Plasma proteomics uncovers divergent molecular signatures in ischemic stroke and intracerebral hemorrhage

The current prognostic models for mortality and functional outcome after intracerebral hemorrhage (ICH) are not simple enough. To predict the outcome of ICH, a new simple model, ICH index (ICHI), was established and evaluated in this study. Medical records of all cases with ICH in our hospital from January 2008 to August 2009 were reviewed. Multiple linear regression analyses were used to assess the contributions of independent variables to hospital mortality after ICH. Age, serum glucose, white blood cell counts (WBC), and Glasgow Coma Scale (GCS) score were found to be greatly associated with mortality. A formula of ICH index [ICHI = age (years)/10 + glucose (mmol/L) + WBC (10(9) /L) - GCS score] was established. Furthermore, the receiver operating characteristic (ROC) analyses were performed to estimate the predictive value of the ICHI. The model showed an area under the ROC curve (AURC) of 0.923 (95% CI: 0.883-0.963, P < 0.001). The best cut-off value of ICHI for mortality was 18, which gave sensitivity, specificity, and Youden's index of 0.65, 0.95, and 0.60, respectively. The hospital mortality was extremely increased when 18 < ICHI < 28 (mortality 72.0%) and when ICHI ≥ 28 (mortality 100%), in contrast with overall mortality (21.6%). The ICHI can be a simple predictive model and complementary to other prognostic models.

Lipoprotein-associated Phospholipase A2 during the Hyperacute Stage of Ischemic and Hemorrhagic Strokes

In the last decade, increasing attention has been paid to understanding the components of care that might contribute to the stroke unit effect. Early mobilization, in its many guises, is one component of care proposed to contribute to the survival and recovery benefits of stroke unit care.1 This topical review provides an overview of the current evidence, research, and practice recommendations for early mobilization after stroke. As a term, early mobilization is problematic. There is no common understanding of the meaning of early (eg, hours, days, weeks, months) or mobilization (movement of, eg, cells, joints, limbs, people). A recurring theme in this review, inadequate definition currently limits our ability to synthesize information on the topic. For example, in some clinical trials of mobility interventions started soon after stroke, mobilization is used to describe a program of task-specific standing and walking retraining (rehabilitation) delivered by therapists or nurses and continued throughout the acute hospital stay.2,3 In other cases, mobilization refers simply to moving a patients’ limbs in bed or sitting them out of bed. The timing of commencement of activity is also highly variable and often hard to determine. As both what we do (intervention type, intensity, frequency, amount), and when we do it, may confer benefit or harm, we highlight variations in definition where relevant. We have focused our review on out-of-bed interventions commencing in the first 24 to 72 hours after stroke, as this is the period of greatest clinical uncertainty. Early mobilization was first discussed at a Swedish consensus conference on stroke care in the mid-1980s (Bo Norving and Bent Indredavik, personal communication, 2014) with several local guidelines in Norway and Sweden recommending the practice. Early mobilization became more prominent in the literature in the early 1990s when Indredavik and colleagues reported their clinical …

Surgical Evacuation of Intracerebral Hemorrhage: The Potential Importance of Timing.

Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence.

Introduction/Hypothesis: Stroke onset during sleep is common and sleep related pathologies have been associated with increased stroke risk. Based on available preliminary data, we tested the hypothesis that stroke during sleep is associated with small vessel disease (SVD). Methods: Prospectively collected data from patients consecutively enrolled after an intracerebral hemorrhage (ICH) related to SVD or after an ischemic stroke (IS) were analyzed. Symptom onset was recorded in relation to sleep vs. awake. Etiology of ICH was coded as cerebral amyloid angiopathy (CAA, per Boston criteria) and hypertensive deep ICH (HTN-ICH). The IS cohort was characterized based on the Causative Classification of Stroke system (5 subtype CCS). We compared frequencies of stroke onset during sleep between the SVD-related ICH and IS cohorts. Event rates, proportions of strokes during sleep and its associations (etiology, risk factors and stroke characteristics) were also analyzed within each cohort. Results: We analyzed 1,038 ICH (mean age: 72.5y +/- 13.0y, 45.4% female) and 1,812 IS patients (mean age: 67.9y +/- 15.9y, 46.4% female). Stroke while asleep was significantly more common among ICH patients (n=282, 26.6%) when compared to IS (n=363, 20.0%, p&lt;0.001). This association between SVD-related ICH and stroke during sleep remained significant after controlling for age, gender and other risk factors (p&lt;0.001). CAA-related ICH and small artery occlusion (SAA) related IS were etiologic subtypes more common among patients who had a stroke during sleep within their respective cohorts (asleep vs awake for CAA within ICH: 57.2% vs. 48.0%, p=0.008 and for SAA within IS: 19.3% vs. 9.1%, p&lt;0.001). CAA and SAA etiologic types remained independent predictors of ICH and IS during sleep in respective multivariate models including other clinical features and risk factors (p=0.019 and p=0.011). Conclusions: Stroke during sleep was strongly associated with SVD-related ICH when compared to all IS. CAA within ICH group and SAA etiology within IS cohort were related to stroke during sleep in univariate and multivariate models. Presence of SVD can interact with sleep pathologies and/or sleep related hemodynamic changes to cause ischemic and hemorrhagic stroke.

P3718Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage

An Update on Neurocritical Care for the Patient With Kidney Disease

Clinical Relevance of Cerebral Small Vessel Diseases.

Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P<0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P<0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Although imaging is the mainstay to differentiate ischemic stroke (IS) from intracerebral hemorrhage (ICH), these facilities are not available everywhere. The present study observed if any blood biomarker(s) could potentially help differentiate between ischemic stroke and intracerebral hemorrhage. 250 patients with acute stroke within 24 hours of onset (187 IS and 63 patients with ICH) were recruited in the present study. The blood samples were collected closest to the hospital presentation time, but within 24 hours of stroke onset. Blood was analyzed for five biomarkers [S100, glial fibrillary acidic protein (GFAP), N-methyl-D-aspartate receptor subunit antibody (NR2), interleukin 6 (IL6) and brain natriuretic peptide (BNP)] to assess discriminatory ability of each biomarker to differentiate ICH and IS. S100 levels were statistically higher among patients with ICH compared with IS (8 pg/ml versus 4.2 pg/ml respectively, P = 0.003) and IL6 was higher in patients with IS compared with ICH (12.9 pg/ml vs 8.76 pg/ml, P = 0.02). The discriminatory ability to differentiate ICH from IS was better using a combination of the above two biomarkers. The overall discriminatory ability of all biomarkers were low (Area under curve for S100 65%; GFAP 56%; NR2 53%; IL6 59% and BNP 49.8%). Although the positive predictive value of each biomarker was low, the negative predictive value was higher for all biomarkers to diagnose ICH. S100 and IL6 are potential biomarkers for further study and validation. Newer biomarkers with higher discriminatory ability are required in the future for diagnostic use.

A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke

Marc Fisher MD Kennedy Lees MD Section Editors: Hypertension is the most important modifiable risk factor for stroke.1,2 It is estimated that 25% or more of strokes may be attributable to hypertension. Because many patients with stroke have mild hypertension or prehypertension, we have shifted our focus and now think of stroke on a continuum of risk based on blood pressure (BP) level rather than on a threshold effect.3 Because high BP may not exist in isolation, a wider definition of hypertension has been proposed that also takes into account the absolute risk of cardiovascular events and associated metabolic factors or early disease markers.3 Lowering BP reduces the risk of stroke. Epidemiological studies have shown that for each 10 mm Hg lower systolic blood pressure (SBP), there is a decrease in risk of stroke of approximately one third in persons aged 60 to 79 years. This association is continuous down to levels of at least 115/75 mm Hg and is consistent across sexes, regions, stroke subtypes, and for fatal and nonfatal events.4 Lowering diastolic blood pressure (DBP) was once the main target to achieve stroke and other cardiovascular event reduction, but SBP has now become the target.3 As recently shown, even the elderly with sustained SBP elevation may gain from BP reduction in relation to less fatal or nonfatal stroke, death, and heart failure.5 Although the role of longer-term BP control to improve outcomes in patients with stroke is undisputed, BP management immediately after a stroke remains controversial. In an effort to resolve this controversy, several pilot clinical trials have been initiated. In this review, we discuss the results of some of these trials and available evidence-based guidelines for BP control in the settings of acute ischemic and hemorrhagic stroke (excluding subarachnoid hemorrhage) and …

Investigating the short and long-term signaling mechanisms via small extracellular vesicles (sEVs) in peripheral blood following human Ischemic Stroke (IS) and Intracerebral Hemorrhage (ICH) is of great interest. The sEV’s cargo can induce distant responses which can be used to derive potential novel therapeutic targets and biomarkers to differentiate the two brain pathologies. Thus, we sequenced the miRNA cargo derived from peripheral blood sEVs in IS (n=3), ICH (n=3), and Vascular Risk Factor-matched Control (VRFC; n=3) subjects. Subjects were divided into contrast groups (IS vs VRFC, ICH vs VRFC, ICH vs IS), and log2 transformed expression underwent Kruskal-Wallis tests to identify differentially expressed (DE; p&lt;0.05) miRNAs. We found 55 DE miRNAs in IS vs VRFC, 38 in ICH vs VRFC, and 45 in ICH vs IS ( Fig. 1A ). The combination of these miRNAs differentiated the three groups on Principal Components Analysis ( Fig. 1B ). IS associated miRNA included miR-30a, miR-30b, and miR-144. miR-30a is involved in hematopoietic stem cell self-renewal and can impair B cell differentiation. miR-30b may be an immune suppressor via Notch1. In male mice, miR-144 is protective against atherosclerosis. ICH associated miRNA included miR-195, miR-1-3p, and miR-20b-5p. miR-195 can inhibit the pro-inflammatory roles of macrophages. miR-1-3p is involved in cardiomyocyte development, can target TLR1 (Toll-Like Receptor 1), and may regulate autophagy. miR-20b-5p reduces Amyloid Precursor Protein (APP) mRNA and protein levels; vascular accumulation of APP is one cause of Lobar ICH. We show differential expression of sEV-derived miRNAs in peripheral blood of human IS and ICH patients that are involved in relevant signaling processes. sEV cargo profiles pose a largely underexplored intercellular signaling mechanism in IS and ICH with the potential to better characterize long distance signaling from injured brain to peripheral blood leukocytes in these brain disorders.

Major Ongoing Stroke Trials