Stroke

IntroductionPathophysiological distinctions among stroke subtypes--acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and other nontraumatic intracranial hemorrhage (ONIH)--are well described, but their associations with long-term mortality, cognitive outcomes, and dementia risk remain incompletely characterized. We examined whether stroke subtypes differ in post-stroke survival, cognitive performance, dementia risk, and neuroimaging phenotypes. MethodsUsing data from the UK Biobank, we evaluated subtype-specific associations with all-cause mortality, incident all-cause dementia, post-stroke cognitive performance, and white matter hyperintensity (WMH) burden. We assessed time to mortality and all-cause dementia using multivariable Cox proportional hazards models. Cognitive outcomes were compared cross-sectionally between stroke subtypes and stroke-free participants using covariate-adjusted linear models with ANOVA and Tukey post hoc tests. Neuroimaging analyses assessed associations between stroke subtype and WMH volume. ResultsMortality risk varied substantially by stroke subtype. Of UKB participants who had a stroke during surveillance (n=14,806), we found that 69.24% of strokes were ischemic, 9.51% subarachnoid, 9.78% ONIH, and 11.78% ICH. Compared with stroke-free person-time, intracerebral hemorrhage was associated with the highest post-stroke hazard of death (HR 7.62, 95% CI 7.10-8.18), followed by other nontraumatic intracranial hemorrhage (HR 5.41, 95% CI 4.89-5.98), subarachnoid hemorrhage (HR 3.89, 95% CI 3.52-4.31), and ischemic stroke (HR 3.99, 95% CI 3.82-4.16). At 1 year after stroke, absolute mortality risk was highest following ICH (36.4%), followed by ONIH (31.9%) and SAH (26.0%), while ischemic stroke was associated with substantially lower risk (11.7%); by 5 years, corresponding risks increased to 43.5%, 39.8%, 30.0%, and 20.0%, respectively. Dementia risk also differed by subtype, with the highest risk observed following ICH. Post-stroke cognitive performance varied across domains, with slower reaction times observed across multiple stroke subtypes and lower fluid intelligence scores among AIS and ICH patients. Reaction time and fluid intelligence assessments were completed a median of approximately 6-9 years after stroke. WMH burden was higher in ICH and AIS compared with stroke-free participants. ConclusionsStroke subtype is associated with distinct patterns of mortality, dementia risk, cognitive performance, and brain imaging phenotypes. These findings highlight the heterogeneity of long-term outcomes following stroke and support the importance of subtype-aware post-stroke monitoring and prognostication.

BackgroundAdult hippocampal neurogenesis is markedly altered after cerebral ischemia. Although stroke increases the production of newborn neurons, many of these cells display aberrant morphological and positional features that impair their functional integration and contribute to long-term cognitive decline. Given the clinical heterogeneity of ischemic stroke and the persistent translational failures of preclinical approaches relying on single-model studies it remains unknown whether post-stroke neurogenic alterations are conserved across different experimental paradigms. This study aimed to define common and model-specific features of hippocampal neurogenesis across complementary focal ischemia models. MethodsWe performed a multi-center, multimodel analysis within the STROKE-IMPaCT consortium using permanent and transient middle cerebral artery occlusion (MCAO) paradigms (MCAO via ligation or cauterization under normoxic (dMCAO) or hypoxic conditions (dMCAO+Hypoxia); and filament-based tMCAO across six international sites. Brains from adult C57BL/6J mice were collected 3 days, 7 days, or 2 months after ischemia, sham, or naive conditions. Hippocampal cell proliferation (Ki67) and neuroblast density (DCX) were quantified, and the morphological maturation of newborn neurons was evaluated using high-resolution analyses of dendritic architecture and somatodendritic polarity. All analyses were performed blind to experimental group. ResultsAcross all stroke models, ischemia induced a robust bilateral increase in hippocampal cell proliferation, most pronounced at 3 days and still elevated at 7 days, with levels returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized by 2 months. Despite recovery in cell number, long-term morphological analysis revealed a consistent reduction in apical dendrite length and a higher proportion of neurons exhibiting aberrant features including ectopic localization, multipolar or inverted polarity, and abnormal lateral growth across all models. These abnormalities were observed both when pooling data across sites and when analyzing each model or center individually. ConclusionsIschemia induces an early, transient increase in hippocampal neurogenesis across diverse stroke paradigms, but the newborn neurons generated after stroke consistently display maladaptive morphological features. These cross-model, cross-site abnormalities indicate that aberrant hippocampal neurogenesis represents a robust hallmark of post-stroke pathology within the investigated species, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across experimental stroke models. Our findings support the concept that maladaptive neurogenesis may contribute to chronic post-stroke cognitive impairment and underscore the need to consider the quality not only the quantity of newborn neurons when developing therapeutic strategies.

BackgroundAcute basilar artery occlusion (BAO) causes devastating strokes. Despite the benefit of endovascular treatment, the optimal management remains sometimes controversial, such as for patients with mild deficits, and would benefit from robust prognostic tools. Given the dense white matter networks within the posterior fossa, we tested whether quantifying disconnections from acute diffusion-weighted imaging (DWI) could improve outcome prediction and responders to recanalization compared with conventional metrics. MethodsWe conducted a secondary analysis from a prospective multicenter stroke registry, including consecutive patients (2017-2024) with BAO and admission MRI. Ultra-high-resolution diffusion MRI was acquired in healthy participants to build normative tractograms with optimized posterior fossa quality. Patient infarcts delineated on DWI were projected onto these tractograms to estimate disconnected fiber volume. The primary outcome was 90-day modified Rankin Scale (mRS) 0-3 vs 4-6. Predictive performance of disconnected fiber volume was compared with baseline NIHSS, infarct volume, and posterior circulation ASPECTS (pc-ASPECTS) using logistic regressions and areas under receiver operating characteristic curves (AUC). Ordinal regressions tested associations across the full mRS spectrum, stratified by recanalization status. Analyses were repeated in patients with NIHSS [&le;]10. ResultsAmong 201 patients (median age 70; NIHSS 10), 97 (48.3%) had poor outcome. Despite small median infarct volume (4.75 mL), disconnected fiber volume was substantial (median 25.15 mL). Disconnected fiber volume achieved an AUC of 0.84, outperforming NIHSS (0.67; p<0.0001), infarct volume (0.75; p=0.00059), and pc-ASPECTS (0.76; p=0.0127). Low disconnected fiber volume predicted better outcomes across the full mRS (OR=0.12 [95% CI, 0.065-0.204]) and greater benefit from successful recanalization (OR=0.33 [95% CI, 0.15-0.70]). In patients with NIHSS [&le;]10 (n=102), disconnected fiber volume remained the strongest predictor (AUC=0.83). ConclusionsDisconnected fiber volume derived indirectly is a robust prognostic marker of BAO outcomes that outperforms conventional predictors and may support future treatment decisions. Registrationhttps://clinicaltrials.gov - NCT03776877.

ObjectiveTo compare early cerebrospinal fluid (CSF) cytokine profiles in intracerebral hemorrhage (ICH) versus subarachnoid hemorrhage (SAH), with a focus on angiography-negative SAH (anSAH). MethodsWe conducted a retrospective observational cohort study of adults with spontaneous hemorrhagic stroke (ICH or SAH). For cytokine analyses, we included patients with external ventricular drains (EVDs) and analyzed the first CSF sample obtained within 72 hours of symptom onset. Cytokines were measured using a multiplex bead-based assay and included interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A (VEGF-A), C-C motif chemokine ligand-2 (CCL2), and granulocyte colony-stimulating factor (G-CSF). Cytokine concentrations were log-transformed due to non-normal distribution. Functional outcomes were assessed using the modified Rankin Scale (mRS) at discharge and 3 months. ResultsCSF cytokine analyses included 120 patients with available CSF samples (43 ICH and 77 SAH), while functional outcome analyses included a broader cohort of 490 patients with ICH or SAH to characterize discharge and 3-month outcomes across hemorrhage subtypes. Compared with SAH, ICH demonstrated higher early CSF log[IL-8] and log[VEGF-A] and had worse functional outcomes at discharge and 3 months. Within SAH, anSAH had higher log[IL-8] and log[VEGF-A] than aSAH, and its cytokine profile more closely aligned with that of primary ICH in hemorrhages without vascular malformations. DiscussionEarly CSF cytokine patterns suggest anSAH shares a more ICH-like inflammatory signature than aneurysmal SAH, supporting anSAH as a potentially biologically distinct SAH phenotype.

Abstract Objective: To compare the safety and efficacy of bridging intravenous thrombolysis (IVT) plus endovascular thrombectomy (EVT) versus direct EVT in patients with acute ischemic stroke (AIS) due to anterior circulation large vessel occlusion (LVO) treated within the 6- to 24-hour time window. Methods: This is a retrospective analysis of prospective EVT registry from 10 comprehensive stroke centers in China and Singapore between 2019 and 2024. Eligible patients had anterior circulation LVO, underwent EVT within 6-24 hours of onset, had ASPECTS 6, NIHSS 6, and pre-stroke mRS 2. Patients were stratified into bridging IVT + EVT (IVT group) versus direct EVT alone (non-IVT group). Propensity score matching (1:2 ratio) was performed to balance baseline covariates. The primary outcome was 3-month favorable functional outcome (mRS 0-2). Secondary outcomes included successful recanalization (mTICI 2b-3), symptomatic intracranial hemorrhage (sICH), hemorrhagic transformation (HT) and 3-month mortality. In the matched cohort, binary outcomes were compared using the Cochran-Mantel-Haenszel test. Results: Of 772 included patients, 110 (14.2%) received bridging IVT and 662 (85.8%) received direct EVT. After propensity score matching, 202 non-IVT patients were matched to 101 IVT patients, with all covariates well-balanced (absolute SMD <0.10). In the matched cohort, bridging IVT was not associated with a significant difference in 3-month favorable outcome (44.55% vs. 47.03%; common OR 0.91; 95% CI 0.56-1.46), successful recanalization (91.09% vs. 90.10%; OR 1.11; 0.51-2.44), sICH (5.94% vs. 9.41%; OR 0.61; 0.24-1.58), HT (23.76% vs. 23.27%; OR 1.03; 0.57-1.85), or 3-month mortality (15.84% vs. 13.37%; OR 1.22; 0.62-2.37). Conclusion: In this large multicenter propensity score-matched analysis, bridging intravenous thrombolysis before endovascular thrombectomy in the 6- to 24-hour time window was not significantly associated with improved efficacy or increased safety risks compared with direct endovascular therapy alone.

BackgroundHemorrhagic transformation (HT) after endovascular thrombectomy (EVT) is a principal determinant of clinical outcome. Artificial intelligence (AI) algorithms for spontaneous hemorrhage detection exist, but none has been validated for post-procedural HT across multiple imaging modalities. MethodsWe conducted a multicenter diagnostic accuracy study within the Clinical Research Collaboration for Stroke in Korea registry (18 centers, 2022-2023). Patients who underwent EVT and received follow-up NCCT, GRE, or SWI within 168 hours were included. AI-derived hemorrhage volumes were compared against expert-determined ECASS classification. Three-month modified Rankin Scale (mRS) scores were evaluated for volume-outcome association. ResultsAmong 1,490 patients (median age 73; 57.4% male), HT was present in 41.4% and parenchymal hemorrhage (PH) in 11.1%. PH detection sensitivity exceeded 94% across all modalities (NCCT 95.4%, GRE 94.4%, SWI 98.3%), with AUCs of 0.900, 0.943, and 0.953, respectively. AI-derived volume correlated with 3-month mRS (Spearman {rho} = 0.353, P < 0.001); good outcome (mRS 0-2) declined from 61.8% to 6.7% across increasing volume categories. Among ECASS 0 cases, AI-positive patients had significantly worse outcomes than true-negatives (good outcome 48.2% vs 67.2%, mortality 10.7% vs 4.6%, P < 0.001). ConclusionsAI-based hemorrhage quantification provides high detection of clinically significant PH after EVT and demonstrates a dose-response association with functional outcome. AI-derived volume may serve as a continuous prognostic biomarker that identifies at-risk subgroups beyond categorical ECASS grading.

Objectives: Among individuals attending stroke rehabilitation, we aimed to determine the proportion who participated in cardiorespiratory exercise, identify patient characteristics predicting participation, and describe exercise characteristics. Design, setting, and participants: This was an observational cohort study involving all patients admitted to four stroke rehabilitation centres in Ontario, Canada, during March or October 2019, or over 12 months starting in 2021. Main measures: Patient characteristics extracted during chart review included age, sex, marital status, employment status, date of stroke, time post-stroke at admission, length of stay for rehabilitation, past medical history that could affect exercise participation, Functional Independence Measure, Functional Ambulation Category, mobility aid use, Chedoke-McMaster Stroke Assessment, Montreal Cognitive Assessment, National Institutes of Health Stroke Scale, and details describing cardiorespiratory exercise completed. Results: 40.1% of stroke patients participated in cardiorespiratory exercise, with 26.4% having it included in their treatment plan. Diagnosed cardiac disease (OR=0.74), poor left ventricular function (OR=0.09), history of mental health conditions (OR=0.69), lower functional ambulation ability (OR=0.74), and wheelchair use at rehabilitation admission (OR=0.46) were associated with lower odds of participating in cardiorespiratory exercise after stroke (p-values<0.05). Use of a walker or rollator at rehabilitation admission (OR=3.22), having a cardiorespiratory exercise goal (OR=2.13), and longer lengths of stay (OR=1.01) were associated with higher odds of participating in cardiorespiratory exercise after stroke (p-values<0.05). Only 1.5% of patients (N=9/601) who participated in cardiorespiratory exercise completed it with recommended intensity and duration. Conclusion: Improving participation in cardiorespiratory exercise during stroke rehabilitation may require addressing cardiovascular, mental health, and mobility-related barriers.

BackgroundFunctional recovery after ischemic stroke is a complex and polygenic process influenced by genetically regulated molecular pathways. Although genome-wide association studies (GWAS) have identified variants associated with stroke outcome, translating these findings into actionable therapeutic targets remains challenging. Transcriptome-wide association studies (TWAS) provide a framework to link genetic variation to gene expression and functional phenotypes, enabling mechanism-driven drug repurposing strategies. ObjectiveTo identify candidate compounds capable of improving long-term functional outcome after ischemic stroke by integrating GWAS summary statistics with brain transcriptomic data and large-scale perturbational drug signatures. MethodsWe performed TWAS integrating summary statistics from a stringent GWAS of long-term stroke outcome (modified Rankin Scale at three months, mRS3; N = 1,791; 8,895,027 variants) from the GODS study with brain eQTL data from ten regions in the GTEx project. Pathway enrichment analysis was conducted using WebGestalt. Drug repurposing was performed using the Trans-phar pipeline by comparing TWAS-derived transcriptional signatures with compound-induced gene expression profiles from the Connectivity Map (CMap) L1000 dataset across five neural cell lines. Compounds showing inverse transcriptional correlations were prioritized and further evaluated based on existing clinical and preclinical evidence in stroke. ResultsTWAS identified 22 genes consistently ranked within the top 10% across all ten regions. Pathway enrichment analysis highlighted transcriptional regulation processes, with the RNA polymerase pathway reaching statistical significance after FDR correction in the broader gene set. Drug repurposing analysis identified nine compounds whose transcriptional signatures inversely correlated with genetically predicted expression profiles associated with poor functional outcome. Among these, anandamide and progesterone had prior clinical evidence in stroke, while Z-guggulsterone demonstrated preclinical neuroprotective potential. ConclusionsIntegration of GWAS and brain eQTL data identifies robust transcriptional signatures associated with long-term stroke outcome and supports transcriptomics-driven drug repurposing strategies. This human genetics-guided framework prioritizes candidate compounds with potential translational relevance for improving functional recovery after ischemic stroke.

PurposeIntracranial atherosclerotic disease-related large vessel occlusion (ICAD-LVO) presents distinct challenges, particularly regarding the high risk of reocclusion and the need for specific management strategies. While several prediction scores exist to differentiate ICAD-LVO from embolic LVO (EMB-LVO), their external validity remains unproven. We aimed to externally validate six established prediction scores for differentiating the two. MethodsWe analyzed data from a prospectively maintained, two-center stroke registry (June 2021-March 2025). Consecutive patients who underwent mechanical thrombectomy and had complete clinical and imaging data necessary for calculating six scores (ISAT, REMIT, ABC2D, ATHE, ICAS-LVO, and Score-ICAD) were included. LVO etiology was defined based on angiographic findings during endovascular treatment. The discriminative performance of each score was assessed using the area under the receiver operating characteristic curve (AUC). ResultsOf 1,288 screened admissions, 91 patients met the inclusion criteria (ICAD-LVO, n = 18; embolic occlusion, n = 73). The AUCs (95% confidence interval) for differentiating etiology were: ISAT, 0.870 (0.664-1.000; P = 0.064); REMIT, 0.793 (0.676-0.911; P <0.001); Score-ICAD, 0.707 (0.582-0.833; P = 0.013); ABC2D, 0.627 (0.504-0.751; P = 0.095); ATHE, 0.600 (0.451-0.749; P = 0.230); and ICAS-LVO, 0.465 (0.301-0.630; P = 0.650). ConclusionIn this external validation, REMIT demonstrated the most robust and statistically significant discrimination between ICAD-LVO and EMB-LVO. Overall, scores incorporating imaging features outperformed those relying on clinical variables. These findings support the concept that ICAD-LVO represents a distinct pathophysiological entity from embolic occlusion and that accurate mechanism inference requires comprehensive imaging assessment of intracranial atherosclerotic disease beyond the occlusion site.

Background: Stroke guidelines recommend intravenous thrombolysis (IVT) within 4.5 hours of symptom onset for patients with minor acute ischemic stroke (AIS) but disabling symptoms. However, such patients are often overlooked for treatment, increasing their risk of stroke-related disability. Tenecteplase is endorsed as an alternative to alteplase for IVT in patients with AIS. More evidence is required regarding its efficacy and safety in the minor stroke population. Methods: This post hoc analysis of the ORIGINAL randomized clinical trial aimed to evaluate the efficacy and safety of tenecteplase versus alteplase in the patient subgroup with minor (National Institutes of Health Stroke Scale [NIHSS] 5) disabling stroke. Primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 at Day 90. Results: Data were analyzed for 299 patients treated with tenecteplase 0.25 mg/kg and 297 patients treated with alteplase 0.9 mg/kg. At Day 90, 86.3% of tenecteplase recipients and 82.8% of alteplase recipients achieved a mRS score of 0 or 1 (risk ratio=1.04 [95% confidence interval 0.971?1.114]; non-significant). No heterogeneity of treatment effect was observed across predefined subgroups according to baseline NIHSS score, time to drug administration, sex, age, presence (yes/no) of atrial fibrillation and diabetes and thrombectomy performed. No statistically significant differences were observed between tenecteplase and alteplase across secondary efficacy and safety outcomes. Conclusions: The comparable efficacy and safety of tenecteplase 0.25 mg/kg and alteplase 0.9 mg/kg in the minor stroke population of the ORIGINAL randomized clinical trial suggests that tenecteplase is a suitable alternative to alteplase in this setting. Trial registration: ClinicalTrials.gov NCT04915729 (ORIGINAL randomized clinical trial; https://clinicaltrials.gov/study/NCT04915729). Submitted 4 June 2021. Key words: acute ischemic stroke, alteplase, intravenous thrombolysis, minor stroke, tenecteplase

ImportanceHigh-intensity interval training (HIIT) improves peak oxygen uptake (VO2peak) and walking post-stroke. However, previous HIIT trials have primarily implemented maximal exercise testing, limiting clinical implementation. ObjectiveEvaluate the preliminary efficacy of HIIT, compared to moderate-intensity continuous training (MICT) using a submaximal exercise test. Hypothesis: HIIT will produce greater improvements than MICT in VO2peak, vascular measures, and walking outcomes. DesignThis was a randomized preliminary efficacy trial conducted between July 2023 and December 2025. SettingUniversity of Kansas Medical Center. ParticipantsParticipants with chronic stroke, 20-85 years of age, were randomized to HIIT or MICT. InterventionHIIT and MICT were performed on a total-body recumbent stepper 3 times per week for 4 weeks, with intensity prescribed using peak power output (PPO) to achieve target heart rate zones derived from a submaximal exercise test. HIIT was performed for 25 minutes with 1-minute vigorous-intensity intervals (65-95% PPO) interspersed with 1-minute active recovery intervals. MICT was performed continuously at 45-65% PPO for 25 minutes. Main OutcomesThe primary outcome was change in predicted VO2peak. Secondary outcomes included middle cerebral artery velocity, peripheral vascular function, and arterial stiffness with gait speed and walking endurance as tertiary outcomes. ResultsForty-nine participants (HIIT: n=25, MICT: n=24) were randomized (62.4(12.5) years, 42.9% female), attended 99.5(2.0)% of sessions, and achieved target intensity zones. No study-related serious adverse events occurred. Our results showed no significant between-group differences (p=0.54) for study outcomes. Both groups significantly improved VO2peak (HIIT: +1.13 mL*kg-1*min-1 (95% CI: 0.05-2.21), p=0.04; MICT: +1.58 mL*kg-1*min-1 (95% CI: 0.18-2.97), p=0.03) and with fast gait speed and walking endurance. Peripheral vascular function significantly improved following HIIT. Conclusions and RelevanceHIIT can be safely implemented in individuals with chronic stroke using a submaximal exercise test. Both HIIT and MICT elicited clinically meaningful gains in VO2peak and walking. However, only HIIT led to a significant improvement in peripheral vascular function, suggesting a biologic signal for intensity-dependent vascular adaptation. Trial RegistrationClinicalTrials.gov identifier: NCT05936008. Key PointsO_ST_ABSQuestionC_ST_ABSIn individuals with chronic stroke, does high-intensity interval training (HIIT) improve predicted VO2peak more than moderate-intensity continuous training (MICT)? FindingsIn this randomized clinical trial of 49 participants with chronic stroke, both HIIT and MICT achieved prescribed intensity targets with high adherence and resulted in clinically meaningful improvements in predicted VO2peak and walking outcomes after 4 weeks, with no significant between-group difference in our primary outcome of VO2peak. MeaningThese findings suggest that when aerobic exercise is prescribed to achieve target intensity, both HIIT and MICT produce meaningful improvements in fitness and walking after stroke, supporting the importance of appropriate exercise dosing.

Background: Prospective stroke registries have advanced our understanding of cerebrovascular disease, yet most reduce neuroimaging to categorical variables, forfeiting the multidimensional information inherent in clinical imaging. We describe the CRCS-K Imaging Repository, a prospective multicenter platform that systematically collects all stroke neuroimaging and integrates artificial intelligence (AI)-based automated quantification with clinical and outcome data through a dedicated research platform, AISCAN. Methods: Building upon the Clinical Research Collaboration for Stroke in Korea (CRCS-K), a nationwide prospective registry, all neuroimaging (computed tomography [CT], magnetic resonance [MR], and angiography) performed during index hospitalization of consecutive acute ischemic stroke patients was collected from 18 comprehensive stroke centers. Imaging underwent centralized quality verification, sequence classification, and AI-based quantification. As a proof-of-concept application, we examined the association between pre-treatment imaging modality, treatment workflow efficiency, and functional outcomes in patients receiving intravenous thrombolysis (IVT) or endovascular treatment (EVT). Results: From June 2022 through May 2025, 225,159 imaging sequences were collected from 20,792 patients. AI-based quantification modules converted these into standardized numeric features encompassing ischemic lesion volumes, perfusion parameters, white matter hyperintensity burden, and cerebral microbleed counts. Substantial inter-hospital variation in imaging modality selection was observed, with MR-first workflows ranging from 1.0% to 56.7% across centers. In the proof-of-concept analysis, each additional imaging sequence was associated with prolonged door-to-treatment times for both IVT and EVT. Propensity score overlap-weighted analyses suggested numerically more favorable functional outcomes with CT-based imaging among EVT-treated patients, whereas differences among IVT-treated patients were smaller and less consistent. Conclusions: The CRCS-K Imaging Repository demonstrates the feasibility of large-scale, prospective neuroimaging collection integrated with AI-based quantification and clinical data. The infrastructure enables clinically consequential questions that conventional registries cannot address.

ImportancePrognosticating functional independence after an acute stroke is critical for anticipatory guidance and rehabilitation planning. Here we demonstrate that poor brain health at the time of incident stroke is linked to worse functional outcomes for women compared to men. ObjectiveTo determine if brain health at time of stroke presentation has a differential effect on functional outcomes between men and women. DesignRetrospective cross-sectional study. SettingAnalysis conducted in 2025 with multi-center patient data that included participants from two large acute ischemic stroke cohorts; local (GASROS) and multinational (MRI-GENIE) between the years 2003 and 2011. ParticipantsClinical data collected for enrolled study participants included demographic data, medical history of hypertension, diabetes mellitus, hyperlipidemia, smoking status, acute stroke severity as measured by National Institutes of Health Stroke Scale (NIHSS), stroke etiology, and modified Rankin Scale (mRS) score at 90 days post-stroke. Brain health was quantified as effective reserve derived from acute neuroimaging data. Exposure(s)designated sex, retrieved from registration records. Main OutcomeFunctional outcome was measured by mRS scores at 90 days post-stroke, in men and women with poor, moderate, or good brain health at time of stroke injury. ResultsA total of 1039 patients were included in the analysis, 37.8 % women, median age 67 [interquartile range 56-77]. Women with poor brain health (i.e. lowest quartile of effective reserve) had worse functional outcomes at 90 days (55.6% with mRS>2) compared to men with poor brain health (31.2% with mRS>2: p < 0.001). This difference between men and women was not observed in categories of moderate or good brain health. There was no observed significant difference in stroke severity, volume of acute lesion, burden of white matter hyperintensities, or stroke etiology between men and women with poor brain health. Conclusions and RelevanceBrain health at the time of incident stroke has a differential effect on functional outcomes at 90 days between men and women. Women with poor brain health endure disproportionately worse outcomes compared to men. This highlights an important step in understanding sex-specific vulnerability in early recovery post-stroke, and can inform disposition, rehabilitation services, and resource allocation planning.

BackgroundEndovascular thrombectomy (EVT) has transformed the treatment of acute ischemic stroke (AIS). However, a substantial proportion of AIS patients experience poor outcomes despite successful recanalization, often due to severe neurological deterioration or life-threatening complications. Early identification of these high-risk patients remains a major unmet need. In this study, we developed and validated machine-learning (ML) models that integrate automated quantitative cerebrovascular morphology and collateral grading with demographic, clinical, laboratory, and imaging variables to predict major post-EVT complications and early neurological outcomes. MethodsUsing a prospectively collected database of 727 AIS patients that underwent EVT, we developed ML models to incorporate patient-specific vascular morphometry with conventional clinical, laboratory, and imaging data to predict emergence of early neurological deterioration (END), symptomatic intracranial hemorrhage (sICH), malignant brain edema (MBE) requiring surgical decompression, and neurogenic respiratory failure and dysphagia requiring tracheostomy/gastrostomy (TC/PEG). ResultsOur analysis of morphological features, including increased tortuosity and reduced vessel diameter, showed strong associations with complications. Morphology-informed (MI) models consistently outperformed baseline-clinical (BC) models for patients with END (AUROC 0.81 for MI model vs. 0.73 for BC), sICH (AUROC 0.68 MI vs. 0.56 BC model), MBE (AUROC 0.67 MI model vs. 0.56 BC), or patients who underwent TC/PEG (AUROC 0.66MI vs. 0.58 BC model). Statistical testing confirmed significant AUROC improvements for END, sICH and mRS (p < 0.05), Finally, patient-specific calibrated probability profiles enabled individualized, multidimensional risk stratification, revealing distinct complication-specific risk patterns across patients. ConclusionsThese findings demonstrate that cerebrovascular structure--an often overlooked yet physiologically fundamental determinant of ischemic injury and reperfusion dynamics--provides significant predictive information that is not captured by standard clinical or visual imaging assessments. Automated vascular segmentation and collateral grading techniques enable rapid and objective integration of cerebrovascular metrics into prognostic models, offering a scalable tool for precision risk stratification, supporting earlier intervention, targeted monitoring, and improved post-EVT management.

Background: The past decade has witnessed rapid growth of clinical-trial programs in Europe and Asia, with randomized clinical trials (RCTs) publications from these regions outpacing those of the U.S. However, limited data exist quantifying their relative influence on practice-defining results. Here, we evaluate these shifts by analyzing geographic origin, funding source, and clinical impact of practice-changing RCTs. Methods: From the 2018 and 2026 American Heart Association/American Stroke Association (AHA/ASA) Acute Ischemic Stroke (AIS) Guidelines, we identified RCTs supporting new recommendations and extracted geographic origin (China/Europe/USA/Other), funding source (government/academic/non-profit vs. industry (private/mixed); NIH vs. non-NIH), and research topic (endovascular therapy (EVT), thrombolysis, imaging, poststroke care, and prehospital and systems of care). Analyses used unweighted, reference-density-weighted, and clinical-impact-weighted strategies. Temporal trends were assessed using the chi-square/Fisher?s exact tests, with Rao-Scott adjusted chi-square tests accounting for weighting. Results: We identified 21 new recommendations (47 RCTs) in 2018 and 45 (89 RCTs) in 2026. In 2018, Europe led (51.1%), followed by the U.S. (31.9%), while China and other regions contributed minimally. By 2026, Europe remained first (36%), China rose to second (29.2%), and the U.S. declined to the smallest share (14.6%), across all weighted analyses (p<0.01). NIH-funded trials declined significantly from 21.3% (unweighted), 27.4% (reference-density-weighted), and 27.3% (clinical-impact-weighted) in 2018 to 4.5%, 4.8%, and 3.4%, respectively in 2026 (p<0.01 across all weighted strategies). Conclusion: In this analysis, we identify a shift away from U.S.-based clinical trials and increasing contributions from China. U.S.-based RCTs fell from the second most cited to the least cited sources of practice-changing recommendations. NIH-funded research fell from nearly one-quarter in 2018 to <5% in 2026, highlighting increasing dependence on non-U.S. studies for U.S.-based care. These findings raise questions about the effectiveness of current AIS research paradigms in the U.S. Keywords: Acute Ischemic Stroke, Endovascular Thrombectomy, Thrombolytic Therapy, NIH Funding

IntroductionThe ischaemic penumbra is the principal therapeutic target in acute ischaemic stroke (AIS). Although perfusion imaging enables identification of salvageable tissue, its availability is limited and iodinated contrast exposure carries risk. Validated blood-based biomarkers could serve as scalable surrogates for imaging-defined penumbra. ObjectiveWe conducted a systematic review and meta-analysis to assess the association between blood-based biomarkers reported in the literature and the ischaemic penumbra. MethodsWe searched Ovid MEDLINE, Embase (Ovid), PsycINFO (Ovid), and Web of Science until December 3, 2025, for studies involving human subjects with AIS aged over 18 years or animal subjects that reported the presence of infarct and ischaemic penumbra. The primary outcome was the difference in mean biomarker levels in subjects with and without ischaemic penumbrae as defined by the study authors. We used the QUADAS-2 tool to assess risk of bias. We calculated each biomarkers pooled standardized mean difference (SMD) and 95% CI where possible. Protein-protein interaction network (PPI) and pathway analyses were conducted in Cytoscape and the enrichR R package (PROSPERO: CRD42023453175). ResultsWe identified 11 studies (1765 human subjects and 8 nonhuman primates) that assessed 53 candidate blood-based biomarkers. Two studies had a low risk of bias, while nine had a risk of bias. A meta-analysis was conducted for seven biomarkers in humans from four studies. Of these, three biomarkers demonstrated significant association with penumbrae in humans: mid-regional pro-adrenomedullin (MR-proADM; SMD 0.80 [95% CI 0.49 to 1.10]), interleukin-10 (IL-10; SMD 1.94 [0.85 to 3.03]), and neuron-specific enolase (NSE; SMD -0.71 [-1.40 to -0.01]). However, substantial statistical heterogeneity was observed for several pooled biomarkers (I{superscript 2} >90%), limiting confidence in effect size precision. Amongst biomarkers where meta-analysis was not possible, 37 biomarkers showed significant association with presence of a penumbra. Oxygen radical absorbance capacity after perchloric acid treatment (ORACPCA; SMD 0.31 [0.01 to 0.60]) showed significant association with penumbra presence; 34 genes (e.g., STK26 r = 0.58, p = 0.003; MGA r = 0.58, p = 0.004; IL1B r = -0.59, p = 0.003; NUP98 r = -0.71, p < 0.001), circOGDH (r = 0.962, p = 0.002), and NT-proBNP (r = 0.199, p < 0.001) were significantly correlated with penumbra volume. PPI analysis identified IL-1{beta} as the most highly connected node (10 interactions), followed by IL-10 and HDAC1/HCAR2. Cdc42 was reported to be significantly associated with penumbrae in nonhuman primates, but there were insufficient data to calculate SMD. Pathway enrichment revealed positive associations with angiogenesis and IL-12 signalling, and negative associations with leukocyte migration, chemokine signalling, and platelet activation. ConclusionsCurrently reported biomarkers of ischaemic penumbra are not ready for clinical implementation. Although implicated pathways converge on inflammatory regulation, haemostasis, and cerebral perfusion, rigorous prospective validation is required before integration into prehospital or emergency triage workflows.

BackgroundStenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small vessel disease (cSVD) remain contentious. We investigated associations of large artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. MethodsWe prospectively recruited patients with lacunar or mild non-lacunar stroke, with demographic, stroke-related, cognitive, functional, and MRI (index and incident infarcts, cSVD markers) assessments at baseline and one year. LAS was defined as [&ge;]50% intracranial or cervical artery stenosis; basilar artery dolichoectasia (BADE) by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated using multivariable regression adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large artery pathology and cSVD. ResultsAmong 229 patients (mean age 65.9{+/-}11.1 years; 131 [57.2%] lacunar stroke), LAS and BADE were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio [OR], 0.49; 95%CI, 0.23-0.99) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, BADE was strongly associated with lacunar stroke (OR, 4.67; 95%CI, 1.87-13.14), higher cSVD scores (ordinal analysis; OR, 2.57; 95%CI, 1.28-5.25), incident infarcts (75% subcortical; OR, 2.29; 95%CI, 1.01-5.14), and greater progression of white matter hyperintensities over one year ({beta}, 0.15; 95%CI, 0.01-0.29; per log10-transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. ConclusionscSVD, including lacunar stroke, was unrelated to LAS, but strongly associated with dolichoectasia and wider arteries. These findings support a non-atheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABS[bullet] Large artery stenosis was unlikely to represent a causal mechanism for lacunar stroke and showed no association with cerebral small vessel disease (cSVD) imaging markers. [bullet]Dolichoectasia and intracranial arterial widening emerged as vascular phenotypes strongly associated with cSVD, including its progression and lacunar stroke subtype. What Are the Clinical Implications?[bullet] Distinct large artery phenotypes have divergent etiopathological implications for cSVD. Our findings support a non-atheromatous, intrinsic microvascular pathology as the principal mechanism of lacunar stroke and cSVD. [bullet]Mechanism-based therapeutic strategies for lacunar stroke and cSVD, moving beyond conventional approaches focused on atherosclerosis or cardioembolism, are warranted.

BACKGROUND AND PURPOSEThe role of immune checkpoint B7-H3 in acute ischemic stroke prognosis and post-stroke immunosuppression remains uninvestigated, despite the clinical significance of immune checkpoints with inflammaging and post-stroke infections. We recently reported the neuroprotective effects of acute B7-H3 inhibition after stroke in adult and aged mice. In this study, we investigated the mechnsistic association of regulating the cerebral induction of B7-H3 after acute ischemic stroke on brain damage, neuroinflammation, vascular integrity, host defense gene regulation, and functional outcomes. METHODSC57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (i.v.) with either B7-H3 siRNA or a negative (non-targeting) siRNA at 5 min after reperfusion. At 24 hours of reperfusion, magnetic resonance imaging (MRI) of the mouse brain was performed using a 9.4 T scanner to assess brain damage (T2, ADC, and Kurtosis). Real-time qPCR and NanoString nCounter(R) Neuroinflammation Panels were used to determine the acute changes in overall neuroinflammatory functions that are mediated by B7-H3. Motor function (beam walk, rotarod tests, and grip strength) was assessed between days 1 and 7 of reperfusion. RESULTSEarly inhibition of B7-H3 after stroke significantly reduced the brain damage and promoted the functional outcomes. Post-stroke neuroinflammation was reprogrammed with B7-H3 inhibition towards balancing of neuroprotective anti-inflammatory mechanisms without compromising the immune response that is crucial for preventing post-stroke infections. CONCLUSIONSOur results demonstrate that the induction of B7-H3 during the acute period after stroke is a mediator of post-stroke neuroinflammation and secondary brain damage.

Background Outcome after stroke varies according to stroke subtype by location, but healthcare systems data studies do not include subtyping information. We linked natural language processing (NLP) of brain imaging reports to routinely collected data to estimate risk of death and other outcomes after stroke subtypes in a nationwide dataset. Methods We applied a previously validated NLP algorithm to all CT and MRI head scan reports in Scotland between 2010 and 2018. We linked the reports to hospital readmissions, prescriptions and death data to identify and characterize people with stroke, and to categorize into deep and cortical ischemic stroke, deep and lobar intracerebral hemorrhage (ICH), subarachnoid hemorrhage, and subdural hemorrhage. We used a matched cohort design, and age- and sex-matched four controls per case who never had a stroke. By subtype, we estimated rehospitalization with stroke, myocardial infarction (MI), cancer, dementia, epilepsy and death, accounting for confounders and competing risk of death. Results From 785,331 people with a head scan, we identified 64,219 with clinical stroke phenotypes (mean age 73.4yrs, 49.5% male), and subtyped 12,616 with deep ischaemic stroke; 14,103 with cortical ischaemic stroke; 1,814 with deep ICH; and 1,456 with lobar ICH. There was higher absolute rate of 1-year hospital readmission for lobar compared with deep ICH (4.9% [95%CI 3.9% - 6.1%] vs 3.4% [2.6% - 4.3%]), higher risk of dementia beyond 6 months after lobar ICH compared to controls than for other stroke subtypes (aHR 3.5 [2.3-5.3]); and higher risk of MI within 6 months of cortical ischemic stroke than for other stroke subtypes (aHR 4.6 [3.4-6.3]). Conclusions NLP of free-text reports linked to coded data successfully subtyped stroke at scale, and we estimated risk of clinically relevant outcomes. Future work should use free text to enable large-scale audit and epidemiology of people with stroke.

BackgroundHyperglycemia after intracerebral hemorrhage (ICH) may be associated with worse outcomes. In this study, we evaluated the association of early post-ICH glucose trajectories and clinical outcomes. MethodsWe performed a secondary analysis of the ATACH-2 trial dataset. Hyperglycemia was defined as a blood glucose of [&ge;]140 mg/dl. Glucose levels at 0h, 24h, 48h, and 72h were analyzed using a linear mixed effects model, with fixed effects for time and random intercept/slopes. Patient-specific estimates were used to predict glucose values at 0h and 72h, informed by all four timepoints, to classify patients into the following glycemic trajectory groups: (1) early hyperglycemia, (2) late hyperglycemia, (3) persistent hyperglycemia, and (4) persistent normoglycemia. Outcomes were compared using univariate analysis and log-rank test survival analysis. Good outcomes were defined as a modified Rankin Score of 0 to 2. The association between glycemic trajectories and functional outcomes was tested using logistic regression models adjusted for patient demographics and clinical variables. ResultsOf 1000 patients (median age 62 [IQR 52-71]; 38% female) in the study, 81 (8.1%) had early hyperglycemia, 59 (5.9%) late hyperglycemia, 225 (22.5%) persistent hyperglycemia, and 635 (63.5%) persistent normoglycemia. On univariate analysis, 45.8% of patients with persistent normoglycemia had favorable 90-day functional outcomes compared to 30.9% in early, 30.5% in late, and 32.0% in persistent hyperglycemia patients (p<0.001). The late hyperglycemia patients had the highest rate of hematoma expansion (35.3%, p=0.029) and the lowest Kaplan Meier-estimated survival (86%, p=0.015). In adjusted multivariable regression models, early hyperglycemia was significantly associated with a poor functional outcome (OR 2.27, 95% CI 1.10-4.68, p=0.026). ConclusionEarly hyperglycemia was associated with worse functional outcomes, while late and persistent hyperglycemia were associated with worse survival rates. These findings suggest that glycemic trajectories may affect or predict prognosis. This highlights the importance of continuous glucose monitoring and glycemic control strategies after ICH.