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Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. Eligible patients were aged 30–80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared. In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

Background and Purpose: To determine whether obstructive sleep apnea (OSA) is associated with intracerebral hemorrhage (ICH) risk, we assessed premorbid OSA exposure of patients with nontraumatic ICH and matched controls. Methods: Ethnic/Racial Variations of Intracerebral Hemorrhage is a multicenter, case-control study evaluating risk factors for ICH that recruited 3000 cases with ICH and 3000 controls. OSA status was ascertained using the Berlin Questionnaire as a surrogate for premorbid OSA. We performed logistic regression analyses to evaluate the association between OSA and ICH. Results: Two thousand and sixty-four (71%) cases and 1516 (52%) controls were classified as having OSA by the Berlin Questionnaire. Cases with OSA were significantly more likely to be male and have hypertension, heart disease, hyperlipidemia, and higher body mass index compared with those without OSA. OSA was more common among cases compared with controls (71% versus 52%, odds ratio, 2.28 [95% CI, 2.05–2.55]). In a multivariable logistic regression model, OSA was associated with increased risk for ICH (odds ratio, 1.47 [95% CI, 1.29–1.67]). Conclusions: OSA is a risk factor for ICH.

Introduction The risk of intracerebral haemorrhage (ICH) associated with hypertension (HTN) is well documented. While the prevalence of HTN increases with age, the greatest odds ratio (OR) for HTN as a risk for ischemic stroke is at an early age. We sought to evaluate if the risk for ICH from HTN was higher in the youngest patients of each race. Patients and methods The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Participants were divided into age groups based on race-specific quartiles. Cases in each race/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). The probability of ICH among cases and controls for each race were compared against independent variables of HTN, quartile of age and interaction of quartile and age also using logistic regression. Results Overall, 2033 non-lobar ICH cases and 2060 controls, and 913 lobar ICH cases with 927 controls were included. ORs were highest in the youngest age quartile for non-lobar haemorrhage for blacks and Hispanics and highest in the youngest quartile for lobar haemorrhage for all races. The formal test of interaction between age and HTN was significant in all races for all locations with the exception of lobar ICH in whites (p = 0.2935). Discussion Hypertension is a strong independent risk factor for ICH irrespective of location among persons of younger age, consistent with the hypothesis that first exposure to HTN is a particularly sensitive time for all locations of ICH.

Background and Purpose: In intracerebral hemorrhage (ICH), preexisting cognitive impairment has been identified as a risk factor for increased mortality and morbidity. However, previous studies examined predominantly White populations; therefore, the prevalence and effect of preICH cognitive impairment has not been studied in a multiethnic cohort. This limits the generalizability of previous findings. We sought to investigate the role of preexisting cognitive impairment in a multiethnic population on short-term mortality and functional outcomes after ICH. Methods: Patients with ICH were prospectively enrolled as cases for the GERFHS III (Genetic and Environmental Risk Factors for Hemorrhagic Stroke) Study and the Ethnic/Racial Variations of ICH (ERICH) Study. Cognitive impairment before ICH was defined as positive history of dementia or treatment with donepezil, galantamine, memantine, or rivastigmine on chart abstraction or baseline interview. Specific outcomes—modified Rankin Scale score at 3 months (0–2 versus ≥3), Barthel Index score ( Results: Of the 3537 cases of ICH, 304 patients had cognitive impairment predating ICH. Cognitively impaired subjects were more likely to experience withdrawal of care during hospitalization, and for survivors, greater disability (modified Rankin Scale score of ≥3) and lower Barthel scores after ICH. After propensity score matching, preexisting cognitive impairment was associated with a lower modified Rankin Scale at 3 months in the White, Black, and Hispanic subgroups. Conclusions: Preexisting cognitive impairment was associated with loss of independence 3-month post-ICH, when matching for risk factors of cognitive impairment, in the White, Black, and Hispanic subgroups. This suggests that preexisting cognitive impairment has a negative effect in obtaining functional independence following ICH, irrespective of race/ethnicity.

Background In patients with spontaneous intracerebral hemorrhage (ICH), pre-hospital markers of disease severity might be useful to potentially triage patients to undergo early interventions. Objective Here, we tested whether loss of consciousness (LOC) at the onset of ICH is associated with intraventricular hemorrhage (IVH) on brain computed tomography (CT). Methods Among 3000 ICH cases from ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage study, NS069763), we included patients with complete ICH/IVH volumetric CT measurements and excluded those with seizures at ICH onset. Trained investigators extracted data from medical charts. Mental status at symptom onset (categorized as alert/oriented, alert/confused, drowsy/somnolent, coma/unresponsive/posturing) and 3-month disability (modified Rankin score, mRS) were assessed through standardized interviews of participants or dedicated proxies. We used logistic regression and mediation analysis to assess relationships between LOC, IVH, and unfavorable outcome (mRS 4–6). Results Two thousand seven hundred and twenty-four patients met inclusion criteria. Median admission Glasgow Coma Score was 15 (interquartile range 11–15). 46% had IVH on admission or follow-up CT. Patients with LOC (mental status: coma/unresponsive, n = 352) compared to those without LOC (all other mental status, n = 2372) were younger (60 vs. 62 years, p = 0.005) and had greater IVH frequency (77 vs. 41%, p p p p Conclusion LOC at ICH onset may be a useful pre-hospital marker to identify patients at risk of having or developing IVH.

INTRODUCTION: We sought to determine the feasibility and validity of estimating post-stroke outcomes using information available in the electronic medical record (EMR) through comparison with outcomes obtained from telephone interviews. METHODS: The Greater Cincinnati Northern Kentucky Stroke Study is a retrospective population-based epidemiology study that ascertains hospitalized strokes in the study region. As a sub-study, we identified all ischemic stroke patients who presented to a system of 4 hospitals during the study period 1/1/2015–12/31/2015 and were discharged alive. Enrolled subjects (or proxies for cognitively-disabled patients) were contacted by telephone at 3 and 6 months post-stroke to determine current place of residence and two functional outcomes—the modified Rankin Score (mRS) and the EuroQol (EQ-5D). Concurrently, the lead study coordinator, blinded to the telephone assessment outcomes, reviewed all available EMRs to estimate outcome status. Agreement between outcomes estimated from the EMR with “gold-standard” data obtained from telephone interviews was analyzed using the kappa statistic or interclass correlation (ICC), as appropriate. For each outcome, EMR-determined results were evaluated for added value beyond the information readily available from the stroke hospital stay. RESULTS: Of 381 ischemic strokes identified, 294 (median [IQR] age 70 [60–79] years, 4% black, 52% female) were interviewed post-stroke. Agreement between EMR and telephone for 3-month residence was very good (kappa=0.84, 95% CI 0.74–0.94), good for mRS (weighted kappa=0.75, 95% CI 0.70–0.80), and good for EQ-5D (ICC=0.74, 95% CI 0.68–0.79). Similar results were observed at 6 months post stroke. At both 3 and 6 months post stroke, EMR-determined outcomes added value in predicting the gold standard telephone results beyond the information available from the stroke hospitalization; the added fraction of new information ranged from 0.25 to 0.59. CONCLUSIONS: Determining place of residence, mRS, and EQ-5D outcomes derived from information recorded in the EMR post-stroke, without patient contact, is feasible and has good agreement with data obtained from direct contact. However, we note that the level of agreement for mRS and EQ-5D was higher for proxy interviews and that the EMR often reflects health care providers’ judgments that tend to overestimate disability and underestimate quality of life.

ObjectiveTo test the hypothesis that thrombogenic atrial cardiopathy may be relevant to stroke-related racial disparities, we compared atrial cardiopathy phenotypes between Black vs White patients with ischemic stroke.MethodsWe assessed markers of atrial cardiopathy in the Greater Cincinnati/Northern Kentucky Stroke Study, a study of stroke incidence in a population of 1.3 million. We obtained ECGs and reports of echocardiograms performed during evaluation of stroke during the 2010/2015 study periods. Patients with atrial fibrillation (AF) or flutter (AFL) were excluded. Investigators blinded to patients' characteristics measured P-wave terminal force in ECG lead V1 (PTFV1), a marker of left atrial fibrosis and impaired interatrial conduction, and abstracted left atrial diameter from echocardiogram reports. Linear regression was used to examine the association between race and atrial cardiopathy markers after adjustment for demographics, body mass index, and vascular comorbidities.ResultsAmong 3,426 ischemic stroke cases in Black or White patients without AF/AFL, 2,391 had a left atrial diameter measurement (mean, 3.65 ± 0.70 cm). Black race was associated with smaller left atrial diameter in unadjusted (β coefficient, −0.11; 95% confidence interval [CI], −0.17 to −0.05) and adjusted (β, −0.15; 95% CI, −0.21 to −0.09) models. PTFV1 measurements were available in 3,209 patients (mean, 3,434 ± 2,525 μV*ms). Black race was associated with greater PTFV1 in unadjusted (β, 1.59; 95% CI, 1.21–1.97) and adjusted (β, 1.45; 95% CI, 1.00–1.80) models.ConclusionsWe found systematic Black–White racial differences in left atrial structure and pathophysiology in a population-based sample of patients with ischemic stroke.Classification of EvidenceThis study provides Class II evidence that atrial cardiopathy phenotypes differ in Black people with acute stroke compared to White people.

ObjectiveTo examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS).MethodsFor the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool–based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes.ResultsPatients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all p < 0.001). Median WMHv in all patients with AIS was 5.86 cm3 (interquartile range 2.18–14.61 cm3) and differed significantly across CCS subtypes (p < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all p < 0.001), and diabetes mellitus (p = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes (p < 0.001).ConclusionIn this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke.

OBJECTIVEThe utility of ICP monitoring and its benefit with respect to outcomes after ICH is unknown. The aim of this study was to compare intracerebral hemorrhage (ICH) outcomes in patients who underwent intracranial pressure (ICP) monitoring to those who were managed by care-guided imaging and/or clinical examination alone.METHODSThis was a retrospective analysis of data from the Ethnic/Racial variations of Intracerebral Hemorrhage (ERICH) study between 2010 and 2015. ICH patients who underwent ICP monitoring were propensity-score matched, in a 1:1 ratio, to those who did not undergo ICP monitoring. The primary outcome was 90-day mortality. Secondary outcomes were in-hospital mortality, hyperosmolar therapy use, ICH evacuation, length of hospital stay, and 90-day modified Rankin Scale (mRS) score, excellent outcome (mRS score 0–1), good outcome (mRS score 0–2), Barthel Index, and health-related quality of life (HRQoL; measured by EQ-5D and EQ-5D visual analog scale [VAS] scores). A secondary analysis for patients without intraventricular hemorrhage was performed.RESULTSThe ICP and no ICP monitoring cohorts comprised 566 and 2434 patients, respectively. The matched cohorts comprised 420 patients each. The 90-day and in-hospital mortality rates were similar between the matched cohorts. Shift analysis of 90-day mRS favored no ICP monitoring (p < 0.001). The rates of excellent (p < 0.001) and good (p < 0.001) outcome, Barthel Index (p < 0.001), EQ-5D score (p = 0.026), and EQ-5D VAS score (p = 0.004) at 90 days were lower in the matched ICP monitoring cohort. Rates of mannitol use (p < 0.001), hypertonic saline use (p < 0.001), ICH evacuation (p < 0.001), and infection (p = 0.001) were higher, and length of hospital stay (p < 0.001) was longer in the matched ICP monitoring cohort. In the secondary analysis, the matched cohorts comprised 111 patients each. ICP monitoring had a lower rate of 90-day mortality (p = 0.041). Shift analysis of 90-day mRS, Barthel Index, and HRQoL metrics were comparable between the matched cohorts.CONCLUSIONSThe findings of this study do not support the routine utilization of ICP monitoring in patients with ICH.

OBJECTIVE:To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). PATIENTS AND METHODS:This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. RESULTS:Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm3) was associated with age (β -0.3 [per 14.4 years]), male sex (β 1.0), and prior stroke (β -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (β -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. CONCLUSION:Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery.

Background and Purpose— Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre–intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome. Methods— Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed “continuous”), and post-ICH only (termed “new”). Using multivariable modeling, associations were sought between pre-ICH SSRI use and ICH risk in the case-control set, and associations between post-ICH SSRI use and 3-month outcome were analyzed in the ICH case set. Exploratory analyses sought to assess influence of race/ethnicity in models. Results— The final study cohort consisted of 2287 ICH cases and 2895 controls. Pre-ICH SSRI use was not associated with ICH risk (odds ratio, 0.824 [95% CI, 0.632–1.074]) nor potentiation of ICH risk with anticoagulant or antiplatelet use. New post-ICH SSRI use was associated with unfavorable modified Rankin Scale score at 3 months after ICH (odds ratio, 1.673 [95% CI, 1.162–2.408]; P =0.006) in multivariable analyses. Additional propensity score analysis indicated a similar trend but did not reach statistical significance ( P =0.107). When stratified by race/ethnicity, multivariable modeling demonstrated reduced ICH risk with pre-ICH SSRI use in Hispanics (odds ratio, 0.513 [95% CI, 0.301–0.875]; P =0.014), but not non-Hispanic whites or blacks, and no associations between post-ICH SSRI use and 3-month outcome in any racial/ethnic group. Conclusions— In a large multiethnic cohort, pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcome after ICH. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01202864.

Background and Purpose— Volumes of hemorrhage and perihematomal edema (PHE) are well-established biomarkers of primary and secondary injury, respectively, in spontaneous intracerebral hemorrhage. An automated imaging pipeline capable of accurately and rapidly quantifying these biomarkers would facilitate large cohort studies evaluating underlying mechanisms of injury. Methods— Regions of hemorrhage and PHE were manually delineated on computed tomography scans of patients enrolled in 2 intracerebral hemorrhage studies. Manual ground-truth masks from the first cohort were used to train a fully convolutional neural network to segment images into hemorrhage and PHE. The primary outcome was automated-versus-human concordance in hemorrhage and PHE volumes. The secondary outcome was voxel-by-voxel overlap of segmentations, quantified by the Dice similarity coefficient (DSC). Algorithm performance was validated on 84 scans from the second study. Results— Two hundred twenty-four scans from 124 patients with supratentorial intracerebral hemorrhage were used for algorithm derivation. Median volumes were 18 mL (interquartile range, 8–43) for hemorrhage and 12 mL (interquartile range, 5–30) for PHE. Concordance was excellent (0.96) for automated quantification of hemorrhage and good (0.81) for PHE, with DSC of 0.90 (interquartile range, 0.85–0.93) and 0.54 (0.39–0.65), respectively. External validation confirmed algorithm accuracy for hemorrhage (concordance 0.98, DSC 0.90) and PHE (concordance 0.90, DSC 0.55). This was comparable with the consistency observed between 2 human raters (DSC 0.90 for hemorrhage, 0.57 for PHE). Conclusions— We have developed a deep learning-based imaging algorithm capable of accurately measuring hemorrhage and PHE volumes. Rapid and consistent automated biomarker quantification may accelerate powerful and precise studies of disease biology in large cohorts of intracerebral hemorrhage patients.

ObjectivesWe investigated the predictors of functional outcome in young patients enrolled in a multiethnic study of intracerebral hemorrhage (ICH).MethodsThe Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study is a prospective multicenter study of ICH among adult (age ≥18 years) non-Hispanic white, non-Hispanic black, and Hispanic participants. The study recruited 1,000 participants per racial/ethnic group. The present study utilized the subset of ERICH participants aged ResultsOf the 3,000 patients with ICH enrolled in ERICH, 418 were studied (mean age 43 years, 69% male), of whom 48 (12%) were white, 173 (41%) were black, and 197 (47%) were Hispanic. For supratentorial ICH, black participants (odds ratio [OR], 0.42; p = 0.046) and Hispanic participants (OR, 0.34; p = 0.01) had better outcomes than white participants after adjustment for other factors associated with poor outcome: age, baseline disability, admission blood pressure, admission Glasgow Coma Scale score, ICH volume, deep ICH location, and intraventricular extension.ConclusionsIn young patients with supratentorial ICH, black and Hispanic race/ethnicity is associated with better functional outcomes, compared with white race. Additional studies are needed to identify the biological and social mediators of this association.

ObjectiveTo estimate the risk of intracerebral hemorrhage (ICH) recurrence in a large, diverse, US-based population and to identify racial/ethnic and socioeconomic subgroups at higher risk.MethodsWe performed a longitudinal analysis of prospectively collected claims data from all hospitalizations in nonfederal California hospitals between 2005 and 2011. We used validated diagnosis codes to identify nontraumatic ICH and our primary outcome of recurrent ICH. California residents who survived to discharge were included. We used log-rank tests for unadjusted analyses of survival across racial/ethnic groups and multivariable Cox proportional hazards regression to determine factors associated with risk of recurrence after adjusting for potential confounders.ResultsWe identified 31,355 California residents with first-recorded ICH who survived to discharge, of whom 15,548 (50%) were white, 6,174 (20%) were Hispanic, 4,205 (14%) were Asian, and 2,772 (9%) were black. There were 1,330 recurrences (4.1%) over a median follow-up of 2.9 years (interquartile range 3.8). The 1-year recurrence rate was 3.0% (95% confidence interval [CI] 2.8%–3.2%). In multivariable analysis, black participants (hazard ratio [HR] 1.22; 95% CI 1.01–1.48; p = 0.04) and Asian participants (HR 1.29; 95% CI 1.10–1.50; p = 0.001) had a higher risk of recurrence than white participants. Private insurance was associated with a significant reduction in risk compared to patients with Medicare (HR 0.60; 95% CI 0.50–0.73; p < 0.001), with consistent estimates across racial/ethnic groups.ConclusionsBlack and Asian patients had a higher risk of ICH recurrence than white patients, whereas private insurance was associated with reduced risk compared to those with Medicare. Further research is needed to determine the drivers of these disparities.

Background and Objective The aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH). Methods CSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of leukoaraiosis and cerebral atrophy using visual rating scales. The associations of leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing. Results A total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0–25.3) mL. IVH was detected in 971 patients (38%). Neither leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend P Conclusions Leukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.

ObjectiveTo examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways.MethodsMR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, spatially normalized and parcellated into atlas-defined brain regions. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within a purpose-built machine learning and Bayesian regression framework. In particular, interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for the covariates age, age2, sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts.ResultsA total of 928 AIS patients contributed to stroke severity analyses (mean age: 64.8(14.5), 40% women), 698 patients to functional outcome analyses (mean age: 65.9(14.7), 41% women). Individual stroke lesions were represented in five anatomically distinct left-hemispheric and five right-hemispheric lesion patterns. Across all patients, acute stroke severity was substantially explained by three of these patterns, that were particularly focused on bilateral subcortical and left-hemispherically pronounced cortical regions. In high WMH burden patients, two lesion patterns consistently emerged as more pronounced in case of stroke severity: the first pattern was centered on left-hemispheric insular, opercular and inferior frontal regions, while the second pattern combined right-hemispheric temporo-parietal regions. Bilateral subcortical regions were most relevant in explaining long term unfavorable outcome. No WMH-specific lesion patterns of functional outcomes were substantiated. However, a higher overall WMH burden was associated with higher odds of unfavorable outcomes.ConclusionsHigher WMH burden increases stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). These findings may contribute to augment stroke outcome predictions and motivate a WMH burden and stroke lesion pattern-specific clinical management of AIS patients.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological brain age. We here first examine whether radiomics analysis of the texture of brain T2-FLAIR MRI images can be used to predict brain age in stroke patients. We then assess the clinical determinants of accelerated brain aging and, finally, its impact on post-stroke functional outcomes. Leveraging a multisite cohort of 4,163 ischemic stroke patients, we show that older-appearing patients have more hypertension, diabetes mellitus, prior strokes, and smoking history and are more likely to develop worse post-stroke outcomes than their younger-appearing counterparts. Our results strengthen the importance of preventive medicine for maintaining brain health in stroke patients as they age and suggest a novel methodology to capture previously undescribed prognostic information available on commonly acquired MRI sequences during routine stroke care.

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health. NIH-NINDS (MRI-GENIE: R01NS086905 - PI NR; K23NS064052, R01NS082285 - NR; SiGN: U01 NS069208 - JR, SK; R01NS059775, R01NS063925, R01NS082285, P50NS051343, R01NS086905, U01 NS069208 - OW); NIH NIBIB (NAC P41EB015902 PG, U01NS030678 Kissela, Kleindorfer; EB015325 OW); ISGS (R01NS423733 P.I. JM, Swedish Heart and Lung Foundation, Lund University, Region Skåne, the Freemasons Lodge of Instruction Eos Lund, Skåne University Hospital, the Foundation of Färs &Frosta (One of Sparbanken Skånes ownership Foundations), and the Swedish Stroke Association - AL, Swedish Research Council and the Swedish Heart and Lung Foundation, the Swedish State under the ALF agreement CJ, Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (Funding for Research in Health PI051737, PI10/02064, PI12/01238 and PI15/00451 JJ-C), Fondos FEDER/EDRF Red de Investigación Cardiovascular (RD12/0042/0020 JJ-C), Fundació la Marató TV3 (76/C/2011 - JJ-C) and Recercaixa13 (JJ086116 JJ-C), Wistron Corporation (PG); The European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 753896 - MS; RL is a senior clinical investigator of FWO Flanders; MB was supported by the ISITE-ULNE Fundation, the Société Française de Neuroradiologie, the Société Française de Radiologie, the Thérèse and René Planiol Fundation; ME was supported by the American Academy of Neurology and MGH Executive Council on Research; TT was supported by the Helsinki University Central Hospital, Sigrid Juselius Foundation, Sahlgrenska University Hospital, and University of Gothenburg. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article of the decision to submit it for publication.

Key Points Question Does the prevalence and burden of risk factors for lobar and nonlobar intracerebral hemorrhage (ICH) differ among Black, Hispanic, and White populations? Findings In this case-control study of 3000 cases of ICH among Black, Hispanic, and White patients, the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E, were associated with lobar ICH in White but not Black and Hispanic patients; hypertension was a risk factor for both lobar and nonlobar ICH in all groups; and the mean age for ICH among Black and Hispanic patients was more than 10 years younger than that of their White counterparts. Black and Hispanic patients had a higher attributable risk percentage for treated or untreated hypertension and lack of health insurance than White patients. Meaning These findings suggest that potentially modifiable risk factors and social determinants of health are important contributors to the disproportionate ICH burden experienced by Black and Hispanic populations., This case-control study examines the prevalence, odds, and population attributable risk for established and novel risk factors for intracerebral hemorrhage, stratified by intracerebral hemorrhage location and racial/ethnic group., Importance Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations. Objective To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group. Design, Setting, and Participants The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020. Main Outcomes and Measures Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location. Results There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals. Conclusions and Relevance This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.

ObjectiveNeuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.MethodsWe analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA).ResultsRadiomic features were predictive of WMH burden (R2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1–6 < 0.001, p-valueCV7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes.ConclusionRadiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients’ brain health.

Objectives Population-level estimates of the median intracerebral hemorrhage (ICH) volume would allow for the evaluation of clinical trial external validity and determination of temporal trends. We previously reported the median ICH volume in 1988. However, differences in risk factor management, neuroimaging, and demographics may have affected ICH volumes. The goal of this study is to determine the median volume of ICH within a population-based cross-sectional study, including whether it has changed over time. Methods The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was a population-based study of ICH among residents of the Greater Cincinnati/Northern Kentucky region from 2008 through 2012. This study utilizes those data and compares with ICH cases from the same region in 1988. Initial computed tomography images of the head were reviewed, and ICH volumes were calculated using consistent methodology. Results From 2008 through 2012, we identified 1117 cases of ICH. The median volume of ICH was 14.0 mL and was lower in black (11.6) than in white (15.5) patients. Median volumes of lobar and deep ICH were 28.8 mL and 9.8 mL, respectively. Median ICH volume changed significantly from 1988 to 2008–2012, with age-and-race-adjusted volume decreasing from 18.3 mL to 13.76 mL (p = 0.025). Conclusions Median volume of ICH was 13.76 mL, and this should be considered in clinical trial design. Median ICH volume has apparently decreased from 1988 to 2008–2012.

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke., Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.

ObjectiveBlack and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk.MethodsWe analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)–related, hypertensive arteriopathy (HTNA)–related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk.ResultsWe analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD (p = 0.011) and HTNA burden (p = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all p < 0.05).ConclusionsWe uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.

OBJECTIVES Intracerebral hemorrhage (ICH) has the highest morbidity and mortality rate of any stroke subtype and clinicians often administer prophylactic antiseizure medications (ASMs) as a means of preventing post-stroke seizures, particularly following lobar ICH. However, evidence for ASM efficacy in preventing seizures and reducing disability is lacking given limited randomized trials. Herein, we report analysis from a large prospective observational study that evaluates the effect of primary prophylactic ASM administration on seizure occurrence and disability following ICH. MATERIALS AND METHODS Primary analysis was performed on 1630 patients with ICH enrolled in the ERICH study. A propensity score for administration of prophylactic ASM was developed and patients were matched by the closest propensity score (difference

Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Our prior research identified a significant association with monocyte level and ICH mortality. To advance our understanding, we sought to identify gene expression after ICH using a swine model to test the hypothesis that ICH would induce peripheral blood mononuclear cell (PBMC) gene expression. In 10 pigs with ICH, two PBMC samples were drawn from each with the first immediately prior to ICH induction and the second six hours later. RNA-seq was performed with subsequent bioinformatics analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity® Pathway Analysis (IPA). There were 182 significantly upregulated and 153 significantly down-regulated differentially expressed genes (DEGs) after ICH. Consistent with findings in humans, significant GO and KEGG pathways were primarily related to inflammation and the immune response. Five genes, all upregulated post-ICH and known to be associated with monocyte activation, were repeatedly DEGs in the significant KEGG pathways: CD14, TLR4, CXCL8, IL-18, and CXCL2. In IPA, the majority of upregulated disease/function categories were related to inflammation and immune cell activation. TNF and LPS were the most significantly activated upstream regulators, and ERK was the most highly connected node in the top network. ICH induced changes in PBMC gene expression within 6 h of onset related to inflammation, the immune response, and, more specifically, monocyte activation. Further research is needed to determine if these changes affect outcomes and may represent new therapeutic targets.

Background and Purpose— We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods— Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0–2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs—a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results— The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P =0.0007; odds ratio=0.89; 95% CI, 0.82–0.95 and SiGN/GISCOME: P =0.0036; odds ratio=0.94; 95% CI, 0.91–0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80–0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89–0.98) whereas imbalance without ohnologs lacked such an association. Conclusions— Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P =1.70×10 −9 ). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Introduction: Elevations in troponin (cTn) are common in patients with acute ischemic stroke, yet their significance remains uncertain. Hypothesis: Elevated cTn at the time of acute ischemic stroke is associated with ischemic stroke recurrence. Methods: We included all adult patients with acute ischemic stroke who were residents of the Greater Cincinnati/Northern Kentucky region and who presented to an emergency department (ED) in 2015 and who had a cTn measured within 24 hours of ED arrival. Our exposure variable was an elevated cTn, defined as a value exceeding the laboratory’s 99 th percentile. Our primary outcome was ischemic stroke recurrence, defined as a new ischemic stroke with radiographic confirmation in the 3 years following the index ischemic stroke event. Cox proportional hazards model was used to evaluate the association between elevated cTn and ischemic stroke recurrence while adjusting for demographics, vascular risk factors, and stroke severity. In a secondary analysis, we excluded patients with a concomitant adjudicated myocardial infarction (MI) at the time of the index ischemic stroke. Results: Among 2,334 patients with acute ischemic stroke, 1,992 (85%) had a cTn assay within 24 hours of ED arrival and were included in the analysis. 402 (20%) patients had an elevated cTn and 259 (13%) patients had a recurrent ischemic stroke. 66 (3%) patients had an elevated cTn and a concomitant acute MI and 336 (17%) patients had an elevated cTn without a concomitant acute MI. After adjustment for demographics, vascular risk factors, and stroke severity, we found an association between elevated cTn and recurrent ischemic stroke (hazards ratio [HR], 1.5; 95% CI, 1.1-2.0). Our results were unchanged after excluding patients with a concomitant adjudicated MI (HR 1.4; 95% CI, 1.03-2.0). Conclusions: Among patients with acute ischemic stroke, elevated cTn even in the absence of concomitant adjudicated MI, was associated with ischemic stroke recurrence. Further mechanistic studies are necessary to explore the underlying etiology of hypertroponinemia among patients with acute ischemic stroke in order to guide targeted therapies to reduce stroke recurrence.

Introduction: Klotho is a transmembrane protein highly expressed in the kidneys and choroid plexus. Klotho modulates insulin sensitivity and suppresses oxidative stress. Two missense variants in the Klotho gene ( KL ) form the functional haplotype KL-VS . Heterozygosity for KL-VS ( KL-VS-Het+ ) increases serum levels of Klotho and attenuates the excess risk of Alzheimer’s Disease conferred by APOE epsilon 4. We tested the hypothesis that KL-VS-Het+ lowers the risk of spontaneous intracerebral hemorrhage (ICH) and the excess in this risk conferred by the APOE epsilon variants. Methods: We conducted a genetic association study that combined publicly available data from 3 case-control studies of ICH in Europeans. We identified the two genetic variants that define KL-VS (rs9536314 and rs9527025) and the two genetic variants that define the APOE epsilon alleles (rs429358 and rs7412). We tested for association between KL-VS-Het+ and ICH risk via study-specific logistic regression followed by fixed-effects, inverse-variance weighted meta-analysis using I 2 to quantify heterogeneity. Given the known biological differences between lobar and non-lobar ICH, we conducted stratified analyses based on location. Additionally, we evaluated the role of KL-VS-Het+ in carriers of APOE epsilon 2 and 4 variants. Results: A total of 1066 ICH cases (464 lobar and 602 non-lobar) and 1073 controls were included in the study (mean age 69 [SD 14], female sex 919 [47%]). KL-VS-Het+, present in 554 (26%) participants, was associated with a lower risk of ICH (OR 0.81, 95%CI 0.67-0.99; p=0.04) without heterogeneity across studies (I 2 =0%). Stratified analyses indicated that KL-VS-Het+ was associated with a lower risk of lobar ICH (OR 0.68, 95%CI 0.52-0.88; p=0.004) but not of non-lobar ICH (OR 0.92, 95%CI 0.73-1.16; p=0.48). In secondary analyses, KL-VS-Het+ was associated with a lower risk of ICH in carriers of APOE epsilon 2 (OR 0.52, 95%CI 0.28-0.96; p=0.037; I 2 =0%) but not epsilon 4 (OR 0.82, 95%CI 0.5-1.33; p=0.42). Conclusion: KL-VS -Het+ is associated with a lower risk of ICH. This protective association was stronger in lobar hemorrhages and in carriers of APOE epsilon 2. Further research should evaluate these associations in non-Europeans and identify the mediating molecular pathways.

Background: Hemorrhagic transformation (HT) of ischemic stroke can have devastating consequences, leading to longer hospitalizations, increased morbidity and mortality. We sought to identify the rate of HT in stroke patients not treated with tPA within a large, biracial population. Methods: The GCNKSS is a population-based stroke epidemiology study from five counties in the Greater Cincinnati region. During 2015, we captured all hospitalized strokes by screening ICD-9 codes 430-436 and ICD-10 codes I60-I68, and G45-46. Study nurses abstracted all potential cases and physicians adjudicated cases, including classifying the degree of HT. Patients treated with thrombolytics were excluded. Incidence rates per 100,000 and associated 95% confidence intervals (CI) were estimated for HT cases, age and sex adjusted to the 2000 US population. Multiple logistic regression was used to examine risk factors associated with HT. Results: In 2015, there were 2301 ischemic strokes included in the analysis. Of these 104 (4.5%) had HT; 23 (22.1%) symptomatic, 55 (52.9%) asymptomatic and 26 (25%) unknown. Documented reasons for not receiving tPA in these patients were: time (71, 68.3%), anticoagulant use (1, 1.0%), other (18,17.3%) and unknown (14, 13.5%), which were not significantly different compared to those without HT. Only 29/104 (18.3%) had HT classified as PH-1 or PH-2. The age, sex and race-adjusted rate of HT was 9.8 (7.9, 11.6) per 100,000. The table shows rates of potential risk factors and the adjusted odds of developing HT. 90 day all-cause case fatality for patients with HT was significantly higher, 27.9% vs. 15.7%, p Conclusion: We found that 4.5% of non-tPA treated IS patients had HT. These patients had more severe strokes, were more likely to have abnormal coagulation tests or anticoagulant use, and were more likely to die within 90 days. We also report the first population-based incidence rate of HT in non-tPA treated of 9.8/100,000, a rate similar to the incidence of SAH.

Background: Intracerebral hemorrhage (ICH) has the highest morbidity and mortality rate of the major stroke subtypes. Volume is a well-established predictor of outcome. Theoretically, ICH should expand more in areas of less resistance. We hypothesize that 1) expansion perpendicular to neural tracts (axially) will be less great than expansion parallel to tracts (vertically) and 2) differing effect on outcome will occur based on axial and vertical areas of hemorrhage. Methods: The Genetic and Environmental Risk Factors of Hemorrhagic Stroke (GERFHS) study is a population-based case-control study. Each case of ICH within the 5 county region of Greater Cincinnati was evaluated for volume of hemorrhage with a subset completing 3 month telephone follow-up to obtain data including modified Rankin Scale (mRS). Baseline variables were assessed for poor outcome, defined as mRS greater than or equal to 3 at 90 days. Results: From July 2009 to December 2012, 1205 cases of ICH were identified, of which 304 had 3-month follow up. The table presents univariate association with outcome. More than 86% of hemorrhages had greater vertical area than axial area. On multivariable analysis controlling for ICH score variables, vertical area showed a trend toward worse outcome (OR 1.09, p= 0.06) vs axial area (OR 0.97, p=0.69) which was not found to have a significant effect on outcome independent of total volume. Conclusion: Most patients have greater vertical expansion of ICH than axial expansion. This pattern of hemorrhage growth is consistent with neural tracts having less resistance vertically. If the greater impact on outcome is confirmed, improved outcome and trial inclusion criteria may be determined.

Background: Hypertension is an important risk factor in the development of acute ischemic stroke (AIS). African American (AA) race is strongly associated with both hypertension and uncontrolled hypertension despite treatment, yet little is known about racial differences in presenting blood pressure (BP) in AIS. This study sought to describe differences in presenting BP and acute antihypertensive treatment between AA and white AIS patients who received and did not receive alteplase within a population. Methods: Using the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) database for years 2005, 2010 and 2015, we selected patients with a diagnosis of AIS using ICD-9/10 codes in adults ≥ 18 yrs of age presenting to a local ED within 4.5 hrs of symptom onset. Candidates were stratified by race and alteplase use. Socio-demographics, stroke risk factors, stroke severity, BP on arrival, and acute BP treatment were compared using chi-square, t-tests or Wilcoxon rank sum test, as appropriate. Results (Table 1): Of 1838 AIS patients included in the analysis, 392 (21%) received IV alteplase. AA patients were younger in both groups who received and did not receive alteplase. On presentation, AA stroke patients had higher diastolic BP. AA patients were more likely to receive 2 or more BP lowering medications compared to white patients in the alteplase treated group and the untreated group. Conclusion: AA patients presenting within 4.5 hours of AIS symptom onset are more likely to have elevated diastolic BP and to receive multiple BP lowering medications compared to white patients. These findings were significant regardless of alteplase treatment. To our knowledge, we report the first population-based distribution of BP, and medical treatment of BP, upon presentation to an ED in AIS. Further study is needed to determine if these racial differences in elevated BP and refractoriness of BP and/or aggressive treatment contribute to outcome differences.

Introduction: Patients without prior functional deficits who suffer mild stroke (NIHSS Methods: Hospitalized strokes from the Greater Cincinnati Northern Kentucky Stroke Study were used. Included patients had an initial NIHSS Results: Of 1268 ischemic strokes, 353 (28%) were functionally dependent at discharge. Increased baseline NIHSS was associated with worse outcome on the mRS. Leg, LOC questions, and sensation NIHSS subscores were the best predictors of outcome. Multivariable analysis identified age, race, hypertension, chronic kidney disease, heart failure, and post-stroke dysphagia as independently associated with discharge mRS ≥3. Discussion: Our results agree with and complement the results of prior studies. They are not limited by inclusion/exclusion criteria or referral bias. Rather, our major limitation is the retrospective estimation of NIHSS and mRS based on physician descriptive documentation rather than direct score assessment. Our results may allow for modeling to better predict outcome which in turn can inform clinical decision making and trial design.

Introduction: Despite emerging evidence, trajectories of cognitive impairment (CI) among patients with spontaneous intracerebral hemorrhage (ICH) are not well characterized. Methods: We conducted a systematic review of literature within PubMed, using keywords [“Intracerebral hemorrhage” OR “ICH”] AND “Cognitive Impairment,” after 2010. Articles reporting assessments of post ICH CI were included. Articles limited to pre-clinical (animal) studies, non-English literature, other intracranial hemorrhages, traumatic ICH, narrative reviews, and patient under 18 years were excluded. Results: Based on selection criteria, we included 16 articles (graphic) that provide an assessment of post-ICH CI. Post-ICH CI had a reported incidence of up to 85% within the first 2 weeks. The proportion of ICH patients who experience an incident CI across a longer follow up time period have been reported with a high degree of variability; with reports at 3 (32.5 - 71%), 4 (78%), 6 (37 - 63.3%), 9 (47.1 - 100%), 18 (51%), 30 (25.8%), 40 (23%), 45.6 (52 - 64%) and 60 (37.4%) months. Though the assessment scales utilized are variable; 12 (75%) reports employed a version of Montreal Cognitive Assessment or Information Questionnaire on Cognitive Decline in the Elderly. Lobar ICH was well identified, while non-lobar ICHs were variably grouped. Imaging markers have been reported in 10 (62.5%) reports. Though most studies report comorbidities and sociodemographic factors; stroke-specific severity / functional scales and genetic factors have only been considered by 2 (12.5%) articles each. Conclusions: At least 1 in 3 ICH survivors experience post-ICH CI over 12 months. There is an overall paucity of data on post-ICH CI, which highlights a critical need to characterize the natural history of post ICH CI in prospective cohorts and develop standardized assessment protocols for CI among ICH patients.

Introduction: A main goal for hospital admission following acute ischemic stroke (AIS) is to establish the mechanism of stroke (MoS) allowing for patient specific secondary prevention of stroke interventions. We previously reported on diagnostic testing trends and MoS determination from 1993 through 2010. We updated this analysis with 2015 data to better understand the effects of trends in diagnostic testing on MoS determination. Methods: Patients with AIS aged > 20 years from all study time periods (Table) of the population based GCNKSS were included. Charts were abstracted in a systematic way for tests performed during the hospital stay. Only first-ever ischemic stroke cases, evaluated in an emergency department were used for this analysis. Stroke experts reviewed these events and adjudicated the mechanism of stroke according to modified TOAST criteria. We looked at and compared trends for testing and MoS. Results: Our analysis included 7226 patients. Basic patient demographics, MoS categories and tests across study periods are detailed in the Table. There were significant increases in EKG (7%), TTE (35%), TEE (7%), HCT (4%), brain MRI (65%), MRA (30%) and CTA (28%). Across study periods, cardioembolic (4.1%), small vessel disease (3%), large artery disease (0.9%) and other (1.5%) MoS increased while unknown MoS decreased (-9.5%). Discussion: From 1993/1994 to 2015 there has been a significant increase of in-hospital testing in AIS and decreases in undetermined MoS. Cardioembolic and small vessel disease MoS categories increased the most. Despite a significant increase in vessel imaging, large artery disease and “other determined” MoS categories are largely unchanged. Further research is required to elucidate the occult MoS underlying the undetermined category. Based on our analysis it appears unlikely to be significantly associated with our current definition of stroke associated with large artery disease defined as ≥ 50% ipsilateral stenosis.

Introduction: Location specific Intracerebral Hemorrhage (ICH) characteristics and outcomes are important for risk stratification and clinical trial design. However, they have not been described at the population level. Methods: We analyzed the National Inpatient Sample (90% of US hospitalizations) from 09/2015 to 12/2017 and utilized ICD-10 codes to identify ICH patients with a primary diagnosis of either supra-tentorial (ST) or infra-tentorial (IT) hemorrhage; excluding intraventricular or unspecified location. Utilizing sampling weights, nationally representative proportions of ST and IT ICH patients across demographic, comorbidity, healthcare utilization, disease acuity and outcomes are provided. We fit survey design logistic regression models for in-hospital mortality (IHM) and home discharge (HD). Odds Ratios (OR) and 95% confidence Intervals (CI) are reported. Results: Across the analysis time period, a total of 161,395 ICH patients were identified, of whom 51,025 (31.6%) and 20,135(12.5%) had ST and IT ICH respectively. IT ICH patients (vs. ST ICH) were younger (66.9 vs. 67.9 years), with higher proportions of Black (19.1% vs. 17.6%) and un-insured (5.9% vs. 4.7%). A significantly greater proportion of IT ICH patients had prior myocardial infarction, congestive heart failure, atrial fibrillation, renal disease and hypertension. Whereas the prior cerebrovascular disease, dementia, depression and alcohol abuse was associated with ST ICH. Smaller proportion of IT ICH patients (vs. ST ICH) were treated in urban teaching hospitals (81.4% vs. 83.2%). A greater proportion of IT ICH underwent invasive mechanical ventilation (58.1% vs. 46.7%), ventriculostomy (18.2% vs. 10.2%), and tracheostomy (6.4% vs. 4.6%). The total charges and charges per day were significantly higher for IT ICH patients. The overall IHM was 22.6%. A greater proportion of IT ICH patients (vs. ST ICH) experienced IHM (28.2% vs. 17.3%) and smaller proportion had HD (16.7% vs. 20.7%). In the fully adjusted models, IT ICH was associated with a significantly higher IHM (OR, CI: 1.47, 1.26 - 1.71) and lower likelihood of HD (OR, CI: 0.56, 0.46 - 0.68). Conclusion: ST and IT ICH patients have distinctive risk factor and demographic profiles. IT ICH is associated with poor outcomes.

Introduction: The availability of rapid tissue and vessel imaging for TIA has increased, but the utilization rates of these and other diagnostic and management strategies for TIA over time are unknown. Objective: To investigate trends in TIA diagnostic and management strategies over time in the Greater Cincinnati Northern Kentucky Stroke Study (GCNKSS). Methods: The GCNKSS is a population-based study of 1.3 million people living in a 5-county area of southern Ohio and Northern Kentucky. For this study, all physician-adjudicated, first-ever cases of TIA (defined clinically as sudden onset of focal symptoms lasting < 24 hours) presenting to an emergency department over five study periods (1993/4, 1999, 2005, 2010, 2015) were included. Use of AHA-recommended aspects of TIA management as well as disposition of TIA patients (admission to hospital or discharge from ED) and length of stay were compared across study periods. Rates of acute infarct on MRI were also reported. Trends were examined using the Cochran-Armitage test for trend. Results: In total, over all study periods, there were 2251 first-ever TIAs. Overall, 14% (n=311) occurred in Black individuals, and 57% (n=1275) occurred in women. Utilization of diagnostic modalities [non-contrast CT brain, vascular imaging (CTA, MRA, or carotid dopplers), tissue imaging (MRI), and echocardiogram] increased significantly over time (all p Conclusions: The management of TIA has changed significantly over time. Utilization of tissue and vessel imaging as well as echocardiogram during the hospital stay has increased; in 2015, the vast majority of patients with TIA in this population-based study received each of these testing modalities and were admitted to a hospital for TIA work-up. Further work is needed to understand the best practices for work-up of suspected TIA.

Background: Substantial practice variability exists with respect to the diagnostic workup and disposition of patients with TIA. Identifying the workup needed to prevent adverse outcomes is critical. We aimed to determine whether there is an association between specific elements of TIA management and outcomes. Methods: The GCNKSS is a population-based study of 1.3 million people living in a 5-county area of southern Ohio/ Northern Kentucky. For this study, all physician adjudicated, first-ever TIAs (clinically defined as sudden onset, focal neurologic symptoms lasting < 24 hours, with or without MRI correlate) presenting to the ED during 2015 were included; those with prior stoke or TIA were excluded. Multivariable logistic regression was performed to investigate associations between specific aspects of TIA management and an adverse outcome, defined as stroke, recurrent TIA, or all-cause mortality within 30 days, adjusted for demographics, co-morbidities, and symptom type and length as classified in the ABCD2 score. Results: In 2015, there were 477 adjudicated first ever TIA events presenting to the ED. Overall, 13% (n=62) occurred in Black individuals and 51% (n=243) in women. Regarding outcomes, 3% (n=16) had a stroke within 30 days, 6% (n=30) had a recurrent TIA within 30 days, and 1% (n=4) died within 30 days (all-cause mortality). 16.4% had acute infarct on MRI. In multivariable analysis, having an MRI was associated with reduced risk of adverse outcome, while performance of vessel imaging, echocardiogram, or admission to hospital were not significantly associated with outcomes (Table). Conclusions: Among common diagnostic and management strategies for TIA, only performance of MRI was associated with a lower likelihood of having an adverse outcome within 30 days. Possible contributors include variability in care between hospitals with differing MRI performance rates and changes in management of risk factors based on MRI results, though further work is needed.

Background: Functional outcomes are improved when AIS patients receive faster treatment. The first medical contact for many AIS patients is with emergency medical services (EMS) providers. We hypothesize that AIS treatment is faster when EMS providers suspect stroke. Methods: We performed a retrospective analysis of the Greater Cincinnati/Northern Kentucky Stroke Study, a comprehensive study of stroke patients in a large geographical area with 1.3 million inhabitants whose demographics are representative of the United States. We compared AIS patients age ≥18 years transported by EMS in 2015 with an EMS impression of “stroke” or “weakness/numbness” to those with other EMS impressions. Primary outcome was thrombolysis rate, and secondary outcomes were times from EMS scene arrival to ED arrival, CT, and treatment and times from ED arrival to CT and treatment. Chi-square and Mann-Whitney U-tests were used to compare treatment rates and times, respectively. Logistic regression (for rates) and median regression (for times) adjusted for NIHSS, GCS, age, sex, race, and prior stroke history. Results: Among 2,486 confirmed AIS patients from 1/1/2015-12/31/2015, 868 were transported by EMS, including 595 (69%) with EMS suspected stroke. Compared to EMS non-suspected strokes, patients with EMS suspected stroke patients were more likely to receive thrombolysis (18% vs 8%; OR 2.67, 95% CI 1.63-4.47) and had faster prehospital transport (30 vs 32 min, p=0.02), ED arrival to CT (27 vs 46 min, p Conclusions: In a large population-based study, EMS stroke identification is associated with a higher rate of and faster thrombolysis. Efforts to increase accuracy of EMS stroke identification is likely to have significant clinical impact by shortening treatment times.

Introduction: Perihematomal Edema (PHE) is a neuroimaging biomarker of secondary brain injury in patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH). There are limited data on racial/ethnic differences in the development of PHE. This dearth of data is partially driven by the time-consuming process of manually segmenting PHE. Leveraging a validated automated pipeline for PHE segmentation, we evaluated whether race and ethnicity influence baseline PHE volume in patients with ICH. Methods: The Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter study of ICH that recruited 1,000 adult participants from each of three racial/ethnic groups (non-Hispanic White, non-Hispanic Black, and Hispanic). We applied a previously validated deep learning algorithm to automatically determine PHE volumes on baseline CTs in these study participants. Quality control procedures were used to include only sufficiently accurate PHE measurements. Linear regression was used to identify factors associated with log-transformed PHE volume and to identify differences across Ethnic/Racial groups. Results: Our imaging pipeline provided good quality baseline PHE measurements on 2,008 out of 3,000 ERICH study participants. After excluding infratentorial hemorrhages (273) and those with missing or null baseline ICH volume (49), 1,686 remained for analysis (median age 59 [IQR 51-71], 687 [41%] female sex). Median PHE volume was 12.0 (IQR 4.8-27.1) for whites, 11.9 (IQR 4.5-26.1) for Hispanics and 8.3 (IQR 3.0-19.2) for blacks. Compared to Blacks, Hispanics (beta 0.22; 95%CI 0.11-0.32; p Conclusion: Race and ethnicity influence the volume of baseline PHE. Further studies are needed to validate our results and investigate the biological underpinnings of this difference.

Introduction: About 21% of acute ischemic stroke (AIS) patients present to medical attention with an elevated cardiac troponin (cTn). Previously, we described that elevated cTn is associated with an increased case-fatality at 1 year. However, it is not clear if there is a dose-dependent relationship between cTn and case-fatality, or if this effect is related to causes of death. Methods: Within a catchment area of 1.3 million we screened local hospital admissions using ICD-9/10 codes 430-436/I60-I68, G45-46 in 2014/2015, and ascertained all physician-confirmed AIS cases by retrospective chart review. Positive cTn was defined by the standard 99th percentile. To account for by hospital variance in cTn results in machine brands and normal ranges, cTn values were log-transformed and centered. Case fatality at 1 year and cause of death was obtained from the National Death Index database. Logistic regression evaluated the impact of cTn on case fatality, and included demographic and clinical risk factors in the model. The percentage with all-cause and cardiac/non-cardiac case-fatality was computed by quartiles of centered cTn levels and compared using the chi-square test. Results: In 2014/2015, there were 2989 AIS cases ascertained, which were 53% female, 30% black, with a mean age of 70 (SD 14). 441 patients with hypertropinemia were included in the analysis. See Table for case fatality at 1 year by quartile of centered cTn levels. There was no association between cTN and non-cardiac case-fatality. After adjustment for demographic and clinical characteristics, every 0.5 point increase in the centered cTn level increased the cardiac case-fatality by OR 1.19 (1.09, 1.31), p Discussion: We found that the impact of hypertropinemia on case fatality after AIS appears to be a dose-dependent association: as cTn increases, so does the cardiac case-fatality. This suggests that the degree of cTn elevation is likely an important prognostic marker for cardiac death in AIS patients.

Background: Data from the Greater Cincinnati Northern Kentucky Stroke Study (GCNKSS) have demonstrated stable or increasing stroke incidence rates in young adults with differences by sex and race, suggesting the need for targeted approaches to stroke prevention in the young. We aimed to describe trends over time in prevalence of stroke risk factors among adults ages 20-54 with stroke by sex and race. Methods: Cases of incident stroke (IS, ICH, SAH) occurring in those 20-54 years old and living in a 5-county area of southern Ohio/northern Kentucky were ascertained during 5 study periods (1993-1994, 1999, 2005, 2010, 2015). All physician-adjudicated inpatient events and a sampling of outpatient events were included, excluding nursing home events. Data on risk factors (hypertension, diabetes, obesity (BMI≥30), and high cholesterol) diagnosed prior to stroke were abstracted from medical records, and prevalence of each risk factor was reported over time in race/sex groups. Trends over time were examined using the Cochran-Armitage test. Results: Over the 5 study periods, 1204 incident strokes were included; 49% were women, 33% were black, and mean age was 46 (SD 7) years. Premorbid hypertension increased over time in Black women (48% in 1993/4 to 76% in 2015, p=0.005) but not in any other race/sex group (all p>0.05). Premorbid high cholesterol increased significantly in all race/sex groups (Figure, all p Conclusions: Among patients aged 20-54 with incident stroke in a large population-based study, the change in the prevalence of hypertension and high cholesterol differed by sex and race, while obesity and diabetes were stable over time in all race/sex groups. Future research is needed to address risk factor control at a population level and to understand the role of undiagnosed pre-stroke risk factors in the young.

OBJECTIVES To test the hypothesis that admission hemoglobin levels are associated with outcome in primary, nontraumatic intracerebral hemorrhage. DESIGN Individual patient data meta-analysis of three studies of intracerebral hemorrhage. SETTING Two randomized clinical trials and one multiethnic observational study. PATIENTS Patients with spontaneous, nontraumatic intracerebral hemorrhage. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Our exposure of interest was admission hemoglobin levels and the primary outcome was 3-month postintracerebral hemorrhage-dichotomized modified Rankin Scale (0-3 vs 4-6). Intermediate outcomes were admission hematoma volume and hematoma expansion defined as 6 mL or 33% increase in hemorrhage size on repeat CT. A total of 4,172 intracerebral hemorrhage patients were included in the study (mean age 63 [sd = 14]; female sex 1,668 [40%]). Each additional g/dL of admission hemoglobin was associated with 14% (odds ratio, 0.86; 95% CI, 0.82-0.91) and 7% (odds ratio, 0.93; 95% CI, 0.88-0.98) reductions in the risk of poor outcome in unadjusted and adjusted analyses, respectively. Dose-response analyses indicated a linear relationship between admission hemoglobin levels and poor outcome across the entire evaluated range (test-for-trend p < 0.001). No consistent associations were found between the admission hemoglobin levels and hematoma volume or hematoma expansion. CONCLUSIONS Higher hemoglobin levels are associated with better outcome in intracerebral hemorrhage. Further research is needed to evaluate admission hemoglobin levels as both a therapeutic target and predictor of outcome.

IntroductionNeuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of describing the texture of conventional images beyond what meets the naked eye, radiomic analyses hold potential for evaluating brain health. We sought to: 1) evaluate this novel approach to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and 2) uncover associations between predictive radiomic features and patients’ clinical phenotypes.MethodsOur analyses were based on a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images and corresponding deep-learning-generated total brain and WMH segmentation. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with the most stable selected features predictive of WMH burden and then related this signature to clinical variables (age, sex, hypertension (HTN), atrial fibrillation (AF), diabetes mellitus (DM), coronary artery disease (CAD), and history of smoking) using canonical correlation analysis.ResultsRadiomic features were highly predictive of WMH burden (R2=0.855±0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1-6CV7=.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and DM, CV4 by HTN, CV5 by AF and DM, CV6 by CAD, and CV7 by CAD and DM.ConclusionRadiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes. Further research could evaluate radiomics to predict the progression of WMH.Research in contextEvidence before this studyWe did a systematic review on PubMed until December 1, 2020, for original articles and reviews in which radiomics were used to characterize stroke or cerebrovascular diseases. Radiomic analyses cover a broad ensemble of high-throughput quantification methods applicable to digitalized medical images that extract high-dimensional data by describing a given region of interest by its size, shape, histogram, and relationship between voxels. We used the search terms “radiomics” or “texture analysis”, and “stroke”, “cerebrovascular disease”, “small vessel disease”, or “white matter hyperintensities”. Our research identified 24 studies, 18 studying radiomics of stroke lesions and 6 studying cerebrovascular diseases. All the latter six studies were based on MRI (T1-FLAIR, dynamic contrast-enhanced imaging, T1 & T2-FLAIR, T2-FLAIR post-contrast, T2-FLAIR, and T2-TSE images). Four studies were describing small vessel disease, and two were predicting longitudinal progression of WMH. The average sample size was small with 96 patients included (maximum: 204). One study on 141 patients identified 7 T1-FLAIR radiomic features correlated with cardiovascular risk factors (age and hyperlipidemia) using univariate correlations. All studies were monocentric and performed on a single MRI scanner.Added value of this studyTo date and to the best of our knowledge, this is the largest radiomics study performed on cerebrovascular disease or any topic, and one of the very few to include a great diversity of participating sites with diverse clinical MRI scanners. This study is the first one to establish a radiomic signature of WMH and to interpret its relationship with common cardiovascular risk factors. Our findings add to the body of evidence that damage caused by small vessel disease extend beyond the visible white matter hyperintensities, but the added value resides in the detection of that subvisible damage on routinely acquired T2-FLAIR imaging. It also suggests that cardiovascular phenotypes might manifest in distinct textural patterns detectable on conventional clinical-grade T2-FLAIR images.Implications of all the available evidenceAssessing brain structural integrity has implications for treatment selection, follow-up, prognosis, and recovery prediction in stroke patients but also other neurological disease populations. Measuring cerebral parenchymal structural integrity usually requires advanced imaging such as diffusion tensor imaging or functional MRI. Translation of those neuroimaging biomarkers remains uncommon in clinical practice mainly because of their time-consuming and costly acquisition. Our study provides a potential novel solution to assess brains’ structural integrity applicable to standard, routinely acquired T2-FLAIR imaging.Future research could, for instance, benchmark this radiomics approach against diffusion or functional MRI metrics in the prediction of cognitive or functional outcomes after stroke.

BACKGROUND: Antithrombotic-associated subdural hematomas (SDHs) are increasingly common, and the possibility of clinical deterioration in otherwise stable antithrombotic-associated SDH patients may prompt unnecessary admissions to intensive care units. It is unknown whether all antithrombotic regimens are equally associated with the need for critical care interventions. We sought to compare the frequency of critical care interventions and poor functional outcomes among three cohorts of noncomatose SDH patients: patients on no antithrombotics, patients on anticoagulants, and patients on antiplatelets alone. METHODS: We performed a retrospective cohort study on all noncomatose SDH patients (Glasgow Coma Scale > 12) presenting to an academic health system in 2018. The three groups of patients were compared in terms of clinical course and functional outcome. Multivariable logistic regression was used to determine predictors of need for critical care interventions and poor functional outcome at hospital discharge. RESULTS: There were 281 eligible patients presenting with SDHs in 2018, with 126 (45%) patients on no antithrombotics, 106 (38%) patients on antiplatelet medications alone, and 49 (17%) patients on anticoagulants. Significant predictors of critical care interventions were coagulopathy (OR 5.1, P

Acute subdural hematomas (ASDHs) are highly morbid and increasingly common. Hematoma expansion is a potentially fatal complication, and few studies have examined whether factors associated with hematoma expansion vary over time. To answer this, we performed a case-control study in a cohort of initially conservatively managed patients with ASDH. Two time periods were considered, early (72 h from injury). Cases were defined as patients who developed ASDH expansion in the appropriate period; controls were patients who had stable imaging. Associated factors were determined with logistic regression. We identified 68 cases and 237 controls in the early follow-up cohort. Early ASDH expansion was associated with coagulopathy (adjusted odds ratio [aOR] 2.3, 95 % CI: 1.2-4.5; p = 0.02), thicker ASDHs (aOR 1.1, 95% CI: 1.03-1.2; p = 0.006), additional intracranial lesions (aOR 3, 95% CI: 1.6-6.2; p = 0.002), no/minimal trauma history (aOR 0.4, 95% CI: 0.2-0.9; p = 0.03), and duration between injury and initial scan (aOR 0.9, 95% CI: 0.8-0.97; p = 0.04). In the delayed follow-up cohort, there were 41 cases and 126 controls. Delayed ASDH expansion was associated with older age (aOR 1.3 per 10 years, 95% CI: 1.1-1.6; p = 0.01), systolic blood pressure (SBP) >160 on hospital presentation (aOR 4.5, 95% CI: 1.8-11.3; p = 0.001), midline shift (aOR 1.5 per 1 mm, 95% CI: 1.3-1.9; p < 0.001), and convexity location (aOR 14.1, 95% CI: 2.6-265; p = 0.013). We conclude that early and delayed ASDH expansion are different processes with different associated factors, and that elevated SBP may be a modifiable risk factor of delayed expansion.

BackgroundEndogenous apoliloprotein E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apolipoprotein E-mimetic peptides can effectively penetrate the brain and down-regulate acute inflammation. CN-105 is a novel apolipoprotein E-mimetic pentapeptide with excellent preclinical evidence as an acute intracerebral hemorrhage (ICH) therapeutic. TheCN-105 in participants withAcute supraTentorial intraCerebralHemorrhage (CATCH) trial is a first-in-disease-state, multi-center, open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.MethodsEligible patients were age 30-80 years, had confirmed primary supratentorial ICH, and able to intiate CN-105 administration (1.0 mg/kg every 6 hours for 72 hours) within 12 hours of symptom onset.A prioridefined safety endpoints, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes were analyzed. For comparisons, CATCH participants were matched 1:1 with a contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on Days 0, 1, 2, and 5 and ordinal modified Rankin Score at 30 days after ICH were compared.ResultsIn 39 participants enrolled across six study sites in the United States, adverse events occurred at expected rate without increase in hematoma expansion or neurological deterioration or significant serum accumulation. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day mRS, after adjustment for ICH Score, sex, and race/ethnicity, compared to matched contemporary cohort.ConclusionCN-105 administration represents an excellent translational candidate as an actue ICH therapeutic due to its safety, dosing feasibility, favorable pharmacokinetics, and evidence of improved neurological recovery.

Acute ischemic stroke affects men and women differently in many ways. In particular, women are oftentimes reported to experience a higher acute stroke severity than men. Here, we derived a low-dimensional representation of anatomical stroke lesions and designed a sex-aware Bayesian hierarchical modelling framework for a large-scale, well phenotyped stroke cohort. This framework was tailored to carefully estimate possible sex differences in lesion patterns explaining acute stroke severity (NIHSS) in 1,058 patients (39% female). Anatomical regions known to subserve motor and language functions emerged as relevant regions for both men and women. Female patients, however, presented a more widespread pattern of stroke severity-relevant lesions than male patients. Furthermore, particularly lesions in the posterior circulation of the left hemisphere underlay a higher stroke severity exclusively in women. These sex-sensitive lesion pattern effects could be discovered and subsequently robustly replicated in two large independent, multisite lesion datasets. The constellation of findings has several important conceptual and clinical implications: 1) suggesting sex-specific functional cerebral asymmetries, and 2) motivating a sex-stratified approach to management of acute ischemic stroke. To go beyond sex-averaged stroke research, future studies should explicitly test whether acute therapies administered on the basis of sex-specific cutoff volumes of salvageable tissue will lead to improved outcomes in women after acute ischemic stroke.

BackgroundA previous study suggested that intracranial aneurysms are more likely to occur in the same arterial territory within families. We aimed to replicate this analysis in independent families and in a sample limited to intracranial aneurysms that ruptured.MethodsAmong families with ≥2 first-degree relatives with intracranial aneurysms, we randomly matched index families to comparison families, and compared concordance in intracranial aneurysm territory between index and comparison families using a conditional logistic events/trials model. We analyzed three European cohorts separately, and pooled the results with those of the Familial Intracranial Aneurysm study by performing an inverse variance fixed effects meta-analysis. The main analysis included both unruptured and ruptured intracranial aneurysms, and a secondary analysis only ruptured intracranial aneurysms.ResultsAmong 70 Dutch, 142 Finnish, and 34 French families, concordance regarding intracranial aneurysm territory was higher within families than between families, although not statistically significant. Meta-analysis revealed higher concordance in territory within families overall (odds ratio [OR] 1.7, 95%CI 1.3-2.2) and for each separate territory except the anterior cerebral artery. In the analysis of ruptured intracranial aneurysms, overall territory concordance was higher within families than between families (OR 1.8; 95%CI 1.1-2.7) but the territory-specific analysis showed statistical significance only for the internal carotid artery territory.ConclusionsWe confirmed that familial intracranial aneurysms are more likely to occur in the same arterial territory within families. Moreover, we found that ruptured aneurysms were also more likely to occur in the same arterial territory within families.