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Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Background and Purpose: We investigated the effect of higher therapeutic exercise doses on walking during inpatient rehabilitation, typically commencing 1 to 4 weeks poststroke. Methods: This phase II, blinded-assessor, randomized controlled trial recruited from 6 Canadian inpatient rehabilitation units, between 2014 and 2018. Subjects (n=75; 25/group) were randomized into: control (usual care) physical therapy: typically, 1 hour, 5 days/week; Determining Optimal Post-Stroke Exercise (DOSE1): 1 hour, 5 days/week, more than double the intensity of Control (based on aerobic minutes and walking steps); and DOSE2: 2 hours, 5 days/week, more than quadruple the intensity of Control, each for 4 weeks duration. The primary outcome, walking endurance at completion of the 4-week intervention (post-evaluation), was compared across these groups using linear regression. Secondary outcomes at post-evaluation, and longitudinal outcomes at 6 and 12-month evaluations, were also analyzed. Results: Both DOSE1 (mean change 61 m [95% CI, 9–113], P =0.02) and DOSE2 (mean change 58 m, 6–110, P =0.03) demonstrated greater walking endurance compared with Control at the post-evaluation. Significant improvements were also observed with DOSE2 in gait speed (5-m walk), and both DOSE groups in quality of life (EQ-5D-5 L) compared with Control. Longitudinal analyses revealed that improvements in walking endurance from the DOSE intervention were retained during the 1-year follow-up period over usual care. Conclusions: This study provides the first preliminary evidence that patients with stroke can improve their walking recovery and quality of life with higher doses of aerobic and stepping activity within a critical time period for neurological recovery. Furthermore, walking endurance benefits achieved from a 4-week intervention are retained over the first-year poststroke. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01915368.

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

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

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

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

BACKGROUND: Orthostatic hypotension (OH) has been independently associated with increased risk of stroke and other cardiovascular events. We sought to investigate the relationship between OH at follow up and recurrent stroke risk in SPS3 (Secondary Prevention of Small Subcortical Strokes) trial patient cohort. This is a retrospective cohort analysis. METHODS: We included all SPS3 trial participants with blood pressure measurements in both sitting and standing position per protocol at baseline, with at least 1 follow up visit to establish the relationship between OH at follow up and recurrent stroke risk (primary outcome). Secondary outcomes included major vascular events, myocardial infarction (MI), all-cause mortality, and, ischemic and hemorrhagic stroke subtypes. Participants were classified as having OH at baseline and at each follow up visit based on a systolic BP decline ≥ 20 mm Hg or a diastolic BP decline ≥ 10 mm Hg on position change from sitting to standing. We used Cox proportional hazards regression modeling to compare the risk of outcomes among those with and without OH. RESULTS: A total of 2275 patients were included with a mean follow up time 3.2 years (standard deviation = 1.6 years). 39% (881/2275) had OH at some point during their follow up. Of these, 41% (366/881) had orthostatic symptoms accompanying the BP drop. In a fully adjusted model, those with OH had a 1.8 times higher risk of recurrent stroke than those without OH (95% CI: 1.1–3.0). The risk of ischemic stroke, major vascular events, and all-cause mortality was similarly elevated among the OH group. CONCLUSION: Orthostatic hypotension was associated with increased recurrent stroke risk, vascular events, and all-cause death in this large cohort of lacunar stroke patients. Whether minimizing OH in the management of post-stroke hypertension in patients with lacunar stroke reduces recurrent stroke risk deserves further study.

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10(−8)). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10(−4), Beta = 3.09, diastolic BP response P = 5 × 10(−3), Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients’ subgroup (P = 2.35 × 10(−4), odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

Introduction – Randomised controlled trials (RCTs) have shown that antiplatelet and anticoagulant (antithrombotic) agents reduce the risk of stroke and other major vascular events for a variety of patients despite increasing the risk of bleeding. However, patients with intracranial haemorrhage were not included in these RCTs, so the risks and benefits of antithrombotic agents after intracranial haemorrhage are uncertain. Methods and analysis – The Collaboration Of Controlled Randomised trials of long-term Oral Antithrombotic drugs after spontaneous intraCranial Haemorrhage (COCROACH) aims to perform an individual participant data meta-analysis (IPDMA) in order to provide reliable information about the effects of antithrombotic agents on the risks of major vascular events after spontaneous intracranial haemorrhage overall, and in clinically important sub-groups. The protocol of the corresponding Cochrane Review (8 April 2016) specified the methods used by this IPDMA for searching the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase, and online registries of RCTs. RCTs are eligible for inclusion in this IPDMA if they are registered with a trial registry, include participants with spontaneous intracranial haemorrhage who are allocated at random to long-term use of any oral antithrombotic agent(s) or to placebo, open control, another antithrombotic agent, or another intervention for the prevention of major vascular events, and their chief investigator agrees to share participant-level de-identified data. COCROACH was initiated at the European Stroke Organisation Conference on 17 May 2017 before the results of any RCTs were known. This protocol was agreed after the publication of one RCT of antiplatelet agents (RESTART ISRCTN71907627) and the presentation of one trial of an oral anticoagulant agent (NASPAF-ICH NCT02998905), but before the majority of RCT results were known. We will perform two-step IPDMA of included RCTs using their intention-to-treat datasets using fixed effects models as the primary analysis. We will conduct separate IPDMAs, grouping RCTs into distinct dyads of intervention (antithrombotic agent class) and comparator, as allocated by randomisation. The primary outcome for each IPDMA will be a composite outcome of major vascular events that are appropriate to the intervention-comparator dyad. Secondary outcomes will include major ischaemic events and major haemorrhagic events. We will assess interactions with the effects of antithrombotic agents on the primary outcome in demographic, clinical, imaging, and treatment-related sub-groups. Ethics and dissemination – All participant data will be shared with the University of Edinburgh by included RCTs with the intention of addressing the same research question for which they were acquired. Participant-level data will be de-identified and shared unless forbidden by individual participants or regulatory authorities. We will disseminate the results of this IPDMA in peer-reviewed journals.

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

Context Lacunar strokes and diabetes are risk factors for cognitive dysfunction. Elucidating modifiable risk factors for cognitive dysfunction has great public health implications. One factor may be glycemic status, as measured by glycated hemoglobin (A1c). Objective The aim of this study was to assess the relationship between A1c and cognitive function in lacunar stroke patients with diabetes. Methods The effect of baseline and follow-up A1c on the baseline and the change in Cognitive Assessment Screening Instrument (CASI) score over time among participants with a median of 2 cognitive assessments (range, 1-5) was examined in 942 individuals with diabetes and a lacunar stroke who participated in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (ClinicalTrials.gov No. NCT00059306). Results Every 1% higher baseline A1c was associated with a 0.06 lower standardized CASI z score (95% CI, –0.101 to –0.018). Higher baseline A1c values were associated with lower CASI z scores over time (P for interaction = .037). A 1% increase in A1c over time corresponded with a CASI score decrease of 0.021 (95% CI, –0.0043 to –0.038) during follow-up. All these remained statistically significant after adjustment for age, sex, education, race, depression, hypertension, hyperlipidemia, body mass index, cardiovascular disease, obstructive sleep apnea, diabetic retinopathy, nephropathy insulin use, and white-matter abnormalities. Conclusion This analysis of lacunar stroke patients with diabetes demonstrates a relationship between A1c and change in cognitive scores over time. Intervention studies are needed to delineate whether better glucose control could slow the rate of cognitive decline in this high-risk population.

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

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

OBJECTIVE To determine whether cerebral small vessel disease or disability modify the effect of SBP treatment on cognitive and vascular outcomes in older patients with recent lacunar stroke. METHODS Participants aged at least 65 years of the Secondary Prevention of Small Subcortical Strokes Trial were randomized to a higher (130-149 mmHg) or lower (

Background & Objective Both lacunar strokes and diabetes are risk factors for dementia and cognitive dysfunction. Thus, elucidating modifiable risk factors for cognitive dysfunction in people with type 2 diabetes who experienced a lacunar infarct has large public health implications. One such factor may be glycemic status, as measured by glycosylated hemoglobin (A1C). Thus, the aim of this study was to assess the relationship between A1C and cognitive function in people with diabetes after a lacunar stroke. Research Design & Methods The effect of baseline and follow-up A1C on the baseline and the change in Cognitive Assessment Screening Instrument (CASI) score over time among participants with a median of 2 cognitive assessments (range 1-5) was examined in of 942 individuals with diabetes and a lacunar stroke who participated in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (ClinicalTrials.gov number, NCT00059306). Results Every 1 % higher baseline A1C was associated with a 0.06 lower standardized CASI z-score (95% CI -0.101, -0.018). Higher baseline A1C values were associated with lower CASI z-score over time (p for interaction=0.037). A 1% increase in A1C over time, corresponded with a CASI score decrease of 0.021 (95% CI -0.0043, -0.038) during follow-up. All these remained statistically significant after adjustment for age, sex, education, race, depression, hypertension, hyperlipidemia, BMI, CVD, OSA, diabetic retinopathy, nephropathy insulin use and White Matter Abnormalities. Conclusion This analysis of 942 individuals with diabetes after a lacunar stroke demonstrates a relationship between A1C and change in cognitive scores over time. Intervention studies are needed in order to delineate if better glucose control could slow the rate of cognitive decline in this high risk population.

Background and Purpose— Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods— DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results— A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0–2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778–6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03–1.12]; P =0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions— Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02295826.

Background: Stroke in middle-aged persons is emerging as a distinct entity from previously described "stroke in the young.” Risk factors for recurrence of vascular events in middle-aged stroke survivors have not been well described in a large, racially diverse US-based population. Methods: We performed a retrospective longitudinal analysis of claims data from all hospitalizations in California (2005-2011), Florida (2005-2014), and New York (2005-2014). We included survivors of first-ever ischemic stroke (IS) and non-traumatic intracerebral hemorrhage (ICH). We used validated ICD-9 codes to identify recurrent vascular events, defined as a readmission with a primary diagnosis of IS, ICH, or myocardial infarction (MI). We used survival analysis and Cox proportional hazards regression to determine factors associated with recurrence risk in middle-aged (40-60 years) versus older (>60 years) adults. Results: We identified 123,212 non-fatal hospitalizations for first-ever IS or ICH in middle-aged adults. There were 14,721 readmissions for recurrent vascular events (11.9%) over a mean follow-up of 4.0 years (standard deviation [SD] 2.8 years). The 1-year and 10-year recurrence rates were 5.5% (95% confidence interval [CI], 5.3%-5.6%) and 19.4% (95% CI, 19.0%-19.8%) respectively. In multivariable analysis, black (hazard ratio [HR] 1.44; 95% CI, 1.39-1.50; p Conclusions: Black race and diabetes were the strongest risk factors for recurrence of vascular events in a middle-aged population. Further study of interventions to reduce recurrence and resulting disability in this younger, higher risk population is needed.

Background: The precise role of stroke risk factors in middle-aged people remains a significant knowledge gap. Confounding risk factors conferred by young and elderly stroke are largely avoided, providing a unique opportunity to understand the relationship between traditional risk factors and stroke. We aimed to determine the predictors of stroke and myocardial infarction (MI) in a unique middle-aged cohort with MRI-defined lacunar stroke. Methods: We conducted a reanalysis of data from the Secondary Prevention of Small, Subcortical Strokes (SPS3) clinical trial. We focused on middle-aged study participants, defined as those aged 40-60 years at study entry. We used multivariate Cox regression models to estimate the risk of recurrent stroke or MI. Results: Out of 3,020 total subjects from SPS3, 1,312 (mean age 53 [SD 5], 445 females [34%]) were in the middle-aged category and were included in this analysis. Of these, there were 619 (47%) white, 297 (23%) black, and 283 (22%) Hispanic subjects. Over a mean follow-up time of 3.90 years, there were 123 strokes (2.6% per patient-year) and 33 MIs (0.7% per patient-year). The rates (% per patient-year) of having a stroke or MI differed significantly across white (n=59, 2.7%), black (n=54, 5.1%), and Hispanic (n=27, 2.8%) ethnic groups (p=0.006). Significant risk factors for recurrent stroke or MI are described for middle-aged and all SPS3 subjects in the table. Conclusions: In middle-aged individuals with prior stroke, diabetes, greater white matter disease severity, black race, and family history were potent predictors of recurrent stroke. Male sex, diabetes, and heart disease were potent predictors of MI. Compared to the entire SPS3 cohort, these predictors confer a greater risk for recurrent stroke or MI in the middle-aged. These data identify modifiable risk factors and target populations that are especially vulnerable to vascular events or complications.

Rationale A top priority in stroke rehabilitation research is determining the appropriate exercise dose to optimize recovery. Although more intensive rehabilitation very early after stroke may be deleterious to recovery, inpatient rehabilitation, occurring after acute care, may be a more appropriate setting to assess therapeutic dose on neurological recovery. Hypothesis Individuals receiving higher intensity and dose exercise programs will yield greater improvements in walking ability over usual inpatient physical therapy care. Methods and design Seventy-five individuals across seven inpatient rehabilitation sites in Canada will be randomized into one of three treatment programs, each 5 days/week, for four weeks and monitored for exertion (heart rate) and repetitions (step count). Study outcomes The primary outcome measure is the 6 min walk and secondary outcomes include functional independence, cognitive, and quality-of-life measures. Outcome data will be assessed at four time points. Summary This trial will contribute to our knowledge of the therapeutic intensity and dose necessary to maximize functional recovery at a very important stage of rehabilitation and neural recovery poststroke.

PURPOSE: We applied cluster analysis to identify discrete patterns of concomitant responses of systolic (SBP), diastolic (DBP) and pulse pressure (PP) during intensive BP lowering; and to evaluate their clinical relevance and association with risk of mortality, major vascular events (MVEs), and stroke. MATERIAL AND METHODS: We used an unsupervised cluster procedure to identify distinct patterns of BP change during the first 9 months of anti-hypertensive therapy intensification among 1,331 participants in the Secondary Prevention of Small Subcortical Strokes Trial who were previously randomized to lower BP target (SBP

Background and Purpose— We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. Methods— We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2–4, ≥5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2). Results— In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09–2.07; P =0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73–5.35; P P =0.014), PH ( P =0.013), and PHr ( P 10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10–3.12; P =0.020; and odds ratio: 3.99; 95% confidence interval: 1.55–10.22; P =0.004, respectively). Conclusions— Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

OBJECTIVE To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment. METHODS SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs

Objective To describe the systematic development of the Stroke Coach, a theory- and evidence-based intervention to improve control of lifestyle behavior risk factors in patients with stroke. Design Intervention development. Setting Community. Participants Individuals who have had a stroke. Interventions We used intervention mapping to guide the development of the Stroke Coach. Intervention mapping is a systematic process used for intervention development and composed of steps that progress from the integration of theory and evidence to the organization of realistic strategies to facilitate the development of a practical intervention supported by empirical evidence. Social cognitive theory was the underlying premise for behavior change, whereas control theory methods were directed toward sustaining the changes to ensure long-term health benefits. Practical evidence-based strategies were linked to behavioral determinants to improve stroke risk factor control. Main Outcome Measures Not applicable. Results The Stroke Coach is a patient-centered, community-based, telehealth intervention to promote healthy lifestyles after stroke. Over 6 months, participants receive seven 30- to 60-minute telephone sessions with a lifestyle coach who provides education, facilitates motivation for lifestyle modification, and empowers participants to self-management their stroke risk factors. Participants also receive a self-management manual and a self-monitoring kit. Conclusions Through the use of intervention mapping, we developed a theoretically sound and evidence-grounded intervention to improve risk factor control in patients with stroke. If empirical evaluation of the Stroke Coach produces positive results, the next step will be to develop an implementation intervention to ensure successful uptake and delivery of the program in community and outpatient settings.

Background and Purpose— Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and β-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by β-blocker treatment in patients with a history of stroke. Methods— Nine hundred and twenty-six participants of the SPS3 trial’s (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan–Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). Results— MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P =0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00–2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01–3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03–1.26) in SiGN. In SPS3, β-blocker-treated Gly49 carriers had increased MACE versus non–β-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20–3.45). No associations were observed with the Arg389Gly polymorphism. Conclusion— Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among β-blocker-treated individuals. Further research is needed to define β-blocker benefit among ischemic stroke patients by ADRB1 genotype. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00059306.

We critically evaluate the evidence for the use of antiplatelet therapy for stroke prevention following lacunar stroke and in patients with hemorrhage-prone cerebral small vessel disease. Pooled lacunar stroke subgroup analyses of all relevant randomized controlled trials to date suggest a 22% relative risk reduction in recurrent stroke by single antiplatelet therapy (RR 0.77, 95% CI 0.62–0.97) compared with placebo, no consistent suggestion of variable efficacy amongst specific antiplatelet agents, and the absence of clear benefit with dual over single antiplatelet therapy. Current data does not support withholding antiplatelet therapy where otherwise indicated in patients with cerebral microbleeds on MRI or those who have suffered intracerebral hemorrhage. Antiplatelet monotherapy appears to provide persistent secondary stroke prevention in patients with lacunar stroke. Whether phosphodiesterase inhibitors, particularly cilostazol, provide additional advantage in patients with cerebral small vessel disease is worthy of further investigation.

Background We aimed to determine whether cerebral white matter hyperintensities ( WMHs ) can distinguish stroke survivors susceptible to rapid kidney function decline from intensive blood pressure ( BP ) lowering. Methods and Results The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial randomized participants with recent lacunar stroke to systolic BP targets of 130 to 149 and WMH measured by clinical magnetic resonance imaging at baseline and serum creatinine measured during follow‐up. We tested interactions between BP target and WMH burden on the incidence of rapid kidney function decline (≥30% decrease from baseline estimated glomerular filtration rate at 1‐year follow‐up) and recurrent stroke. Rapid kidney function decline incidence was 11.0% in the lower‐ BP ‐target arm and 8.1% in the higher‐target arm (odds ratio=1.40; 95% CI=1.07–1.84). Odds ratio for rapid kidney function decline between lower‐ and higher‐target groups ranged from 1.26 in the lowest WMH tertile (95% CI , 0.80–1.98) to 1.71 in the highest tertile (95% CI , 1.05–2.80; P for interaction=0.65). Overall incidence of recurrent stroke was 7.9% in the lower‐target arm and 9.6% in the higher‐target arm (hazard ratio=0.80; 95% CI , 0.63–1.03). Hazard ratio for recurrent stroke in the lower‐target group was 1.13 (95% CI , 0.73–1.75) within the lowest WMH tertile compared with 0.73 (95% CI , 0.49–1.09) within the highest WMH tertile ( P for interaction=0.04). Conclusions Participants with higher WMH burden appeared to experience greater benefit from intensive BP lowering in prevention of recurrent stroke. By contrast, intensive BP lowering increased the odds of kidney function decline, but WMH burden did not significantly distinguish this risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00059306.

Background: Obesity is a recognized risk factor for stroke. But, it is uncertain whether obesity is related to burden of cerebral small vessel disease (CSVD). We explored burden of CSVD, stroke recurrence and mortality in obese and non-obese patients with lacunar infarcts. Method: Data was from the SPS3 (Secondary Prevention of Small Subcortical Strokes) trial. Participants were according to BMI categories: normal /underweight (30.0). Baseline MRI findings were explored with multivariable logistic regression and outcomes using multivariable Cox proportional hazards. Results: Compared with participants who were normal/underweight (n=691, 23%) overweight (n=1256, 42%) and obese (n=1072, 36%) participants tended to be younger, male and with a higher prevalence of vascular risk factors. Compared to obese participants, normal/underweight had a higher burden of SVD on MRI: odds were 1.40 ( 95% CI 1.15 - 1.69) for severe burden of white matter disease, 1.23 (1.01 - 1.52) for 1+ old lacunes, and, in those 1278 participants with baseline T2*-weighted gradient echo MRI, 1.64 (1.35-2.00) times as likely to have 1+ microbleeds. During a mean follow-up of 3.3 years, overweight and obese subjects also had a lower risk of stroke recurrence (HR 0.74, 95% CI 0.5-1.0 and HR 0.71, 95% CI 0.5-1.0, respectively) and death (HR 0.71 95% CI 0.5-1.0 and HR 0.61, 95% CI 0.4-0.9, respectively). Conclusion: In this cohort, unexpectedly, being overweight or obese was associated with less CSVD, stroke recurrence and mortality. Further research is required to elucidate the mechanisms for this relationship.

Combination aspirin and clopidogrel reduces risk of recurrent ischemic stroke, but was also associated with risk of non-central nervous system (CNS) major bleeding in the Platelet-Oriented Inhibition in New TIA or minor stroke clinical trial. The loss-of-function CYP2C19*2 allele potentially reduces clopidogrel efficacy, while the gain-of-function CYP2C19*17 allele may increase bleeding risk. The clinical application of these alleles is unclear. SNP genotyping of CYP2C19*2 and CYP2C19*17 are available in the Secondary Prevention of Small Subcortical Strokes clinical trial, a 2x2 factorial study in patients with lacunar infarcts where one arm tested the efficacy of secondary stroke prevention with aspirin plus clopidogrel versus aspirin alone. We hypothesized that patients carrying CYP2C19*2 would have more clopidogrel failure events (defined as a composite of ischemic stroke, transient ischemic attack, and cognitive decline), while patients carrying at least one CYP2C19*17 allele, would have more major bleeding, including sub-analysis of CNS and non-CNS major bleeding. The associations of CYP2C19*2 with treatment failure and CYP2C19*17 with major bleeding were assessed through logistic regression, adjusting for age, gender, race, and excluding CYP2C19*2/*17 carriers. The mean age of the cohort (n=522) was 62 (62% male). There were no significant differences in treatment failure events between *2 carriers and *2 non-carriers (Odds ratio (OR) [95% confidence interval (CI)] = 1.60 [0.66-3.87], p-value=0.29), adjusting for *17. Patients with a *17 allele had a significantly higher odds of a non-CNS hemorrhage (OR [95% CI] =2.50 [1.03-6.09], p-value=0.043), and a trend for significance after adjusting for *2, p-value=0.06. Only two CNS hemorrhages occurred in the total cohort; both occurred in normal CYP2C19 metabolizers. Although limited by sample size, the study suggests that CYP2C19 carrier status may contribute to non-CNS major bleeding risks seen in dual antiplatelet therapy secondary stroke prevention trials. Further studies are needed to confirm whether the presence of CYP2C19*17 or absence of *2 increases the risk of bleeding complications, which could have implications for treatment decisions in a precision medicine approach.

Background: Transient ischaemic attack (TIA) and minor ischaemic stroke patients are at high risk for recurrent events. Anticoagulants are associated with reduced recurrent ischemic stroke rates, but also increased risk of haemorrhagic transformation (HT). Dabigatran, a novel oral anticoagulant associated with reduced risk of intracranial bleeding compared with warfarin in atrial fibrillation patients, has not been assessed in acute brain ischemia. We hypothesised that HT rates are not increased by dabigatran relative to aspirin after acute ischaemic stroke/TIA. Methods: DAbigatran Treatment of Acute Stroke II (DATAS II) was a prospective, randomised open label, blinded endpoint trial of dabigatran versus aspirin in acute stroke/TIA (clinicatrials.gov NCT02295826). Non-cardio-embolic stroke/TIA patients (NIHSS score ≤9, infarct volume < 25 ml) who did not receive thrombolytic therapy or thrombectomy were randomised 1:1 to dabigatran 150 mg BID (110 mg BID in patients ≥80 or if CrCl

Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

Background Pontine infarcts are common and often attributed to small vessel disease (“small deep infarcts”) or basilar branch atherosclerosis (“wedge shaped”). A well-described morphological differentiation using magnetic resonance images has not been reported. Furthermore, whether risk factors and outcomes differ by morphology, or whether infarct morphology should guide secondary prevention strategy, is not well characterized. Methods All participants in the Secondary Prevention of Small Subcortical Strokes Study with magnetic resonance imaging -proven pontine infarcts were included. Infarcts were classified as well-circumscribed small deep (small deep infarct, i.e. lacunar), paramedian, atypical paramedian, or other based on diffusion-weighted imaging, T2/fluid-attenuated inversion recovery, and T1-magnetic resonance images. Inter-rater reliability was high (90% agreement, Cohen’s kappa = 0.84). Clinical and radiologic features independently associated with small deep infarct versus paramedian infarcts were identified (multivariable logistic regression). Differences in stroke risk and death were assessed using Cox proportional hazards. Results Of the 3020 patients enrolled, 644 had pontine infarcts; 619 images were available: 302(49%) small deep infarct, 245 (40%) paramedian wedge, 35 (6%) atypical paramedian, and 37 (6%) other. Among vascular risk factors, only smoking (OR 2.1, 95% CI 1.3–3.3) was independently associated with small deep infarct versus paramedian infarcts; on neuroimaging, old lacunes on T1/fluid-attenuated inversion recovery (OR 1.8, 1.3–2.6) and intracranial stenosis (any location) ≥50% (OR 0.62, 0.41–0.96). Small deep infarct versus paramedian was not predictive of either recurrent stroke or death, and there was no interaction with assigned treatment. Conclusions Pontine infarcts can be reliably classified based on morphology using clinical magnetic resonance images. Few risk factors differed between small deep infarct and paramedian infarcts with no differences in recurrent stroke or mortality. There was no difference in response to different antiplatelet or blood pressure treatment strategies between these two groups. Registration http://www.clinicaltrials.gov/NCT00059306 .

Background and Purpose— We hypothesized that concentrations of interleukin 6 (IL-6), serum amyloid A, tumor necrosis factor-α receptor 1, CD40 ligand, and monocyte chemoattractant protein 1 would predict recurrent ischemic stroke and major vascular events after recent lacunar stroke. Methods— Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within the Secondary Prevention of Small Subcortical Strokes (SPS3) study, a Phase III trial in patients with recent lacunar stroke. Crude and Adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CI) for recurrence risks. Results— Among 1244 patients with lacunar stroke (mean age, 63.3±10.8 years), there were 115 major vascular events (stroke, myocardial infarction, and vascular death). The risk of major vascular events increased with elevated concentrations of both tumor necrosis factor-α receptor 1 (adjusted HR per SD, 1.21; 95% CI, 1.05–1.41; P =0.01) and IL-6 (adjusted HR per SD, 1.10; 95% CI, 1.02–1.19; P =0.008). Compared with the bottom quartile (tumor necrosis factor-α receptor 1 3.63 ng/L) were at twice the risk of major vascular events after adjusting for demographics (partially adjusted HR, 1.98; 95% CI, 1.11–3.52), though the effect attenuated after adjusting for other risk factors and statin use (adjusted HR, 1.68; 95% CI, 0.93–3.04). Serum amyloid A, CD40 ligand, and monocyte chemoattractant protein 1 were not associated with prognosis. Conclusions— Among recent lacunar stroke patients, IL-6 and TNF receptor concentrations predict risk of recurrent vascular events, and they are associated with the effect of antiplatelet therapies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00059306.

Background— The effect of intensive blood pressure (BP) lowering on kidney function among individuals with established cerebrovascular disease and preserved estimated glomerular filtration rate (eGFR) is not established. Methods and Results— Among 2610 participants randomized to a lower (30%) using linear mixed models and logistic regression, respectively. We assessed associations of both treatment and kidney function decline with stroke, major vascular events, and the composite of stroke, death, major vascular events, or myocardial infarction using multivariable Cox regression, separately and jointly including a test for interaction. Analyses were conducted by treatment arm. Mean age was 63±11 years; 949 participants (36%) were diabetic; and mean eGFR was 80±19 mL·min −1 ·1.73 m −2 . At 9 months, achieved systolic BP was 137±15 versus 127±14 mm Hg in the higher versus lower BP group, and differences were maintained throughout follow-up (mean, 3.2 years). Compared with the higher target, the lower BP target had a −0.50–mL·min −1 ·1.73 m −2 per year (95% confidence interval [CI], −0.79 to −0.21) faster eGFR decline. Differences were most pronounced during the first year (−2.1 mL·min −1 ·1.73 m −2 ; 95% CI, −0.97 to −3.2), whereas rates of eGFR decline did not differ after year 1 (−0.095; 95% CI, −0.47 to 0.23). A total of 313 patients (24%) in the lower BP group had rapid kidney function decline compared with 247 (19%) in the higher BP group (odds ratio, 1.4; 95% CI, 1.1–1.6). Differences in rapid decline by treatment arm were apparent in the first year (odds ratio, 1.4; 95% CI, 1.1–1.8) but were not significant after year 1 (odds ratio, 1.0; 95% CI, 0.73–1.4). Rapid decline was associated with higher risk for stroke, major vascular events, and composite after full adjustment among individuals randomized to the higher BP target (stroke hazard ratio, 1.93; 95% CI, 1.15–3.21) but not the lower BP arm (stroke hazard ratio, 0.93; 95% CI, 0.50–1.75; all P for interaction Conclusions— In patients with prior lacunar stroke and relatively preserved kidney function, intensive BP lowering was associated with a greater likelihood of rapid kidney function decline. Differences were observed primarily during the first year of antihypertensive treatment. Rapid kidney function decline was not associated with increased risk for clinical events among those undergoing intensive BP lowering. Clinical Trial Registration— URL: http://www.clinicalTrials.gov . Unique identifier: NCT00059306.

Abstract— Studies suggest a J-shaped association between blood pressure and cardiovascular events in the setting of intensive systolic blood pressure control; whether there is a similar association with stroke remains less well established. The Secondary Prevention of Small Subcortical Strokes was a randomized trial to evaluate higher (130–149 mm Hg) versus lower (P P =0.02 for interaction. The lowest risk of all events occurred at a nadir of ≈120 to 128 mm Hg systolic blood pressure and 65 to 70 mm Hg diastolic blood pressure. Future studies should evaluate the impact of excessive blood pressure reduction, especially in older populations with preexisting vascular disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00059306.

Objective: Hemorrhagic transformation (HT) is common in patients with acute ischemic stroke and is associated with poor outcome. However, the accurate prevalence and risk factors for HT are uncertain. We aim to characterize rates, risk factors and prognosis of HT. Methods: We conducted a systematic review and meta-analysis of all published English literature of patients with acute ischemic stroke and HT. Medline and EMBASE were searched between 1985 and 2017, 2,099 relevant publications were identified. To obtain comparable data we included only studies that used the ECASS-2 definitions of Hemorrhagic Transformation and Parenchymal Hematoma (PH). Patients treated with intravenous thrombolysis (IV-tPA) were compared with those who did not receive thrombolysis. Results: Eligible studies (n=65) with 17,259 patients in total were included in this analysis. The overall prevalence of HT was 27% (95% CI 23-30); Patients not treated with IV-tPA had a prevalence of 20% (95% CI 14-27) vs. 32% (95% CI 27-37) in those treated. The overall prevalence of PH was 9% (95% CI 8-11); in untreated patients prevalence was 5% (95% CI 4-7) vs. 12% (95% CI 10-15) in the IV-tPA treated patients. The risk of HT was higher with: history of atrial fibrillation (OR 2.94, CI 2-4), use of anticoagulants (OR 2.47, 95% CI 1.6-4), higher NIHSS score (Hedge’s G 0.96, 95% CI 0.5-1.4), DWI infarct volume (Hedge’s G 0.8, 95% CI 0.01-1.5) and glucose level (Hedge’s G 0.4, CI 0.16-0.6). LDL was negatively correlated with HT (Hedge’s G -0.3, 95% CI -0.12- -0.48). Interactions were explored for factors associated with HT and thrombolysis treatment. In patients treated with IV-tPA, risk of PH was associated with antiplatelet use (OR 3, 95% CI 1-7), statin treatment (OR 4, 95% CI 1-9) and history of hypertension (OR 1.5, 95% CI 1.1-2). Poor 90-day outcome (mRS 5-6) was associated with HT (OR 3) and PH (OR 8). Conclusion: HT is common, even in patients not treated with IV-tPA, and tends to occur in patients with large and severe strokes. HT, and PH in particular, are associated with poor outcomes. Risk factors for HT should be identified to reduce burden of disability and future high quality . Prospective Longitudinal studies are warranted.

Background: Cerebral microbleeds (CMBs) have been associated with cognitive dysfunction. However, characterization of CMBs and cognitive dysfunction in a large population of stroke patients is lacking. We aimed to characterize the association of CMBs with cognitive function in lacunar stroke patients and the response to assigned treatments in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. Methods: SPS3 was a randomized trial comparing two systolic blood pressure targets and two antiplatelet regimens in 3020 dementia-free patients with symptomatic, MRI-confirmed lacunar stroke. Participants underwent detailed neuropsychological testing covering multiple domains, including short delay recall, long delay recall, discriminability, block design, symbol search, grooved pegboard, controlled oral word association and clock drawing, at baseline and then annually for 5 years. Participants with axial MRI T2*- GRE sequences allowing for CMB detection and Cognitive Abilities Screening Instrument (CASI) Z scores available at baseline were included in the current analysis. Results: CMBs were present in 30% of 1225 eligible patients (mean age 63 years, 35% women) with median follow up of 3 years. Patients with CMBs had greater proportion of mild cognitive impairment (MCI; 56% vs. 42%, p Conclusions: In this largest reported cohort assessing the association between CMBs and post-stroke cognitive impairment, CMBs were associated with lower cognitive scores and greater rates of MCI at baseline. However, changes over time in cognition were similar in lacunar stroke patients with and without CMBs who receive adequate vascular risk management.

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, “high risk” elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58–2.89 and adj-HR: 2.09; 95% CI: 1.71–2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68–8.08 and adj-HR: 3.93; 95% CI: 2.71–5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24–1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00–1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

Objectives: We used a prospective clinical trial to examine the risks conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent strokes in the Secondary Prevention of Small Subcortical Strokes (SPS3) study cohort. Methods: The SPS3 trial enrolled 3,020 patients with lacunar strokes. Participants were stratified into groups of METS only, DM only, both, or neither using American Heart Association/National Heart, Lung, and Blood Institute and World Health Organization guidelines. Annualized event rates of strokes, myocardial infarction (MI), and all-cause mortality were calculated, and hazard ratios (HRs) referencing the “neither” group were computed, controlling for significantly associated baseline characteristics. Results: Among 2,999 participants, 25% had METS only, 6% had DM only, 32% had both conditions, and 37% had neither. Over a median of 3.8 years of follow-up, there were 274 recurrent strokes (240 ischemic, 34 hemorrhagic) and 74 MIs; among the 240 ischemic strokes, 134 (56%) were lacunar. The rates of any recurrent stroke (HR 1.7, 95% confidence interval [CI] 1.3–2.3) or lacunar stroke (HR 2.4, 95% CI 1.5–3.7) were significantly higher for those with concurrent METS and DM compared with those who had neither. Risk of incident MI was higher in participants with DM (HR 2.8, 95% CI 1.1–7.0) or concurrent DM and METS (HR 2.6, 95% CI 1.4–4.9). Conclusion: METS and DM were significant comorbid conditions in lacunar stroke patients and they were associated with stroke recurrence. In patients with lacunar infarcts, a vigilant approach to prevent development of DM in those with METS may be a potential strategy to reduce recurrent strokes.