquartile range 51-63 years), 46.3% male). Independent of genetic risk, a 5-point increase in BCS corresponded to lowered hazards of stroke (hazard ratio [HR] 0.70, 95% CI 0.68-0.73), LLD (HR 0.65, 95% CI 0.63-0.67), and dementia (HR 0.82, 95% CI 0.78-0.85). Incidences of all 3 outcomes were higher among participants with high genetic risk of these outcomes. However, these increased risks were offset for individuals with a higher BCS (incidence rates per 1,000 person-years were 2.76 vs 1.19 for stroke, 7.34 vs 4.46 for LLD, and 3.64 vs 2.05 for dementia, when comparing low and high BCS)., Discussion: Across different genetic predispositions for stroke, LLD, and dementia, healthier lifestyle behaviors are protective for brain health, demonstrating the nondeterminism of genetic risk. Furthermore, differences in BCS behave as aggregate risk estimators of all 3 outcomes. Further work is needed to prospectively investigate the utility and performance of the BCS as a targeted intervention in populations at elevated genetic risk of age-related brain disease.

Background and Objectives: Mounting evidence points to a strong connection between cardiovascular risk during middle age and brain health later in life. The American Heart Association's Life's Essential 8 (LE8) constitutes a research and public health construct capturing key determinants of cardiovascular health. However, the overall effect of the LE8 on global, clinically relevant metrics of brain health is still unknown. We tested the hypothesis that worse LE8 profiles are associated with higher composite risk of the most important clinical endpoints related to poor brain health., Methods: We conducted a two-stage (discovery and replication) prospective study using data from the UK Biobank (UKB) and All of Us (AoU), 2 large population studies in the United Kingdom and the United States, respectively. The primary exposure was the LE8 score, a validated tool that captures 8 modifiable cardiovascular risk factors (blood pressure, glucose, cholesterol, body mass index, smoking, physical activity, diet, and sleep duration), organized in 3 categories (optimal, intermediate, and poor). The primary outcome was a composite of stroke, dementia, or late-life depression. We evaluated associations using multivariable Cox proportional hazard models., Results: The discovery stage included 316,127 UKB participants (mean age 56, 52% female). Over a mean (SD) follow-up time of 4.9 (0.4) years, the unadjusted risk of the composite outcome was 0.7% (95% CI 0.61-0.74), 1.2% (95% CI 1.11-1.22), and 1.8% (95% CI 1.70-1.91) in participants with optimal, intermediate, and poor cardiovascular health, respectively ( p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health hazard ratio [HR], 1.37; 95% CI 1.24-1.52, and poor vs optimal cardiovascular health HR, 2.11; 95% CI 1.88-2.36, p trend <0.001). The replication stage included 68,407 AoU participants (mean age 56, 60% female). Over a mean (SD) follow-up time of 2.9 (1.41) years, the unadjusted risk of the composite outcome was 2.8% (95% CI 2.49-3.05), 6% (95% CI 5.76-6.22), and 9.7% (95% CI 9.24-10.24) in participants with optimal, intermediate, and poor cardiovascular health, respectively ( p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health, HR 1.35; 95% CI 1.21-1.51, and poor vs optimal cardiovascular health, HR 1.94; 95% CI 1.72-2.18; p trend <0.001)., Discussion: Among middle-aged adults enrolled in 2 large population studies, poor cardiovascular health profiles were associated with two-fold higher risk of developing a composite outcome that captures the most important diseases related to poor brain health. Because the evaluated risk factors are all modifiable, our findings highlight the potential brain health benefits of using the Life's Essential 8 to guide cardiovascular health optimization.

Background: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor's risk of PSE., Methods: We conducted a case-control genetic association study nested within the UK Biobank, a large UK-based prospective cohort. Our exposures of interest were 2 distinct polygenic risk scores-generalized and focal epilepsy-modeled as deciles and constructed using genetic variants identified in the latest International League Against Epilepsy genome-wide association study meta-analysis. We aimed to evaluate the association between these polygenic risk scores and their corresponding subtype of PSE-generalized and focal. In sensitivity analyses, we evaluated participants of European ancestry separately and considered focal and generalized epilepsy outcomes in participants without a history of stroke. In secondary analyses, we evaluated the polygenic risk of PSE by stroke subtype (ischemic, hemorrhagic, or any stroke). Multivariable logistic regression models were fitted, adjusting for age, sex, genetic ancestry, and the first 5 principal genetic components., Results: Among 17 549 UK Biobank stroke survivors with available genetic information (mean age, 61; 43% female), 185 (1%) developed generalized PSE, while 124 (0.7%) developed focal PSE. Multivariable logistic regression results showed that, when compared against the lowest decile, participants within the highest PRS decile for generalized PSE had 5-fold higher odds of developing generalized PSE (OR, 5.05 [95% CI, 2.37-12.5]; P trend<0.001). Similarly, when compared against the lowest decile, participants within the highest polygenic risk score decile for focal PSE had 3-fold higher odds of developing focal PSE (OR, 3.20; [5% CI, 1.25-9.82]; P trend=0.024). Sensitivity analyses among participants of European ancestry yielded similar results., Conclusions: Our findings suggest that, like other forms of epilepsy, genetic predisposition plays an essential role in PSE. These results underscore the need for future studies to elucidate the mechanisms underlying PSE development and to identify novel therapeutic avenues.

Objective: The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome., Methods: Inclusion criteria in our study were a neuroimaging-confirmed ICH. We evaluated whether sex was associated with ICH severity (hematoma volume and expansion) and poor functional outcomes (modified Rankin Scale >3) 3 or 6 months after the ICH., Results: A total of 4,812 ICH patients were evaluated (mean age 62, 40% female). Males with ICH were younger, more likely to be smokers and have diabetes, and less likely to be on anticoagulants (all p < 0.05). In multivariable analyses, male sex was associated with non-lobar location (odds ratio [OR]: 1.63; 95% confidence interval [CI]: [1.39-1.92]; p < 0.001), larger hemorrhages (beta: 0.16 [0.08-0.23]; p < 0.001) and a higher risk of hematoma expansion (OR: 1.43 [1.20-1.71]; p < 0.001). Despite the larger hemorrhage volume and higher risk of expansion, male sex was associated with a 24% lower risk of poor outcomes (OR: 0.76 [0.64-0.90]; p = 0.002)., Interpretation: Compared to females, males with ICH have larger bleeds and higher risk of hematoma expansion. Despite the larger bleeds and higher risk of hematoma expansion, males with ICH have lower risk of poor outcomes. Our results suggest that the biology and clinical trajectory are different in females and males with ICH, supporting sex-specific research in this condition. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Introduction: It is important to understand the socioeconomic and medical determinants of subjective cognitive decline (SCD) at a population level in the United States., Methods: The primary outcomes are state-level rates of SCD and SCD-related functional impairment in adults aged ≥ 45, both measured in the Behavioral Risk Factor Surveillance System from 2016 to 2022. The exposures are state-level rates of poverty, unemployment, homelessness, college education, racial and ethnic minorities, uninsurance, smoking, hypertension, diabetes, and obesity as well as household income and physician density., Results: The strongest state-level associations with rates of SCD were the prevalence of diabetes (rho = 0.64), hypertension (rho = 0.59), and poverty (rho = 0.58; all p < 0.001), and with SCD-related functional impairment were prevalence of poverty (rho = 0.71), diabetes (rho = 0.68), and hypertension (rho = 0.53; all p < 0.001)., Discussion: This study highlights critical links between SCD and socioeconomic and medical determinants in adults aged ≥ 45 in the United States, including the prevalence of poverty, diabetes, and hypertension., Highlights: State-level analysis reveals socioeconomic and medical risk factors for subjective cognitive decline (SCD) at a population level. The prevalence of poverty is a critical contributor to the state-level prevalence of SCD. The prevalence of diabetes and hypertension are also strong state-level determinants of SCD. Addressing the burden of cognitive decline at the population level necessitates targeting socioeconomic and medical factors., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Sexual and gender minority (SGM) groups have been historically underrepresented in neurologic research, and their brain health disparities are unknown. We aim to evaluate whether SGM persons are at higher risk of adverse brain health outcomes compared with cisgender straight (non-SGM) individuals., Methods: We conducted a cross-sectional study in the All of Us Research Program, a US population-based study, including all participants with information on gender identity and sexual orientation. We used baseline questionnaires to identify sexual minority (lesbian, gay, bisexual, diverse sexual orientation; nonstraight sexual orientation) and gender minority (gender diverse and transgender; gender identity different from sex assigned at birth) participants. The primary outcome was a composite of stroke, dementia, and late-life depression, assessed using electronic health record data and self-report. Secondarily, we evaluated each disease separately. Furthermore, we evaluated all subgroups of gender and sexual minorities stratified by sex assigned at birth. We used multivariable logistic regression (adjusted for age, sex assigned at birth, race/ethnicity, cardiovascular risk factors, other relevant comorbidities, and neighborhood deprivation index) to assess the relationship between SGM groups and the outcomes., Results: Of 413,457 US adults enrolled between May 31, 2017, and June 30, 2022, we included 393,041 participants with available information on sexual orientation and gender identity (mean age 51 [SD 17] years), of whom 39,632 (10%) belonged to SGM groups. Of them, 38,528 (97%) belonged to a sexual minority and 4,431 (11%) to a gender minority. Compared with non-SGM, SGM persons had 15% higher odds of the brain health composite outcome (odds ratio [OR] 1.15, 95% CI 1.08-1.22). In secondary analyses, these results persisted across sexual and gender minorities separately (all 95% CIs > 1). Assessing individual diseases, all SGM groups had higher odds of dementia (SGM vs non-SGM: OR 1.14, 95% CI 1.00-1.29) and late-life depression (SGM vs non-SGM: OR 1.27, 95% CI 1.17-1.38) and transgender women had higher odds of stroke (OR 1.68, 95% CI 1.04-2.70)., Discussion: In a large US population study, SGM persons had higher odds of adverse brain health outcomes. Further research should explore structural causes of inequity to advance inclusive and diverse neurologic care.

Introduction: Rocky Mountain Spotted Fever (RMSF) is a tick-borne disease caused by Rickettsia rickettsii (R. rickettsii). RMSF presents after a tick bite with fever, rash, and headache but can also cause more serious neurological manifestations. We report a case of RMSF encephalitis presenting with altered sensorium and rapid progression to coma, fever, and petechial rash, and an magnetic resonance imaging (MRI) brain notable for a "starry sky" pattern., Case Report: A 61-year-old woman presented with confusion and fever and was diagnosed with a urinary tract infection. Two days later, she became comatose. MRI brain revealed lacunar infarcts in the right centrum semiovale and splenium of the corpus callosum. Lumbar puncture was notable for neutrophilic pleocytosis and elevated protein with negative bacterial and viral cultures. Empiric meningitis therapy was initiated, and she was transferred to our institution. On transfer, she was febrile, comatose, and had a diffuse petechial rash. Repeat MRI brain demonstrated diffuse, innumerable punctate foci of diffusion restriction with susceptibility-weighted signal attenuation throughout cerebral hemispheres in a "starry sky" pattern. Skin biopsy revealed perivascular lymphocytic infiltrates. Serologic RSMF antibody titers were obtained, and doxycycline was initiated for presumed RMSF encephalitis. The family opted to pursue palliative measures, given no clinical improvement. RSMF titers and postmortem PCR from brain tissue were positive for R. rickettsii., Conclusions: This case report highlights the clinical presentation of RMSF encephalitis. RMSF encephalitis should be suspected in a patient presenting with encephalopathy, fever, petechial rash, and MRI brain findings of diffuse punctate foci of diffusion restriction and susceptibility-weighted signal attenuation in a "starry-sky" pattern., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Dementia often involves comorbid Alzheimer's and vascular pathology, but their combined impact warrants additional study., Methods: We analyzed the Systolic Blood Pressure Intervention Trial and categorized white matter hyperintensity (WMH) volume into highest versus lowest/mid tertile and the amyloid beta (Aβ)42/40 ratio into lowest versus mid/highest ratio tertile. Using these binary variables, we created four exposure categories: (1) combined low risk, (2) Aβ risk, (3) WMH risk, and (4) combined high risk., Results: In the cohort of 467 participants (mean age 69.7 ± 7.1, 41.8% female, 31.9% nonwhite or Hispanic) during 4.8 years of follow-up and across the four exposure categories the rates of cognitive impairment were 5.3%, 7.8%, 11.8%, and 22.6%. Compared to the combined low-risk category, the adjusted hazard ratio for cognitive impairment was 4.12 (95% confidence interval, 1.71 to 9.94) in the combined high-risk category., Discussion: This study emphasizes the potential impact of therapeutic approaches to dementia prevention that target both vascular and amyloid pathology., Highlights: White matter hyperintensity (WMH) and plasma amyloid (Aβ42/40) are additive risk factors for the development of cognitive impairment in the SPRINT MIND trial. Individuals in the high-risk categories of both WMH and Aβ42/40 had a near fivefold increase in risk of cognitive impairment during 4.8 years of follow-up on average. These findings suggest that treatment strategies targeting both vascular health and amyloid burden warrant further research., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Clinical trials in older adults are increasingly focused on functional outcomes, and the composite outcome of dementia, disability, and death is gaining pivotal importance. Genetic variation, particularly the APOE epsilon(ε) variants, may modify responses to new treatments. Although APOE ε4 is known to influence these outcomes separately, the magnitude of its effect on this composite outcome remains unknown. We tested the hypothesis that APOE ε4 increases, whereas APOE ε2 decreases, the risk of a composite outcome of dementia, disability, and death., Methods: We evaluated clinical and genomic data from the Health and Retirement Study collected from 1992 to 2020. We used variants rs429358 and rs7412 to determine APOE genotypes, modeled dominantly (carriers/noncarriers). We conducted survival analysis, using multivariable Cox proportional hazards models with a composite endpoint of dementia, disability, and death. Our primary analysis evaluated participants with genetic data and no previous dementia or disability. In secondary analyses, we focused on persons aged > = 75 years without heart disease or stroke, a subpopulation increasingly important in clinical trials of older adults., Results: We included 14,527 participants in the primary analysis. Over a median of 18 (Interquartile Range [IQR] 12-24) years, 6711 (46%) participants developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.15, 95%CI:1.09-1.22) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.92, 95%CI:0.86-0.99). In the secondary analysis, we included 3174 participants. Over a median of 7 (IQR 4-11) years, 1326 participants (42%) developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.25, 95%CI:1.10-1.41) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.84, 95%CI:0.71-0.98)., Conclusions: APOE ε variants are linked to the risk of dementia, disability, and death in older adults. By examining these variants in clinical trials, we can better elucidate how they might alter the effectiveness of tested interventions. Importantly, this genetic information could help identify participants who may have greater absolute benefit from such interventions., (© 2024 The American Geriatrics Society.)

Objectives: To investigate associations between health-related behaviors as measured using the Brain Care Score (BCS) and neuroimaging markers of white matter injury., Methods: This prospective cohort study in the UK Biobank assessed the BCS, a novel tool designed to empower patients to address 12 dementia and stroke risk factors. The BCS ranges from 0 to 21, with higher scores suggesting better brain care. Outcomes included white matter hyperintensities (WMH) volume, fractional anisotropy (FA), and mean diffusivity (MD) obtained during 2 imaging assessments, as well as their progression between assessments, using multivariable linear regression adjusted for age and sex., Results: We included 34,509 participants (average age 55 years, 53% female) with no stroke or dementia history. At first and repeat imaging assessments, every 5-point increase in baseline BCS was linked to significantly lower WMH volumes (25% 95% CI [23%-27%] first, 33% [27%-39%] repeat) and higher FA (18% [16%-20%] first, 22% [15%-28%] repeat), with a decrease in MD (9% [7%-11%] first, 10% [4%-16%] repeat). In addition, a higher baseline BCS was associated with a 10% [3%-17%] reduction in WMH progression and FA decline over time., Discussion: This study extends the impact of the BCS to neuroimaging markers of clinically silent cerebrovascular disease. Our results suggest that improving one's BCS could be a valuable intervention to prevent early brain health decline.

Background: Patients with post-traumatic stress disorder (PTSD) experience higher risk of adverse cardiovascular (CV) outcomes. This study explores shared loci, and genes between PTSD and CV conditions from three major domains: CV diagnoses from electronic health records (CV-EHR), cardiac and aortic imaging, and CV health behaviors defined in Life's Essential 8 (LE8)., Methods: We used genome-wide association study (GWAS) of PTSD (N=1,222,882), 246 CV diagnoses based on EHR data from Million Veteran Program (MVP; N=458,061), UK Biobank (UKBB; N=420,531), 82 cardiac and aortic imaging traits (N=26,893), and GWAS of traits defined in the LE8 (N = 282,271 ~ 1,320,016). Shared loci between PTSD and CV conditions were identified using local genetic correlations (rg), and colocalization (shared causal variants). Overlapping genes between PTSD and CV conditions were identified from genetically regulated proteome expression in brain and blood tissues, and subsequently tested to identify functional pathways and gene-drug targets. Epidemiological replication of EHR-CV diagnoses was performed in AllofUS cohort (AoU; N=249,906)., Results: Among the 76 PTSD-susceptibility risk loci, 33 loci exhibited local rg with 45 CV-EHR traits (|rg|≥0.4), four loci with eight heart imaging traits(|rg|≥0.5), and 44 loci with LE8 factors (|rg|≥0.36) in MVP. Among significantly correlated loci, we found shared causal variants (colocalization probability > 80%) between PTSD and 17 CV-EHR (in MVP) at 11 loci in MVP, that also replicated in UKBB and/or other cohorts. Of the 17 traits, the observational analysis in the AoU showed PTSD was associated with 13 CV-EHR traits after accounting for socioeconomic factors and depression diagnosis. PTSD colocalized with eight heart imaging traits on 2 loci and with LE8 factors on 31 loci. Leveraging blood and brain proteome expression, we found 33 and 122 genes, respectively, shared between PTSD and CVD. Blood proteome genes were related to neuronal and immune processes, while the brain proteome genes converged on metabolic and calcium-modulating pathways (FDR p <0.05). Drug repurposing analysis highlighted DRD2, NOS1, GFAP, and POR as common targets of psychiatric and CV drugs., Conclusion: PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms., Competing Interests: 7COMPETING INTERESTS Dr. Polimanti reports a research grant from Alkermes outside the scope of this study. Drs. Polimanti and Gelernter are paid for their editorial work on the journal Complex Psychiatry. Dr. Gelernter is named as an inventor on PCT patent application no. 15/878,640 entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. Dr. Stein has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Delix Pharmaceuticals, EmpowerPharm, Engrail Therapeutics, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech; has stock options in Oxeia Biopharmaceuticals and EpiVario; and has been paid for editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry).Dr. O’Donnell an employee of Novartis Pharmaceuticals). Dr. Koller is the founder and CEO of EndoCare Therapeutics, but the company conducts research unrelated to the present study. The other authors declare no competing interests.

Background: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO 2 ) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation., Methods: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO 2 . Autoregulatory function was measured by interrogating changes in ICP and PbtO 2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP., Results: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO 2  < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO 2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05)., Conclusions: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Purpose: Computed Tomography Angiography (CTA) is the first line of imaging in the diagnosis of Large Vessel Occlusion (LVO) strokes. We trained and independently validated end-to-end automated deep learning pipelines to predict 3-month outcomes after anterior circulation LVO thrombectomy based on admission CTAs., Methods: We split a dataset of 591 patients into training/cross-validation (n = 496) and independent test set (n = 95). We trained separate models for outcome prediction based on admission "CTA" images alone, "CTA + Treatment" (including time to thrombectomy and reperfusion success information), and "CTA + Treatment  + Clinical" (including admission age, sex, and NIH stroke scale). A binary (favorable) outcome was defined based on a 3-month modified Rankin Scale ≤ 2. The model was trained on our dataset based on the pre-trained ResNet-50 3D Convolutional Neural Network ("MedicalNet") and included CTA preprocessing steps., Results: We generated an ensemble model from the 5-fold cross-validation, and tested it in the independent test cohort, with receiver operating characteristic area under the curve (AUC, 95% confidence interval) of 70 (0.59-0.81) for "CTA," 0.79 (0.70-0.89) for "CTA + Treatment," and 0.86 (0.79-0.94) for "CTA + Treatment + Clinical" input models. A "Treatment + Clinical" logistic regression model achieved an AUC of 0.86 (0.79-0.93)., Conclusion: Our results show the feasibility of an end-to-end automated model to predict outcomes from admission and post-thrombectomy reperfusion success. Such a model can facilitate prognostication in telehealth transfer and when a thorough neurological exam is not feasible due to language barrier or pre-existing morbidities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sommer, Dierksen, Zeevi, Tran, Avery, Mak, Malhotra, Matouk, Falcone, Torres-Lopez, Aneja, Duncan, Sansing, Sheth and Payabvash.)

Introduction: The 21-point Brain Care Score (BCS) is a novel tool designed to motivate individuals and care providers to take action to reduce the risk of stroke and dementia by encouraging lifestyle changes. Given that late-life depression is increasingly recognized to share risk factors with stroke and dementia, and is an important clinical endpoint for brain health, we tested the hypothesis that a higher BCS is associated with a reduced incidence of future depression. Additionally, we examined its association with a brain health composite outcome comprising stroke, dementia, and late-life depression., Methods: The BCS was derived from the United Kingdom Biobank baseline evaluation in participants with complete data on BCS items. Associations of BCS with the risk of subsequent incident late-life depression and the composite brain health outcome were estimated using multivariable Cox proportional hazard models. These models were adjusted for age at baseline and sex assigned at birth., Results: A total of 363,323 participants were included in this analysis, with a median BCS at baseline of 12 (IQR: 11-14). There were 6,628 incident cases of late-life depression during a median follow-up period of 13 years. Each five-point increase in baseline BCS was associated with a 33% lower risk of incident late-life depression (95% CI: 29%-36%) and a 27% lower risk of the incident composite outcome (95% CI: 24%-30%)., Discussion: These data further demonstrate the shared risk factors across depression, dementia, and stroke. The findings suggest that a higher BCS, indicative of healthier lifestyle choices, is significantly associated with a lower incidence of late-life depression and a composite brain health outcome. Additional validation of the BCS is warranted to assess the weighting of its components, its motivational aspects, and its acceptability and adaptability in routine clinical care worldwide., Competing Interests: CA receives sponsored research support from the US National Institutes of Health, the American Heart Association, and Bayer AG, and has consulted for ApoPharma. GF receives sponsored research support from the National Institute of Mental Health Clinical Global Mental Health Research T32 Fellowship, receives royalties or licenses from Johns Hopkins University Press, University of Chicago Press, Belvoir Press, and the American Psychiatric Press, is on a Data Safety Monitoring Board or Advisory Board of Healthy Hearts Healthy Minds DSMB, is a Board of Directors member at the Rosalynn Carter Institute, and has stock or stock options from Revival Therapeutics Consultant. LG-M receives sponsored research support from the American Heart grant number 963719. JR receives sponsored research support from the US National Institutes of Health and the American Heart Association, and receives payments for expert testimony and consulting fees from the National Football League. EM is an employee of Regeneron Genetics Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​ The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Singh, Rivier, Papier, Chemali, Gutierrez-Martinez, Parodi, Mayerhofer, Senff, Clocchiatti-Tuozzo, Nunley, Newhouse, Ouyang, Westover, Tanzi, Lazar, Pikula, Ibrahim, Brouwers, Howard, Howard, Yechoor, Littlejohns, Sheth, Rosand, Fricchione, Anderson and Falcone.)

Importance: Intravenous alteplase (IV-tPA) can be administered to patients with acute ischemic stroke but is associated with symptomatic intracerebral hemorrhage (sICH). It is unclear if patients taking prestroke dual antiplatelet therapy (DAPT) are at higher risk of sICH., Objective: To determine the associated risk of sICH in patients taking prestroke dual antiplatelet therapy receiving alteplase for acute ischemic stroke using propensity score matching analysis., Design, Setting, and Participants: This cohort study used data from the American Heart Association and American Stroke Association Get With The Guidelines-Stroke (GWTG-Stroke) registry between 2013 and 2021. Data were obtained from hospitals in the GWTG-Stroke registry. This study included patients hospitalized with acute ischemic stroke and treated with IV-tPA. Data were analyzed from January 2013 to December 2021., Exposures: Prestroke DAPT before treatment with IV-tPA for acute ischemic stroke., Main Outcome Measures: sICH, In-hospital death, discharge modified Rankin scale score, and other life-threatening systemic hemorrhages., Results: Of 409 673 participants, 321 819 patients (mean [SD] age, 68.6 [15.1] years; 164 587 female [51.1%]) who were hospitalized with acute ischemic stroke and treated with IV-tPA were included in the analysis. The rate of sICH was 2.9% (5200 of 182 344), 3.8% (4457 of 117 670), and 4.1% (893 of 21 805) among patients treated with no antiplatelet therapy, single antiplatelet therapy (SAPT), and DAPT, respectively (P < .001). In adjusted analyses after propensity score subclassification, both SAPT (odds ratio [OR], 1.13; 95% CI, 1.07-1.19) and DAPT (OR, 1.28; 95% CI, 1.14-1.42) were associated with increased risks of sICH. Prestroke antiplatelet medications were associated with lower odds of discharge mRS score of 2 or less compared with no medication (SAPT OR, 0.92; 95% CI, 0.90-0.95; DAPT OR, 0.94; 95% CI, 0.88-0.98). Results of a subgroup analysis of patients taking DAPT exposed to aspirin-clopidogrel vs aspirin-ticagrelor combination therapy were not significant (OR, 1.35; 95% CI, 0.84-1.86)., Conclusions and Relevance: Prestroke DAPT was associated with a significantly elevated risk of sICH among patients with ischemic stroke who were treated with thrombolysis; however, the absolute increase in risk was small. Patients exposed to antiplatelet medications did not have excess sICH compared with landmark trials, which demonstrated overall clinical benefit of thrombolysis therapy for acute ischemic stroke.

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., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.R. reports compensation from National Football League for expert witness services from Takeda Development Center Americas and Boehringer Ingelheim for consultant services, all unrelated to this work. C.D.A. has received sponsored research support from Bayer AG and has consulted for ApoPharma unrelated to this work. E.M. is now a full-time employee of Regeneron Pharmaceuticals.

Purpose: To create and validate an automated pipeline for detection of early signs of irreversible ischemic change from admission CTA in patients with large vessel occlusion (LVO) stroke., Methods: We retrospectively included 368 patients for training and 143 for external validation. All patients had anterior circulation LVO stroke, endovascular therapy with successful reperfusion, and follow-up diffusion-weighted imaging (DWI). We devised a pipeline to automatically segment Alberta Stroke Program Early CT Score (ASPECTS) regions and extracted their relative Hounsfield unit (rHU) values. We determined the optimal rHU cut points for prediction of final infarction in each ASPECT region, performed 10-fold cross-validation in the training set, and measured the performance via external validation in patients from another institute. We compared the model with an expert neuroradiologist for prediction of final infarct volume and poor functional outcome., Results: We achieved a mean area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of 0.69±0.13, 0.69±0.09, 0.61±0.23, and 0.72±0.11 across all regions and folds in cross-validation. In the external validation cohort, we achieved a median [interquartile] AUC, accuracy, sensitivity, and specificity of 0.71 [0.68-0.72], 0.70 [0.68-0.73], 0.55 [0.50-0.63], and 0.74 [0.73-0.77], respectively. The rHU-based ASPECTS showed significant correlation with DWI-based ASPECTS (rS = 0.39, p<0.001) and final infarct volume (rS = -0.36, p<0.001). The AUC for predicting poor functional outcome was 0.66 (95%CI: 0.57-0.75). The predictive capabilities of rHU-based ASPECTS were not significantly different from the neuroradiologist's visual ASPECTS for either final infarct volume or functional outcome., Conclusions: Our study demonstrates the feasibility of an automated pipeline and predictive model based on relative HU attenuation of ASPECTS regions on baseline CTA and its non-inferior performance in predicting final infarction on post-stroke DWI compared to an expert human reader., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DF reports receiving personal fees from and holding an equity interest in ai4medicine outside the submitted work. CJG reports receiving honoraria from Stryker and MicroVention outside of the reported work. K.S reports equity interests in Alva Health., (Copyright: © 2024 Mak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Perihematomal edema (PHE) represents secondary brain injury and a potential treatment target in intracerebral hemorrhage (ICH). However, studies differ on optimal PHE volume metrics as prognostic factor(s) after spontaneous, non-traumatic ICH. This study examines associations of baseline and 24-h PHE shape features with 3-month outcomes., Patients and Methods: We included 796 patients from a multicentric trial dataset and manually segmented ICH and PHE on baseline and follow-up CTs, extracting 14 shape features. We explored the association of baseline, follow-up, difference (baseline/follow-up) and temporal rate (difference/time gap) of PHE shape changes with 3-month modified Rankin Score (mRS) - using Spearman correlation. Then, using multivariable analysis, we determined if PHE shape features independently predict outcome adjusting for patients' age, sex, NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), and hematoma volume., Results: Baseline PHE maximum diameters across various planes, main axes, volume, surface, and sphericity correlated with 3-month mRS adjusting for multiple comparisons. The 24-h difference and temporal change rates of these features had significant association with outcome - but not the 24-h absolute values. In multivariable regression, baseline PHE shape sphericity (OR = 2.04, CI = 1.71-2.43) and volume (OR = 0.99, CI = 0. 98-1.0), alongside admission NIHSS (OR = 0.86, CI = 0.83-0.88), hematoma volume (OR = 0.99, CI = 0. 99-1.0), and age (OR = 0.96, CI = 0.95-0.97) were independent predictors of favorable outcomes., Conclusion: In acute ICH patients, PHE shape sphericity at baseline emerged as an independent prognostic factor, with a less spherical (more irregular) shape associated with worse outcome. The PHE shape features absolute values over the first 24 h provide no added prognostic value to baseline metrics., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KNS reports equity interests in Alva Health.

Background: The implementation of preventive therapies among patients with stroke remains inadequately explored, especially when compared with patients with myocardial infarction (MI), despite sharing similar vascular risk profiles. We tested the hypothesis that participants with a history of stroke have a worse cardiovascular prevention profile in comparison to participants with MI., Methods and Results: In cross-sectional analyses within the UK Biobank and All of Us Research Program, involving 14 760 (9193 strokes, 5567 MIs) and 7315 (2948 strokes, 4367 MIs) participants, respectively, we evaluated cardiovascular prevention profiles assessing low-density lipoprotein (<100 mg/dL), blood pressure (systolic, <140 mm Hg; and diastolic, <90 mm Hg), statin and antiplatelet use, and a cardiovascular prevention score that required meeting at least 3 of these criteria. The results revealed that, within the UK Biobank, patients with stroke had significantly lower odds of meeting all the preventive criteria compared with patients with MI: low-density lipoprotein control (odds ratio [OR], 0.73 [95% CI, 0.68-0.78]; P <0.001), blood pressure control (OR, 0.63 [95% CI, 0.59-0.68]; P <0.001), statin use (OR, 0.45 [95% CI, 0.42-0.48]; P <0.001), antiplatelet therapy use (OR, 0.30 [95% CI, 0.27-0.32]; P <0.001), and cardiovascular prevention score (OR, 0.42 [95% CI, 0.39-0.45]; P <0.001). Similar patterns were observed in the All of Us Research Program, with significant differences across all comparisons ( P <0.05), and further analysis suggested that the odds of having a good cardiovascular prevention score were influenced by race and ethnicity as well as neighborhood deprivation levels (interaction P <0.05 in both cases)., Conclusions: In 2 independent national cohorts, patients with stroke showed poorer cardiovascular prevention profiles and lower adherence to guideline-directed therapies compared with patients with MI. These findings underscore the need to explore the reasons behind the underuse of secondary prevention in vulnerable stroke survivors.

The mortality rate of acute intracerebral hemorrhage (ICH) can reach up to 40%. Although the radiomics of ICH have been linked to hematoma expansion and outcomes, no research to date has explored their correlation with mortality. In this study, we determined the admission non-contrast head CT radiomic correlates of survival in supratentorial ICH, using the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) trial dataset. We extracted 107 original radiomic features from n = 871 admission non-contrast head CT scans. The Cox Proportional Hazards model, Kaplan-Meier Analysis, and logistic regression were used to analyze survival. In our analysis, the "first-order energy" radiomics feature, a metric that quantifies the sum of squared voxel intensities within a region of interest in medical images, emerged as an independent predictor of higher mortality risk (Hazard Ratio of 1.64, p < 0.0001), alongside age, National Institutes of Health Stroke Scale (NIHSS), and baseline International Normalized Ratio (INR). Using a Receiver Operating Characteristic (ROC) analysis, "the first-order energy" was a predictor of mortality at 1-week, 1-month, and 3-month post-ICH (all p < 0.0001), with Area Under the Curves (AUC) of >0.67. Our findings highlight the potential role of admission CT radiomics in predicting ICH survival, specifically, a higher "first-order energy" or very bright hematomas are associated with worse survival outcomes.

Importance: Stroke is a leading cause of death and disability in the US. Accurate and updated measures of stroke burden are needed to guide public health policies., Objective: To present burden estimates of ischemic and hemorrhagic stroke in the US in 2019 and describe trends from 1990 to 2019 by age, sex, and geographic location., Design, Setting, and Participants: An in-depth cross-sectional analysis of the 2019 Global Burden of Disease study was conducted. The setting included the time period of 1990 to 2019 in the US. The study encompassed estimates for various types of strokes, including all strokes, ischemic strokes, intracerebral hemorrhages (ICHs), and subarachnoid hemorrhages (SAHs). The 2019 Global Burden of Disease results were released on October 20, 2020., Exposures: In this study, no particular exposure was specifically targeted., Main Outcomes and Measures: The primary focus of this analysis centered on both overall and age-standardized estimates, stroke incidence, prevalence, mortality, and DALYs per 100 000 individuals., Results: In 2019, the US recorded 7.09 million prevalent strokes (4.07 million women [57.4%]; 3.02 million men [42.6%]), with 5.87 million being ischemic strokes (82.7%). Prevalence also included 0.66 million ICHs and 0.85 million SAHs. Although the absolute numbers of stroke cases, mortality, and DALYs surged from 1990 to 2019, the age-standardized rates either declined or remained steady. Notably, hemorrhagic strokes manifested a substantial increase, especially in mortality, compared with ischemic strokes (incidence of ischemic stroke increased by 13% [95% uncertainty interval (UI), 14.2%-11.9%]; incidence of ICH increased by 39.8% [95% UI, 38.9%-39.7%]; incidence of SAH increased by 50.9% [95% UI, 49.2%-52.6%]). The downturn in stroke mortality plateaued in the recent decade. There was a discernible heterogeneity in stroke burden trends, with older adults (50-74 years) experiencing a decrease in incidence in coastal areas (decreases up to 3.9% in Vermont), in contrast to an uptick observed in younger demographics (15-49 years) in the South and Midwest US (with increases up to 8.4% in Minnesota)., Conclusions and Relevance: In this cross-sectional study, the declining age-standardized stroke rates over the past 3 decades suggest progress in managing stroke-related outcomes. However, the increasing absolute burden of stroke, coupled with a notable rise in hemorrhagic stroke, suggests an evolving and substantial public health challenge in the US. Moreover, the significant disparities in stroke burden trends across different age groups and geographic locations underscore the necessity for region- and demography-specific interventions and policies to effectively mitigate the multifaceted and escalating burden of stroke in the country.

Importance: Ischemic stroke is a serious complication of cardiac intervention, including surgery and percutaneous procedures. Endovascular thrombectomy (EVT) is an effective treatment for ischemic stroke and may be particularly important for cardiac intervention patients who often cannot receive intravenous thrombolysis., Objective: To examine trends in EVT for ischemic stroke during hospitalization of patients with cardiac interventions vs those without in the United States., Design, Setting, and Participants: This cohort study involved a retrospective analysis using data for 4888 US hospitals from the 2016-2020 National Inpatient Sample database. Participants included adults (age ≥18 years) with ischemic stroke (per codes from the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification), who were organized into study groups of hospitalized patients with cardiac interventions vs without. Individuals were excluded from the study if they had either procedure prior to admission, EVT prior to cardiac intervention, EVT more than 3 days after admission or cardiac intervention, or endocarditis. Data were analyzed from April 2023 to October 2023., Exposures: Cardiac intervention during admission., Main Outcomes and Measures: The odds of undergoing EVT by cardiac intervention status were calculated using multivariable logistic regression. Adjustments were made for stroke severity in the subgroup of patients who had a National Institutes of Health Stroke Scale (NIHSS) score documented. As a secondary outcome, the odds of discharge home by EVT status after cardiac intervention were modeled., Results: Among 634 407 hospitalizations, the mean (SD) age of the patients was 69.8 (14.1) years, 318 363 patients (50.2%) were male, and 316 044 (49.8%) were female. A total of 12 093 had a cardiac intervention. An NIHSS score was reported in 218 576 admissions, 216 035 (34.7%) without cardiac intervention and 2541 (21.0%) with cardiac intervention (P < .001). EVT was performed in 23 660 patients (3.8%) without cardiac intervention vs 194 (1.6%) of those with cardiac intervention (P < .001). After adjustment for potential confounders, EVT was less likely to be performed in stroke patients with cardiac intervention vs those without (adjusted odds ratio [aOR], 0.27; 95% CI, 0.23-0.31), which remained consistent after adjusting for NIHSS score (aOR, 0.28; 95% CI, 0.22-0.35). Among individuals with a cardiac intervention, receiving EVT was associated with a 2-fold higher chance of discharge home (aOR, 2.21; 95% CI, 1.14-4.29)., Conclusions and Relevance: In this study, patients hospitalized with ischemic stroke and cardiac intervention may be less than half as likely to receive EVT as those without cardiac intervention. Given the known benefit of EVT, there is a need to better understand the reasons for lower rates of EVT in this patient population.

Background: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood., Methods: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics., Results: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL., Conclusions: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke., Competing Interests: Disclosures Dr Harris reports stock holdings in Eli LIlly and stock holdings in GlaxoSmithKline. Dr Iadecola has served on the scientific advisory board for Broadview Ventures. Dr Falcone has received grants from the National Institutes of Health (NIH) and the American Heart Association outside of the submitted work. Dr Sheth reports compensation from Cerevasc for consultant services; service as President for Advanced Innovation in Medicine; a patent pending for Stroke wearables licensed to Alva Health. Dr Goldstein reports compensation from Cayuga for consultant services; compensation from Prothya for consultant services; compensation from AstraZeneca for consultant services; and compensation from Lumosa for consultant services. Dr Qureshi reports compensation from Chiesi Farmaceutici for consultant services and compensation from Chiesi USA, Inc, for consultant services. Dr Awad reports compensation from Medicoegal consulting for expert witness services. Dr Hanley reports grants from US Department of Defense; grants from National Institute of Neurological Disorders and Stroke (NINDS); grants from NINDS to other; grants from NINDS; compensation from Neurelis, Inc, for consultant services; grants from National Center for Advancing Translational Sciences; grants from NINDS; gifts from Jeffrey and Harriet Legum Professorship in Acute Neurological Medicine at Johns Hopkins University. Dr Kamel is a co-principal investigator for the ARCADIA trial ([Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke]; NIH/NINDS U01NS095869), which received in-kind study drug from the Bristol Myers Squibb-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); Deputy Editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; end point adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. Dr Ziai has received grants from the NIH, serves as the Associate Editor of Neurocritical Care. Dr Murthy has received grant support from the NIH. The other authors report no conflicts.

Background: A major driver of individual variation in long-term outcomes following a large vessel occlusion (LVO) stroke is the degree of collateral arterial circulation. We aimed to develop and evaluate machine-learning models that quantify LVO collateral status using admission computed tomography angiography (CTA) radiomics., Methods: We extracted 1116 radiomic features from the anterior circulation territories from admission CTAs of 600 patients experiencing an acute LVO stroke. We trained and validated multiple machine-learning models for the prediction of collateral status based on consensus from two neuroradiologists as ground truth. Models were first trained to predict (1) good vs. intermediate or poor, or (2) good vs. intermediate or poor collateral status. Then, model predictions were combined to determine a three-tier collateral score (good, intermediate, or poor). We used the receiver operating characteristics area under the curve (AUC) to evaluate prediction accuracy., Results: We included 499 patients in training and 101 in an independent test cohort. The best-performing models achieved an averaged cross-validation AUC of 0.80 ± 0.05 for poor vs. intermediate/good collateral and 0.69 ± 0.05 for good vs. intermediate/poor, and AUC = 0.77 (0.67-0.87) and AUC = 0.78 (0.70-0.90) in the independent test cohort, respectively. The collateral scores predicted by the radiomics model were correlated with (rho = 0.45, p = 0.002) and were independent predictors of 3-month clinical outcome ( p = 0.018) in the independent test cohort., Conclusions: Automated tools for the assessment of collateral status from admission CTA-such as the radiomics models described here-can generate clinically relevant and reproducible collateral scores to facilitate a timely treatment triage in patients experiencing an acute LVO stroke.

Background: Patients with ischemic stroke and concomitant COVID-19 infection have worse outcomes than those without this infection, but the impact of COVID-19 on hemorrhagic stroke remains unclear. We aimed to assess if COVID-19 worsens outcomes in intracerebral hemorrhage (ICH)., Methods and Results: We conducted an observational study of ICH outcomes using Get With The Guidelines Stroke data. We compared patients with ICH who were COVID-19 positive and negative during the pandemic (March 2020-February 2021) and prepandemic (March 2019-February 2020). Main outcomes were poor functional outcome (defined as a modified Rankin scale score of 4 to 6 at discharge), mortality, and discharge to a skilled nursing facility or hospice. The first stage included 60 091 patients with ICH who were COVID-19 negative and 1326 COVID-19 positive. In multivariable analyses, patients with ICH with versus without COVID-19 infection had 68% higher odds of poor outcome (odds ratio [OR], 1.68 [95% CI, 1.41-2.01]), 51% higher odds of mortality (OR, 1.51 [95% CI, 1.33-1.71]), and 66% higher odds of being discharged to a skilled nursing facility/hospice (OR, 1.66 [95% CI, 1.43-1.93]). The second stage included 62 743 prepandemic and 64 681 intrapandemic cases with ICH. In multivariable analyses, patients with ICH admitted during versus before the COVID-19 pandemic had 10% higher odds of poor outcomes (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 a skilled nursing facility/hospice (OR, 0.93 [95% CI, 0.90-0.95])., Conclusions: The pathophysiology of the COVID-19 infection and changes in health care delivery during the pandemic played a role in worsening outcomes in the patient population with ICH.

Hematoma expansion (HE) is a modifiable risk factor and a potential treatment target in patients with intracerebral hemorrhage (ICH). We aimed to train and validate deep-learning models for high-confidence prediction of supratentorial ICH expansion, based on admission non-contrast head Computed Tomography (CT). Applying Monte Carlo dropout and entropy of deep-learning model predictions, we estimated the model uncertainty and identified patients at high risk of HE with high confidence. Using the receiver operating characteristics area under the curve (AUC), we compared the deep-learning model prediction performance with multivariable models based on visual markers of HE determined by expert reviewers. We randomly split a multicentric dataset of patients (4-to-1) into training/cross-validation (n = 634) versus test (n = 159) cohorts. We trained and tested separate models for prediction of ≥6 mL and ≥3 mL ICH expansion. The deep-learning models achieved an AUC = 0.81 for high-confidence prediction of HE ≥6 mL and AUC = 0.80 for prediction of HE ≥3 mL , which were higher than visual maker models AUC = 0.69 for HE ≥6 mL (p = 0.036) and AUC = 0.68 for HE ≥3 mL (p = 0.043). Our results show that fully automated deep-learning models can identify patients at risk of supratentorial ICH expansion based on admission non-contrast head CT, with high confidence, and more accurately than benchmark visual markers., (© 2024. The Author(s).)

Importance: Intracerebral hemorrhage (ICH) is a serious complication of brain arteriovenous malformation (AVM). Apolipoprotein E (APOE) ε4 is a well-known genetic risk factor for ICH among persons without AVM, and cerebral amyloid angiopathy is a vasculopathy frequently observed in APOE ε4 carriers that may increase the risk of ICH., Objective: To assess whether APOE ε4 is associated with a higher risk of ICH in patients with a known AVM., Design, Setting, and Participants: This cross-sectional study including 412 participants was conducted in 2 stages (discovery and replication) using individual-level data from the UK Biobank (released March 2012 and last updated October 2023) and the All of Us Research Program (commenced on May 6, 2018, with its latest update provided in October 2023). The occurrence of AVM and ICH was ascertained at the time of enrollment using validated International Classification of Diseases, Ninth Revision and Tenth Revision, codes. Genotypic data on the APOE variants rs429358 and rs7412 were used to ascertain the ε status., Main Outcomes and Measures: For each study, the association between APOE ε4 variants and ICH risk was assessed among patients with a known AVM by using multivariable logistic regression., Results: The discovery phase included 253 UK Biobank participants with known AVM (mean [SD] age, 56.6 [8.0] years, 119 [47.0%] female), of whom 63 (24.9%) sustained an ICH. In the multivariable analysis of 240 participants of European ancestry, APOE ε4 was associated with a higher risk of ICH (odds ratio, 4.58; 95% CI, 2.13-10.34; P < .001). The replication phase included 159 participants with known AVM enrolled in All of Us (mean [SD] age, 57.1 [15.9] years; 106 [66.7%] female), of whom 29 (18.2%) sustained an ICH. In multivariable analysis of 101 participants of European ancestry, APOE ε4 was associated with higher risk of ICH (odds ratio, 4.52; 95% CI, 1.18-19.38; P = .03)., Conclusions and Relevance: The results of this cross-sectional study of patients from the UK Biobank and All of Us suggest that information on APOE ε4 status may help identify patients with brain AVM who are at particularly high risk of ICH and that cerebral amyloid angiopathy should be evaluated as a possible mediating mechanism of the observed association.

Importance: Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage in older patients. Although other types of intracranial hemorrhage can occur in conjunction with CAA-related intracerebral hemorrhage, the association between CAA and other subtypes of intracranial hemorrhage, particularly in the absence of intracerebral hemorrhage, remains poorly understood., Objective: To determine whether CAA is an independent risk factor for isolated nontraumatic subdural hemorrhage (SDH)., Design, Setting, and Participants: A population-based cohort study was performed using a 2-stage analysis of prospectively collected data in the UK Biobank cohort (discovery phase, 2006-2022) and the All of Us Research Program cohort (replication phase, 2018-2022). Participants included those who contributed at least 1 year of data while they were older than 50 years, in accordance with the diagnostic criteria for CAA. Participants with prevalent intracranial hemorrhage were excluded. Data were analyzed from October 2022 to October 2023., Exposure: A diagnosis of CAA, identified using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code., Main Outcomes and Measures: The outcome was an isolated nontraumatic SDH, identified using ICD-10-CM codes. Two identical analyses were performed separately in the 2 cohorts. First, the risk of SDH in patients with and without CAA was assessed using Cox proportional hazards models, adjusting for demographic characteristics, cardiovascular comorbidities, and antithrombotic medication use. Second, multivariable logistic regression was used to study the association between CAA and SDH., Results: The final analytical sample comprised 487 223 of the total 502 480 individuals in the UK Biobank cohort and 158 008 of the total 372 082 individuals in the All of Us cohort. Among the 487 223 participants in the discovery phase of the UK Biobank, the mean (SD) age was 56.5 (8.1) years, and 264 195 (54.2%) were female. There were 649 cases of incident SDH. Of the 126 participants diagnosed with CAA, 3 (2.4%) developed SDH. In adjusted Cox regression analyses, participants with CAA had an increased risk of having an SDH compared with those without CAA (hazard ratio [HR], 8.0; 95% CI, 2.6-24.8). Multivariable logistic regression analysis yielded higher odds of SDH among participants with CAA (odds ratio [OR], 7.6; 95% CI, 1.8-20.4). Among the 158 008 participants in the All of Us cohort, the mean (SD) age was 63.0 (9.5) years, and 89 639 (56.7%) were female. The findings were replicated in All of Us, in which 52 participants had CAA and 320 had an SDH. All of Us participants with CAA had an increased risk of having an SDH compared with those without CAA (HR, 4.9; 95% CI, 1.2-19.8). In adjusted multivariable logistic regression analysis, CAA was associated with higher odds of SDH (OR, 5.2; 95% CI, 0.8-17.6)., Conclusions and Relevance: In 2 large, heterogeneous cohorts, CAA was associated with increased risk of SDH. These findings suggest that CAA may be a novel risk factor for isolated nontraumatic SDH.

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., (© 2023 American Neurological Association.)

Competing Interests: Disclosures None.

Background: Hematoma expansion (HE) following an intracerebral hemorrhage (ICH) is a modifiable risk factor and a treatment target. We examined the association of HE with neurological deterioration (ND), functional outcome, and mortality based on the time gap from onset to baseline CT., Methods: We included 567 consecutive patients with supratentorial ICH and baseline head CT within 24 h of onset. ND was defined as a ≥4-point increase on the NIH stroke scale (NIHSS) or a ≥2-point drop on the Glasgow coma scale. Poor outcome was defined as a modified Rankin score of 4 to 6 at 3-month follow-up., Results: The rate of HE was higher among those scanned within 3 h (124/304, 40.8%) versus 3 to 24 h post-ICH onset (53/263, 20.2%) ( p < 0.001). However, HE was an independent predictor of ND ( p < 0.001), poor outcome ( p = 0.010), and mortality ( p = 0.003) among those scanned within 3 h, as well as those scanned 3-24 h post-ICH ( p = 0.043, p = 0.037, and p = 0.004, respectively). Also, in a subset of 180/567 (31.7%) patients presenting with mild symptoms (NIHSS ≤ 5), hematoma growth was an independent predictor of ND ( p = 0.026), poor outcome ( p = 0.037), and mortality ( p = 0.027)., Conclusion: Despite decreasing rates over time after ICH onset, HE remains an independent predictor of ND, functional outcome, and mortality among those presenting >3 h after onset or with mild symptoms.

Background: Vascular brain injury (VBI) may be an under-recognised contributor to mobility impairment. We examined associations between MRI VBI biomarkers and impaired mobility., Methods: We separately analysed Atherosclerosis Risk in Communities (ARIC) and UK Biobank (UKB) study cohorts. Inclusion criteria were no prevalent clinical stroke, and available brain MRI and balance and gait data. MRI VBI biomarkers were (ARIC: ventricular and white matter hyperintensity (WMH) volumes, non-lacunar and lacunar infarctions, microhaemorrhage; UKB: ventricular, brain and WMH volumes, fractional anisotropy (FA), mean diffusivity (MD), intracellular and isotropic free water volume fractions). Quantitative biomarkers were categorised into tertiles. Mobility impairment outcomes were imbalance and slow walk in ARIC and recent fall and slow walk in UKB. Adjusted multivariable logistic regression analyses were performed., Results: We included 1626 ARIC (mean age 76.2 years; 23.4% imbalance, 25.0% slow walk) and 40 098 UKB (mean age 55 years; 15.8% falls, 2.8% slow walk) participants. In ARIC, imbalance associated with four of five VBI measures (all p values<0.05), most strongly with WMH (adjusted OR, aOR 1.64; 95% CI 1.18 to 2.29). Slow walk associated with four of five VBI measures, most strongly with WMH (aOR 2.32; 95% CI 1.66 to 3.24). In UKB, falls associated with all VBI measures except WMH, most strongly with FA (aOR 1.16; 95% CI 1.08 to 1.24). Slow walking associated with WMH, FA and MD, most strongly with FA (aOR 1.57; 95% CI 1.32 to 1.87)., Conclusions: VBI is associated with mobility impairment in community-dwelling, clinically stroke-free cohorts. Consequences of VBI may extend beyond clinically apparent stroke to include mobility., Competing Interests: Competing interests: RS reports grants from NIH Clinical Centre. AdH has received investigator-initiated clinical research funding from Regeneron, AMGEN and AMAG pharmaceuticals, and has equity in TitinKM and Certus. HK reports receiving personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, F-Prime, Tesseract/4Catalyst, Martin/Baughman Law Firm, Arnold and Porter Law Firm, and Siegfried and Jensen Law Firm; being a cofounder of HugoHealth, a personal health information platform; being a cofounder of Refractor Health, an Enterprise Health Care artificial intelligence-augmented data management company; having contracts with the Centers for Medicare & Medicaid Services Association through Yale New Haven Hospital, to develop and maintain performance measures that are publicly reported; and receiving grants from Johnson & Johnson outside the submitted work. GJF reports grants from the Neurocritical Care Society Research Fellowship. KNS reports compensation from CSL Behring for consultant services; compensation from Sense for data and safety monitoring services; compensation from Cerevasc for consultant services; compensation from Rhaeos for consultant services; compensation from Certus for consultant services; service as President for Advanced Innovation in Medicine; a patent pending for Stroke wearables licensed to Alva Health. The other authors report no conflicts., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Poor oral health is a modifiable risk factor that is associated with clinically observed cardiovascular disease. However, the relationship between oral and brain health is not well understood. We tested the hypothesis that poor oral health is associated with worse neuroimaging brain health profiles in middle-aged persons without stroke or dementia., Methods: We performed a 2-stage cross-sectional neuroimaging study using UK Biobank data. 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. 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 linked to increased composite risk of dentures or teeth that are decayed, missing, or filled. Neuroimaging markers of brain health included white matter hyperintensity (WMH) volume and aggregate measures of fractional anisotropy (FA) and mean diffusivity (MD), 2 metrics indicative of white matter tract disintegrity obtained through diffusion tensor imaging across 48 brain regions., Results: We included 40,175 persons (mean age 55 years, female sex 53%) enrolled from 2006 to 2010, who underwent a dedicated research brain MRI between 2014 and 2016. Among participants, 5,470 (14%) had poor oral health. Poor oral health was associated with a 9% increase in WMH volume (β = 0.09, SD = 0.014, p < 0.001), 10% change in aggregate FA score (β = 0.10, SD = 0.013, p < 0.001), and 5% change in aggregate MD score (β = 0.05, SD = 0.013, p < 0.001). Genetically determined poor oral health was associated with a 30% increase in WMH volume (β = 0.30, SD = 0.06, p < 0.001), 43% change in aggregate FA score (β = 0.43, SD = 0.06, p < 0.001), and 10% change in aggregate MD score (β = 0.10, SD = 0.03, p < 0.01)., Discussion: Among middle age Britons without stroke or dementia, poor oral health was associated with worse neuroimaging brain health profiles. Genetic analyses confirmed these associations, supporting a potentially causal association. Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health.

Background: The American Heart Association's Life's Simple 7, a public health construct capturing key determinants of cardiovascular health, became the Life's Essential 8 after the addition of sleep duration. The authors tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults., Methods and Results: The authors conducted a prospective magnetic resonance neuroimaging study in middle-aged individuals without stroke or dementia enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (<7 hours), optimal (7-<9 hours), or long (≥9 hours). Evaluated neuroimaging markers included the presence of white matter hyperintensities (WMHs), volume of WMH, and fractional anisotropy, with the latter evaluated as the average of 48 white matter tracts. Multivariable logistic and linear regression models were used to test for an association between sleep duration and these neuroimaging markers. The authors evaluated 39 771 middle-aged individuals. Of these, 28 912 (72.7%) had optimal, 8468 (21.3%) had short, and 2391 (6%) had long sleep duration. Compared with optimal sleep, short sleep was associated with higher risk of WMH presence (odds ratio, 1.11 [95% CI, 1.05-1.18]; P <0.001), larger WMH volume (beta=0.06 [95% CI, 0.04-0.08]; P <0.001), and worse fractional anisotropy profiles (beta=-0.04 [95% CI, -0.06 to -0.02]; P =0.001). Compared with optimal sleep, long sleep duration was associated with larger WMH volume (beta=0.04 [95% CI, 0.01-0.08]; P =0.02) and worse fractional anisotropy profiles (beta=-0.06 [95% CI, -0.1 to -0.02]; P =0.002), but not with WMH presence ( P =0.6)., Conclusions: Among middle-aged adults without stroke or dementia, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because these neuroimaging markers precede stroke and dementia by several years, these findings are consistent with other findings evaluating early interventions to improve this modifiable risk factor.

Introduction: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative condition caused by prion proteins. Cortical and subcortical diffusion-weighted imaging restriction on magnetic resonance imaging (MRI) is associated with sCJD. Posterior reversible encephalopathy syndrome (PRES) results from impaired vessel autoregulation due to an identifiable trigger, which is associated with subcortical fluid-attenuated inversion recovery changes on MRI. We report a case of sCJD initially presenting with PRES., Case Report: A 70-year-old woman presented to an outside hospital with progressive confusion and difficulty in managing activities of daily living. Initial examination revealed stuporous mental state and stimulus-induced myoclonus. MRI revealed bilateral subcortical occipital lobe T2-fluid-attenuated inversion recovery hyperintensities without contrast enhancement suggestive of PRES. Electroencephalogram (EEG) revealed frequent generalized periodic discharges meeting criteria for nonconvulsive status epilepticus. Clinical examination and EEG did not improve despite escalating antiseizure medications. Initial lumbar puncture was unremarkable. She was transferred to our hospital with a presumptive diagnosis of PRES, although there was no clear trigger. Continuous EEG revealed ongoing generalized periodic discharges with myoclonic activity meeting criteria for myoclonic seizures that were refractory to multiple antiseizure medications. Repeat MRI showed resolution of PRES but revealed subtle diffuse cortical diffusion-weighted imaging restriction. Repeat lumbar puncture was performed and 14-3-3 and real-time quaking-induced conversion returned positive, confirming sCJD., Conclusions: This case reports highlights that sCJD can present with neuroimaging consistent with PRES. The diagnosis of sCJD should be considered in patients with PRES who continue to show neurological decline despite optimal management and radiographic improvement of PRES on MRI. Further research is needed to identify a pathophysiological relationship between these clinical phenotypes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection., Methods: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances., Results: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively., Conclusions: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH., Competing Interests: Disclosures Dr Sheth is the principal investigator. Dr Sheth reports compensation from CSL Behring for consultant services; grants from BARD; compensation from Astrocyte for consultant services; compensation from Rhaeos for consultant services; compensation from Certus for consultant services; grants from Novartis; a patent pending for Stroke wearables licensed to Alva Health; compensation from Cerevasc for consultant services; compensation from ZOLL Medical Corporation for data and safety monitoring services; grants from Hyperfine; employment by Yale School of Medicine; compensation from Sense for data and safety monitoring services; grants from Hyperfine to other; and grants from Biogen. Dr Kimberly reports grants from NControl Therapeutics; compensation from Astrocyte Pharmaceuticals for consultant services; compensation from Acasti Pharmaceuticals for consultant services; grants from Hyperfine Research Inc; a patent pending for No. 16/486 687, Methods and Compositions for Treating a Brain Injury. licensed to NControl Therapeutics; grants from Biogen; stock holdings in Woolsey Pharmaceuticals; and compensation from NControl Therapeutics for consultant services. Dr de Havenon reports compensation from Novo Nordisk for consultant services; compensation from Integra for consultant services; grants from National Institutes of Health (NIH); stock options in Certus; and stock options in TitinKM. Dr Rosen reports grants from American Heart Association (AHA), Advanced Research Projects Agency–Energy (ARPA-E), Department of Energy (DOE), and the NIH. Dr Rosen is on the scientific advisory board of ABQMR, Synex Medical, Inc, Nanalysis, Inc, O2M Technologies, Inc, Quantum Catalyzer, Inc, and Lincoln Agritech LTD. Dr Rosen is a Founder and equity holder of Hyperfine, Vizma Life Sciences, Intact Data Services, and Q4ML. He acknowledges the support of the Kiyomi and Ed Baird Research Scholar award. Dr Matouk reports compensation from Silk Road Medical, Inc, for consultant services; compensation from MicroVention, Inc, for consultant services; and compensation from Penumbra, Inc, for consultant services. Dr Falcone reports grants from AHA and grants from National Institutes of Health. Dr Sorby-Adams reports grants from Australian-American Fulbright Commission and grants from AHA. The other authors report no conflicts.

Background and Purpose: Perihematomal edema (PHE) represents the secondary brain injury after intracerebral hemorrhage (ICH). However, neurobiological characteristics of post-ICH parenchymal injury other than PHE volume have not been fully characterized. Using intravoxel incoherent motion imaging (IVIM), we explored the clinical correlates of PHE diffusion and (micro)perfusion metrics in subacute ICH., Materials and Methods: In 41 consecutive patients scanned 1-to-7 days after supratentorial ICH, we determined the mean diffusion (D), pseudo-diffusion (D*), and perfusion fraction (F) within manually segmented PHE. Using univariable and multivariable statistics, we evaluated the relationship of these IVIM metrics with 3-month outcome based on the modified Rankin Scale (mRS)., Results: In our cohort, the average (± standard deviation) age of patients was 68.6±15.6 years, median (interquartile) baseline National Institute of Health Stroke Scale (NIHSS) was 7 (3-13), 11 (27 %) patients had poor outcomes (mRS>3), and 4 (10 %) deceased during the follow-up period. In univariable analyses, admission NIHSS (p < 0.001), ICH volume (p = 0.019), ICH+PHE volume (p = 0.016), and average F of the PHE (p = 0.005) had significant correlation with 3-month mRS. In multivariable model, the admission NIHSS (p = 0.006) and average F perfusion fraction of the PHE (p = 0.003) were predictors of 3-month mRS., Conclusion: The IVIM perfusion fraction (F) maps represent the blood flow within microvasculature. Our pilot study shows that higher PHE microperfusion in subacute ICH is associated with worse outcomes. Once validated in larger cohorts, IVIM metrics may provide insight into neurobiology of post-ICH secondary brain injury and identify at-risk patients who may benefit from neuroprotective therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Seyedmehdi Payabvash reports a relationship with National Institutes of Health that includes: funding grants. Seyedmehdi Payabvash reports a relationship with Doris Duke Charitable Foundation that includes: funding grants. Seyedmehdi Payabvash reports a relationship with Foundation of the American Society of Neuroradiology that includes: funding grants. Emily J Gilmore reports a relationship with National Institutes of Health that includes: funding grants. Emily J Gilmore reports a relationship with UCB that includes: consulting or advisory. Emily J Gilmore reports a relationship with Intracranial Bioanalytics that includes: non-financial support. Guido J. Falcone reports a relationship with National Institutes of Health that includes: funding grants. Guido J. Falcone reports a relationship with Neurocritical Care Society that includes: funding grants. Guido J. Falcone reports a relationship with Yale Pepper Scholar Award that includes: funding grants. Guido J. Falcone reports a relationship with American Heart Association that includes: funding grants. Kevin N. Sheth reports a relationship with National Institutes of Health that includes: funding grants. Kevin N. Sheth reports a relationship with American Heart Association that includes: funding grants. Kevin N. Sheth reports a relationship with Hyperfine Research Inc that includes: funding grants. Adam de Havenon reports a relationship with National Institutes of Health that includes: funding grants. Adam de Havenon reports a relationship with American Academy of Neurology that includes: funding grants. Adam de Havenon reports a relationship with Novo Nordisk that includes: consulting or advisory. Adam de Havenon reports a relationship with Integra that includes: consulting or advisory. Adam de Havenon reports a relationship with Titin KM that includes: equity or stocks. Adam de Havenon reports a relationship with UpToDate that includes: paid expert testimony., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: We 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., Methods: Using 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., Results: We 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 p<0.001). In mediation analysis, the averaged FA of external capsule, internal capsule anterior limb and superior cerebellar peduncle mediated 13%, 9% and 13% of SBP effects on fluid intelligence, while the averaged MD of external capsule, internal capsule anterior and posterior limbs, and superior corona radiata mediated 5%, 7%, 7% and 6% of SBP effects on fluid intelligence, respectively., Discussion: Among 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To devise and validate radiomic signatures of impending hematoma expansion (HE) based on admission non-contrast head computed tomography (CT) of patients with intracerebral hemorrhage (ICH)., Methods: Utilizing a large multicentric clinical trial dataset of hypertensive patients with spontaneous supratentorial ICH, we developed signatures predictive of HE in a discovery cohort ( n = 449) and confirmed their performance in an independent validation cohort ( n = 448). In addition to n = 1,130 radiomic features, n = 6 clinical variables associated with HE, n = 8 previously defined visual markers of HE, the BAT score, and combinations thereof served as candidate variable sets for signatures. The area under the receiver operating characteristic curve (AUC) quantified signatures' performance., Results: A signature combining select radiomic features and clinical variables attained the highest AUC (95% confidence interval) of 0.67 (0.61-0.72) and 0.64 (0.59-0.70) in the discovery and independent validation cohort, respectively, significantly outperforming the clinical ( p discovery = 0.02, p validation = 0.01) and visual signature ( p discovery = 0.03, p validation = 0.01) as well as the BAT score ( p discovery < 0.001, p validation < 0.001). Adding visual markers to radiomic features failed to improve prediction performance. All signatures were significantly ( p < 0.001) correlated with functional outcome at 3-months, underlining their prognostic relevance., Conclusion: Radiomic features of ICH on admission non-contrast head CT can predict impending HE with stable generalizability; and combining radiomic with clinical predictors yielded the highest predictive value. By enabling selective anti-expansion treatment of patients at elevated risk of HE in future clinical trials, the proposed markers may increase therapeutic efficacy, and ultimately improve outcomes., Competing Interests: KS reports equity interests in Alva Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, SP, declared a past co-authorship with one of the author DW to the handling editor TS., (Copyright © 2023 Haider, Qureshi, Jain, Tharmaseelan, Berson, Zeevi, Werring, Gross, Mak, Malhotra, Sansing, Falcone, Sheth and Payabvash.)

Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10 -8 ), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10 -11 ). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Background and Objectives: Mounting evidence indicates that hypertension leads to a higher risk of dementia. Hypertension is a highly heritable trait, and a higher polygenic susceptibility to hypertension (PSH) is known to associate with a higher risk of dementia. We tested the hypothesis that a higher PSH leads to worse cognitive performance in middle-aged persons without dementia. Confirming this hypothesis would support follow-up research focused on using hypertension-related genomic information to risk-stratify middle-aged adults before hypertension develops., Methods: We conducted a nested cross-sectional genetic study within the UK Biobank (UKB). Study participants with a history of dementia or stroke were excluded. We categorized participants as having low (≤20th percentile), intermediate, or high (≥80th percentile) PSH according to results of 2 polygenic risk scores for systolic and diastolic blood pressure (BP) generated with data on 732 genetic risk variants. A general cognitive ability score was calculated as the first component of an analysis that included the results of 5 cognitive tests. Primary analyses focused on Europeans, and secondary analyses included all race/ethnic groups., Results: Of the 502,422 participants enrolled in the UKB, 48,118 (9.6%) completed the cognitive evaluation, including 42,011 (8.4%) of European ancestry. Multivariable regression models using systolic BP-related genetic variants indicated that compared with study participants with a low PSH, those with intermediate and high PSH had reductions of 3.9% (β -0.039, SE 0.012) and 6.6% (β -0.066, SE 0.014), respectively, in their general cognitive ability score ( p < 0.001). Secondary analyses including all race/ethnic groups and using diastolic BP-related genetic variants yielded similar results ( p < 0.05 for all tests). Analyses evaluating each cognitive test separately indicated that reaction time, numeric memory, and fluid intelligence drove the association between PSH and general cognitive ability score (all individual tests, p < 0.05)., Discussion: Among nondemented, community-dwelling, middle-aged Britons, a higher PSH is associated with worse cognitive performance. These findings suggest that genetic predisposition to hypertension influences brain health in persons who have not yet developed dementia. Because information on genetic risk variants for elevated BP is available long before the development of hypertension, these results lay the foundation for further research focused on using genomic data for the early identification of high-risk middle-aged adults., (© 2023 American Academy of Neurology.)

Background It remains unclear if white matter hyperintensity (WMH) on magnetic resonance imaging adds relevant cerebrovascular prognostic information beyond vascular risk factors and demographics alone. Methods and Results We performed a post hoc analysis of hypertensive individuals in SPRINT-MIND (Systolic Blood Pressure Intervention Trial-Memory and Cognition in Decreased Hypertension). The primary outcome was incident stroke or cognitive impairment (mild cognitive impairment or dementia). We fit logistic regression models with the predictors of Atherosclerotic Cardiovascular Disease Risk Score, age, sex, race, education, current cigarette smoking, and the SPRINT-MIND randomization arm. WMH was subsequently included in the model to determine if it improved area under the receiver operating curve using the DeLong test. We used a structural equation model to determine the indirect effect on the primary outcome mediated through WMH. We included 727 individuals (mean age at baseline 67.7±8.4 years, 61.1% were men, 62.6% were non-Hispanic White, and mean years of follow-up was 3.6±0.9). Of the 727 individuals, 67 (9.2%) developed incident stroke or cognitive decline. The area under the receiver operating curve of the baseline model (without WMH) was 0.75 (95% CI, 0.70-0.81), and after the addition of WMH it increased to 0.81 (95% CI, 0.76-0.86) ( P =0.004 for difference). The mediation analysis showed that 26.3% of the vascular risk's effect on the primary outcome is indirectly mediated through WMH. Conclusions In adult hypertensive individuals, we found that the addition of WMH to models predicting incident stroke or cognitive impairment improved the prognostic ability above vascular risk and demographics alone to a level consistent with excellent prediction. Registration Information REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Background White matter hyperintensity (WMH) on magnetic resonance imaging (MRI) of the brain is associated with vascular cognitive impairment, cardiovascular disease, and stroke. We hypothesized that portable magnetic resonance imaging (pMRI) could successfully identify WMHs and facilitate doing so in an unconventional setting. Methods and Results In a retrospective cohort of patients with both a conventional 1.5 Tesla MRI and pMRI, we report Cohen's kappa (κ) to measure agreement for detection of moderate to severe WMH (Fazekas ≥2). In a subsequent prospective observational study, we enrolled adult patients with a vascular risk factor being evaluated in the emergency department for a nonstroke complaint and measured WMH using pMRI. In the retrospective cohort, we included 33 patients, identifying 16 (49.5%) with WMH on conventional MRI. Between 2 raters evaluating pMRI, the interrater agreement on WMH was strong (κ=0.81), and between 1 rater for conventional MRI and the 2 raters for pMRI, intermodality agreement was moderate (κ=0.66, 0.60). In the prospective cohort we enrolled 91 individuals (mean age, 62.6 years; 53.9% men; 73.6% with hypertension), of which 58.2% had WMHs on pMRI. Among 37 Black and Hispanic individuals, the Area Deprivation Index was higher (versus White, 51.8±12.9 versus 37.9±11.9; P <0.001). Among 81 individuals who did not have a standard-of-care MRI in the preceding year, we identified WMHs in 43 of 81 (53.1%). Conclusions Portable, low-field imaging could be useful for identifying moderate to severe WMHs. These preliminary results introduce a novel role for pMRI outside of acute care and the potential role for pMRI to reduce disparities in neuroimaging.

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 <5), intermediate (≥5 and <15), and high (HFRS ≥15). Last, we implemented Mendelian Randomization analyses to evaluate whether genetically determined frailty is associated with stroke risk., 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 <0.001), not-frail versus intermediate HFRS (HR, 11.4 [CI, 8.3-15.7]; P <0.001) and not-frail versus high HFRS (HR, 42.8 [CI, 31.2-58.6]; P <0.001). We found similar associations when evaluating ischemic and hemorrhagic stroke separately ( P value for all comparisons <0.05). Mendelian Randomization confirmed this association by indicating that genetically determined frailty was independently associated with risk of any stroke (OR, 1.45 [95% CI, 1.15-1.84]; 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., Competing Interests: Disclosures None.

Background and Purpose: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE)., Methods: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs)., Results: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (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., (© 2023 European Academy of Neurology.)

Importance: Aside from widely known cardiovascular implications, higher weight in children may have negative associations with brain microstructure and neurodevelopment., Objective: To evaluate the association of body mass index (BMI) and waist circumference with imaging metrics that approximate brain health., Design, Setting, and Participants: This cross-sectional study used data from the Adolescent Brain Cognitive Development (ABCD) study to examine the association of BMI and waist circumference with multimodal neuroimaging metrics of brain health in cross-sectional and longitudinal analyses over 2 years. From 2016 to 2018, the multicenter ABCD study recruited more than 11 000 demographically representative children aged 9 to 10 years in the US. Children without any history of neurodevelopmental or psychiatric disorders were included in this study, and a subsample of children who completed 2-year follow-up (34%) was included for longitudinal analysis., Exposures: Children's weight, height, waist circumference, age, sex, race and ethnicity, socioeconomic status, handedness, puberty status, and magnetic resonance imaging scanner device were retrieved and included in the analysis., Main Outcomes and Measures: Association of preadolescents' BMI z scores and waist circumference with neuroimaging indicators of brain health: cortical morphometry, resting-state functional connectivity, and white matter microstructure and cytostructure., Results: A total of 4576 children (2208 [48.3%] female) at a mean (SD) age of 10.0 years (7.6 months) were included in the baseline cross-sectional analysis. There were 609 (13.3%) Black, 925 (20.2%) Hispanic, and 2565 (56.1%) White participants. Of those, 1567 had complete 2-year clinical and imaging information at a mean (SD) age of 12.0 years (7.7 months). In cross-sectional analyses at both time points, higher BMI and waist circumference were associated with lower microstructural integrity and neurite density, most pronounced in the corpus callosum (fractional anisotropy for BMI and waist circumference at baseline and second year: P < .001; neurite density for BMI at baseline: P < .001; neurite density for waist circumference at baseline: P = .09; neurite density for BMI at second year: P = .002; neurite density for waist circumference at second year: P = .05), reduced functional connectivity in reward- and control-related networks (eg, within the salience network for BMI and waist circumference at baseline and second year: P < .002), and thinner brain cortex (eg, for the right rostral middle frontal for BMI and waist circumference at baseline and second year: P < .001). In longitudinal analysis, higher baseline BMI was most strongly associated with decelerated interval development of the prefrontal cortex (left rostral middle frontal: P = .003) and microstructure and cytostructure of the corpus callosum (fractional anisotropy: P = .01; neurite density: P = .02)., Conclusions and Relevance: In this cross-sectional study, higher BMI and waist circumference among children aged 9 to 10 years were associated with imaging metrics of poorer brain structure and connectivity as well as hindered interval development. Future follow-up data from the ABCD study can reveal long-term neurocognitive implications of excess childhood weight. Imaging metrics that had the strongest association with BMI and waist circumference in this population-level analysis may serve as target biomarkers of brain integrity in future treatment trials of childhood obesity.

Background: White matter hyperintensities (WMHs) are linked to cognitive decline and stroke. We investigate the impact of race on WMH progression in the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORDION MIND) trial., Materials and Methods: The primary outcome is WMH progression in milliliters, evaluated by fitting linear regression to WMH volume on the month 80 magnetic resonance imaging (MRI) and including the WMH volume on the baseline MRI. The primary predictor is patient race, with the exclusion of patients defined as "other" race. We also derived predicted probabilities of our outcome for systolic blood pressure (SBP) levels., Results: We included 276 patients who completed the baseline and month 80 MRI, of which 207 (75%) were White, 48 (17%) Black, and 21 (8%) Hispanic. During follow-up, the mean number of SBP, low-density lipoprotein (LDL), and A1c measurements per patient was 21, 8, and 15. The median (IQR) WMH progression was 1.5 mL (0.5 to 3.9) for Black patients, 1.0 mL (0.4 to 4.0) for Hispanics, and 1.3 mL (0.5 to 2.7) for Whites (Kruskal-Wallis test, P =0.59). In the multivariate regression model, Black, compared with White, patients had significantly more WMH progression (β Coefficient 1.26, 95% confidence interval 0.45 to 2.06, P =0.002). Hispanic, compared with White, patients neither have significantly different WMH progression ( P =0.392), nor was there a difference when comparing Hispanic to Black patients ( P =0.162). The predicted WMH progression was significantly higher for Black compared with White patients across a mean SBP of 117 to 139 mm Hg., Conclusions: Black diabetic patients in Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORDION MIND) have a higher risk of WMH progression than White patients across a normal range of SBP., Competing Interests: A.d.H. has received investigator-initiated clinical research funding from Regeneron, AMGEN and AMAG pharmaceuticals, royalties from UptoDate, consulting fees from Inegra, and stock options in Certus. G.J.F. reports funding from the NIH, American Heart Association and the Yale Claude D. Pepper Older Americans Independence Center. S.P. reports received funds from NIH, AHRQ, Abbvie, and UpToDate. K.N.S. reports funding from Biogen, Novartis, Bard, and Hyperfine. He holds equity in Astrocyte, Alva Health, and Certus and serves as DSMB Chair for a Zoll study. A.L.H. declares no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)