Modeling Intracerebral Hemorrhage Growth and Response to Anticoagulation

The mechanism for hemorrhage enlargement in the brain, a key determinant of patient outcome following hemorrhagic stroke, is unknown. We performed computer-based stochastic simulation of one proposed mechanism, in which hemorrhages grow in “domino” fashion via secondary shearing of neighboring vessel segments. Hemorrhages were simulated by creating an initial site of primary bleeding and an associated risk of secondary rupture at adjacent sites that decayed over time. Under particular combinations of parameters for likelihood of secondary rupture and time-dependent decay, a subset of lesions expanded, creating a bimodal distribution of microbleeds and macrobleeds. Systematic variation of the model to simulate anticoagulation yielded increases in both macrobleed occurrence (26.9%, 53.2%, and 70.0% of all hemorrhagic events under conditions simulating no, low-level, and high-level anticoagulation) and final hemorrhage size (median volumes 111, 276, and 412 under the same three conditions), consistent with data from patients with anticoagulant-related brain hemorrhages. Reversal from simulated high-level anticoagulation to normal coagulation was able to reduce final hemorrhage size only if applied relatively early in the course of hemorrhage expansion. These findings suggest that a model based on a secondary shearing mechanism can account for some of the clinically observed properties of intracerebral hemorrhage, including the bimodal distribution of volumes and the enhanced hemorrhage growth seen with anticoagulation. Future iterations of this model may be useful for elucidating the effects of hemorrhage growth of factors related to secondary shearing (such as small vessel pathology) or time-dependent decay (such as hemostatic agents)

Screening for Familial APP Mutations in Sporadic Cerebral Amyloid Angiopathy

Background Advances in genetic technology have revealed that variation in the same gene can cause both rare familial and common sporadic forms of the same disease. Cerebral amyloid angiopathy (CAA), a common cause of symptomatic intracerebral hemorrhage (ICH) in the elderly, can also occur in families in an autosomal dominant pattern. The majority of affected families harbor mutations in the Beta amyloid Peptide (Aβ) coding region of the gene for amyloid precursor protein (APP) or have duplications of chromosomal segments containing APP. Methodology/Principal Findings A total of 58 subjects with a diagnosis of probable or definite CAA according to validated criteria were included in the present study. We sequenced the Aβ coding region of APP in 58 individuals and performed multiplex ligation-dependent probe amplification to determine APP gene dosage in 60. No patient harbored a known or novel APP mutation or gene duplication. The frequency of mutations investigated in the present study is estimated to range from 0% to 8% in individuals with probable CAA in the general population, based on the ascertained sample size. Conclusions/Significance We found no evidence that variants at loci associated with familial CAA play a role in sporadic CAA. Based on our findings, these rare highly-penetrant mutations are unlikely to be seen in sporadic CAA patients. Therefore, our results do not support systematic genetic screening of CAA patients who lack a strong family history of hemorrhage or dementia.National Institute of Neurological Disorders and Stroke (U.S.) (grant K23NS042695)American Heart AssociationAmerican Stroke Association (Bugher Foundation for Stroke Prevention Research

Apolipoprotein E4 Polymorphism and Outcomes from Traumatic Brain Injury : A Living Systematic Review and Meta-Analysis

The mortality of traumatic brain injury (TBI) has been largely static despite advances in monitoring and imaging techniques. Substantial variance exists in outcome, not fully accounted for by baseline characteristics or injury severity, and genetic factors likely play a role in this variance. The aims of this systematic review were to examine the evidence for a link between the apolipoprotein E4 (APOE4) polymorphism and TBI outcomes and where possible, to quantify the effect size via meta-analysis. We searched EMBASE, MEDLINE, CINAHL, and gray literature in December 2017. We included studies of APOE genotype in relation to functional adult TBI outcomes. Methodological quality was assessed using the Quality in Prognostic Studies Risk of Bias Assessment Instrument and the prognostic studies adaptation of the Grading of Recommendations Assessment, Development and Evaluation tool. In addition, we contacted investigators and included an additional 160 patients whose data had not been made available for previous analyses, giving a total sample size of 2593 patients. Meta-analysis demonstrated higher odds of a favorable outcome following TBI in those not possessing an ApoE e4 allele compared with e4 carriers and homozygotes (odds ratio 1.39, 95% confidence interval 1.05 to 1.84; p = 0.02). The influence of APOE4 on neuropsychological functioning following TBI remained uncertain, with multiple conflicting studies. We conclude that the ApoE e4 allele confers a small risk of poor outcome following TBI, with analysis by TBI severity not possible based on the currently available published data. Further research into the long-term neuropsychological impact and risk of dementia is warranted.Peer reviewe

Disparities in brain health comorbidity management in intracerebral hemorrhage

BackgroundIntracerebral hemorrhage (ICH) disproportionally affects underserved populations, and coincides with risk factors for cardiovascular events and cognitive decline after ICH. We investigated associations between social determinants of health and management of blood pressure (BP), hyperlipidemia, diabetes, obstructive sleep apnea (OSA), and hearing impairment before and after ICH hospitalization.MethodsSurvivors of the Massachusetts General Hospital longitudinal ICH study between 2016 and 2019 who received healthcare at least 6 months after ICH were analyzed. Measurements of BP, LDL and HbA1c and their management in the year surrounding ICH and referrals for sleep studies and audiology up to 6 months after ICH were gathered from electronic health records. The US-wide area deprivation index (ADI) was used as proxy for social determinants of health.ResultsThe study included 234 patients (mean 71 years, 42% female). BP measurements were performed in 109 (47%) before ICH, LDL measurements were performed in 165 (71%), and HbA1c measurements in 154 (66%) patients before or after ICH. 27/59 (46%) with off-target LDL and 3/12 (25%) with off-target HbA1c were managed appropriately. Of those without history of OSA or hearing impairment before ICH, 47/207 (23%) were referred for sleep studies and 16/212 (8%) to audiology. Higher ADI was associated with lower odds of BP, LDL, and HbA1c measurement prior to ICH [OR 0.94 (0.90–0.99), 0.96 (0.93–0.99), and 0.96 (0.93–0.99), respectively, per decile] but not with management during or after hospitalization.ConclusionSocial determinants of health are associated with pre-ICH management of cerebrovascular risk factors. More than 25% of patients were not assessed for hyperlipidemia and diabetes in the year surrounding ICH hospitalization, and less than half of those with off-target values received treatment intensification. Few patients were evaluated for OSA and hearing impairment, both common among ICH survivors. Future trials should evaluate whether using the ICH hospitalization to systematically address co-morbidities can improve long-term outcomes

Leukocyte Count and Intracerebral Hemorrhage Expansion

BACKGROUND AND PURPOSE: Acute leukocytosis is a well-established response to intracerebral hemorrhage (ICH). Leukocytes, because of their interaction with platelets and coagulation factors, may in turn play a role in hemostasis. We investigated whether admission leukocytosis was associated with reduced bleeding following acute ICH. METHODS: Consecutive patients with primary ICH were prospectively collected from 1994 to 2015 and retrospectively analyzed. We included subjects with a follow-up CT scan available and automated complete white blood cell (WBC) count performed within 48 h from onset. Baseline and follow-up hematoma volumes were calculated with semi-automated software and hematoma expansion was defined as volume increase > 30% or 6 mL. The association between WBC count and ICH expansion was investigated with multivariate logistic regression. RESULTS: 1302 subjects met eligibility criteria (median age 75 years, 55.8 % males), of whom 207 (15.9 %) experienced hematoma expansion. Higher leukocyte count on admission was associated with reduced risk of hematoma expansion (Odds Ratio for 1000 cells increase [OR] 0.91, 95 % Confidence Interval [CI] 0.86–0.96, p=0.001). The risk of hematoma expansion was inversely associated with neutrophil count (OR 0.90, 95 % CI 0.85–0.96, p=0.001) and directly associated with monocyte count (OR 2.71, 95 % CI 1.08–6.83, p=0.034). There was no association between lymphocyte count and ICH expansion (OR 0.96, 95 % CI 0.79–1.17, p=0.718). CONCLUSIONS: Higher admission WBC count is associated with lower risk of hematoma expansion. This highlights a potential role of the inflammatory response in modulating the coagulation cascade following acute ICH

Whole blood microRNA expression associated with stroke: Results from the Framingham Heart Study

Emerging evidence suggests microRNAs (miRNAs) may play an important role in explaining variation in stroke risk and recovery in humans, yet there are still few longitudinal studies examining the association between whole blood miRNAs and stroke. Accounting for multiple testing and adjusting for potentially confounding technical and clinical variables, here we show that whole blood miR-574-3p expression was significantly lower in participants with chronic stroke compared to non-cases. To explore the functional relevance of our findings, we analyzed miRNA-mRNA whole blood co-expression, pathway enrichment, and brain tissue gene expression. Results suggest miR-574-3p is involved in neurometabolic and chronic neuronal injury response pathways, including brain gene expression of DBNDD2 and ELOVL1. These results suggest miR-574-3p plays a role in regulating chronic brain and systemic cellular response to stroke and thus may implicate miR-574-3p as a partial mediator of long-term stroke outcomes

Common NOTCH3 Variants and Cerebral Small-Vessel Disease.

BACKGROUND AND PURPOSE: The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. METHODS: We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency>0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. RESULTS: We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. CONCLUSIONS: Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease.Collection of the UK Young Lacunar Stroke DNA Study (DNA lacunar) was primarily supported by the Wellcome Trust (WT072952) with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA lacunar samples, and Dr Traylor, was supported by a Stroke Association Grant (TSA 2013/01). Funding for the genotyping at Massachusetts General Hospital was provided by the Massachusetts General Hospital- Deane Institute for the Integrative Study of Atrial Fibrillation and Stroke and the National Institute of Neurological Disorders and Stroke (U01 NS069208). Dr Rutten-Jacobs was supported by a project grant from the Stroke Association/British Heart Foundation grant (TSA BHF 2010/01). Dr Adib-Samii was supported by a Medical Research Council (United Kingdom) training fellowship. Drs Markus and Bevan were supported by the National Institute for Health Research Cambridge University Hospitals Comprehensive Biomedical Research Centre. Dr Markus was supported by a National Institute for Health Research Senior Investigator award. Dr Thijs was supported by a Clinical Investigator Grant from the scientific research fund, Fonds Wetenschappelijk Onderzoek Flanders. Dr Rost was supported by a National Institute of Neurological Disorders and Stroke grant (R01 NS082285-01).This is the final published version. It first appeared at http://stroke.ahajournals.org/content/46/6/1482.long