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BackgroundIn the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.Methods and ResultsIn the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.ConclusionThe CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

Introduction: Sphingolipids are fundamental components of brain structure and function. They are located in the myelin sheath insulating neuronal axons and in the cell membranes of neurons, astrocytes, and microglia involved in signal transduction. Although circulating sphingolipid profiles reflect clinical neurodegeneration, few prospective studies have investigated their utility as pre-clinical risk markers in community-based cohorts. For heart disease and diabetes, themselves risk factors for dementia, associations with sphingolipids differed across species and the length of the saturated fatty acid carried. Hypothesis: We hypothesized that plasma levels of sphingolipid species containing palmitic acid (16:0) would be positively associated with incident dementia risk and cognitive decline, while those with arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) would be associated with lower risk. Methods: We measured 18 sphingolipid species in plasma samples from 4612 participants of the Cardiovascular Health Study (CHS) (mean age 76.2 years; 40% male; and 25% APOE ε4 allele carriers). Cognitive decline was assessed across 6 years using annual 100-point modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST) scores. A total of 3088 non-demented participants were enrolled in the CHS Cognition Study and followed with adjudication for dementia. To correct the analyses for multiple comparisons, we applied a false discovery rate (FDR) correction and used a significance threshold of 0.05. Results: Higher baseline levels of lactosylceramide-24:0 (LacCer-24) were associated with a faster 6-year cognitive decline (time x sphingolipid interaction p=0.04 for 3MSE and 0.03 for DSST). Conversely, higher baseline plasma levels of hexosylceramide -16:0 (HexCer-16) and sphingomyelin-22:0 (SM-22) were associated with slower cognitive decline measured with DSST (time x sphingolipid interaction p=0.02 for HexCer and p=0.05 for SM-22). During a median follow-up of 4.5 years, we identified 366 incident dementia cases. In proportional Cox regression analyses, higher plasma levels of ceramide-16:0 (Cer-16) were positively associated with incident dementia upon adjustment for demographics, lifestyle factors, medical history, C-reactive protein, and lipids [hazard ratio per SD: 1.18 (95% CI, 1.06; 1.31)]. Conclusions: In older adults without dementia, higher plasma levels of Cer-16, a species previously associated with cardiovascular disease and mortality, were associated with higher risk of clinical dementia as we hypothesized. LacCer-24 was associated with faster, and HexCer-16 and SM-22 with slower, cognitive decline, but these species were not statistically associated with dementia risk. These novel and inconsistent findings will need to be replicated in other longitudinal studies.

Introduction: Despite known socioeconomic and health disparities affecting Indigenous populations in developed countries, stroke incidence data are sparse. With Indigenous Advisory Board oversight, we undertook a systematic review to compare Indigenous with non-Indigenous stroke incidence rates in countries with a very high Human Development Index (HDI). Methods: We identified population-based stroke incidence studies published from 1990-2022 in Indigenous adult populations of developed countries using PubMed, EMBASE and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with Results: Among 13,041 publications, 24 studies (19 full text, 5 abstracts) from 7 countries met inclusion criteria. Compared with respective non-Indigenous populations (Fig 1), age-standardised incidence rates were greater in Aboriginal and Torres Strait Islander Australians (ratios ranging from 1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), with higher rate ratios at younger ages. Studies had substantial heterogeneity in design and risk of bias. Few investigators reported Indigenous stakeholder involvement. Conclusions: In countries with a very high HDI, available data suggest marked disparities in stroke incidence in Indigenous populations, although there are gaps in data availability and quality. Indigenous stakeholder involvement in studies is infrequently reported. A greater understanding of stroke incidence in these populations is imperative for informing effective societal responses.

Background: Identification of novel biomarkers of cerebral small vessel disease is critical to elucidate pathophysiology and guide therapeutic development for prevention. We evaluated plasma proteomic associations of clinically asymptomatic, covert brain infarction (cBI) and white matter hyperintensity (WMH) burden on cranial magnetic resonance imaging (MRI) in the population-based Cardiovascular Health Study (CHS). Methods: Eligible CHS participants underwent one or two cranial MRI scans (~5 years apart) and aptamer-based SOMAScan platform measurement of up to 7288 plasma proteins concurrent with the initial MRI. cBI was defined by MRI signal characteristics and size ≥ 3 mm, and WMH burden was graded (WMG) 0 (least) to 9 (most severe). The relationship between 1-standard deviation increase in each log 2 -normalized plasma protein fluorescence was modeled separately with incident cBI and WMG worsening (≥1 grade increase) using multivariable relative risk regression, adjusting for demographics, estimated glomerular filtration rate (eGFR), and stroke risk factors. In secondary analyses, multivariable linear regression evaluated the cross-sectional relationship between each plasma protein with number of cBI and WMG on initial MRI. Bonferroni correction, based on the number of principal components that explained 99% of the protein fluorescence variance in CHS participants, accounted for multiple comparisons (p-5 (0.05/2377)). Results: For eligible participants (n=2615), mean age was 74.4 ± 4.9 years, 61.7% were women, and 16.4% were Black. After adjustment for demographics, eGFR, and stroke risk factors, multiple circulating proteins were associated with cBI and WMG (Table). Conclusion: Multiple plasma proteins - implicated in systemic inflammation, fatty acid metabolism, neuronal adhesion/migration, and cellular cytoskeletal integrity/remodeling - were independently associated with cBI and WMG in a cohort of older adults.

Objective:Recent studies have shown that global cognitive ability tends to decline faster over time in older adults (≥65 years) with epilepsy compared with older adults without epilepsy. Scarce data exist about the role of vascular risk factors (VRFs) on cognitive course in epilepsy. We assessed whether the associations of individual VRFs with cognitive trajectory differed depending on the presence of prevalent epilepsy.Methods:The Cardiovascular Health Study is a population-based longitudinal cohort study of 5,888 US adults aged ≥65 years. Cognitive function was assessed annually with Modified Mini-Mental State Exam (3MS; global cognitive ability) and Digit Symbol Substitution Test (DSST; information processing speed). We used linear mixed models to estimate the individual and joint associations of epilepsy and VRFs with cognitive decline by modeling epilepsy × VRF interactions one by one, each adjusted for all other VRFs considered, including demographics, health behaviors, clinical characteristics, and comorbid diagnoses. From these models, we estimated excess mean cognitive decline due to interaction of epilepsy with each VRF.Results:We observed excess mean decline in global cognitive ability (3MS) due to interactions of epilepsy with hypertension (6.6 points greater mean 8-year decline than expected if no interaction; 95% CI: 1.3, 12.0) and with abstaining from alcohol (5.8 points greater than expected; 95% CI: 0.3, 11.3). We also observed excess mean decline in information processing speed (DSST) due to interactions of epilepsy with prior stroke (18.1 points greater mean 9-year decline than expected; 95% CI: 7.6, 28.5), with abstaining from alcohol (6.1 points greater than expected; 95% CI: 2.5, 9.8), and with higher triglyceride levels (2.4 points greater than expected per standard deviation; 95% CI: 0.4, 4.3).Conclusion:Associations of some VRFs with cognitive decline in older adults are stronger in the presence of epilepsy, suggesting a need for greater attention to vascular protection for preserving brain health in older adults with epilepsy.

Previous studies report that obesity can be a risk and a protective factor for cognitive health. However, they have not examined whether white matter hyperintensities (WMH) mediate the association between mid- or late-life body mass index (BMI) and late-life cognitive performance. We examined this question in American Indians, a population underrepresented in neuropsychological research.We used longitudinal data from the cerebrovascular disease and its consequences in American Indians (n = 817), with BMI data collected at midlife (1989-91) and lat-life (2010-13). Cognitive data were collected in late life, with tests for general cognition, processing speed, verbal fluency, and memory. Neuroradiologist-scored WMH severity and volume using standard analysis pipelines. We examined associations among BMI, WMH severity and volume, and cognitive scores using linear regression and the Baron and Kenny method to estimate mediation.High BMI in late life was associated with a 1.79-point higher score in general cognition (95% CI 0.63-2.95, p-value = 0.002), but not the other tests. Mediated by WMH severity, high late-life BMI was associated with a 1.53-point higher score in general cognition (95% CI 0.37-2.69) and, by WMH volume, 1.63 points higher (95% CI 0.49-2.77). The association between late-life obesity and cognitive performance is stronger for females (β = 1.74, 95% CI 0.35-3.13, p-value = 0.014) than for males (β = 1.66, 95% CI -0.63-3.95, p-value = 0.158).In American Indians, high late-life BMI was positively associated with cognitive performance, with a stronger association for females. WMH severity and volume partly attenuate these associations.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10−8), was associated with F2 expression in blood (P = 6.4 × 10−5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood–brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood–brain barrier possibly due to disrupted cell–cell and cell–extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood–brain barrier disruption.

ImportanceFamily members of patients with severe acute brain injury (SABI) are at risk for poor psychological outcomes.ObjectiveTo explore the utility of the early use of a palliative care needs checklist in identifying care needs of patients with SABI and family members who are at risk of poor psychological outcomes.Design, Setting, and ParticipantsThis prospective cohort study included patients with SABI in an intensive care unit (ICU) for 2 days or more and a Glasgow Coma Scale score of 12 or lower and their family members. This single-center study was conducted at an academic hospital in Seattle, Washington, from January 2018 to June 2021. Data were analyzed from July 2021 to July 2022.ExposureAt enrollment, a 4-item palliative care needs checklist was completed separately by clinicians and family members.Main Outcomes and MeasuresA single family member for each enrolled patient completed questionnaires assessing symptoms of depression and anxiety, perception of goal-concordant care, and satisfaction in the ICU. Six months later, family members assessed their psychological symptoms, decisional regret, patient functional outcome, and patient quality of life (QOL).ResultsA total of 209 patient–family member pairs (family member mean [SD] age, 51 [16] years; 133 women [64%]; 18 Asian [9%], 21 Black [10%], 20 [10%] Hispanic, and 153 White [73%] participants) were included. Patients had experienced stroke (126 [60%]), traumatic brain injury (62 [30%]), and hypoxic-ischemic encephalopathy (21 [10%]). At least 1 need was identified for 185 patients or their families (88%) by family members and 110 (53%) by clinicians (κ = −0.007; 52% agreement). Symptoms of at least moderate anxiety or depression were present in 50% of family members at enrollment (87 with anxiety and 94 with depression) and 20% at follow-up (33 with anxiety and 29 with depression). After adjustment for patient age, diagnosis, and disease severity and family race and ethnicity, clinician identification of any need was associated with greater goal discordance (203 participants; relative risk = 1.7 [95% CI, 1.2 to 2.5]) and family decisional regret (144 participants; difference in means, 17 [95% CI, 5 to 29] points). Family member identification of any need was associated with greater symptoms of depression at follow-up (150 participants; difference in means of Patient Health Questionnaire–2, 0.8 [95% CI, 0.2 to 1.3] points) and worse perceived patient QOL (78 participants; difference in means, −17.1 [95% CI, −33.6 to −0.5] points).Conclusions and RelevanceIn this prospective cohort study of patients with SABI and their families, palliative care needs were common, although agreement on needs was poor between clinicians and family members. A palliative care needs checklist completed by clinicians and family members may improve communication and promote timely, targeted management of needs.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.To evaluate whether DSI is associated with incident dementia in older adults.This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05).In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

Introduction: Atrial fibrillation (AF), a well-defined ischemic stroke (IS) risk factor whose prevalence increases with age, is associated with higher stroke severity. We aimed to evaluate stroke severity and hospital mortality in a nationally representative sample of AF-related IS patients. Methods: We utilized data from the National (Nationwide) Inpatient Sample databases from 2015 - 2018 using ICD-10 diagnostic codes to identify individuals with IS and comorbid AF. The NIHSS was used to characterize stroke severity in a subset of cases after 10/1/2016. Nonparametric statistics and logistic regression analyses were conducted to evaluate associations between AF and hospital death. Results: Of the 382,758 IS cases, 99,566 (26%) had comorbid AF. AF increased linearly with age, reaching at 47% of all hospitalized IS patients 85+ years of age or older (Figure). Higher age, male sex, white race, obesity, and higher median income were associated with comorbid AF, whereas diabetes, hypertension, tobacco use, and hyperlipidemia were associated with reduced odds of comorbid AF. While 5.8% of all IS patients died during hospitalization, mortality was increased nearly two-fold in those with AF (9.0% vs. 4.6%, p Conclusion: The burden of AF in a nationally representative sample of hospitalized IS patients is substantial, present in nearly 50% of the 85+ age group. AF-related IS is more severe and more likely to be fatal. As our population ages, the prevalence of AF will only increase. Understanding the severity and fatality of AF-related IS will have profound implications for health systems and may better facilitate anticipatory guidance and AF treatment.

Introduction: Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) and prolonged P-wave terminal force in V1 (PTFV1) on 12-lead ECG are associated with increased risk of atrial fibrillation and stroke. Age is positively associated with NT-proBNP, men have lower levels than women, and Blacks have lower levels than Whites. Although both weight and height are positively related to risk of atrial fibrillation, both are negatively associated with NT-proBNP. We explored associations among these variables in patients with embolic stroke of undetermined source (ESUS). Methods: In an ongoing randomized trial of secondary stroke prevention, AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), as of 2021 August, 2616 ESUS patients were consented for the trial and screened for atrial cardiopathy with serum NT-proBNP and PTFV1. Baseline information on age, sex, race, weight, and height were used in sequential linear regression analyses to understand associations with ln(NT-proBNP) and ln(PTFV1). Results: In age-adjusted models of ln(NT-proBNP), significant negative associations were found for weight (beta -0.004, p=0.02) and height (beta -0.013, p Conclusions: In a population of patients with ESUS, associations of weight and height with NT-proBNP are confounded not by age but by sex. Key associations with NT-proBNP include age, sex, and race. In ARCADIA, understanding these associations may be important in individualizing predictions about which ESUS patients with atrial cardiopathy are most likely to benefit from apixaban over aspirin for secondary stroke prevention.

Background: Cerebrovascular complications (ischemic stroke (IS), intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH)) of infective endocarditis (IE) are common and substantially increase morbidity and mortality. We aimed to identify risk factors for stroke in a nationally representative population of hospitalized IE patients from the US. Methods: Patient hospitalizations for IE and stroke were identified using validated International Classification of Diseases 10 diagnosis codes from the Q4 2015-2018 National Inpatient Sample. We evaluated the association between demographics, known risk factors (opioid use, cardiac valve replacement, and mitral valve disease), and Elixhauser comorbidity index-defined factors with the diagnosis of stroke using logistic regression. Results: Of the 53,557 patients with a diagnosis of IE, 5,754 (10.7%) had a concurrent diagnosis of stroke (75% IS, 6.9% ICH, 4.5% SAH, 14% multiple stroke types). The mean age at IE diagnosis was 59 years; 42.3% were female; 71.8% Caucasian, 14.2% Black, 7.8% Hispanic, 2.7% Asian, and 0.8% Native American; 9.2% of patients died during hospitalization (7.5% without stroke, 23% with stroke, p Conclusion: In this large, nationally representative sample of hospitalized IE patients, comorbidities independently associated with higher odds of stroke included mitral valve disease, metastatic cancer, coagulopathy, weight loss, and electrolyte disorders. Detailed clinical data, not available from this administrative data set, may allow better prediction of stroke, but our findings may suggest areas for additional research.

Background: Recent data suggest biomarkers of atrial cardiopathy (ACP) can potentially identify a subset of patients with cryptogenic stroke who may benefit from anticoagulation. However, the specificity of these markers for atrial disease and their independence from measures of more global cardiac dysfunction remain unclear. We hypothesized that biomarkers of ACP collectively reflect left atrial pathology and are not strongly affected by coexisting left ventricular dysfunction. Methods: ARCADIA is an ongoing multicenter trial comparing standard dose apixaban to aspirin therapy in patients with Embolic Stroke of Undetermined Source (ESUS) with ACP, defined as either N-terminal pro-brain natriuretic peptide [NT-proBNP] > 250 pg/mL; P wave terminal force velocity on ECG lead V1 [PTFV1] > 5000 μV*ms; or echocardiographic left atrial diameter index [LADI] ≥ 3 cm/m 2 . Pearson correlation coefficients and descriptive statistics were used to examine the relationship between left ventricular ejection fraction (LVEF) and ACP biomarkers. Results: Among 2,616 ESUS patients screened, 1,046 met ≥ 1 ACP criterion (665 BNP, 531 PTFV1, 14 LADI). Patients with ACP were older (68 ± 11 vs 64 ± 10 years) and 54.5% were women. The great majority (84%) of subjects with ACP had normal LVEF (≥55%). Among them there was no correlation between LVEF and NT-proBNP (r= -0.01, P= 0.5) or PTFV1 (r=0.002, P=0.9). In patients with abnormal LVEF, there was a strong inverse correlation of LVEF with NT-proBNP (r=-0.4, P250 pg/mL and measured LVEF (n=435), only 19% had abnormal LVEF. Compared to patients with abnormal NT-proBNP alone, those with both abnormal NT-proBNP and abnormal LVEF were younger (66.4 ± 11.0 vs. 71.6 ± 11.0, P Conclusion: Left ventricular dysfunction (EF ≤ 55%) is uncommon in patients with ACP as defined in ARCADIA. These findings suggest that, among patients with ESUS, atrial cardiopathy may represent a separate entity from LV dysfunction.

Background: Increased carotid intima-media thickness (cIMT) and moderate-severe carotid artery atherosclerosis (CAA≥50%) are associated with increased risk of stroke. We evaluated proteomic determinants of increased cIMT and CAA≥50% in the population-based Cardiovascular Health Study (CHS). Methods: Eligible participants underwent carotid artery ultrasound and aptamer-based SOMAScan platform measurement of 1298 serum proteins from the concurrent study visit. cIMT was defined as the average of the standardized values of the maximal common carotid artery IMT and maximal internal carotid artery IMT. CAA≥50% was defined as carotid plaque resulting in ≥50% luminal stenosis. The relationship between each log-normalized protein concentration with cIMT and CAA≥50% was modeled separately using multivariable linear regression and logistic regression, respectively, adjusting for demographics, estimated glomerular filtration rate (eGFR), and CAA risk factors. Bonferroni correction, based on the number of principal components that explained 95% of the protein concentration variance in CHS participants, was employed to account for multiple hypothesis testing, yielding a p -value for significance of -5 (0.05/661). Results: For eligible participants (n=2783), mean age was 74.4 ± 4.9 years, 39.5% were men, and 15.8% were Black. After adjustment for demographics, eGFR, and CAA risk factors, 13 proteins were independently associated with increased cIMT (Table). The magnitude and direction of the associations were similar in subgroups defined by sex and race. Three proteins were associated with CAA≥50%, after adjusting for eGFR and demographics (Table); however, associations were no longer significant after adjusting for CAA risk factors. Conclusion: Multiple novel serum proteins - implicated in extracellular matrix remodeling, systemic inflammation, and coagulation - were independently associated with increased cIMT in a cohort of older adults.

Introduction: Socioeconomic status (SES) is an upstream determinant of cerebrovascular disease comorbidities and subsequently ischemic stroke. Here we examined the association of SES and modifiable ischemic stroke risk factors. Methods: Hospitalized ischemic stroke patient data from 10/1/2015 - 12/31/2018 was obtained via the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS). Demographic characteristics of age, sex, race, US region, SES (defined as median household income range by zip code) and ischemic stroke risk factors of atrial fibrillation/flutter (AF), type II diabetes (DM), hypertension (HTN), hyperlipidemia (HLD), tobacco use, and obesity were identified using published ICD-10 codes. Multivariable logistic regression was used to assess each condition individually and identify which comorbidities were associated with specific socioeconomic quartiles (Q1, Q4) when adjusted for the abovementioned demographics. Results: Of the 382,734 adult ischemic stroke patients identified, mean age was 70 ±14.2 years and 50.3% were female. Socioeconomic status quartiles ranged from $73,000 (Q4); 30.9% of ischemic stroke patients were in SES Q1 (vs 19.1% in SES Q4). Patients in Q1 experienced ischemic stroke at a younger age (67.9 ±14.1) as compared to patients in Q4 (72.4 ±14), p Conclusion: Lower SES was associated with higher odds of specific ischemic stroke risk factors. While the etiology of the risk factor variance is beyond the scope of current data analysis, the cause is likely multifactorial and influenced by underlying detection bias, income inequity, and level of education/health literacy. Further research and subgroup analysis is warranted as it may impact future preventative measures and treatment protocols.

Introduction: Creatine kinase BB isoenzyme (CK-BB) levels in CSF after cardiac arrest (CA) have been shown to predict never awakening though have not been evaluated in patients treated with therapeutic hypothermia (TH). Clinically, CSF CK-BB is tested in those who have not already awakened and are suspected of having a poor prognosis. We aimed to evaluate CSF CK-BB as a prognostic biomarker in the era of TH. Methods: We performed a retrospective cohort study at a single institution of CA patients admitted between 2010 and 2020 and with CSF CK-BB assayed between 36 and 84 hours after CA. We examined the proportion of patients who awakened at hospital discharge and latest follow up in the electronic health record for various CSF CK-BB thresholds. We examined concordance and additive value somatosensory evoked potentials (SSEP). Awakening was defined as following commands or having comprehensible speech. Results: Among 214 eligible patients, mean age was 55 ± 15 years, 72% were male, 33% were non-white, 17% had initial ventricular fibrillation or tachycardia, 90% were out-of-hospital CA, and 83% had TH. A total of 19 (9%) awoke at a mean of 22 ± 28 days. Two patients in a vegetative state at discharge later awoke at 73 (CSF CK-BB 163 U/L) and 101 days (228 U/L). A CSF CK-BB cut-off of ≥ 230 U/L predicted never awakening with a specificity of 100% (binomial 95% CI 82-100%) and a sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent SSEP, the specificity remained 100% while the sensitivity increased to 80% (95% CI 73-85%). Results were similar after excluding 165 (77%) who had withdrawal of life-sustaining treatment. Discordant findings among 149 patients who had both studies were seen in 13 (9%) with intact SSEP bilaterally but CSF CK-BB ≥ 230 U/L and in 20 (13%) with absent SSEP bilaterally but CSF CK-BB < 230, none of whom awoke. Conclusion: CSF CK-BB levels accurately predict never awakening among CA survivors treated with TH. As part of multimodal prognostic testing with SSEP, the CSF CK-BB cutoff of 230 can optimize sensitivity while maintaining a specificity of 100%. These results are susceptible to a self-fulfilling prophecy, and specificity has a large confidence interval because only a small number of eligible patients awakened.

Background: Whether HDL (high-density lipoprotein) is associated with risk of vascular brain injury is unclear. HDL is comprised of many apo (apolipoprotein) species, creating distinct subtypes of HDL. Methods: We utilized sandwich ELISA to determine HDL subspecies from plasma collected in 1998/1999 from 2001 CHS (Cardiovascular Health Study) participants (mean age, 80 years). Results: In cross-sectional analyses, participants with higher apoA1 in plasma and lower apoE in HDL were less likely to have prevalent covert magnetic resonance imaging–defined infarcts: odds ratio for apoA1 Q4 versus Q1, 0.68 (95% CI, 0.50–0.93), and odds ratio for apoE Q4 versus Q1, 1.36 (95% CI, 1.01–1.84). Similarly, apoA1 in the subspecies of HDL that lacked apoC3, apoJ, or apoE was inversely related to covert infarcts, and apoE in the subspecies of HDL that lacked apoC3 or apoJ was directly related to covert infarcts in prospective analyses. In contrast, the concentrations of apoA1 and apoE in the complementary subspecies of HDL that contained these apos were unrelated to covert infarcts. Patterns of associations between incident overt ischemic stroke and apoA1, apoE, and apoA1 and apoE in subspecies of HDL were similar to those observed for covert infarcts but less pronounced. Conclusions: This study highlights HDL subspecies defined by apo content as relevant biomarkers of covert and overt vascular brain injury.

Supranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of supranormal left ventricular ejection fraction (LVEF)-assessed by cardiac magnetic resonance (CMR)-in healthy, community-dwelling individuals is unknown.The purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD.Participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index.The study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 [95% CI: 1.01-1.60], P = 0.04; DHS: HR = 1.72 [95% CI: 1.05-2.79], P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume.Among community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume.

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed >24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and trans fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996–1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)‐6 polyunsaturated, n‐3 polyunsaturated, and trans fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5‐year follow‐up period. Total n‐3 (hazard ratio [HR], 0.77 [95% CI, 0.61–0.97]) and n‐6 (HR, 1.32 [95% CI, 1.01–1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo‐γ‐linolenic acid (20:3n‐6) was associated with higher risk (HR, 1.29 [95% CI, 1.02–1.63]), whereas cis ‐7‐hexadecenoic acid (16:1n‐9 c ) and arachidonic acid (20:4n‐6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47–0.97]; HR, 0.81 [95% CI. 0.65–1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n‐3 subclass and dihomo‐γ‐linolenic acid are diet derived and may be potential biomarkers for total stroke risk.

Effective shared decision-making relies on some degree of alignment between families and the medical team regarding a patient's likelihood of recovery. Patients with severe acute brain injury (SABI) are often unable to participate in decisions, and therefore family members make decisions on their behalf. The goal of this study was to evaluate agreement between prognostic predictions by families, physicians, and nurses of patients with SABI regarding their likelihood of regaining independence and to measure each group's prediction accuracy.This observational cohort study, conducted from 01/2018 to 07/2020, was based in the neuroscience and medical/cardiac intensive care units of a single center. Patient eligibility included a diagnosis of SABI-specifically stroke, traumatic brain injury, or hypoxic ischemic encephalopathy-and a Glasgow Coma Scale ≤ 12 after hospital day 2. At enrollment, families, physicians, and nurses were asked separately to predict a patient's likelihood of recovering to independence within 6 months on a 0-100 scale, regardless of whether a formal family meeting had occurred. True outcome was based on modified Rankin Scale assessment through a family report or medical chart review. Prognostic agreement was measured by (1) intraclass correlation coefficient; (2) mean group prediction comparisons using paired Student's t-tests; and (3) prevalence of concordance, defined as an absolute difference of less than 20 percentage points between predictions. Accuracy for each group was measured by calculating the area under a receiver operating characteristic curve (C statistic) and compared by using DeLong's test.Data were collected from 222 patients and families, 45 physicians, and 103 nurses. Complete data on agreement and accuracy were available for 187 and 177 patients, respectively. The intraclass correlation coefficient, in which 1 indicates perfect correlation and 0 indicates no correlation, was 0.49 for physician-family pairs, 0.40 for family-nurse pairs, and 0.66 for physician-nurse pairs. The difference in mean predictions between families and physicians was 23.5 percentage points (p 0.001), 25.4 between families and nurses (p 0.001), and 1.9 between physicians and nurses (p = 0.38). Prevalence of concordance was 39.6% for family-physician pairs, 30.0% for family-nurse pairs, and 56.2% for physician-nurse pairs. The C statistic for prediction accuracy was 0.65 for families, 0.82 for physicians, and 0.76 for nurses. The p values for differences in C statistics were 0.05 for family-physician and family-nurse groups and 0.18 for physician-nurse groups.For patients with SABI, agreement in predictions between families, physicians, and nurses regarding likelihood of recovery is poor. Accuracy appears higher for physicians and nurses compared with families, with no significant difference between physicians and nurses.

Clonal hematopoiesis of indeterminate potential (CHIP) occurs when hematopoietic stem cells (HSCs) acquire a mutation, most commonly a null variant in TET2 or DNMT3A, that confers a selective advantage. Blood cancers may result if additional cooperating mutations are acquired. However, CHIP may also cause atherosclerosis and other inflammatory diseases because these mutations alter the function or development of effector immune cells derived from the HSCs. Genome-wide association studies have implicated microglia, the resident myeloid cells in the brain, as key players in the biology of Alzheimer's disease (AD). Here, we asked whether CHIP associated with AD dementia or neuropathologic change, and whether mutant marrow-derived cells could be found in the brains of CHIP carriers. To test for an association, we used data from the Trans-omics for Precision Medicine project (TOPMed) and the Alzheimer's Disease Sequencing Project (ADSP), where whole genome or exome sequencing data as well as AD phenotype data was available on 5,730 persons. TOPMed contained population-based cohorts unselected for AD, while ADSP was a case-control study for AD. We surprisingly discovered that the presence of CHIP was associated with a reduced risk of AD dementia in both projects (fixed-effects meta-analysis odds ratio 0.64, p = 3.0 x 10-5, adjusted for age, sex and APOE genotype) (Figure 1). The protective effect of CHIP was strongest in those with APOE e3 or e4 alleles, but not seen in those with APOE e2 allele. No substantial differences in AD risk were seen based on mutated driver gene. In addition, the presence of CHIP was associated with a reduced burden of amyloid plaques and neurofibrillary tangles in the brains of those without dementia. In sum, our human genetic analyses indicated that CHIP was robustly associated with protection from AD dementia and AD-related neuropathologic changes. A causal link between CHIP and AD would be strengthened by finding the mutated cells infiltrating the brain. However, it is presumed that bone marrow progenitors have minimal contribution to the adult microglial pool. To determine if the mutations seen in the blood of CHIP carriers could also be found in the brain, we obtained 8 occipital cortex samples from autopsy of donors with CHIP, 6 of whom were cognitively normal at the time of death. The 8 CHIP carriers had mutations in DNMT3A, TET2, ASXL1, SF3B1, and GNB1 with the highest frequency in DNMT3A and TET2, which is representative of the relative proportion of these mutations in the general population. We detected the CHIP somatic variants in the microglia enriched (NeuN- c-Maf+) fraction of brain in 7 out of 8 CHIP carriers, with a VAF ranging from 0.02 to 0.28 (representing 4% to 56% of nuclei) (Figure 2), but at low levels or absent in the other fractions of brain. We then performed single-cell ATAC-sequencing on brain samples from 2 CHIP carriers and 1 control to specify the cellular population harboring CHIP mutations. This revealed that hematopoietic cells in the 3 samples formed a single myeloid cluster that had accessible chromatin at the microglia marker genes TMEM119, P2RY12, and SALL1, but not in genes specific to monocytes or dendritic cells. We further determined that the proportion of cells in this cluster bearing the CHIP mutations ranged from ~40-80% in these two samples, indicating widespread replacement of the endogenous microglial pool by mutant cells. We show here that, unexpectedly, the presence of CHIP is associated with protection from AD dementia. CHIP is also associated with lower levels of neuritic plaques and neurofibrillary tangles in those without dementia, indicating a possible modulating effect of CHIP on the underlying pathophysiology of AD. Consistent with this hypothesis, we also detect substantial infiltration of brain by marrow-derived mutant cells which adopt a microglial-like phenotype. We speculate that the mutations associated with CHIP confer circulating precursor cells with an enhanced ability to engraft in the brain, to differentiate into microglia once engrafted, and/or to clonally expand relative to unmutated cells in the brain microenvironment. These non-mutually exclusive possibilities could provide protection from AD by supplementing the phagocytic capacity of the endogenous microglial system during aging. Figure 1 Figure 1. Disclosures Jaiswal: Novartis: Consultancy, Honoraria; Foresite Labs: Consultancy; Genentech: Consultancy, Honoraria; AVRO Bio: Consultancy, Honoraria; Caylo: Current holder of stock options in a privately-held company.