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Background: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. Methods: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. Results: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P P P =0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P =0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy. Conclusions: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

Background: Intracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores that quantify bleeding risk can guide decision-making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score into an existing risk factor–based CRS could improve risk stratification for anticoagulation-related ICH. Methods: We constructed 153 genetic risk scores from genome-wide association data of 1545 ICH cases and 1481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with a combined clinical and genetic risk score incorporating an additional point for high genetic risk for ICH. Results: Among anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared with the lowest genetic risk score tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (hazard ratio, 2.08 [95% CI, 1.22–3.56]). Although the CRS predicted incident ICH with a hazard ratio of 1.24 per 1-point increase (95% CI [1.01–1.53]), adding a point for high genetic ICH risk led to a stronger association (hazard ratio of 1.33 per 1-point increase [95% CI, 1.11–1.59]) with improved risk stratification (C index 0.57 versus 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new clinical and genetic risk score showed 19% improvement in high-risk classification among individuals with ICH and a net reclassification improvement of 0.10. Conclusions: Among anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision-making.

Background: Blood pressure (BP) control represents a crucial intervention to improve long-term outcomes following spontaneous intracerebral hemorrhage (ICH). However, fewer than half of ICH survivors achieve target treatment goals. ICH survivors are also at very high risk for poststroke depression, which may contribute to inadequate BP control. We, therefore, sought to determine whether depressive symptoms after ICH are associated with inadequate BP control. We also investigated whether associations between depression after ICH and BP measurements were mediated by treatment with selective serotonin reuptake inhibitors or norepinephrine-serotonin reuptake inhibitors antidepressants. Methods: We leveraged data from a single-center longitudinal study of ICH conducted at Massachusetts General Hospital (Boston, MA) between 2006 and 2018. We collected data from semiautomated review of electronic health records, baseline and follow-up interviews, and computed tomography imaging. Information on BP measurements, depression diagnoses, antidepressants medication use, and medical visits were collected longitudinally and analyzed using mixed effects models. Primary outcomes included systolic and diastolic BP measurements during long-term follow-up after ICH. Results: We included 1243 consecutive ICH patients without pre-stroke depression history. Of these, 721 (58%) were diagnosed with incident depression over a median follow-up time of 52.8 months (interquartile range, 42.1–60.5). Depression onset was associated with subsequent increase in systolic (+8.3 mm Hg, SE, 2.4 mm Hg, P =0.012) and diastolic (+4.4 mm Hg, SE, 1.2 mm Hg) BP measurements. Resolution of depressive symptoms was associated with subsequent decrease in systolic (−5.9 mm Hg, SE, 1.4 mm Hg, P =0.031) and diastolic (−3.4 mm Hg, SE, 1.1 mm Hg, P =0.041) BP measurements. We also found associations between higher systolic BP measurements and use of selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor antidepressants, independent of whether depression symptoms were active or not (all P Conclusions: ICH survivors displayed increasing BP values after receiving a diagnosis of depression, followed by decreasing values among those experiencing resolution of depressive symptoms. Use of selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor antidepressants was independently associated with higher systolic BP measurements. Clinicians ought to closely monitor BP for ICH survivors being treated for depression, especially using selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor. Future studies will also be required to investigate the mechanisms underlying these associations.

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.

IntroductionLong-term cardiac monitoring studies have unveiled low-burden, occult atrial fibrillation (AF) in some patients with otherwise cryptogenic stroke (CS), but occult AF is also found in some individuals without a stroke history and in patients with stroke of a known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal vs. incidental.MethodsThrough a systematic search, we identified all case–control and cohort studies applying identical long-term monitoring techniques to both patients with CS and KS. We performed a random-effects meta-analysis across these studies to determine the best estimate of the differential frequency of occult AF in CS and KS among all patients and across age subgroups. We then applied Bayes' theorem to determine the probability that occult AF is causal or incidental.ResultsThe systematic search identified three case–control and cohort studies enrolling 560 patients (315 CS, 245 KS). Methods of long-term monitoring were implantable loop recorder in 31.0%, extended external monitoring in 67.9%, and both in 1.2%. Crude cumulative rates of AF detection were CS 47/315 (14.9%) vs. KS 23/246 (9.3%). In the formal meta-analysis, the summary odds ratio for occult AF in CS vs. KS in all patients was 1.80 (95% CI, 1.05–3.07), p = 0.03. With the application of Bayes' theorem, the corresponding probabilities indicated that, when present, occult AF in patients with CS is causal in 41.2% (95% CI, 15.5–77.7%) of patients. Analyses stratified by age suggested that detected occult AF in patients with CS was causal in 62.3% (95 CI, 0–87.1%) of patients under the age of 65 years and 28.5% (95 CI, 0–63.7%) of patients aged 65 years and older but estimates had limited precision.ConclusionCurrent evidence is preliminary, but it indicates that in cryptogenic stroke when occult AF is found, it is causal in about 41.2% of patients. These findings suggest that anticoagulation therapy may be beneficial to prevent recurrent stroke in a substantial proportion of patients with CS found to have occult AF.

Background and objective: Small, single-center studies point to biological and clinical differences in women and men who sustain a spontaneous, non-traumatic intracerebral hemorrhage (ICH). Leveraging data from four landmark studies of ICH, we investigated the impact of sex on risk factors, location, severity and outcome of ICH. Design: Individual patient data meta-analysis of four studies of ICH, including three randomized clinical trials and one multi-ethnic observational study. Setting: Academic medical centers in the United States. Patients: Patients with neuroimaging confirmed ICH. Measurements: We conducted an individual patient data meta-analysis of four landmark studies of ICH: ERICH, ATACH-II, FAST and MISTIE-III. We evaluated whether sex was associated with specific risk factor profiles, hemorrhage location (deep or lobar), neuroimaging severity (hematoma volume and expansion), and poor 90-day functional outcomes (defined as a modified Rankin scale 4 to 6). Main Results: A total of 4,812 ICH patients were evaluated (mean age 62, 60% males). Men with ICH were younger, more likely to be smokers and diabetics, and less likely to be on anticoagulants (all p Conclusions: Men with ICH are more likely to have vascular risk factors, have larger hemorrhage volumes, and have higher risk of hemorrhage expansion. They are also more likely to have a good outcome at 90 days compared to women.

Background and Purpose: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). Methods: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. Results: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance ( P −9 ) and 4 novel loci at genome-wide significance ( P −8 ), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke ( P −6 ). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2 , HDAC9 , ZFHX3 , and LRCH1 . Conclusions: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

Background: Intracerebral hemorrhage (ICH) survivors are at high risk for recurrent stroke and cardiovascular events. Blood pressure (BP) control represents the most potent intervention to lower these risks, but optimal treatment targets in this patient population remain unknown. We sought to determine whether survivors of ICH achieving more intensive BP control than current guideline recommendations (systolic BP Methods: We analyzed data for 1828 survivors of spontaneous ICH from 2 cohort studies. Follow-up BP measurements were recorded 3 and 6 months after ICH, and every 6 months thereafter. Outcomes of interest were major adverse cardiovascular and cerebrovascular events (recurrent ICH, incident ischemic stroke, myocardial infarction), vascular mortality (defined as mortality attributed to recurrent ICH, ischemic stroke, or myocardial infarction), and all-cause mortality. Results: During a median follow-up of 46.2 months, we observed 166 recurrent ICH, 68 ischemic strokes, 69 myocardial infarction, and 429 deaths. Compared with survivors of ICH with systolic BP 120 to 129 mmHg, participants who achieved systolic BP 75 years or with modified Rankin Scale score 4 to 5, systolic BP Conclusions: Targeting systolic BP

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

Background The middle frontal gyrus (MFG) is involved in attention, working memory, and language-related processing. A detailed understanding of the subcortical white matter tracts connected within the MFG can facilitate improved navigation of white matter lesions in and around this gyrus and explain the postoperative morbidity after surgery. We aimed to characterize the fiber tracts within the MFG according to their connection to neuroanatomic structures through the use of diffusion spectrum imaging-based fiber tractography and validate the findings by gross anatomic dissection for qualitative visual agreement. Methods Tractography analysis was completed using diffusion imaging data from 10 healthy, adult subjects enrolled in the Human Connectome Project. We assessed the MFG as a whole component according to its fiber connectivity with other neural regions. Mapping was completed on all tracts within both hemispheres, with the resultant tract volumes used to calculate a lateralization index. A modified Klingler technique was used on 10 postmortem dissections to demonstrate the location and orientation of the major tracts. Results Two major connections of the MFG were identified: the superior longitudinal fasciculus, which connects the MFG to parts of the inferior parietal lobule, posterior temporal lobe, and lateral occipital cortex; and the inferior fronto-occipital fasciculus, which connected the MFG to the lingual gyrus and cuneus. Intra- and intergyral short association, U-shaped fibers were also identified. Conclusions Subcortical white matter pathways integrated within the MFG include the superior longitudinal fasciculus and inferior fronto-occipital fasciculus. The MFG is implicated in a variety of tasks involving attention and memory, making it an important cortical region. The postoperative neurologic outcomes related to surgery in and around the MFG could be clarified in the context of the anatomy of the fiber bundles highlighted in the present study.

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.

Introduction: Combining biologically related traits in genome-wide association studies has been demonstrated to increase the power for genetic discovery and to identify new genes associated with intracerebral hemorrhage (ICH). Given the pathological relationship between lobar ICH and cerebral amyloid angiopathy (CAA), and between the latter and levels of CSF amyloid-β 42 (CSF-Aβ 42 ), we leveraged genetic predisposition for lower CSF Aβ 42 levels, as a proxy phenotype for CAA, in pleiotropy analysis for lobar ICH. Methods: We used publicly available GWAS data for Aβ 42 levels (n=3,146) and for lobar ICH (n=1,813) from the International Stroke Genetics Consortium. To evaluate the association between lobar ICH risk and CSF-Aβ 42 , we computed a polygenic risk score (PRS) for CSF-Aβ 42 in lobar ICH patients. We then applied multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aβ 42 . Gene-level associations based on the MTAG result were further tested using S-Predixcan. Results: We found a significant association between CSF-Aβ 42 PRS and ICH risk (β = -0.35; P = 0.04). MTAG analyses identified one novel near-genome-wide significant association within CDH9 (rs1007589; minor allele frequency=0.09; MTAG β = -0.12 and P = 5.4x10 -8 ; lobar ICH β = 0.34 and P = 2.4x10 -3 ; CSF-Aβ 42 β = -0.03 and P = 4.5x10 -6 ). According to the BRAINEAC brain tissue gene expression database, rs1007589 is significantly associated with increased expression of CDH9 in both temporal and occipital cortices. Discussion: This pleiotropy analysis was designed to identify genetic determinants of lobar ICH driven by amyloid-related mechanisms. We identified a variant in one novel gene associated with both traits, CDH9 , which causes differential expression in two brain regions characteristically affected by vascular amyloid pathology. CDH9 encodes for one subtype of the cadherin superfamily, which regulates intercellular adhesion. Cadherins have been involved in blood-brain barrier integrity and are elevated in AD patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.

Introduction: Epidemiologic studies of intracerebral hemorrhage (ICH) have consistently demonstrated variation in incidence, location, comorbidity burden, age-of-onset, and outcome by race and ethnicity, and genetic studies have identified differences in risk mediated by genetic risk factors such as Apolipoprotein E (APOE). We report the design and methods of the largest multi-ethnic genome-wide association study (GWAS) of ICH risk and outcome conducted to date. Methods: The Ethnic/Racial Variations of ICH Genetics (ERICH-GENE) study is an international, multi-center, genetic case-control study of ICH. Cases are individuals with confirmed primary ICH with biosample availability and consent compatible with shareable genome-wide genotyping or previous genotyping. Central neuroimaging phenotype harmonization of case status, hemorrhage location, and imaging characteristics of cerebral small vessel disease including leukoaraiosis, atrophy, microbleeds, intraventricular hemorrhage severity and volume of ICH measurements will be performed. Controls are ICH-free individuals of compatible age and race/ethnicity from existing studies and biorepositories. Results: As of August 2021, 2,002 ICH cases have been collected and genotyped, in addition to 2,558 already-genotyped ICH cases from the multi-ethnic ERICH study. 5,600 total new ICH cases will be genotyped under ERICH-GENE, with planned meta-analyses across existing ICH GWAS datasets and international biobanks totaling >20,000 cases. We are on schedule to meet our genotyping goal within the study period. Non-European ancestry cases are being prioritized for genotyping and ~66% of the previously genotyped ERICH cases are black or Hispanic. From available cases, a total of 10,621 neuroimaging studies have been uploaded for central adjudication to date with 6,278 having undergone harmonization. Conclusions: ERICH-GENE is a large, multi-ethnic, international, centrally harmonized GWAS of ICH risk and outcome that will identify genetic risk factors across diverse populations for biological discovery and population-specific risk stratification.

Introduction: Long-term cardiac monitoring studies have unveiled low-burden, occult atrial fibrillation (AF) in some patients with otherwise cryptogenic stroke (CS). But occult AF is also found in some normal individuals and patients with stroke of known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal versus incidental. Methods: Through systematic search, we identified all case-control and cohort studies applying identical long-term monitoring techniques to both CS and KS patients. We performed a random-effects meta-analyses across these studies to determine the best estimate of the differential frequency of occult AF in CS and KS among all patients, and across age subgroups. We then applied Bayes’ theorem (method of Alsheikh-Ali et al, Stroke 2009) to determine the probability that occult AF is causal or incidental. Results: The systematic search identified 3 case-control and cohort studies enrolling 575 patients (337 CS, 238 KS). Methods of long-term monitoring were implantable loop recorder in 191 (33.2%), extended mobile external cardiac monitor in 277 (48.2%), and patch/event/Holter monitoring in 107 (18.6%). In formal meta-analysis, the summary odds ratio for occult AF in CS vs KS in all patients was 1.72 (95%CI 0.91-3.25) (Figure). With application of Bayes theorem, the corresponding probabilities indicated that, when present, occult AF in CS patients is causal in 44.4% and incidental in 55.6%. Only one study reported age-specific subgroup data: these suggested occult AF in CS patients was causal in 93% of patients Conclusions: In patients with cryptogenic stroke, when occult AF is found, it is likely causal in about 44% of patients, who may benefit from anticoagulation, and likely incidental in about 56% of patients, who may not benefit from anticoagulation. Figure

ObjectiveTo determine whether MRI-based cerebral small vessel disease (CSVD) burden assessment, in addition to clinical and CT data, improved prediction of cognitive impairment after spontaneous intracerebral hemorrhage (ICH).MethodsWe analyzed data from ICH survivors enrolled in a single-center prospective study. We employed 3 validated CSVD burden scores: global, cerebral amyloid angiopathy (CAA)–specific, and hypertensive arteriopathy (HTNA)–specific. We quantified cognitive performance by administering the modified Telephone Interview for Cognitive Status test. We utilized linear mixed models to model cognitive decline rates, and survival models for new-onset dementia. We calculated CSVD scores' cutoffs to maximize predictive performance for dementia diagnosis.ResultsWe enrolled 612 ICH survivors, and followed them for a median of 46.3 months (interquartile range 35.5–58.7). A total of 214/612 (35%) participants developed dementia. Higher global CSVD scores at baseline were associated with faster cognitive decline (coefficient −0.25, standard error [SE] 0.02) and dementia risk (sub–hazard ratio 1.35, 95% confidence interval 1.10–1.65). The global score outperformed the CAA and HTNA scores in predicting post-ICH dementia (all p < 0.05). Compared to a model including readily available clinical and CT data, inclusion of the global CSVD score resulted in improved prediction of post-ICH dementia (area under the curve [AUC] 0.89, SE 0.02 vs AUC 0.81, SE 0.03, p = 0.008 for comparison). Global CSVD scores ≥2 had highest sensitivity (83%) and specificity (91%) for dementia diagnosis.ConclusionsA validated MRI-based CSVD score is associated with cognitive performance after ICH and improved diagnostic accuracy for predicting new onset of dementia.

ObjectiveLeveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes.MethodsWe used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization.ResultsA PRS for lower eGFR was associated with higher large artery stroke (LAS) risk (p = 1 × 10−4). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38–3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12–4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH.ConclusionsImpaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease.

Translational genomics represents a broad field of study that combines genome and transcriptome-wide studies in humans and model systems to refine our understanding of human biology and ultimately identify new ways to treat and prevent disease. The approaches to translational genomics can be broadly grouped into two methodologies, forward and reverse genomic translation. Traditional (forward) genomic translation begins with model systems and aims at using unbiased genetic associations in these models to derive insight into biological mechanisms that may also be relevant in human disease. Reverse genomic translation begins with observations made through human genomic studies and refines these observations through follow-up studies using model systems. The ultimate goal of these approaches is to clarify intervenable processes as targets for therapeutic development. In this review, we describe some of the approaches being taken to apply translational genomics to the study of diseases commonly encountered in the neurocritical care setting, including hemorrhagic and ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, and status epilepticus, utilizing both forward and reverse genomic translational techniques. Further, we highlight approaches in the field that could be applied in neurocritical care to improve our ability to identify new treatment modalities as well as to provide important information to patients about risk and prognosis. Electronic supplementary material The online version of this article (10.1007/s13311-020-00838-1) contains supplementary material, which is available to authorized users.

Objective To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. Methods We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. Results Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose. Interpretation Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (−3.47, −3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [−0.05 mg/dl per year, (−0.07, −0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

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.

Background Cognitive impairment and depressive symptoms are highly prevalent after Intracerebral Hemorrhage (ICH). We leveraged Latent Profile Analysis (LPA) to identify profiles for cognitive decline and depression onset after ICH. We also investigated differences in clinical, genetic and neuroimaging characteristics across patients’ profiles. Methods We analyzed data from the ICH study conducted at Massachusetts General Hospital between January 1998 and December 2019. We collected information from electronical health records, follow-up interviews, CT and MRI imaging, and APOE genotype. We conducted LPA and multinomial logistic regression analyses to: 1) identify distinct profiles for cognitive decline and depression onset after ICH; 2) identify clinical, neuroimaging and genetic factors predicting individuals’ likelihood to express a specific profile. Results We followed 784 ICH survivors for a median of 45.8 months. We identified four distinct profiles in cognitive and depressive symptoms after ICH: low depression and dementia risk, early-onset depression and dementia, late-onset depression and dementia, high depression with low dementia risk. Cerebral small vessel disease severity and APOE genotype were specifically associated with the late-onset profile (both p < 0.05). Acute hematoma characteristics (size, intraventricular extension) and functional disability were specifically associated with the early-onset profile (all p < 0.05). Conclusion We identified four distinct profiles for cognitive and depressive symptoms after ICH, each displaying specific associations with individual patients’ clinical, genetic and neuroimaging data. These associations reflect separate biological mechanisms influencing dementia and depression risk after ICH. Our findings support employing LPA in future ICH studies, and is likely applicable to stroke survivors at large.

The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.

Background and Purpose: Intracerebral hemorrhage (ICH) is an acute manifestation of cerebral small vessel disease (CSVD), usually cerebral amyloid angiopathy or hypertensive arteriopathy. CSVD-related imaging findings are associated with increased depression incidence in the general population. Neuroimaging may, therefore, provide insight on depression risk among ICH survivors. We sought to determine whether CSVD CT and magnetic resonance imaging markers are associated with depression risk (before and after ICH), depression remission, and effectiveness of antidepressant treatment. Methods: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital. Participants underwent CT and magnetic resonance imaging imaging and were followed longitudinally. We extracted information for neuroimaging markers of CSVD subtype and severity. Outcomes of interest included pre-ICH depression, new-onset depression after ICH, resolution of depressive symptoms, and response to antidepressant treatment. Results: We followed 612 ICH survivors for a median of 47.2 months. Multiple CSVD-related markers were associated with depression risk. Survivors of cerebral amyloid angiopathy-related lobar ICH were more likely to be diagnosed with depression before ICH (odds ratio, 1.68 [95% CI, 1.14–2.48]) and after ICH (sub-hazard ratio, 1.52 [95% CI, 1.12–2.07]), less likely to achieve remission of depressive symptoms (sub-hazard ratio, 0.69 [95% CI, 0.51–0.94]), and to benefit from antidepressant therapy ( P =0.041). Cerebral amyloid angiopathy disease burden on magnetic resonance imaging was associated with depression incidence and treatment resistance (interaction P =0.037), whereas hypertensive arteriopathy disease burden was only associated with depression incidence after ICH. Conclusions: CSVD severity is associated with depression diagnosis, both before and after ICH. Cerebral amyloid angiopathy-related ICH survivors are more likely to experience depression (both before and after ICH) than patients diagnosed with hypertensive arteriopathy-related ICH, and more likely to report persistent depressive symptoms and display resistance to antidepressant treatment.

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.

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.

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: 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.

Introduction: Intracerebral Hemorrhage (ICH) is an acute manifestation of underlying Cerebral Small Vessel Disease (CSVD), usually Cerebral Amyloid Angiopathy (CAA) or Hypertensive Arteriopathy (HTNA). CSVD-related imaging and histopathology findings were previously associated with increased depression incidence in the general population. CSVD evaluation via neuroimaging may therefore provide insight on depression risk among ICH survivors. We sought to determine whether hematoma location and CSVD MRI markers are associated with depression risk (before and after ICH) and resistance to treatment. Methods: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital (MGH-ICH) since 1994 and currently ongoing. All participants underwent CT and MRI imaging, and were then followed longitudinally via a combination of semi-automated review of Electronic Medical Records (EMR) and phone-based research interviews. We extracted information for hematoma location and MRI neuroimaging markers of CSVD subtype and severity. We conducted univariable and multivariable analyses of depression prevalence before ICH, new-onset of depression after ICH, and resolution of depressive symptoms during follow-up. Results: We enrolled 612 ICH survivors, and followed them for a median of 46.3 months (Inter-Quartile Range: 35.5-58.7). Multiple CSVD-related markers were associated with depression outcomes of interest. Survivors of CAA-related lobar ICH were at highest risk for depression (before and after ICH), as well as treatment resistance (all p Conclusions: CSVD severity on neuroimaging is associated with depression prevalence and treatment-resistance among ICH survivors. CAA-related ICH survivors are at higher risk for depression (both before and after ICH) than patients diagnosed with HTNA-related ICH. The potential role of CSVD evaluation in guiding care of ICH survivors with -or at high risk for- depression warrants additional investigative efforts

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: 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.

Borrelia-specific antibodies in serum did not contribute to the diagnosis of Borrelia arthritis or Borrelia-associated dermatitis in a young woman with ongoing treatment with rituximab due to multiple sclerosis. The diagnosis was confirmed by the detection of Borrelia-DNA in a skin punch biopsy. The patient history did not reveal any tick exposure. She had suffered for several months from fluctuating pain and swelling of the right knee as well as skin involvement with redness and oedema around the ankle of the same leg. Monoarthritis was confirmed by a rheumatologist. Knee puncture was performed but the synovial fluid was only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were found. Borrelia serology in blood revealed borderline levels of immunoglobulin (Ig)M and IgG, respectively. Treatment with doxycycline resulted in resolution of the joint and skin manifestations within a month. This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. Under these circumstances, detection of the bacterial genome in different body fluids, such as in the skin, can be a useful complement to the diagnosis of Lyme disease. In this young female, the diagnosis would certainly have been further delayed without the detection of Borrelia-DNA in the skin.

Background The middle temporal gyrus (MTG) is understood to play a role in language-related tasks such as lexical comprehension and semantic cognition. However, a more specific understanding of its key white matter connections could promote the preservation of these functions during neurosurgery. Objective To provide a detailed description of the underlying white matter tracts associated with the MTG to improve semantic preservation during neurosurgery. Methods Tractography was performed using diffusion imaging obtained from 10 healthy adults from the Human Connectome Project. All tracts were mapped between cerebral hemispheres with a subsequent laterality index calculated based on resultant tract volumes. Ten postmortem dissections were performed for ex vivo validation of the tractography based on qualitative visual agreement. Results We identified 2 major white matter bundles leaving the MTG: the inferior longitudinal fasciculus and superior longitudinal fasciculus. In addition to long association fibers, a unique linear sequence of U-shaped fibers was identified, possibly representing a form of visual semantic transfer down the temporal lobe. Conclusion We elucidate the underlying fiber-bundle anatomy of the MTG, an area highly involved in the brain's language network. Improved understanding of the unique, underlying white matter connections in and around this area may augment our overall understanding of language processing as well as the involvement of higher order cerebral networks like the default mode network in these functions.

ObjectiveTo investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO).MethodsWe performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression.ResultsWe enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, p = 0.269 and 29.9% vs 31.5%, p = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43–4.89, p = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86–6.44, p < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27–5.28, p = 0.009) and replication (OR 2.43, 95% CI 1.42–4.17, p = 0.001) population.ConclusionHE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.

When considering magnesium and intracranial aneurysms (IAs), the first thing that may come to mind is magnesium supplementation in aneurysmal subarachnoid hemorrhage (aSAH) with the hope of improvement in clinical outcomes. The rationale for this approach relies heavily on the vasodilatory effects of the element. Unfortunately, studies to date have had discouraging results for IV infusion in acute aSAH.1,2

Importance Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat poststroke depression but are associated with increased incidence of first-ever intracerebral hemorrhage (ICH) in the general population. The decision to treat ICH survivors with SSRIs must therefore balance potential risks of ICH recurrence with presumed benefits on depressive symptoms. Objective To determine whether SSRI use among survivors of primary ICH was associated with ICH recurrence and decreased severity of depressive symptoms. Design, Setting, and Participants Longitudinal ICH cohort study at a tertiary care center enrolling from January 2006 to December 2017, with follow-up for a median of 53.2 months (interquartile range, 42.3-61.2 months). The study included 1279 consenting individuals (1049 White, 89 Black, 77 Hispanic, and 64 other race/ethnicity) of 1335 eligible patients presenting with primary ICH and who were discharged alive from initial hospitalization for stroke. Main Outcomes and Measures We conducted univariable and multivariable analyses for ICH recurrence risk and depression severity, including subset analyses for patients with 1 or more of the following characteristics associated with high ICH recurrence risk: (1) lobar ICH; (2) presence of the apolipoprotein e2/e4 gene variants; (3) prior history of ICH/TIA/ischemic stroke; and (4) Black or Hispanic race/ethnicity. Results Mean age of study participants was 71.3 years, with 602 women (47%); of the 1279 participants, 1049 were White, 89 were Black, 77 were Hispanic, and 64 were other race/ethnicity. SSRI exposure was associated with both ICH recurrence (subhazard ratio [SHR], 1.31; 95% CI, 1.08-1.59) and resolution of post-ICH depression (SHR, 1.53; 95% CI, 1.12 2.09). Among those individuals at high risk for recurrent ICH, SSRIs were associated with further elevation in risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22-2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01-1.42;P = .008 for comparison of effect sizes). The association of SSRI with reduced depressive symptoms did not differ between high those at high risk for recurrent ICH and all other ICH survivors. Conclusions and Relevance Selective serotonin reuptake inhibitor exposure after ICH is associated with both improvement in depressive symptoms and increased risk of recurrent hemorrhagic stroke. Clinical history, neuroimaging data, and genetic biomarkers may help to identify survivors of ICH more likely to safely tolerate SSRI use.

Background and Purpose: For survivors of oral anticoagulation therapy (OAT)–associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E ( APOE ) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. Methods: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. Results: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. Conclusions: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

Background and Purpose— Classification of stroke as cardioembolic in etiology can be challenging, particularly since the predominant cause, atrial fibrillation (AF), may not be present at the time of stroke. Efficient tools that discriminate cardioembolic from noncardioembolic strokes may improve care as anticoagulation is frequently indicated after cardioembolism. We sought to assess and quantify the discriminative power of AF risk as a classifier for cardioembolism in a real-world population of patients with acute ischemic stroke. Methods— We performed a cross-sectional analysis of a multi-institutional sample of patients with acute ischemic stroke. We systematically adjudicated stroke subtype and examined associations between AF risk using CHA 2 DS 2 -VASc, Cohorts for Heart and Aging Research in Genomic Epidemiology-AF score, and the recently developed Electronic Health Record–Based AF score, and cardioembolic stroke using logistic regression. We compared the ability of AF risk to discriminate cardioembolism by calculating C statistics and sensitivity/specificity cutoffs for cardioembolic stroke. Results— Of 1431 individuals with ischemic stroke (age, 65±15; 40% women), 323 (22.6%) had cardioembolism. AF risk was significantly associated with cardioembolism (CHA 2 DS 2 -VASc: odds ratio [OR] per SD, 1.69 [95% CI, 1.49–1.93]; Cohorts for Heart and Aging Research in Genomic Epidemiology-AF score: OR, 2.22 [95% CI, 1.90–2.60]; electronic Health Record–Based AF: OR, 2.55 [95% CI, 2.16–3.04]). Discrimination was greater for Cohorts for Heart and Aging Research in Genomic Epidemiology-AF score (C index, 0.695 [95% CI, 0.663–0.726]) and Electronic Health Record–Based AF score (0.713 [95% CI, 0.681–0.744]) versus CHA 2 DS 2 -VASc (C index, 0.651 [95% CI, 0.619–0.683]). Examination of AF scores across a range of thresholds indicated that AF risk may facilitate identification of individuals at low likelihood of cardioembolism (eg, negative likelihood ratios for Electronic Health Record–Based AF score ranged 0.31–0.10 at sensitivity thresholds 0.90–0.99). Conclusions— AF risk scores associate with cardioembolic stroke and exhibit moderate discrimination. Utilization of AF risk scores at the time of stroke may be most useful for identifying individuals at low probability of cardioembolism. Future analyses are warranted to assess whether stroke subtype classification can be enhanced to improve outcomes in undifferentiated stroke.

Introduction: Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used to treat post-stroke depression, but they increase Intracerebral Hemorrhage (ICH) incidence in the general population. ICH survivors must therefore balance ICH recurrence risk with depression treatment benefits when considering SSRI use. We sought to determine risks and benefits of SSRI use among survivors of primary ICH. Hypothesis: SSRI exposure following ICH is associated with increased recurrent ICH risk and decreased depression severity. Methods: We analyzed data from the MGH-ICH study. We collected baseline patient information (demographics, race/ethnicity, medical history), ICH characteristics (location, size, associated functional impairment) and determined genetic (APOE e2/e4) and MRI markers of underlying small vessel disease. Participants were followed by phone and EMR review to determine: 1) recurrent ICH events; 2) onset and severity of depression (using the GDS-4 scale). We conducted univariable and multivariable analyses for ICH recurrence risk and depression severity as a function of SSRI exposure. We conducted a subset analysis for patients with one or more of the following characteristics associated high ICH recurrence risk: 1) probable or possible CAA diagnosis (Boston criteria); 2) presence of APOE e2/e4 gene variants; 3) prior history of ICH/TIA/ischemic stroke; 4) black or Hispanic race/ethnicity. Results: We enrolled and followed longitudinally 1010 ICH survivors. SSRI exposure was associated with both ICH recurrence (HR 1.22, 95% CI 1.06 - 1.40) and improvement of depressive symptoms (OR 0.73 for increase in GDS-4 score quartiles, 95% CI 0.59 - 0.90). Among individuals at high ICH recurrence risk SSRI use was associated with higher risk for ICH recurrence compared to all other ICH survivors (interaction p = 0.012). SSRI effect on depressive symptoms did not differ between high ICH recurrence risk individuals and all other participants. Conclusions: SSRI exposure is associated with both improvement in depressive symptoms after ICH and with increased hemorrhage recurrence risk. Clinical history, neuroimaging data and genetic biomarkers may represent viable tools to identify ICH survivors more likely to safely tolerate SSRI use.

Introduction: Intracerebral hemorrhage (ICH) survivors often have severe hypertension and require multiple antihypertensive agents for blood pressure (BP) control. Adequate BP control is vital for ICH prevention, but the majority of ICH survivors have uncontrolled hypertension. To understand how we might improve BP control, we aimed to identify contributors to uncontrolled hypertension, and determine antihypertensive requirements as well as predictors of the need of ≥3 antihypertensives after ICH. Methods: We studied 1172 ICH survivors from two independent ICH cohorts: Massachusetts General Hospital (MGH) and the University of Hong Kong (HKU). We defined uncontrolled hypertension (BP ≥140/90 mmHg), inadequately medicated hypertension (uncontrolled hypertension on ≤2 antihypertensives), and resistant hypertension (uncontrolled hypertension on ≥3 antihypertensive classes or controlled hypertension on ≥4 classes) six months after ICH. Baseline predictors of the need for ≥3 antihypertensive agents were derived using multivariate logistic regression. Results: At six months post-ICH, 64.3% (502/781) of MGH ICH survivors and 32.7% (128/391) of HKU had uncontrolled hypertension. Resistant hypertension accounted for 33.5% and 29.7% of uncontrolled hypertension in the respective cohorts, while the remaining patients qualified for the designation of inadequately medicated hypertension. Excluding patients with inadequately medicated hypertension, 60.0% of patients in MGH and 37.2% in HKU required ≥3 antihypertensive agents. Age p 190 mmHg (OR 3.46, p p Conclusion: Medication inadequacy accounts for around two-thirds of uncontrolled hypertension after ICH, providing an opportunity for intervention to prevent hypertension-related complications, including ICH recurrence. As most ICH survivors required ≥3 antihypertensives for adequate BP control, early inpatient initiation of triple antihypertensive combination therapy should be considered, especially in patients with admission systolic BP of >190 mmHg, known hypertension and aged

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78–0.92] and lower WMH volume (β = –0.07, 95% CI = −0.12 to −0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75–0.89) and lower WMH volume (β = −0.08, 95% CI = −0.13 to −0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26–2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

Objective Observational studies point to an inverse correlation between low‐density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high‐density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results We identified 410, 339, 393, and 317 lipid‐related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH.

Objective This study tests the hypothesis that certain MRI-based regional brain volumes will show reductions over time in a cohort exposed to repetitive head impacts (RHI). Methods Participants were drawn from the Professional Fighters Brain Health Study, a longitudinal observational study of professional fighters and controls. Participants underwent annual 3T brain MRI, computerized cognitive testing, and blood sampling for determination of neurofilament light (NfL) and tau levels. Yearly change in regional brain volume was calculated for several predetermined cortical and subcortical brain volumes and the relationship with NfL and tau levels determined. Results A total of 204 participants who had at least 2 assessments were included in the analyses. Compared to controls, the active boxers had an average yearly rate of decline in volumes of the left thalamus (102.3 mm3/y [p = 0.0004], mid anterior corpus callosum (10.2 mm3/y [p = 0.018]), and central corpus callosum (16.5 mm3/y [p =