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Background: Recent evidence suggests that higher CRP (C-reactive protein) levels are associated with lower risk of Alzheimer disease, speculating that CRP might be involved in Aβ clearance mechanisms. Testing this hypothesis, we explored whether genetically proxied CRP levels are also associated with lobar intracerebral hemorrhage (ICH), commonly caused by cerebral amyloid angiopathy. Methods: We used 4 genetic variants within the CRP gene that explain up to 64% of the variance of circulating CRP levels and explored in 2-sample Mendelian randomization analyses associations with risk of any, lobar, and deep ICH (1545 cases and 1481 controls). Results: Higher genetically proxied CRP levels were associated with lower odds of lobar ICH (odds ratio per SD increment in CRP, 0.45 [95% CI, 0.25–0.73]) but not deep ICH (odds ratio, 0.72 [95% CI, 0.45–1.14]). There was evidence of colocalization (posterior probability of association, 72.4%) in the signals for CRP and lobar ICH. Conclusions: Our results provide supportive evidence that high CRP levels may have a protective role in amyloid-related pathology.

Background: Despite the high rates of successful reperfusion in the randomized mechanical thrombectomy (MT) trials, only 27% of large vessel occlusion (LVO) patients treated successfully with MT achieved functional independence at 90 days. One proposed theory is impaired distal reperfusion with persistent small thrombi within the microcirculation despite complete recanalization “the no-Reflow phenomenon”. These distal small thrombi would be more suitable to dissolve by thrombolytics. Methods: This is a retrospective cohort obtained from Get with the guidelines stroke (GWGS) database available at Medical University of South Carolina Comprehensive Stroke Center (CSC) for LVO patients presented within 4.5 hours of last known well (LNW) between January/2018- June/2022. We aim to investigate the influence of intravenous thrombolysis (IVTPA) on the functional independence mRS (0-2) after a successful MT defined as modified thrombolysis score (mTICI2c-3). Results: Of 188 LVO patients who achieved successful reperfusion (TICI2c-3) during the study period, 93 (49%) arrived at our CSC within 4.5 hours of LSW, of them 40 patients (43%) received IVTPA. There was no difference in age, gender, race and initial NIHSS between patients who received IVTPA and those who did not receive IVTPA. Patients received IVTPA arrived at the CSC earlier [median LNW 60 min IQR (51 - 151) vs 165 min (IQR 103- 214), p = Conclusion: Intravenous thrombolysis can still influence LVO stroke patients' outcomes with complete revascularization. This positive effect might be related to distal microthrombi thrombolysis and subsequent improvement of the microcirculation flow beyond the occlusion site

BackgroundIntracerebral hemorrhage (ICH), the most fatal form of stroke, has an estimated heritability of 29%. Applying a meta-scoring approach, we developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors.MethodsUsing a meta-analytic approach, we combined genome-wide association data from individuals of European ancestry for ICH and ICH-related traits in a meta-genomic risk score (metaGRS) consisting of 2.6 million variants. We tested associations with ICH and the predictive performance of the metaGRS in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). Furthermore, we tested associations with risk of incident ICH in the population-based UK Biobank cohort (486,784 individuals, 1,526 events, median follow-up 11.3 years).ResultsOne SD increment in the metaGRS was significantly associated with 45% higher odds for ICH (OR 1.45; 95%CI: 1.30-1.63) in age- and sex-adjusted models and 31% higher odds for ICH (OR: 1.31, 95%CI: 1.16-1.48) in models further adjusted for clinical risk factors. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (OR: 4.83, 95%CI: 1.56-21.2). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared with clinical risk factors alone (c-index: 0.695 vs. 0.686). The metaGRS showed similar associations for both lobar and non-lobar ICH, which were independent of the known APOE risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (HR: 1.15, 95%CI: 1.09-1.21). The associations were significant within both a relatively high-risk population of users of antithrombotic medications, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants.ConclusionsWe developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.

Background: Uncontrolled blood pressure (BP) in intracerebral hemorrhage (ICH) survivors is common and associated with adverse clinical outcomes. We investigated whether characteristics of the ICH itself were associated with uncontrolled BP at follow-up. Methods: Subjects were consecutive patients aged ⩾18 years with primary ICH enrolled in the prospective longitudinal ICH study at Massachusetts General Hospital between 1994 and 2015. We assessed the prevalence of uncontrolled BP (mean BP ⩾140/90 mmHg) 6 months after index event. We used multivariable logistic regression models to assess the effect of hematoma location, volume, and event year on uncontrolled BP. Results: Among 1492 survivors, ICH was lobar in 624 (42%), deep in 749 (50%), cerebellar in 119 (8%). Lobar ICH location was associated with increased risk for uncontrolled BP after 6 months (OR 1.35; 95% CI [1.08–1.69]). On average, lobar ICH survivors were treated with fewer antihypertensive drugs compared to the rest of the cohort: 2.1 ± 1.1 vs 2.5 ± 1.2 ( p Conclusions: ICH survivors with lobar hemorrhage were more likely to have uncontrolled BP after 6 months follow-up. This appears to be a result of being prescribed fewer antihypertensive medications. Future treatment strategies should focus on aggressive BP control after ICH independent of hemorrhage location.

Background and ObjectivesAlthough blood pressure (BP) control is considered the most effective measure to prevent functional decline after intracerebral hemorrhage (ICH), fewer than half of survivors achieve treatment goals. We hypothesized that long-term (i.e., prehemorrhage) hypertension severity may be a crucial factor in explaining poor BP control after ICH. We investigated changes in hypertension severity after vs before ICH using latent class analysis (LCA) and identified patient characteristics predictive of individuals' BP trajectories.MethodsWe analyzed data for ICH survivors enrolled in a study conducted at Massachusetts General Hospital (MGH) from 2002 to 2019 in Boston, a high-resource setting with near-universal medical insurance coverage. We captured BP measurements in the 12 months preceding and following the acute ICH hospitalization. Using LCA, we identified patient groups (classes) based on changes in hypertension severity over time in an unbiased manner. We then created multinomial logistic regression models to identify patient factors associated with these classes.ResultsAmong 336 participants, the average age was 74.4 years, 166 (49%) were male, and 288 (86%) self-reported White race/ethnicity. LCA identified 3 patient classes, corresponding to minimal (n = 114, 34%), intermediate (n = 128, 38%), and substantial (n = 94, 28%) improvement in hypertension severity after vs before ICH. Survivors with undertreated (relative risk ratio [RRR] 0.05, 95% CI 0.01–0.23) or resistant (RRR 0.03, 95% CI 0.01–0.06) hypertension before ICH were less likely to experience substantial improvement afterwards. Residents of high-income neighborhoods were more likely to experience substantial improvement (RRR 1.14 per $10,000, 95% CI 1.02–1.28). Black, Hispanic, and Asian participants with uncontrolled hypertension before ICH were more likely to experience minimal improvement after hemorrhagic stroke (interaction p < 0.001).DiscussionMost ICH survivors do not display consistent improvement in hypertension severity after hemorrhagic stroke. BP control after ICH is profoundly influenced by patient characteristics predating the hemorrhage, chiefly prestroke hypertension severity and socioeconomic status. Neighborhood income was associated with hypertension severity after ICH in a high-resource setting with near-universal health care coverage. These findings likely contribute to previously documented racial/ethnic disparities in BP control and clinical outcomes following ICH.

Background Survivors of intracerebral hemorrhage (ICH) are at high risk for recurrent stroke, which is associated with blood pressure control. Because most recurrent stroke events occur within 12 to 18 months of the index ICH, rapid blood pressure control is likely to be crucial. We investigated the frequency and prognostic impact of uncontrolled short‐term hypertension after ICH. Methods and Results We analyzed data from Massachusetts General Hospital (n=1305) and the University of Hong Kong (n=523). We classified hypertension as controlled, undertreated, or treatment resistant at 3 months after ICH and determined the following: (1) the risk factors for uncontrolled hypertension and (2) whether hypertension control at 3 months is associated with stroke recurrence and mortality. We followed 1828 survivors of ICH for a median of 46.2 months. Only 9 of 234 (4%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled hypertension, 755 (41%) had undertreated hypertension, and 360 (20%) had treatment‐resistant hypertension. Black, Hispanic, and Asian race/ethnicity and higher blood pressure at time of ICH increased the risk of uncontrolled hypertension at 3 months (all P P Conclusions Among survivors of ICH, >60% had uncontrolled hypertension at 3 months, with undertreatment accounting for the majority of cases. The 3‐month blood pressure measurements were associated with higher recurrent stroke risk and mortality. Black, Hispanic, and Asian survivors of ICH and those presenting with severe acute hypertensive response were at highest risk for uncontrolled hypertension.

BackgroundThe relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly defined. We aimed to leverage genetic data to investigate reported associations.MethodsGenetic association estimates for liability to Covid-19 and cardiovascular traits were obtained from large-scale consortia. Analyses primarily focused on critical Covid-19, defined as hospitalization with Covid-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical Covid-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both Covid-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical Covid-19 was associated with increased risk of any of the cardiovascular outcomes for which genetic correlation was identified.ResultsThere was evidence of genetic correlation between critical Covid-19 and ischemic stroke (rg=0.29, FDRp-value=4.65×10−3), body mass index (rg=0.21, FDR-p-value=6.26×10−6) and C-reactive protein (rg=0.20, FDR-p-value=1.35×10−4), but none of the other considered traits. In Mendelian randomization analysis, liability to critical Covid-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical Covid-19 liability 1.03, 95% confidence interval 1.00-1.06,p-value=0.03). Similar estimates were obtained when considering ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical Covid-19.ConclusionsThese data support that liability to critical Covid-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe Covid-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

Introduction: Genome-wide association studies (GWAS) have identified genetic associations for many common diseases and traits. However, incorporating genetic information into disease risk prediction has been challenging because any single collection of variants explains a small proportion of risk. We explored whether combining genetic information from related traits could improve our ability to predict ICH. Methods: We constructed an ICH meta-Genetic Risk Score (metaGRS) using 21 polygenic risk scores (PRSs) from GWASs of traits associated with ICH risk: systolic/diastolic blood pressure, pulse pressure, diabetes, hemoglobin A1c, total cholesterol, high/low-density lipoprotein, triglycerides, body mass index, waist-hip ratio, urine albumin-creatinine ratio, kidney disease, eGFR, white matter hyperintensities, small vessel stroke, insomnia, sleep duration, education attainment, alcohol use and smoking. Each PRS contained common, independent variants at p≤5x10 -4 with each trait. PRSs were calculated in 1,867 ICH cases/1,722 controls, using 1,019 cases/928 controls as a training dataset to derive logORs of the PRSs with ICH status, and a validation dataset of 848 cases/794 controls to construct the metaGRS as a weighted average. Results: Patients in higher metaGRS percentiles had higher odds of ICH (Table) , and a one standard deviation increase in metaGRS was associated with odds of ICH (OR 1.42; 95% CI: 1.28-1.57; p=1.6x10 -11 ). Compared to patients in the middle decile of the metaGRS distribution, patients in the top 10% and 5% had increased odds of ICH (OR 1.87; 95% CI: 1.07-3.30; p=0.03, OR 2.72; 95% CI: 1.54-4.92; p=7.4x10 -4 respectively). Conclusions: A metaGRS identified individuals at high risk for ICH with an odds ratio comparable to traditional risk factors, such as hypertension (OR ~1.6). Further studies are needed to investigate the role of incorporating genetic information into clinical care.

Introduction: Survivors of Intracerebral Hemorrhage (ICH) are at high risk of recurrent stroke. This risk is inversely proportional to average Blood Pressure (BP) after ICH. Racial/ethnic minority ICH survivors in the US demonstrate greater hypertension severity after ICH and are at higher risk of recurrent cerebral bleeding. Since most recurrent strokes occur within 12-18 months of index ICH, rapidly achieving BP control is likely to be crucial. We investigated the frequency, prognostic impact, and racial/ethnic disparities in uncontrolled short-term hypertension (HTN) after ICH. Methods: We analyzed data from prospective ICH cohort studies at Massachusetts General Hospital (MGH-ICH, n=1305) and the University of Hong Kong (HK-ICH, n=523). We classified HTN as controlled, uncontrolled or treatment-resistant and determined: 1) risk factors for uncontrolled and treatment-resistant HTN; and 2) whether HTN control at 3 months is associated with long-term BP control, stroke recurrence and mortality across self-reported race/ethnicity groups. Results: We followed 1828 ICH survivors (1128 White, 565 Asian, 59 Hispanic, 49 Black, 27 other) for a median of 46.2 months. Only 9 of 172 (5%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled HTN, 755 (41%) had undertreated HTN, and 360 (20%) had treatment-resistant HTN. BP measurements at 3 months were highly correlated with measurements during follow-up (p Conclusions: Most ICH survivors have inadequate HTN control 3 months after ICH, with under-treatment accounting for the majority of cases. Three-month BP measurements are associated with inadequate long-term HTN control, higher recurrent stroke risk and mortality. ICH survivors self-reporting as Black, Hispanic or Asian appear to be at highest risk for uncontrolled HTN. Optimizing HTN control at 3 months is a unique opportunity to address racial/ethnic disparities in quality of care among survivors of primary ICH.

Introduction: Although elevated blood pressure (BP) is an established risk factor for intracerebral hemorrhage (ICH), the impact of acute BP fluctuations on ICH outcomes remains unclear. In this study, we sought to investigate the effect of acute BP variability (BPV) on mortality and functional outcome in ICH survivors. Methods: Subjects were consecutive ICH patients ≥ 18 years with available inpatient BP data, who survived hospitalization. Four measures of systolic BPV were calculated: standard deviation (SD), coefficient of variation (CoV), average real variability (ARV), and successive variation (SV). Our outcomes were (1) death and (2) poor functional outcome, defined as a modified Rankin Score (mRS) of 3-6 in a period between 60-120 days after discharge. We assessed the effect of hyperacute (ICH event-72 hours) and acute/subacute (72 hours-discharge) BPV on outcomes. We constructed Cox proportional hazards and logistic regression models to investigate the associations of BPV (per 10 mmHg increase) with mortality and poor functional outcome, respectively, after adjustment for potential confounders. Results: We included 345 patients, 120 of whom had available mRS data. 151 (43.8%) patients were female and 280 (81.2%) were white; mean age was 71 (±13) years. SBP ARV and SBP SV were the strongest predictors of mortality (HR 2.53-2.91 per 10 mmHg increase), while SBP SD, CoV, and SV were the strongest predictors of poor functional outcome (OR 2.89-5.14 per 10 mmHg increase) (Table) . These associations remained significant when analyzing both hyperacute as well as acute/subacute BPV. Compared to hyperacute BPV, acute/subacute BPV was more strongly associated with both mortality and poor functional outcome. Conclusion: Inpatient blood pressure variability is an important determinant of mortality and poor functional outcome in ICH survivors. Further studies are needed to investigate the role of addressing BPV as a potential target for intervention.

Background: Recent reports have emerged linking SARS-CoV-2 infection to neurological diseases including stroke. It is unclear whether cerebrovascular disease and SARS-CoV-2 share a common risk mechanism, or whether the specific host response to SARS-CoV-2 increases the risk of stroke. We sought to investigate whether genes and pathways associated with SARS-CoV-2 infection and its systemic host response are also related to risk of ischemic stroke (IS) and intracerebral hemorrhage (ICH). Methods: We constructed gene-sets involved with SARS-CoV-2 infection risk and host response. Brain-specific datasets (ROSMAP and Braineac) were used to build co-expression networks for 5 target genes ( ACE2 , TMPRSS2 , BEST3 , ISLR2 and ADAM17 ) involved in SARS-CoV-2 infection phase. Host response gene-sets were constructed from SARS-CoV-2 post-infection gene expression networks measured from lung, kidney, and blood, extracted from literature review. Gene-based association testing was performed using VEGAS2 on GWAS summary data, as well as on data generated through S-PrediXcan analysis of primary tissues relevant to ICH/IS/subtypes. Fisher’s exact test was used to examine gene-set enrichment. Results: The SARS-CoV-2 risk-related ISLR2 co-expression gene network was significantly associated with genetic risk of the large artery stroke (LAS) subtype, across tissues in multiple brain regions (3/10, FDR-p ≤ 0.05), as well as in LAS-relevant primary tissues such as aorta and tibial arteries (p ≤ 0.05). Among SARS-CoV-2 host response factors, SARS-CoV-2 expression changes in lung were found to be enriched for all-cause ischemic stroke risk (p = 0.03), while lobar ICH risk showed an enrichment (p = 0.04) for genes expressed during antiviral response in the blood compartment. Conclusion: Gene networks specific to SARS-CoV-2 infection suggest enrichment in pathways related to infection and host response in both IS and ICH, informed by gene expression levels in multiple brain tissues. Collectively, these findings suggest that increases in stroke risk reported in patients with SARS-CoV-2 infection, particularly large artery stroke, may be intrinsic to this viral infection rather than a more generalized response to severe illness.