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Background and ObjectivesThe care of patients with large vessel occlusion (LVO) stroke has been revolutionized by endovascular thrombectomy (EVT). While EVT has a large effect size, most patients treated with EVT remain disabled or die within 90 days. A better understanding of outcomes may influence EVT selection criteria, novel therapies, and prognostication. We sought to identify associations between outcomes and brain regions involved in ischemic lesions.MethodsFor this cohort study, consecutive patients with LVO who were treated with EVT and underwent post-EVT MRI were identified from a tertiary referral center (2011–2019). Acute ischemic lesions were manually segmented from diffusion-weighted imaging and spatially normalized. Individual lesions were parcellated (atlas-defined 94 cortical regions, 14 subcortical nuclei, 20 white matter tracts) and reduced to 10 essential lesion patterns with the use of unsupervised dimensionality reduction techniques. Ninety-day modified Rankin Scale (mRS) score (>2) was modeled via bayesian regression, taking the 10 lesion patterns as inputs and controlling for lesion size, age, sex, acute NIH Stroke Scale (NIHSS) score, alteplase, prior stroke, intracerebral hemorrhage, and good reperfusion (Thrombolysis in Cerebral Infarction 2b–3). In comparative analyses, 90-day mRS score was modeled considering covariates only, and compartment-wise relevances for acute stroke severity and 90-day mRS score were evaluated.ResultsThere were 151 patients with LVO identified (age 68 ± 15 years, 52% female). The median NIHSS score was 16 (interquartile range 13–20); 56% had mRS score >2. Lesion locations predictive of 90-day mRS score involved bilateral but left hemispherically more pronounced precentral and postcentral gyri, insular and opercular cortex, and left putamen and caudate (area under the curve 0.91, highest probability density interval [HPDI] covering 90% certainty 0.90–0.92). The lesion location model outperformed the simpler model relying on covariates only (bayesian model comparison of 97% weight to the model with vs 3% weight to the model without lesion location). While lesions affecting subcortical nuclei had the highest relevance for stroke severity (posterior distribution mean 0.75, 90% HPDI 0.256–1.31), lesions affecting white matter tracts had the highest relevance for 90-day mRS score (0.656, 90% HPDI 0.0864–1.12).DiscussionThese data describe the significance for outcomes of specific brain regions involved in ischemic lesions on MRI after EVT. Future work in additional datasets is needed to confirm these granular findings.

BACKGROUND AND PURPOSE Ischemic diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch may be useful in guiding acute stroke treatment decisions given its relationship to onset time and parenchymal viability; however, it relies on subjective grading. Radiomics is an emerging image quantification methodology that may objectively represent continuous image characteristics. We propose a novel radiomics approach to characterize DWI-FLAIR mismatch. METHODS Ischemic lesions were visually graded for FLAIR positivity (absent, subtle, obvious) among consecutive large vessel occlusion stroke patients who underwent hyperacute MRI. Radiomic features were extracted from within the lesions on DWI and FLAIR. The DWI-FLAIR mismatch radiomics signature was built with features systematically selected by a cross-validated ElasticNet linear regression model of mismatch. RESULTS We identified 103 patients with mean age 68 ± 16 years; 63% were female. FLAIR hyperintensity was absent in 25%, subtle in 55%, and obvious in 20%. Inter-rater agreement for visual grading was moderate (Κ = .58). The radiomics signature of DWI-FLAIR mismatch included native FLAIR histogram kurtosis and local binary pattern-filtered FLAIR gray-level cluster shade; both correlated with visual grading (ρ = -.42, p

Background and ObjectivesTo 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 NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3–6 months after stroke were obtained from the MRI–Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning–based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts.ResultsA total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location–specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location.DiscussionHigher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions.

BackgroundRandomized trials have not demonstrated benefit from intravenous thrombolysis among patients undergoing endovascular thrombectomy (EVT). However, these trials included primarily patients presenting directly to an EVT capable hub center. We sought to study outcomes for EVT candidates who presented to spoke hospitals and were subsequently transferred for EVT consideration, comparing those administered alteplase at spokes (i.e., ‘drip-and-ship’ model) versus those not.MethodsConsecutive EVT candidates presenting to 25 spokes from 2018 to 2020 with pre-transfer CT angiography defined emergent large vessel occlusion and Alberta Stroke Program CT score ≥6 were identified from a prospectively maintained Telestroke database. Outcomes of interest included adequate reperfusion (Thrombolysis in Cerebral Infarction (TICI) 2b–3), intracerebral hemorrhage (ICH), discharge functional independence (modified Rankin Scale (mRS) ≤2), and 90 day functional independence.ResultsAmong 258 patients, median age was 70 years (IQR 60–81), median National Institutes of Health Stroke Scale (NIHSS) score was 13 (6-19), and 50% were women. Ninety-eight (38%) were treated with alteplase at spokes and 113 (44%) underwent EVT at the hub. Spoke alteplase use independently increased the odds of discharge mRS ≤2 (adjusted OR 2.43, 95% CI 1.08 to 5.46, p=0.03) and 90 day mRS ≤2 (adjusted OR 3.45, 95% CI 1.65 to 7.22, p=0.001), even when controlling for last known well, NIHSS, and EVT; it was not associated with an increased risk of ICH (OR 1.04, 95% CI 0.39 to 2.78, p=0.94), and there was a trend toward association with greater TICI 2b–3 (OR 3.59, 95% CI 0.94 to 13.70, p=0.06).ConclusionsIntravenous alteplase at spoke hospitals may improve discharge and 90 day mRS and should not be withheld from EVT eligible patients who first present at alteplase capable spoke hospitals that do not perform EVT. Additional studies are warranted to confirm and further explore these benefits.

With the rapid aging of populations, neurological disorders have become among the leading causes of disability and mortality worldwide. Most neurological conditions have a prolonged prodromal phase - even if they tend to manifest with an acute syndrome such as stroke - and can lead to a relentless, often deleterious course creating a major burden on patients, caregivers, and society. This unique nature of neurological diseases signifies the strong need for equally effective primary and secondary prevention strategies and focus on brain health before brain diseases ensue. The field of preventive neurology applies both universal and selective primary prevention strategies to promote brain health both at the public and personal levels. The preventive neurology approach aims to identify and target high risk individuals and protect them from reaching a critical point where overt clinical symptoms are present and disease progression is irreversible. Universal and selective prevention training, along with dovetailed clinical and public health research, are three essential pillars of preventive neurology. The burgeoning field of preventive neurology aims to assess neurological care needs in a society, promote the participation of neurologists in restructuring of the health care policies to promote brain health, and to identify medium and high-risk individuals in order to prevent or delay future neurological events.

Sex-specific differences in ischemic stroke outcomes are prevalent. We sought to investigate sex differences in the determinants of reperfusion and functional outcomes after endovascular thrombectomy (EVT) for emergent large vessel occlusion ischemic stroke (ELVO). Patients presenting to a single referral center with an anterior circulation ELVO that underwent EVT from 2011 to 2019 were included in this retrospective analysis. Sex differences in history, presentation, adequate reperfusion (TICI 2b-3), and 90-day good outcome [delta modified Rankin Scale (mRS) ≤ 2 from pre-stroke] were examined. Multivariable logistic regression analyses were performed to assess sex-specific associations with outcomes. Three hundred and eighty-one consecutive ELVO patients were identified. Women (N = 193) were older (75 vs 64 years, p

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.

Existing literature on white matter hyperintensity volume (WMHV) in stroke patients has rarely focused on post-stroke outcomes related to social functioning limitations, such as transportation, social interaction, food preparation, grocery shopping, and housekeeping. Using prospective data from the VITamin D and OmegA-3 TriaL (VITAL) study, we evaluated the association between WMHV and social functioning limitations among 151 ischemic stroke patients.WMHV was ascertained from magnetic resonance imaging (MRI) collected at the time of the stroke event using a validated semiautomated method, and social functioning limitations were assessed using a stroke outcomes questionnaire administered a median of 1.25 years after the date of the MRI scan. Logistic regression was used to explore the association between WMHV and social functioning limitations.After adjusting for age and sex, a statistically significant association was found between WMHV and limitations in social interaction (OR=2.82; 95% CI: 1.21-7.55). Increased risks were seen for limitations related to food preparation (OR=2.06; 95% CI: 0.99-4.54), transportation (OR=1.39; 95% CI: 0.85-2.27), and housekeeping (OR=1.37; 95% CI: 0.91-2.11); however, the associations did not reach statistical significance. We observed no association between WMHV and limitations in grocery shopping (OR=1.08; 95% CI: 0.61-1.89).Future studies are needed to further explore the biological mechanisms underlying the relationship with limitations in social interaction and to replicate our findings using a larger and more diverse study sample.

BackgroundPersons with pre-existing disabilities represent over one-third of acute stroke presentations, but account for a far smaller proportion of those receiving endovascular thrombectomy (EVT) and thrombolysis. This is despite existing ethical, economic, legal, and social directives to maximize equity for this vulnerable population. We sought to determine associations between baseline modified Rankin Scale (mRS) and outcomes after EVT.MethodsIndividuals who underwent EVT were identified from a prospectively maintained database. Demographics, medical history, presentations, treatments, and outcomes were recorded. Baseline disability was defined as baseline mRS≥2. Accumulated disability was defined as the delta between baseline mRS and absolute 90-day mRS.ResultsOf 381 individuals, 49 had baseline disability (five with mRS=4, 23 mRS=3, 21 mRS=2). Those with baseline disability were older (81 vs 68 years, PConclusionsWhile baseline mRS was associated with absolute 90-day disability, there was no association with accumulated disability or other outcomes. Patients with baseline disability should not be routinely excluded from EVT based on baseline mRS alone.

ObjectiveTo examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS).MethodsFor the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool–based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes.ResultsPatients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all p < 0.001). Median WMHv in all patients with AIS was 5.86 cm3 (interquartile range 2.18–14.61 cm3) and differed significantly across CCS subtypes (p < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all p < 0.001), and diabetes mellitus (p = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes (p < 0.001).ConclusionIn this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke.

OBJECTIVE:To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). PATIENTS AND METHODS:This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. RESULTS:Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm3) was associated with age (β -0.3 [per 14.4 years]), male sex (β 1.0), and prior stroke (β -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (β -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. CONCLUSION:Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery.

Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.

Background The treatment of stroke has been undergoing rapid changes. As treatment options progress, prediction of those under risk for complications becomes more important. Available models have, however, frequently been built based on data no longer representative of today’s care, in particular with respect to acute stroke management. Our aim was to build and validate prediction models for 4 clinically important, severe outcomes after stroke. Methods and Results We used German registry data from 152 710 patients with acute ischemic stroke obtained in 2016 (development) and 2017 (validation). We took into account potential predictors that were available at admission and focused on in‐hospital mortality, intracranial mass effect, secondary intracerebral hemorrhage, and deep vein thrombosis as outcomes. Validation cohort prediction and calibration performances were assessed using the following 4 statistical approaches: logistic regression with backward selection, l 1‐regularized logistic regression, k‐nearest neighbor, and gradient boosting classifier. In‐hospital mortality and intracranial mass effects could be predicted with high accuracy (both areas under the curve, 0.90 [95% CI, 0.90–0.90]), whereas the areas under the curve for intracerebral hemorrhage (0.80 [95% CI, 0.80–0.80]) and deep vein thrombosis (0.73 [95% CI, 0.73–0.73]) were considerably lower. Stroke severity was the overall most important predictor. Models based on gradient boosting achieved better performances than those based on logistic regression for all outcomes. However, area under the curve estimates differed by a maximum of 0.02. Conclusions We validated prediction models for 4 severe outcomes after acute ischemic stroke based on routinely collected, recent clinical data. Model performance was superior to previously proposed approaches. These predictions may help to identify patients at risk early after stroke and thus facilitate an individualized level of care.

International audience; BACKGROUND AND PURPOSE: To determine the influence of the cerebral small vessel disease (SVD) burden on collateral recruitment in patients treated with mechanical thrombectomy (MT) for anterior circulation acute ischemic stroke (AIS). METHODS: Patients with AIS due to large vessel occlusion (LVO) from the Thrombectomie des Artères Cérébrales (THRACE) trial and prospective cohorts from 2 academic comprehensive stroke centers treated with MT were pooled and retrospectively analyzed. Collaterals' adequacy was assessed using the American Society of Interventional and Therapeutic Radiology/Society of Interventional Radiology (ASITN/SIR) score on initial digital subtraction angiography and dichotomized as good (3,4) versus poor (0-2) collaterals. The SVD burden was rated with the global SVD score on MRI. Multivariable logistic regression analyses were used to determine relationships between SVD and ASITN/SIR scores. RESULTS: A total of 312 participants were included (53.2% males, mean age 67.8 ± 14.9 years). Two hundred and seven patients had poor collaterals (66.4%), and 133 (42.6%) presented with any SVD signature. In multivariable analysis, patients demonstrated worse leptomeningeal collaterality with increasing SVD burden before and after adjustment for SVD risk factors (adjusted odds ratio [aOR] 0.69; 95%CI [0.52-0.89] and aOR 0.66; 95%CI [0.5-0.88], respectively). Using individual SVD markers, poor collaterals were significantly associated with the presence of lacunes (aOR 0.40, 95% CI [0.20-0.79]). CONCLUSION: Our study provides evidence that in patients with AIS due to LVO treated with MT, the burden of SVD assessed by pre-treatment MRI is associated with poorer recruitment of leptomeningeal collaterals.

Background Few MRA-based studies have systematically evaluated the prevalence and laterality of a fetal configuration of the posterior cerebral artery (FTP) in ischemic stroke populations versus other populations. This common variant is important in the setting of acute stroke and secondary prevention decisions. Objective To determine the prevalence and laterality of FTP configurations in MRI-DWI verified acute ischemic stroke patients investigated with MRA, and compare the findings with an unselected hospital population investigated with computed tomography angiography (CTA). We also evaluated the association of FTP with posterior cerebral artery (PCA) territory infarctions. Methods We reviewed the MRAs of 1407 ischemic stroke patients with acute lesions on MRI-DWI sequences and 546 consecutive CTAs of patients investigated on any indication in a tertiary hospital. The MRA and CTA assessments were made by neuroradiologists blinded to original reports on stroke location and vessel anatomy. Results The prevalence of any FTP was similar in ischemic stroke patients (31%) and unselected patients (32%). Unilateral FTP was significantly more frequent on the right than on the left side in both groups (15% right vs. 8% left). The presence of FTP ipsilateral to stroke side was not associated with involvement of the PCA territory versus no FTP on the stroke side. Conclusions FTP is present in approximately 30% of ischemic stroke patients and unselected hospital populations and was detected significantly more frequently on the right versus left side in both groups. PCA territory infarction was not associated with the presence of ipsilateral FTP.

Background Increased systolic blood pressure variability (BPV) is associated with stroke, cardiovascular disease, and dementia and mild cognitive impairment. However, prior studies assessing the relationship between BPV and dementia or mild cognitive impairment had infrequent measurement of blood pressure or suboptimal blood pressure control. Methods and Results We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) MIND (Memory and Cognition in Decreased Hypertension) trial. The primary outcome was probable dementia during follow‐up. We defined our exposure period, during which blood pressures were collected, as the first 600 days of the trial, and outcomes were ascertained during the subsequent follow‐up. BPV was measured as tertiles of systolic blood pressure standard deviation. We fit Cox proportional hazards models to our outcome. We included 8379 patients. The mean follow‐up was 3.2±1.4 years, during which 316 (3.8%) patients developed dementia. The mean number of blood pressure measurements was 7.8, and in the tertiles of BPV, the SD was 6.3±1.6, 10.3±1.1, and 16.3±3.6 mm Hg, respectively. The rate of dementia was 2.4%, 3.6%, and 5.4% by ascending tertile, respectively ( P Conclusions In a post hoc analysis of the SPRINT MIND trial, we found that higher BPV was associated with the development of probable dementia despite excellent blood pressure control. Additional research is needed to understand how to reduce BPV and if its reduction lowers the risk of cognitive impairment and dementia.

Background Although primary intraventricular hemorrhage is frequently due to trauma or vascular lesions, the etiology of idiopathic primary intraventricular hemorrhage (IP-IVH) is not defined. Aims Herein, we test the hypothesis that cerebral small vessel diseases (cSVD) including hypertensive cSVD (HTN-cSVD) and cerebral amyloid angiopathy are associated with IP-IVH. Methods Brain magnetic resonance imaging from consecutive patients (January 2011 to September 2019) with non-traumatic intracerebral hemorrhage from a single referral center were reviewed for the presence of HTN-cSVD (defined by strictly deep or mixed-location intracerebral hemorrhage/cerebral microbleeds) and cerebral amyloid angiopathy (applying modified Boston criteria). Results Forty-six (4%) out of 1276 patients were identified as having IP-IVH. Among these, the mean age was 74.4 ± 12.2 years and 18 (39%) were females. Forty (87%) had hypertension, and the mean initial blood pressure was 169.2 ± 40.4/88.8 ± 22.2 mmHg. Of the 35 (76%) patients who received a brain magnetic resonance imaging, two (6%) fulfilled the modified Boston criteria for possible cerebral amyloid angiopathy and 10 (29%) for probable cerebral amyloid angiopathy. Probable cerebral amyloid angiopathy was found at a similar frequency when comparing IP-IVH patients to the remaining patients with primary intraparenchymal hemorrhage (P-IPH) (27%, p = 0.85). Furthermore, imaging evidence for HTN-cSVD was found in 8 (24%) patients with IP-IVH compared to 209 (28%, p = 0.52) patients with P-IPH. Conclusions Among IP-IVH patients, cerebral amyloid angiopathy was found in approximately one-third of patients, whereas HTN-cSVD was detected in 23%—both similar rates to P-IPH patients. Our results suggest that both cSVD subtypes may be associated with IP-IVH.

Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID’s overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.

Introduction: White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype related to the diagnosis and prognosis of acute ischemic stroke. The effect of WMH burden on functional outcome in large vessel occlusion (LVO) stroke has only been sparsely assessed, and direct LVO and non-LVO comparisons are currently lacking. Material and Methods: We reviewed acute ischemic stroke patients admitted between 2009 and 2017 at a large healthcare system in the USA. Patients with LVO were identified and clinical characteristics, including 90-day functional outcomes, were assessed. Clinical brain MRIs obtained at the time of the stroke underwent quantification of WMH using a fully automated algorithm. The pipeline incorporated automated brain extraction, intensity normalization, and WMH segmentation. Results: A total of 1,601 acute ischemic strokes with documented 90-day mRS were identified, including 353 (22%) with LVO. Among those strokes, WMH volume was available in 1,285 (80.3%) who had a brain MRI suitable for WMH quantification. Increasing WMH volume from 0 to 4 mL, age, female gender, a number of stroke risk factors, presence of LVO, and higher NIHSS at presentation all decreased the odds for a favorable outcome. Increasing WMH above 4 mL, however, was not associated with decreasing odds of favorable outcome. While WMH volume was associated with functional outcome in non-LVO stroke (p = 0.0009), this association between WMH and functional status was not statistically significant in the complete case multivariable model of LVO stroke (p = 0.0637). Conclusion: The burden of WMH has effects on 90-day functional outcome after LVO and non-LVO strokes. Particularly, increases from no measurable WMH to 4 mL of WMH correlate strongly with the outcome. Whether this relationship of increasing WMH to worse outcome is more pronounced in non-LVO than LVO strokes deserves additional investigation.

Background White matter hyperintensity of presumed vascular origin is a risk factor for poor stroke outcomes. In patients with acute ischemic stroke, however, the in vivo mechanisms of white matter microstructural injury are less clear. Aims To characterize the directional diffusivity components in normal-appearing white matter and white matter hyperintensity in acute ischemic stroke patients. Methods A retrospective analysis was performed on a cohort of patients with acute ischemic stroke and brain magnetic resonance imaging with diffusion tensor imaging sequences acquired within 48 h of admission. White matter hyperintensity volume was measured in a semi-automated manner. Median fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity values were calculated within normal-appearing white matter and white matter hyperintensity in the hemisphere contralateral to the acute infarct. Linear regression analysis was performed to evaluate predictors of white matter hyperintensity volume and normal-appearing white matter diffusivity metrics. Results In 319 patients, mean age was 64.9 ± 15.9 years. White matter hyperintensity volume was 6.33 cm3 (interquartile range 3.0–12.6 cm3). Axial and radial diffusivity were significantly increased in white matter hyperintensity compared to normal-appearing white matter. In multivariable linear regression, age (β = 0.20, P = 0.003) and normal-appearing white matter axial diffusivity (β = 37.9, P Conclusions Normal-appearing white matter axial diffusivity increases with age and is an independent predictor of white matter hyperintensity volume in acute ischemic stroke.

The brain regions responsible for hallucinations remain unclear. We studied 89 brain lesions causing hallucinations using a recently validated technique termed lesion network mapping. We found that hallucinations occurred following lesions to a variety of different brain regions, but these lesion locations fell within a single functionally connected brain network. This network was defined by connectivity to the cerebellar vermis, inferior cerebellum (bilateral lobule X), and the right superior temporal sulcus. Within this single hallucination network, additional connections with the lesion location dictated the sensory modality of the hallucination: lesions causing visual hallucinations were connected to the lateral geniculate nucleus in the thalamus while lesions causing auditory hallucinations were connected to the dentate nucleus in the cerebellum. Our results suggest that lesions causing hallucinations localize to a single common brain network, but additional connections within this network dictate the sensory modality, lending insight into the causal neuroanatomical substrate of hallucinations.

Human memory is thought to depend on a circuit of connected brain regions, but this hypothesis has not been directly tested. We derive a human memory circuit using 53 case reports of strokes causing amnesia and a map of the human connectome (n = 1000). This circuit is reproducible across discovery (n = 27) and replication (n = 26) cohorts and specific to lesions causing amnesia. Its hub is at the junction of the presubiculum and retrosplenial cortex. Connectivity with this single location defines a human brain circuit that incorporates > 95% of lesions causing amnesia. Lesion intersection with this circuit predicts memory scores in two independent datasets (N1 = 97, N2 = 176). This network aligns with neuroimaging correlates of episodic memory, abnormalities in Alzheimer’s disease, and brain stimulation sites reported to enhance memory in humans., Memory is hypothesised to depend on different brain regions that interact in a network. Here, the authors use case studies of stroke patients with amnesia from the literature to identify brain regions that are part of this network.

BACKGROUND AND PURPOSE: Arterial stiffness is a biomarker of cerebrovascular disease and dementia risk. Studies have shown an association between carotid artery stiffness and increased white matter hyperintensity volume and, as a result, reduced total brain volume on MR imaging, but none have had prolonged follow-up to fully evaluate the slow change seen in white matter hyperintensity volume and total brain volume with time. Our objective was to determine whether common carotid artery stiffness on sonography accurately predicts white matter hyperintensity volume and total brain volume on MR imaging more than 20 years later. MATERIALS AND METHODS: We performed a secondary analysis of the Atherosclerosis Risk in the Community study to compare 5 measurements of carotid artery stiffness, including strain, distensibility, compliance, Stiffness index, and pressure-strain elastic modulus, with the white matter hyperintensity volume and total brain volume on a follow-up MR imaging using linear regression. RESULTS: We included 1402 patients enrolled in the Atherosclerosis Risk in the Community study. There was a significant relationship between increasing carotid artery stiffness and both higher white matter hyperintensity volume and lower total brain volume on MR imaging, measured at a mean of 21.5 years later. In multivariable linear regression models, the carotid strain, distensibility, Stiffness index, and pressure-strain elastic modulus were associated with white matter hyperintensity volume. Only compliance was associated with total brain volume in the multivariate models. CONCLUSIONS: Sonography measurements of carotid artery stiffness are predictive of white matter hyperintensity volume and total brain volume on MR imaging more than 20 years later. The association is more robust for white matter hyperintensity volume than total brain volume. These findings support the role of arterial stiffness as a method for identifying patients at risk of developing white matter hyperintensity volume and as a potential mechanism leading to small-artery disease of the brain.

Background and Purpose— We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods— Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0–2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs—a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results— The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P =0.0007; odds ratio=0.89; 95% CI, 0.82–0.95 and SiGN/GISCOME: P =0.0036; odds ratio=0.94; 95% CI, 0.91–0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80–0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89–0.98) whereas imbalance without ohnologs lacked such an association. Conclusions— Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

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.

The aim of the current study was to explore the whole‐brain dynamic functional connectivity patterns in acute ischemic stroke (AIS) patients and their relation to short and long‐term stroke severity. We investigated resting‐state functional MRI‐based dynamic functional connectivity of 41 AIS patients two to five days after symptom onset. Re‐occurring dynamic connectivity configurations were obtained using a sliding window approach and k‐means clustering. We evaluated differences in dynamic patterns between three NIHSS‐stroke severity defined groups (mildly, moderately, and severely affected patients). Furthermore, we built Bayesian hierarchical models to evaluate the predictive capacity of dynamic connectivity and examine the interrelation with clinical measures, such as white matter hyperintensity lesions. Finally, we established correlation analyses between dynamic connectivity and AIS severity as well as 90‐day neurological recovery (ΔNIHSS). We identified three distinct dynamic connectivity configurations acutely post‐stroke. More severely affected patients spent significantly more time in a configuration that was characterized by particularly strong connectivity and isolated processing of functional brain domains (three‐level ANOVA: p, By employing dynamic functional connectivity analyses, Bonkhoff et al. demonstrate that severe acute ischemic stroke is linked to transiently increased isolated information processing in multiple functional domains. Additionally, they show that dynamic connectivity involving default mode network components significantly correlates with recovery in the first three months poststroke.

Objectives Despite the proven efficacy of endovascular thrombectomy (EVT) for large vessel occlusion stroke, over half treated remain functionally disabled or die. Infarct topography may have implications for prognostication, patient selection, and the development of tissue-specific neuroprotective agents. We sought to quantify white matter injury in anterior circulation acute infarcts post-EVT to understand its significance and identify its determinants. Materials and Methods Demographics, history, presentations, and outcomes for consecutive patients treated with EVT were recorded in a prospectively maintained database at a single center. Acute infarct masks were coregistered to standard space. Standard atlases of white matter, cortex, and basal ganglia were used to determine region-specific infarct volumes. Results 167 individuals were identified with median age 69 years and 53% women. 85% achieved adequate reperfusion (TICI 2b-3) after EVT; 43% achieved 90-day functional independence (mRS 0-2). Median infarct volumes were 45cc (IQR 18-122) for total, 17cc (6-49) for white matter, 21cc (4-53) for cortex, and 5cc (1-8) for basal ganglia. The odds of 90-day mRS 0-2 were reduced in patients with larger white matter infarct volume (cc, OR=0.89, 95%CI=0.81-0.96), independent of cortex infarct volume, basal ganglia infarct volume, age, NIHSS, and TICI 2b-3 reperfusion. Reperfusion-to-MRI time was associated with white matter infarct volume (hr, β=0.119, p=0.017), but not cortical or basal ganglia infarct volume. Conclusions These data quantitatively describe region-specific infarct volumes after EVT and suggest the clinical relevance of white matter infarct volume as a predictor of long-term outcomes. Further study is warranted to examine delayed white matter infarction and the significance of specific white matter tracts.

Background and purpose Endovascular thrombectomy (EVT) has revolutionized large vessel occlusion stroke care. However, not all patients with good endovascular results achieve good outcomes. We sought to understand the clinical significance of magnetic resonance imaging defined infarct growth despite adequate reperfusion and identify associated clinical and radiographic variables. Methods History, presentation, treatments, and outcomes for consecutive EVT patients at a referral center were collected. Adequate reperfusion was defined as thrombolysis in cerebral infarction (TICI) score 2b-3. Region-specific infarct volumes in white matter, cortex, and basal ganglia were determined on diffusion-weighted imaging. Infarct growth was defined as post-EVT minus pre-EVT volume. Good outcome was defined as 90-day modified Rankin Scale ≤2. Results Forty-four patients with adequate reperfusion were identified with median age 72 years; 64% were women. Each region showed infarct growth: white matter (median pre-EVT 7 cubic centimeters [cc], post-EVT 16 cc), cortex (4 cc, 15 cc), basal ganglia (2 cc, 4 cc), total (20 cc, 39 cc). In multivariable regression, total infarct growth independently decreased the odds of good outcome (odds ratio = .946, 95% CI = .897, .998). Further multivariable analyses for determinants of infarct growth identified female sex was associated with less total growth (β = -.294, P = .042), TICI 3 was associated with less white matter growth (β = -.277, P = .048) and cortical growth (β = -.335, P = .017), and both female sex (β = -.332, P = .015) and coronary disease (β = -.337, P = .015) were associated with less cortical growth. Conclusions Infarct growth occurred despite adequate reperfusion, disproportionately in the cortex, and independently decreased the odds of good outcome. Infarct growth occurred while patients were hospitalized and may represent a therapeutic target. Potential determinants of region-specific infarct growth were identified that require confirmation in larger studies.

Intracranial hemorrhage (ICH) is a known risk of oral anticoagulation; delineating ICH attributes may provide nuanced guidance regarding atrial fibrillation management. We evaluated ICH characteristics and outcomes from Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), a randomized trial that compared two edoxaban regimens (higher-dose edoxaban regimen 60/30 mg (HDER), lower-dose edoxaban regimen 30/15 mg (LDER)) with warfarin in patients with atrial fibrillation. Patients who suffered ICH vs those who did not were compared and independent predictors of ICH were calculated. We also assessed ICH subtype and etiology. Of 21,105 randomized patients, 322 (1.53%) had ≥ 1 ICH for a total of 368 events. Intraparenchymal hemorrhage (HDER: HR 0.52 [95% CI 0.35–0.77], LDER: HR 0.22 [0.13–0.38]) and subdural hematoma (HDER: HR 0.29 [0.15–0.55], LDER: HR 0.26 [0.13–0.50]) were lower with both HDER and LDER vs warfarin. Subarachnoid hemorrhage frequency was similar in the HDER vs warfarin groups but lower in LDER. Compared to warfarin, edoxaban was associated with lower risk of spontaneous ICH (HDER: HR 0.47 [0.31–0.69], LDER: HR 0.34 [0.22–0.53]) and traumatic ICH (HDER: HR 0.32 [0.17–0.61], LDER: HR 0.31 [0.16–0.59]). In multivariable analysis, randomization to warfarin, increased age, and risk of falling remained independent predictors of ICH. In ENGAGE AF-TIMI 48, ICH was decreased in edoxaban-treated patients compared to warfarin-treated patients, including ICH of both spontaneous and traumatic causes. Both edoxaban regimens lowered intraparenchymal and subdural hemorrhages compared to warfarin. Patient characteristics and medical history may help guide anticoagulation management.

Cerebral small-vessel disease (cSVD) is a common cause of stroke, functional decline, vascular cognitive impairment, and dementia. Pathological processes in the brain's microcirculation are tightly interwoven with pathology in the brain parenchyma, and this interaction has been conceptualized as the neurovascular unit (NVU). Despite intensive research efforts to decipher the NVU's structure and function to date, molecular mechanisms underlying cSVD remain poorly understood, which hampers the development of cSVD-specific therapies. Important steps forward in understanding the disease mechanisms underlying cSVD have been made using genetic approaches in studies of both monogenic and sporadic SVD. We provide an overview of the NVU's structure and function, the implications for cSVD, and the underlying molecular mechanisms of dysfunction that have emerged from recent genetic studies of both monogenic and sporadic diseases of the small cerebral vasculature.

Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P =1.70×10 −9 ). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Objective Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. Methods The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. Results Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). Interpretation RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. Clinical trial registration Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

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

Purpose of review This article reviews the clinical significance and neuroimaging characteristics of cerebral small vessel disease and the impact on neurologic disease and current and potential therapeutic approaches. Recent findings Cerebral small vessel disease is increasingly prevalent and highly heterogeneous in neuroimaging and clinical presentation. Small subcortical infarcts, lacunes, cerebral microbleeds, cortical microinfarcts, and white matter hyperintensity of presumed vascular origin represent the major neuroimaging markers of small vessel disease. Increasing small vessel disease burden is associated with risk of incident stroke and dementia, as well as other neuropsychiatric symptoms. Current research strategies are targeting elucidation of the mechanisms of small vessel disease pathogenesis and pursuing clinical trials of therapeutic agents to reduce the clinical manifestations of cerebral small vessel disease. Summary Cerebral small vessel disease is common in aging adults and represents a major risk factor for multiple acute and chronic neurologic diseases. Increased awareness of cerebral small vessel disease as a modifiable risk factor holds potential for reducing neurologic disease morbidity and mortality across diverse populations in the United States and worldwide.

Background:Telestroke provides access to vascular neurology expertise for hospitals lacking stroke coverage, and its use has risen rapidly in the past decade. We aim to characterize consultations, spoke behavior, and the relationship between spoke telestroke utilization (number of telestroke consults per year) and spoke alteplase treatment metrics in an academic telestroke network.Methods and Results:We analyzed prospectively collected data on all telestroke consults from 2003 to 2018. Trends in network performance and spoke characteristics were analyzed using generalized estimating equations and Kendall τβ nonparametric tests as appropriate. Unadjusted and adjusted linear regression models determined associations between telestroke utilization and treatment metrics. The network included 2 hubs and 43 spokes with 12 803 consults performed during the study period. Network growth overall was +1.8 spokes per year, and median duration of spoke participation was 7.9 years. The numbers of consults and alteplase-treated patients increased annually, even after adjusting for the number of spokes in the network (PPP=0.02), number of patients treated with alteplase was an additional 1.7 (PP=0.03).Conclusions:Telestroke network size and utilization increased over time. Increased use of teleconsults was associated with increased and timely use of alteplase. Over time, the delivery of timely emergency care has improved significantly among emergency departments participating in this telestroke network. Replication of these findings in other networks is warranted.

Background: Few prospective cohort studies collect detailed information on stroke characteristics among individuals who experience ischemic stroke, including white matter hyperintensity volume, and thus cannot explore how prospectively collected biomarkers prior to the stroke influence white matter hyperintensity volume. We explored the association between a large panel of prospectively collected lipid and inflammatory biomarkers and white matter hyperintensity volume among participants in the Women's Health Study with incident ischemic stroke. Methods: Among Women's Health Study participants with first ischemic stroke who had baseline serum biomarkers and available magnetic resonance imaging, we measured white matter hyperintensity volume using a validated semi-automated method. Linear regression was used to explore the associations between biomarkers and log-transformed white matter hyperintensity volume. Results: After multivariate adjustment, a 1% increment in HbA1c% was associated with an increase in white matter hyperintensity volume (P value = .05). Evidence of a nonlinear association between high density lipoprotein cholesterol levels and ApoA1 levels with white matter hyperintensity volume was noted (P values for nonlinearity = .01 and .001, respectively). No other biomarkers were significantly associated with white matter hyperintensity volume. Conclusions: Chronic hyperglycemia as evidenced by HbA1c levels measured years prior to stroke is associated with white matter hyperintensity volume at the time of stroke. Additional research is needed to explain why low levels of high density lipoprotein cholesterol levels and ApoA1 may be associated with similar white matter hyperintensity volume as high levels.

OBJECTIVES: Delirium is common among patients with acute stroke and associated with worse outcomes. However, it is unclear which stroke locations or types are most associated with delirium. MATERIALS AND METHODS: We systematically reviewed studies of patients with acute stroke that reported stroke locations and types by delirium status. We included papers in any language, through a combined search from January 2010 to June 2021. Case studies with less than 20 patients, case-control studies, and randomized controlled trials were excluded. MEDLINE, EMBASE, PsycINFO, CINAHL, and Alois databases were searched. Pooled relative risks were calculated using bivariate random effects models or network metaanalysis. Methodological quality was assessed across 8 factors. RESULTS: 31 patient samples representing 8,329 patients were included. Delirium was more common in patients with supratentorial lesions than infratentorial (RR [Relative Risk] 2.01, CI [Confidence Interval] 1.49-2.72); anterior circulation lesions than posterior (RR 1.41, CI 1.13-1.78); and cortical lesions than subcortical (RR 1.54, CI 1.25-1.89). Stroke side was not associated with delirium (right vs. left: RR 0.99, CI 0.77-1.28). Delirium was more common in patients with hemorrhagic strokes than ischemic (RR 1.74, CI 1.42-2.11) and patients with preexisting qualitative atrophy (RR 1.66, CI 1.21-2.27). CONCLUSION: Several brain localizations and types of strokes were associated with delirium. Conclusions were in part limited by the heterogeneity of studies and broad or qualitative lesion descriptions. These results may assist in anticipating the risk of delirium in acute stroke and highlight brain networks and pathologies that may be involved in the pathophysiology of delirium.

Stroke-prone spontaneously hypertensive rats (SHRSP) on high-salt diet are characterized by extremely high arterial pressures, and have been endorsed as a model for hypertensive small vessel disease and vascular cognitive impairment. However, rapidly developing malignant hypertension is a well-known cause of posterior reversible encephalopathy syndrome (PRES) in humans, associated with acute neurological deficits, seizures, vasogenic cerebral edema and microhemorrhages. In this study, we aimed to examine the overlap between human PRES and SHRSP on high-salt diet. In SHRSP, arterial blood pressure progressively increased after the onset of high-salt diet and seizure-like signs emerged within three to five weeks. MRI revealed progressive T2-hyperintense lesions suggestive of vasogenic edema predominantly in the cortical watershed and white matter regions. Histopathology confirmed severe blood–brain barrier disruption, white matter vacuolization and microbleeds that were more severe posteriorly. Hematological data suggested a thrombotic microangiopathy as a potential underlying mechanism. Unilateral common carotid artery occlusion protected the ipsilateral hemisphere from neuropathological abnormalities. Notably, all MRI and histopathological abnormalities were acutely reversible upon switching to regular diet and starting antihypertensive treatment. Altogether our data suggest that SHRSP on high-salt diet recapitulates the neurological, histopathological and imaging features of human PRES rather than chronic progressive small vessel disease.

X-linked adrenoleukodystrophy is a neurodegenerative disorder caused by mutations in ABCD1. By applying a vascular model to conventional MR perfusion imaging, Lauer et al. demonstrate that ABCD1 deficiency causes alterations in microvascular flow in white matter areas and developmental stages with the highest probability for conversion to cerebral disease., Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood–brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood–brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.

Background: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from −3 to −8 in a prior independent genetic association study. Results: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13–1.46; P =1.5×10 −4 ) to 1.67 (25 variants; 95% confidence interval, 1.47–1.90; P =9.3×10 −15 ). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39–4.58; P =2.7×10 −3 ). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20–4.40; P =0.01). Conclusions: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.

Acute ischemic stroke represents a major cause of long-term adult disability. Accurate prognostication of post-stroke functional outcomes is invaluable in guiding patient care, targeting early rehabilitation efforts, selecting patients for clinical research, and conveying realistic expectations to families. The involvement of specific brain regions by acute ischemia can alter post-stroke recovery potential. Understanding the influences of infarct topography on neurologic outcomes holds significant promise in prognosis of functional recovery. In this review, we discuss the recent evidence of the contribution of infarct location to patient management decisions and functional outcomes after acute ischemic stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well‐powered meta‐ and mega‐analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large‐scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Registration is a core component of many imaging pipelines. In case of clinical scans, with lower resolution and sometimes substantial motion artifacts, registration can produce poor results. Visual assessment of registration quality in large clinical datasets is inefficient. In this work, we propose to automatically assess the quality of registration to an atlas in clinical FLAIR MRI scans of the brain. The method consists of automatically segmenting the ventricles of a given scan using a neural network, and comparing the segmentation to the atlas ventricles propagated to image space. We used the proposed method to improve clinical image registration to a general atlas by computing multiple registrations - one directly to the general atlas and others via different age-specific atlases - and then selecting the registration that yielded the highest ventricle overlap. Finally, as an example application of the complete pipeline, a voxelwise map of white matter hyperintensity burden was computed using only the scans with registration quality above a predefined threshold. Methods were evaluated in a single-site dataset of more than 1000 scans, as well as a multi-center dataset comprising 142 clinical scans from 12 sites. The automated ventricle segmentation reached a Dice coefficient with manual annotations of 0.89 in the single-site dataset, and 0.83 in the multi-center dataset. Registration via age-specific atlases could improve ventricle overlap compared to a direct registration to the general atlas (Dice similarity coefficient increase up to 0.15). Experiments also showed that selecting scans with the registration quality assessment method could improve the quality of average maps of white matter hyperintensity burden, instead of using all scans for the computation of the white matter hyperintensity map. In this work, we demonstrated the utility of an automated tool for assessing image registration quality in clinical scans. This image quality assessment step could ultimately assist in the translation of automated neuroimaging pipelines to the clinic.

Neuro-Sweet disease (NSD) should be considered in any patient with a history of Sweet syndrome who presents with neurologic symptoms.

Sleep related Stroke (SRS) is common and has been associated with cerebral small vessel diseases (SVD) in ischemic strokes (ISs). We tested the hypothesis that SRS is associated with SVD in both ischemic and hemorrhagic stroke.Prospectively collected data from patients consecutively enrolled after intracerebral hemorrhage (ICH) related to SVD or after IS were analyzed. Symptom onset was recorded as SRS versus awake. Each ICH was grouped according to lobar and deep locations. The IS cohort was etiologically characterized based on the Causative Classification of Stroke system. Frequencies of SRS within and between ICH and IS cohorts as well as its associations (etiology, risk factors) were analyzed.We analyzed 1812 IS (mean age 67.9 years ± 15.9 years, 46.4% female) and 1038 ICH patients (mean age 72.5 years ± 13.0 years, 45.4% female). SRS was significantly more common among SVD-related ICH patients (n = 276, 26.6%) when compared to all IS (n = 363, 20.0%, P.001) and in both, small artery occlusion (SAO) related IS and lobar ICH within the respective IS and ICH cohorts (16.3% SRS versus 9.1% awake for SAO within all IS, P.001; and 57.1% SRS versus 47.7% awake for lobar bleeds within all ICH, P = .008). These associations remained significant after controlling for age, sex and risk factors.SRS was associated with SVD. The SAO etiology and cerebral amyloid angiopathy related lobar ICH suggest that the presence of SVD can interact with sleep or arousal related hemodynamic changes to cause ischemic and hemorrhagic stroke.

[Background and Purpose] Immune cells play a key role in the first 24h poststroke (acute phase), being associated with stroke outcome. We aimed to find genetic risk factors associated with leukocyte counts during the acute phase of stroke., [Methods] Ischemic stroke patients with leukocyte counts data during the first 24h were included. Genome-wide association study and gene expression studies were performed., [Results] Our genome-wide association study, which included 2064 (Discovery) and 407 (Replication) patients, revealed a new locus (14q24.3) associated with leukocyte counts. After Joint analysis (n=2471) 5 more polymorphisms reached genome-wide significance (P, [Conclusions] We have found the first locus associated with leukocyte counts in ischemic stroke, also associated with acute outcome. Genetic analysis of acute endophenotypes could be useful to find the genetic factors associated with stroke outcome. Our findings suggested a different modulation of immune cells in stroke compared with healthy conditions.

Background: White matter hyperintensity (WMH) is a common manifestation of chronic ischemic microvascular disease that heralds greater risk of functional disability, stroke, and dementia. SPRINT MIND recently reported that intensive blood pressure reduction resulted in lower rates of mild cognitive impairment and WMH progression, suggesting that medical interventions could have a measurable impact on WMH. We conducted an anonymous survey of providers in the NINDS StrokeNet to better understand neurologist attitudes about asymptomatic WMH. Methods: We sent a 7-question survey to the 29 Regional Coordinating Centers of the StrokeNet, whose coordinators disseminated the survey to providers “involved in the care of a patient after their stroke.” Results: We received 136 responses. For stroke prevention therapies, including aspirin and statin therapy and blood pressure target, there was substantial equipoise, with no single option receiving >50% endorsement and between 15-32% of respondents choosing the option of “not sure.” 83% of respondents indicated high or moderate enthusiasm for a trial targeting this patient population. The clinical outcomes of reduction in ischemic stroke, cognitive impairment, or dementia were high importance (>70% endorsement), while the remaining radiographic, safety, and clinical endpoints all failed to reach 50% endorsement. Conclusions: Our survey establishes meaningful neurologist attitudes that can inform future WMH research. There is considerable equipoise regarding optimal medical treatment for patients with asymptomatic WMH and providers in StrokeNet, who would be a vital stakeholder in WMH research in the United States, enthusiastically support a clinical trial to resolve open questions on optimal medical management.

Background and Purpose- Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods- Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results- There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions- We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 753896 (M.D. Schirmer). This study was supported by NIH-NINDS (MRI-GENIE: R01NS086905 - PI N.Rost, K23NS064052, R01NS082285 - N. Rost, SiGN: U01 NS069208 - J. Rosand, S. Kittner, R01NS059775, R01NS063925, R01NS082285,P50NS051343, R01NS086905, U01 NS069208 - O. Wu), NIH NIBIBNAC (P41EB015902–P. Golland).