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Background: An increasing number of monogenic conditions underlying stroke are being identified. We explored the possibilities of increasing the diagnostic yield of monogenic stroke in a population under 56 years of age., Methods: Fifty probands ≤55 years at their first stroke episode were characterized clinically and investigated by whole genome sequencing. Probands had one or more of: (1) one or more first to second degree relatives with stroke under 60 years or same stroke-causing condition/disease; (2) no hypertension, hypercholesterolemia, diabetes, heart disease, or smoking; or (3) either multiple stroke episodes or multiple arterial dissections. Variants with minor allele frequency under 0.01, identified by using our stroke gene panels, were assessed. The stroke subtypes, including large artery atherosclerotic, large artery nonatherosclerotic (tortuosity, dolichoectasia, aneurysm, nonatherosclerotic dissection, or occlusion), cerebral small vessel disease, cardioembolic (arrhythmia, heart defect, or cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, or bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma or arteriovenous malformations), metabolic disorders, or cryptogenic embolic, were used for genotype-phenotype correlation. In a final step, we combined genetic and clinical information to determine if the genetic variant likely was the cause of stroke in the patients., Results: Whole genome sequencing of younger patients with stroke identified 17 clinically matching genetic variants in 15 of 50 (30%) patients, while a stronger clinical correlation with stroke was established in only 6 (12%) of them. Stroke-related genetic variants were identified in 4 of 5 (80%) patients with cardioembolic stroke subtype, 3 of 4 (75%) with intracerebral hemorrhage, 7 of 18 (39%) with cryptogenic embolic stroke, 1 of 6 (17%) with small vessel disease, and 3 of 15 (20%) of patients with nonatherosclerotic large artery stroke, including 1 of 11 (9%) with cervical dissection stroke., Conclusions: Careful clinical interpretation of whole genome data using stroke gene panels can detect monogenic causes of early stroke, allowing individualized follow-up and opening new possibilities for potential treatment.

Aging profoundly affects the immune system leading to an increased propensity for inflammation. Age-related dysregulation of immune cells is implicated in the development and progression of numerous age-related diseases such as: cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Monocytes and monocyte-derived macrophages, being important players in the inflammatory response, significantly influence the aging process and the associated increase in inflammatory disease risk. Ischemic stroke is among age-related diseases where inflammation, particularly monocyte-derived macrophages, plays an important deteriorating role but could also strongly promote post-stroke recovery. Also, biological sex influences the incidence, presentation, and outcomes of ischemic stroke, reflecting both biological differences between men and women. Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of genes implicated in stroke-related inflammation and post-stroke tissue regeneration depends on age and sex. A flow cytometry analysis of blood samples from 44 healthy volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of NK-cells increased in females. The proportion of B-cells decreased in both sexes with age. Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increasing age. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes. Understanding these dynamics could pave the way for targeted interventions and personalized approaches in post-stroke care, particularly for the aging population and individuals of different sexes., Competing Interests: Dr Lindgren has served as a national leader for Sweden and Denmark for the NAVIGATE study. He is a national leader for Sweden for 2 ongoing stroke trials and the local PI for the StrokeCLOSE study. He reports personal fees from Arega, Bayer, Astra Zeneca, BMS Pfizer, and Novo Nordisk. The reported competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Tampé et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To systematically evaluate which lesion-based imaging features and methods allow for the best statistical prediction of poststroke deficits across independent datasets., Methods: We utilized imaging and clinical data from three independent datasets of patients experiencing acute stroke (N 1  = 109, N 2  = 638, N 3  = 794) to statistically predict acute stroke severity (NIHSS) based on lesion volume, lesion location, and structural and functional disconnection with the lesion location using normative connectomes., Results: We found that prediction models trained on small single-center datasets could perform well using within-dataset cross-validation, but results did not generalize to independent datasets (median R 2 N1  = 0.2%). Performance across independent datasets improved using large single-center training data (R 2 N2  = 15.8%) and improved further using multicenter training data (R 2 N3  = 24.4%). These results were consistent across lesion attributes and prediction models. Including either structural or functional disconnection in the models outperformed prediction based on volume or location alone (P < 0.001, FDR-corrected)., Interpretation: We conclude that (1) prediction performance in independent datasets of patients with acute stroke cannot be inferred from cross-validated results within a dataset, as performance results obtained via these two methods differed consistently, (2) prediction performance can be improved by training on large and, importantly, multicenter datasets, and (3) structural and functional disconnection allow for improved prediction of acute stroke severity., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Sphingosine-1-phosphate receptors (S1PRs) are promising therapeutic targets in cardiovascular disease, including ischemic stroke. However, important spatiotemporal information for alterations of S1PR expression is lacking. Here, we investigated the role of S1PR3 in ischemic stroke in rodent models and patient samples. We show that S1PR3 is acutely upregulated in perilesional reactive astrocytes after stroke, and that stroke volume and behavioral deficits are improved in mice lacking S1PR3. Further, we find that administration of an S1PR3 antagonist at 4-h post-stroke, but not at later timepoints, improves stroke outcome. Lastly, we observed higher plasma S1PR3 concentrations in experimental stroke and in patients with ischemic stroke. Together, our results establish S1PR3 as a potential drug target and biomarker in ischemic stroke., Competing Interests: A.G.L. is a consultant for Arega, Bayer, NovoNordisk, Astra Zeneca, and BMS Pfizer. Arega, Bayer, NovoNordisk, Astra Zeneca, and BMS Pfizer did not have any financial or intellectual involvement in this article., (© 2024 The Author(s).)

Background: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied., Methods: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death., Results: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days., Conclusions: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Stroke is a leading cause of acquired disability in adults worldwide, and the burden of stroke is projected to increase. Current long-term stroke outcome data including functional status, activity, and participation limitations as well as information on health-related quality of life (HRQoL) are vital for future rehabilitation and resource planning of stroke survivors., Methods: First-ever stroke survivors from a population-based cohort with ischemic stroke or intracerebral hemorrhage were followed up 3-4 years after stroke onset via clinic appointments, home visits, or telephone. Ischemic stroke was stratified by clinical syndrome (Oxfordshire Community Stroke Project classification) and pathogenetic mechanism (TOAST classification). We assessed the participants' functional status and independence with the modified Rankin Scale (mRS) and Barthel Index (BI) and their HRQoL across several domains (Short Form Questionnaire-36, EuroQoL-5D, and Stroke Impact Scale (SIS)). We used logistic and linear regression analyses to analyze potential baseline predictors of 3-4-year outcome., Results: Four hundred individuals were included; 151 died before clinical follow-up and 47 (12%) were lost to detailed follow-up. Two hundred and two individuals (median age: 72, IQR: 65-79; 40% female) were followed up after a median of 3.2 years (IQR: 3.1-3.5). Nineteen individuals (9%) had a recurrent stroke during the 3-4-year follow-up period. Among the 202 follow-up attendees, 147 (73%) had favorable functional outcome (mRS ≤2) and 134 (69%) of the 195 respondents reported good-excellent HRQoL according to SF-36. Age (HR: 1.03; 95% CI: 1.00-1.05), initial stroke severity (HR: 1.16; 95% CI: 1.10-1.22; p &lt; 0.001), living with in-home care or in care facility at baseline (HR: 8.77; 95% CI: 2.98-25.64), and recurrent stroke (HR: 3.58; 95% CI: 1.47-8.77) were predictors of poor functional outcome (mRS&gt;2). Poor functional outcome/death was less common among IS due to Other Causes and Small Artery Occlusion than other pathogenetic mechanisms (20% and 33% vs. 56-68%; p &lt; 0.01). SIS respondents with poor functional outcomes (n = 32) reported worst outcome in the hand domain of SIS (median: 28/100; IQR: 0-73)., Conclusions: Most 3-4-year stroke survivors have favorable functional outcomes and are independent in ADL in a population-based cohort. Despite its relative rarity, recurrent stroke was a predictor of poor functional outcome, emphasizing the need of adequate secondary prevention., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

A quarter of ischaemic strokes are lacunar subtype, typically neurologically mild, usually resulting from intrinsic cerebral small vessel pathology, with risk factor profiles and outcome rates differing from other stroke subtypes. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist with clinical decisions about management of lacunar ischaemic stroke to prevent adverse clinical outcomes. The guideline was developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We addressed acute treatment (including progressive lacunar stroke) and secondary prevention in lacunar ischaemic stroke, and prioritised the interventions of thrombolysis, antiplatelet drugs, blood pressure lowering, lipid lowering, lifestyle, and other interventions and their potential effects on the clinical outcomes recurrent stroke, dependency, major adverse cardiovascular events, death, cognitive decline, mobility, gait, or mood disorders. We systematically reviewed the literature, assessed the evidence and where feasible formulated evidence-based recommendations, and expert concensus statements. We found little direct evidence, mostly of low quality. We recommend that patients with suspected acute lacunar ischaemic stroke receive intravenous alteplase, antiplatelet drugs and avoid blood pressure lowering according to current acute ischaemic stroke guidelines. For secondary prevention, we recommend single antiplatelet treatment long-term, blood pressure control, and lipid lowering according to current guidelines. We recommend smoking cessation, regular exercise, other healthy lifestyle modifications, and avoid obesity for general health benefits. We cannot make any recommendation concerning progressive stroke or other drugs. Large randomised controlled trials with clinically important endpoints, including cognitive endpoints, are a priority for lacunar ischaemic stroke., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. For details, please see Supplemental Table 1.

Background: Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important pathophysiological mechanisms., Methods: Plasma samples were collected from patients with acute ischemic stroke (n=39) at 3 time points after stroke onset: 0 to 6 hours, 12 to 24 hours, and 2 to 6 days, and compared with controls (n=39). Pericyte-derived microvesicles were isolated based on cluster of differentiation 140b expression and quantified by flow cytometry. The protein content was evaluated using a proximity extension assay, and vascular signaling pathways were examined using molecular signature hallmarks and gene ontology., Results: In this case-control study, patients with acute ischemic stroke showed significantly increased numbers of pericyte-derived microvesicles (median, stroke versus controls) at 12 to 24 hours (1554 versus 660 microvesicles/μL; P =0.0041) and 2 to 6 days after stroke (1346 versus 660 microvesicles/μL; P =0.0237). Their proteome revealed anti-inflammatory properties mediated via downregulation of Kirsten rat sarcoma virus and IL (interleukin)-6/JAK/STAT3 signaling at 0 to 6 hours, but proangiogenic as well as proinflammatory signals at 12 to 24 hours. Between 2 and 6 days, proteins were mainly associated with vascular remodeling as indicated by activation of Hedgehog signaling in addition to proangiogenic signals., Conclusions: We demonstrate that the plasma of patients with acute ischemic stroke reflects (1) an early and time-dependent increase of pericyte-derived microvesicles and (2) changes in the protein cargo of microvesicles over time indicating cell signaling specifically related to inflammation and vascular remodeling., Competing Interests: Disclosures Dr Lindgren reports personal fees from Bayer, NovoNordisk, Astra Zeneca, Arega, and BMS Pfizer outside this work. The other authors report no conflicts.

Background and Objectives: Stroke genetic research has made substantial progress in the past decade. Its recovery application, however, remains behind, in part due to its reliance on the modified Rankin Scale (mRS) score as a measure of poststroke outcome. The mRS does not map well to biological processes because numerous psychosocial factors drive much of what the mRS captures. Second, the mRS contains multiple disparate biological events into a single measure further limiting its use for biological discovery. This led us to investigate the effect of distinct stroke recovery phenotypes on genetic variation associations with Genome-Wide Association Studies (GWASs) by repurposing the NIH Stroke Scale (NIHSS) and its subscores., Methods: In the Vitamin Intervention for Stroke Prevention cohort, we estimated changes in cognition, motor, and global impairments over 2 years using specific measures. We included genotyped participants with a total NIHSS score greater than zero at randomization and excluded those with recurrent stroke during the trial. A GWAS linear mixed-effects model predicted score changes, with participant as a random effect, and included initial score, age, sex, treatment group, and the first 5 ancestry principal components., Results: In total, 1,270 participants (64% male) were included with a median NIHSS score of 2 (interquartile range [IQR] 1-3) and median age 68 (IQR 59-75) years. At randomization, 20% had cognitive deficits (NIHSS Cog-4 score >0) and 70% had ≥1 motor deficits (impairment score >1). At 2 years, these percentages improved to 7.2% with cognitive deficits and 30% with motor deficits. GWAS identified novel suggestive gene-impairment associations ( p < 5e -6 ) for cognition ( CAMK2D , EVX2 , LINC0143 , PTPRM , SGMS1 , and SMAD2 ), motor ( ACBD6 , KDM4B , MARK4 , PTPRS , ROBO1 , and ROBO2 ), and global ( MSR1 and ROBO2 ) impairments., Discussion: Defining domain-specific stroke recovery phenotypes and using longitudinal clinical trial designs can help detect novel genes associated with chronic recovery. These data support the use of granular endpoints to identify genetic associations related to stroke recovery.

Deep learning has allowed for remarkable progress in many medical scenarios. Deep learning prediction models often require 10 5 -10 7 examples. It is currently unknown whether deep learning can also enhance predictions of symptoms post-stroke in real-world samples of stroke patients that are often several magnitudes smaller. Such stroke outcome predictions however could be particularly instrumental in guiding acute clinical and rehabilitation care decisions. We here compared the capacities of classically used linear and novel deep learning algorithms in their prediction of stroke severity. Our analyses relied on a total of 1430 patients assembled from the MRI-Genetics Interface Exploration collaboration and a Massachusetts General Hospital-based study. The outcome of interest was National Institutes of Health Stroke Scale-based stroke severity in the acute phase after ischaemic stroke onset, which we predict by means of MRI-derived lesion location. We automatically derived lesion segmentations from diffusion-weighted clinical MRI scans, performed spatial normalization and included a principal component analysis step, retaining 95% of the variance of the original data. We then repeatedly separated a train, validation and test set to investigate the effects of sample size; we subsampled the train set to 100, 300 and 900 and trained the algorithms to predict the stroke severity score for each sample size with regularized linear regression and an eight-layered neural network. We selected hyperparameters on the validation set. We evaluated model performance based on the explained variance ( R 2 ) in the test set. While linear regression performed significantly better for a sample size of 100 patients, deep learning started to significantly outperform linear regression when trained on 900 patients. Average prediction performance improved by ∼20% when increasing the sample size 9× [maximum for 100 patients: 0.279 ± 0.005 ( R 2 , 95% confidence interval), 900 patients: 0.337 ± 0.006]. In summary, for sample sizes of 900 patients, deep learning showed a higher prediction performance than typically employed linear methods. These findings suggest the existence of non-linear relationships between lesion location and stroke severity that can be utilized for an improved prediction performance for larger sample sizes., Competing Interests: A.G.L. reports personal fees from Bayer, Novo Nordisk, AstraZeneca and BMS Pfizer outside this work. N.S.R. has received compensation as scientific advisory consultant from Omniox, Sanofi Genzyme and AbbVie Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke., Methods: The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses., Results: LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses ( P <0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1-2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1-2.5])., Conclusions: We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted., Competing Interests: Disclosures Dr Dumanski is a cofounder and shareholder in Cray Innovation AB. Dr Lindgren reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Novo Nordisk, Pfizer, and Portola Pharmaceuticals. The other authors report no conflicts.

Objective: Most methods to detect copy number variation (CNV) have high false positive rates, especially for small CNVs and in real-life samples from clinical studies. In this study, we explored a novel scatterplot-based method to detect CNVs in microarray samples. Methods: Illumina SNP microarray data from 13,254 individuals were analyzed with scatterplots and by PennCNV. The data were analyzed without the prior exclusion of low-quality samples. For CNV scatterplot visualization, the median signal intensity of all SNPs located within a CNV region was plotted against the median signal intensity of the flanking genomic region. Since CNV causes loss or gain of signal intensities, carriers of different CNV alleles pop up in clusters. Moreover, SNPs within a deletion are not heterozygous, whereas heterozygous SNPs within a duplication show typical 1:2 signal distribution between the alleles. Scatterplot-based CNV calls were compared with standard results of PennCNV analysis. All discordant calls as well as a random selection of 100 concordant calls were individually analyzed by visual inspection after noise-reduction. Results: An algorithm for the automated scatterplot visualization of CNVs was developed and used to analyze six known CNV regions. Use of scatterplots and PennCNV yielded 1019 concordant and 108 discordant CNV calls. All concordant calls were evaluated as true CNV-findings. Among the 108 discordant calls, 7 were false positive findings by the scatterplot method, 80 were PennCNV false positives, and 21 were true CNVs detected by the scatterplot method, but missed by PennCNV (i.e., false negative findings). Conclusion: CNV visualization by scatterplots allows for a reliable and rapid detection of CNVs in large studies. This novel method may thus be used both to confirm the results of genome-wide CNV detection software and to identify known CNVs in hitherto untyped samples., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qiao, Levinson, Chen, Engelter, Erhart, Gaynor, McArdle, Schlicht, Krawczak, Stenman, Lindgren, Cole and Grond-Ginsbach.)

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objectives: While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes., Methods: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input., Results: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p -values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes., Discussion: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke., (© 2022 American Academy of Neurology.)

This article updates our previous Stroke Gene Panels (SGP) from 2017. Online Mendelian Inheritance in Man and PubMed were searched. We divided detected genes into two SGP groups, SGP1: genes reported in at least one person with stroke and associated with one or more clinical subgroups: large artery atherosclerotic, large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection or occlusion), cerebral small vessel diseases, cardio-embolic (arrhythmia, heart defect, cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma, arteriovenous malformations) and metabolism disorders; and SGP2: genes related to diseases that may predispose to stroke. We identified 168 SGP1 genes, 70 of these were validated for clinical practice. We also detected 72 SGP2 genes. Nine genes were removed because of conflicting evidence. The number of genes increased from 168 to 240 during 4.5-years, reflecting a dynamic evolution and the need for regular updates for research and clinical use., (© 2022. The Author(s).)

Background and Objectives: To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways., Methods: MR 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, age 2 , sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts., Results: A 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., Discussion: Higher 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., (© 2022 American Academy of Neurology.)

Background: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown., Methods: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete., Findings: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71])., Interpretation: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke., Funding: Bayer AG., Competing Interests: Declaration of interests All coauthors or their institutions received financial support from Bayer for participation in the PACIFIC-Stroke trial except HM, PC, BK, and CN who are employees of Bayer. HM, PC, BK, and CN do not hold any stock or stock options with Bayer., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background Purpose: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort., Materials and Methods: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome., Results: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL., Conclusion: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only., Competing Interests: ME had received personal fees for consulting from Astra Zeneca and WorldCare Clinical Group. CG had received consulting honoraria from Microvention and Strykere and research funding from Medtronic and Penumbra. AV had received research funding from Cerenovus. AL had received personal fees from Bayer, Astra Zeneca, BMS Pfizer, and Portola. NR had received compensation as scientific advisory consultant from Omniox, Sanofi Genzyme and AbbVie Inc. TU received personal fees for consulting from AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bonkhoff, Ullberg, Bretzner, Hong, Schirmer, Regenhardt, Donahue, Nardin, Dalca, Giese, Etherton, Hancock, Mocking, McIntosh, Attia, Cole, Donatti, Griessenauer, Heitsch, Holmegaard, Jood, Jimenez-Conde, Kittner, Lemmens, Levi, McDonough, Meschia, Phuah, Ropele, Rosand, Roquer, Rundek, Sacco, Schmidt, Sharma, Slowik, Sousa, Stanne, Strbian, Tatlisumak, Thijs, Vagal, Woo, Zand, McArdle, Worrall, Jern, Lindgren, Maguire, Wu, Frid, Rost and Wasselius.)

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: A decrease in ischemic stroke (IS) incidence has been observed in high income countries during the last decades. Whether this has influenced the occurrence of aphasia in IS is uncertain. We therefore examined the incidence rate and potentially related determinants of aphasia in IS., Methods: We prospectively examined consecutive patients admitted to hospital with first-ever acute IS between March 1, 2017, and February 28, 2018, as part of the Lund Stroke Register (LSR) Study, comprising patients from the uptake area of Skåne University Hospital, Lund, Sweden. Patients were assessed with National Institutes of Health Stroke Scale (NIHSS) at stroke onset. Presence of aphasia was evaluated with NIHSS item 9 (language). We registered IS subtypes and risk factors. To investigate possible temporal changes in aphasia incidence, we made comparisons with corresponding LSR data from 2005 to 2006. Incidence rates were calculated and adjusted to the European Standard Population (ESP) and to the Swedish population., Results: Among 308 included IS patients, 30% presented with aphasia (n = 91; 95% CI: 25-35), a proportion of aphasia in IS that was similar to 2005-2006. The incidence rate of aphasia was 31 per 100,000 person-years adjusted to the ESP (95% CI: 25-38 per 100,000 person-years) corresponding to a significant decrease of 30% between 2005-2006 and 2017-2018. The decrease was significantly more pronounced in men. The initial severity of aphasia remained unchanged, with the majority of patients having severe to global aphasia. No significant differences between vascular stroke risk factors were noted among stroke patients with or without aphasia., Conclusion: Even though the overall IS incidence rate has decreased during the first decades of the 21st century, the proportion of IS patients with aphasia at stroke onset remains stable at 30%. Aphasia continues to be an important symptom that needs to be considered in stroke care and rehabilitation., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background and Purpose: Up-to-date population-based information about long-term survival, causes of death and recurrence after stroke is needed., Methods: Four hundred consecutive individuals in a population-based cohort of first-ever stroke between 2015 and 2016 in Lund, Sweden, were followed up to 3 years regarding (i) survival (Swedish Population Register); (ii) causes of death (Swedish Causes of Death Register); and (iii) stroke recurrence (interview and medical chart review). Index and recurrent ischaemic stroke cases were classified using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) and Oxfordshire Community Stroke Project; and comorbidities were classified using the Charlson Comorbidity Index. Cox regression was used to determine predictors for 3-year mortality. Survival rates were compared with three local studies over a 30-year timespan., Results: Amongst 400 first-ever stroke patients, 265 (66%) survived 3 years post-stroke. Age (hazard ratio [HR] 1.09; 95% confidence interval [CI] 1.06-1.11), stroke severity (HR 1.11; 95% CI 1.08-1.13) and comorbidities (HR 1.36; 95% CI 1.22-1.53) were independently related to 3-year mortality. Amongst index ischaemic stroke patients, survival was lowest amongst those with cardio-aortic embolism (51/91; 56%). Cerebrovascular disease (54/135; 40%) and ischaemic heart disease (25/135; 19%) were the most common causes of death. Within 3 years, 30 (8%) had recurrent stroke. Amongst patients with index ischaemic stroke, 16/29 (55%) had a different TOAST pathogenetic mechanism or hemorrhagic stroke upon recurrence. Stroke survival improved between 1983-1985 and 2015-2016 (p = 0.002), but no significant change was observed between 2001-2002 and 2015-2016 (p = 0.48)., Conclusions: Stroke survival rates are relatively high, but their improvement over recent decades may be slowing down, possibly due to the composition of the first-ever stroke population. The common occurrence of changed pathogenetic mechanisms between first-ever and recurrent stroke highlights the value of reassessment in recurrent stroke., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Recent advances in stroke treatment have provided effective tools to successfully treat ischemic stroke, but still a majority of patients are not treated due to late arrival to hospital. With modern stroke treatment, earlier arrival would greatly improve the overall treatment results. This prospective study was performed to asses the capability of bilateral accelerometers worn in bracelets 24/7 to detect unilateral arm paralysis, a hallmark symptom of stroke, early enough to receive treatment. Classical machine learning algorithms as well as state-of-the-art deep neural networks were evaluated on detection times between 15 min and 120 min. Motion data were collected using triaxial accelerometer bracelets worn on both arms for 24 h. Eighty-four stroke patients with unilateral arm motor impairment and 101 healthy subjects participated in the study. Accelerometer data were divided into data windows of different lengths and analyzed using multiple machine learning algorithms. The results show that all algorithms performed well in separating the two groups early enough to be clinically relevant, based on wrist-worn accelerometers. The two evaluated deep learning models, fully convolutional network and InceptionTime, performed better than the classical machine learning models with an AUC score between 0.947-0.957 on 15 min data windows and up to 0.993-0.994 on 120 min data windows. Window lengths longer than 90 min only marginally improved performance. The difference in performance between the deep learning models and the classical models was statistically significant according to a non-parametric Friedman test followed by a post-hoc Nemenyi test. Introduction of wearable stroke detection devices may dramatically increase the portion of stroke patients eligible for revascularization and shorten the time to treatment. Since the treatment effect is highly time-dependent, early stroke detection may dramatically improve stroke outcomes.

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health., Competing Interests: AR was employed by Centogene AG, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hong, Giese, Schirmer, Bonkhoff, Bretzner, Rist, Dalca, Regenhardt, Etherton, Donahue, Nardin, Mocking, McIntosh, Attia, Benavente, Cole, Donatti, Griessenauer, Heitsch, Holmegaard, Jood, Jimenez-Conde, Roquer, Kittner, Lemmens, Levi, McDonough, Meschia, Phuah, Rolfs, Ropele, Rosand, Rundek, Sacco, Schmidt, Enzinger, Sharma, Slowik, Sousa, Stanne, Strbian, Tatlisumak, Thijs, Vagal, Wasselius, Woo, Zand, McArdle, Worrall, Wu, Jern, Lindgren, Maguire, Tomppo, Golland, Rost and the MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortium.)