Stroke

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.

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.

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.

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.

Bakground and Purpose Antiplatelet resistance is a recognized risk factor for recurrent ischemic stroke, yet evidence supporting platelet function test?guided antiplatelet therapy modification in stroke prevention remains limited. We investigated whether VerifyNow-guided antiplatelet therapy modification reduces recurrent ischemic stroke in patients with atherothrombotic or lacunar infarction. Methods This retrospective observational study enrolled consecutive patients with atherothrombotic or lacunar infarction at a single center (April 2023-March 2025). Of 302 patients, 243 were analyzed: 122 in the modified group, whose antiplatelet agent was selected based on VerifyNow Aspirin Reaction Units and P2Y12 Reaction Units, and 121 in the unmodified group, whose agent was empirically selected. The mean follow-up period was 1.62 {+/-} 0.61 years. In the modified group, when both aspirin and clopidogrel showed inadequate inhibition, prasugrel or cilostazol was selected. The primary endpoint was recurrent ischemic stroke; the secondary endpoint was intracranial hemorrhage. Cox proportional hazards models with inverse probability weighting were used to adjust for confounders. Results Recurrent ischemic stroke occurred in 1 patient (0.8%) in the modified group versus 8 (6.6%) in the unmodified group (log-rank P=0.018). After adjustment, the modified group had a significantly lower risk of recurrent stroke (HR, 0.10; 95% CI, 0.012-0.84; P=0.033). Intracranial hemorrhage occurred in 0 (0%) and 1 (0.8%) patients, respectively. Conclusions In Japanese patients with atherothrombotic or lacunar infarction, VerifyNow-guided antiplatelet therapy modification was associated with a significantly lower incidence of recurrent ischemic stroke without increased hemorrhagic risk. Given the single-center retrospective design and small sample size, validation in a multicenter randomized controlled trial is warranted.

Background: Acute treatments for patients with spinal cord strokes (SCS), including lumbar drain, blood pressure augmentation, corticosteroids, antiplatelets, and anticoagulants, are largely extrapolated from literature on cerebral infarcts or based on suspected SCS physiology. This study adds to the knowledge of symptomatology and management of SCS. Methods: This retrospective cohort study included patients from one medical system from 2000-2025. Multivariate ordinal logistic regressions were performed to evaluate associations of SCS treatments with the primary outcome of ambulatory status (independently ambulatory, ambulatory with assistance, non-ambulatory) at first follow-up, as well as secondary outcomes of modified Rankin Scale (mRS) and modified Japanese Orthopedic Association (mJOA) scores. SCS severity by American Spinal Injury Association impairment scale (AIS) with grade A as the comparator, age, sex, and whether SCS was spontaneous/periprocedural were covariates. Odds ratios (OR) greater than 1 were associated with better ambulatory status, lower mRS, and higher mJOA. Results: 130 SCS patients were included. Median age at SCS onset was 62 years, 42% were female, and 39% were periprocedural. Median first follow-up was 57 days. AIS grade was A for 28%, B for 25%, C for 28%, and D for 26%. SCS severity had significant associations with outcomes. For ambulatory status, AIS B OR 2.78, 95% CI 1.03-7.69, p-value 0.045; AIS C OR 16.7, 95% CI 5.56-50.0, p-value <0.01; AIS D OR 125, 95% CI 33.3-500, p-value <0.01. Corticosteroids were associated with improved ambulatory status and mJOA at follow-up (OR 2.38, 95% CI 1.15-5, p-value 0.023 and OR 2.27, 95% CI 1.09-4.76, p-value 0.030, respectively). No treatment had a significant association with mRS. Conclusion: Initial SCS severity had the strongest association with outcomes. Corticosteroids were associated with a better ambulatory status and mJOA. This study can help guide clinician management of patients with SCS.

ObjectiveLevetiracetam is commonly prescribed for seizure prophylaxis after acute ischemic stroke (AIS) and often continued beyond discharge. While its short-term effectiveness for preventing post-stroke seizures is established, it is unclear whether prolonged use improves survival, particularly in older adults. We estimated the effect of continued levetiracetam use on 90-day mortality among Medicare beneficiaries after AIS. MethodsUsing Traditional Medicare claims data (2008-2021), we identified beneficiaries aged [&ge;]66 years hospitalized for AIS who initiated outpatient levetiracetam within 90 days of discharge. After one month of continued post-stroke use of levetiracetam (start of follow-up), we compared 90-day mortality between patients with a new levetiracetam dispensation within a 14-day grace period post-follow up and those without one. We performed cloning, censoring and weighting to address immortal time bias and estimated standardized mortality risks, risk differences, and 95% confidence intervals (CI). ResultsAmong 3,212 eligible beneficiaries, 1,779 (55.4%) received a new levetiracetam dispensation within the 14-day grace period. Median age was 76 years (IQR 70-83); 57.8% were female. After adjustment for demographics, hospitalization characteristics, timing of initiation, and comorbidities, continued use was associated with lower 90-day mortality than discontinuation (53 vs 62 deaths per 1,000; risk difference -9 per 1,000; 95% CI: (-12,-5)). The reduction was observed primarily among patients aged [&ge;]75 years. SignificanceAmong older Medicare beneficiaries who initiated levetiracetam after AIS, continued outpatient use was associated with modestly lower 90-day mortality, particularly in those aged [&ge;]75 years. These findings suggest potential benefits of levetiracetam continuation beyond the immediate post-stroke period.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke associated with higher morbidity and mortality. Posterior circulation aneurysms are considered to have worse prognosis than anterior circulation aneurysms due to anatomical location, hemorrhage severity, and treatment complexity. We aimed to determine whether aneurysm location independently influences clinical outcomes following aSAH Methods: PubMed, Scopus, Embase, and Web of Science were searched from January 2000 to December 2025 for studies reporting outcomes in anterior or posterior circulation aSAH. The outcome analysis included mortality, functional recovery (modified Rankin Scale [mRS] 0-2 and 3-6 at 6 months and 1 year), hydrocephalus, delayed cerebral ischemia (DCI), and symptomatic cerebral vasospasm. Pooled proportions and subgroup comparisons were performed using random-effects meta-analysis (DerSimonian-Laird method). Publication bias was evaluated using contour-enhanced funnel plots and Egger's test. Results: Nineteen analytic entries from 18 studies (anterior: n = 1,625; posterior: n = 986; total N = 2,611) were included. Pooled mortality was 13% (95% CI: 10%-17%; I2 = 84.6%), with no significant difference between the anterior (14%; 95% CI: 10%-20%) and posterior (11%; 95% CI: 7%-18%) circulation subgroups (p = 0.437). Good functional outcome was 60% at 6 months (95% CI: 51%-67%) and 55% at 1 year (95% CI: 46%-64%), with no location-based differences. Hydrocephalus (35% vs 35%; p = 0.979) and DCI (17% vs 17%; p = 0.939) were comparable between subgroups. Symptomatic cerebral vasospasm was the only outcome differing significantly by location, occurring more frequently in anterior circulation aSAH (24% vs 11%; {chi}2 = 5.59; p = 0.018). Conclusion: Aneurysm location does not independently determine mortality, functional recovery, hydrocephalus, or DCI following aSAH. Symptomatic cerebral vasospasm was the only location-specific outcome. Admission neurological grade (World Federation of Neurosurgical Societies [WFNS]), rather than vascular territory, appears to be the primary determinant of mortality. Aneurysm location alone should not guide prognostic decisions or limit aggressive treatment.

BackgroundCerebral ischemia-reperfusion injury (CIRI) is a major determinant of poor outcome after recanalization therapy in acute ischemic stroke. Microglial functional heterogeneity underpins neuroinflammation, yet the molecular mechanisms governing microglial phenotypic transitions remain incompletely understood. Metabolite-driven post-translational modifications (PTMs) have emerged as key regulators of microglial metabolism and inflammation, but whether PTM regulatory enzymes form co-expression modules that define microglial states is unknown. MethodsWe analyzed single-cell RNA-seq datasets from five GEO studies (GSE174574, GSE227651, GSE245386, GSE267240, GSE319237) covering tMCAO reperfusion and permanent ischemia models. Microglia were purified using double filtration (P2ry12/Tmem119/Cx3cr1+, Cd68/Adgre1/Ly6c-). PTM enzyme co-expression modules were identified by non-negative matrix factorization (NMF). Spatiotemporal dynamics were assessed by module projection across timepoints (Sham, 1d, 3d, 7d) and pseudotime analysis. Independent validation was performed in an additional tMCAO dataset (GSE245386). Sex differences were explored in a mixed-sex permanent ischemia dataset (GSE267240). ResultsThree robust PTM enzyme co-expression modules were identified: Metabolic stress-associated (M1), Pro-inflammatory-associated (M2), and Reparative-associated (M3). M1 was enriched in TCA cycle enzymes, M2 in inflammatory pathways (leukocyte activation, chemotaxis), and M3 in vascular development and translation. Module proportions and scores showed dynamic transitions: M1 decreased after reperfusion, M2 peaked at day 1-3, and M3 slightly increased at day 7. Independent validation in GSE245386 yielded high module conservation (cosine similarity = 0.874). Sex-specific differences in module distribution were observed in permanent ischemia ({chi}2 = 14.98, p = 0.00056). ConclusionsPTM enzyme co-expression modules delineate metabolic, pro-inflammatory, and reparative microglial states in CIRI with distinct spatiotemporal dynamics. This transcriptional framework supports the "PTM enzyme code" hypothesis and provides stage-specific targets for stroke therapy.

Ischemic stroke triggers a cascade of molecular and cellular processes leading to fibrotic scar formation, entailing activation of brain platelet-derived growth factor receptor (PDGFR){beta}+ cells. Kruppel-like factor (KLF)4 plays an important role in regulating the activation of peripheral PDGFR{beta}+ perivascular cells in response to hypoxia/ischemia. Herein, we aimed to characterize the spatiotemporal responses of brain PDGFR{beta}+ cells while assessing the contribution of KLF4. This was achieved using transgenic mice that enable tracking or conditionally depleting KLF4 in PDGFR{beta}+ cells, which were subjected to experimental ischemic stroke. Next, we employed point pattern analysis (PPA) and topological data analysis (TDA) to quantitatively characterize cell phenotypic changes and spatial distribution over injury progression after ischemic stroke. We show that brain PDGFR{beta}+ cells rapidly become reactive and early localize to regions prone to irreversible damage. We report the emergence of parenchymal PDGFR{beta}+ cells, which cannot be causally linked to proliferation or vascular detachment. Moreover, our analysis reveals that KLF4 is barely expressed in brain PDGFR{beta}+ cells under normal conditions, and that its expression is slightly induced in reactive cells in the injured brain. Notably, specific attenuation of KLF4 induced expression in PDGFR{beta}+ cells does not affect cell reactivity and spatiotemporal distribution, nor scar formation and injury severity. These observations suggest that in contrast with the periphery, KLF4 is not implicated in regulating the responses of brain PDGFR{beta}+ cells. Our results indicate that the reactivity of brain PDGFR{beta}+ cells after stroke is spatiotemporally diverse, evolve over injury progression, and is distinct from peripheral perivascular cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/712632v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1149c62org.highwire.dtl.DTLVardef@26edaaorg.highwire.dtl.DTLVardef@1bd3d35org.highwire.dtl.DTLVardef@fd8030_HPS_FORMAT_FIGEXP M_FIG C_FIG

Sex specific differences in stroke are recognized. Whether differences in incident stroke risk persists in recent periods needs further elucidation to aid public health preventive efforts. Aim: To determine long-term sex specific trends in stroke and stroke risk factors at different epochs among Framingham Heart Study participants. Methods: We examined age-adjusted 10-year stroke incidence using Cox regression in women and men in five epochs: 1962-1969 (epoch 1, reference), 1971-1976 (epoch 2), 1987-1991 (epoch 3), 1998-2005 (epoch 4), 2015-2021 (epoch 5). We compared stroke incidence by sex across epochs, estimated decade-wise linear trends overall and by sex. We compared risk factors in successive epochs to the first, and estimated sex-specific trends in risk factors. Interactions between baseline risk factors with epoch and trends were assessed by sex. Secondary analyses were repeated in participants <60 years old. Results: Incident stroke occurred in 4.5% (178/3996) in epoch 1, 3.9% (227/5786) in epoch 2, 3.9% (199/5137) in epoch 3, 2.7% (207/7642) in epoch 4, 2.2% (119/5534) in epoch 5. Men had higher risk of incident stroke in each epoch with significant difference in epochs 2 (HR 1.41, 95% CI [1.08, 1.84]) and 4 (HR 1.46, 95% CI [1.11, 1.91]) overall, and in epoch 4 (HR 2.13, 95% CI [1.17, 3.87]) among those <60 years. Stroke incidence declined by 16% per decade in men (HR 0.84, 95% CI [0.79, 0.89]) and 19% per decade in women (HR 0.81, 95% CI [0.76, 0.86]). Among those <60 years, stroke incidence declined by 22% per decade in women (HR 0.78, 95% CI [0.67, 0.95]). Hypertension declined by 8% per decade in women only ([OR] 0.92, 95% CI [0.90, 0.94]), while Atrial fibrillation and diabetes increased in both. Conclusion: Stroke incidence continues to decline in recent periods for women and men. Among participants <60 years, decline was observed only in women, possibly related to decline in hypertension in women.

Background: Poor physical performance, measured by gait speed and chair stands, is associated with mortality; associations may differ by history of cardiovascular disease (CVD). Methods: Among 14,137 REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants, gait speed and chair stand times (2013-2016) were categorized into quartiles and a fifth category with those who were unable to complete the test. Associations with adjudicated CVD and all-cause mortality through 2020 were examined among participants with and without history of CVD. Results: Average age was 72.5 {+/-} 8.5 years. Among participants without history of CVD, those in slowest vs. highest gait speed quartile had HRs of 2.01 (95% CI 1.18-3.43) for CVD and 1.66 (1.33-2.07) for all-cause mortality; among those unable to complete the test, HRs were 2.37 (1.12-5.03) for CVD and 2.33 (1.72-3.17) for all-cause mortality. Among participants with history of CVD, slowest gait speed quartile had HRs of 1.28 (0.96-1.72) for CVD and 1.72 (1.45-2.04) for all-cause mortality; HR among those unable to complete the test were 1.87 (1.29-2.70) for CVD and 2.74 (2.22-3.38) for all-cause mortality (p-interaction between with and without history of CVD <0.05). Inability to complete chair stand test was associated with higher mortality in both groups. Conclusions: Poor physical performance was associated with greater CVD-related and all-cause mortality among both individuals with and without a history of CVD, with the highest risks observed among those who were unable to the assessments.

Post-stroke cognitive recovery is difficult to predict using focal lesion characteristics alone. The brain's capacity to maintain cognitive function depends also on structural integrity of the whole brain. One way to measure brain health is through the severity of cerebral small vessel disease (CSVD) markers, which reflect aging-related pathologies that erode structural integrity. Here, we propose a composite measure of CSVD (cCSVD) integrating three independently validated biomarkers automatically quantified using T1-weighted MRIs: white matter hyperintensity volume (WMH; representing vascular injury), perivascular space count (PVS; putative glymphatic clearance), and brain-predicted age difference (brain-PAD; structural atrophy). We hypothesize that cCSVD, which captures the shared variance across these CSVD biomarkers, will be a robust indicator of whole-brain structural integrity and predict cognitive changes 3 months after stroke. We analyzed 65 early subacute stroke survivors with assessments within 21 days (baseline) and at 90 days (follow-up) post-stroke. WMH volume, PVS count, and brain-PAD were quantified from baseline T1-weighted MRIs, and then residualized for age, sex, days since stroke, and intracranial volume. Principal component analysis (PCA) of the residualized biomarkers was used to derive cCSVD. Beta regression with stability selection using LASSO was used to model three outcomes: baseline Montreal Cognitive Assessment (MoCA) scores, follow-up MoCA scores, and longitudinal change (follow-up score adjusted for baseline score). Logistic regression was used to test if baseline cCSVD predicted improvement in those with baseline cognitive impairment (MoCA < 26). The PCA revealed that the first principal component (PC1) explained 43.1% of the total variance among WMH volume, PVS count, and brain-PAD. The three biomarkers contributed nearly equally to PC1, which was subsequently used as the baseline cCSVD score. Lower baseline cCSVD was significantly associated with better MoCA scores at follow-up ({beta} = -0.19, p = 0.009), even after adjusting for baseline MoCA ({beta} = -0.12, p = 0.042), and, importantly, outperformed all individual biomarkers. Furthermore, lower cCSVD at baseline significantly increased the likelihood of improving to cognitively unimpaired status at three months (OR = 0.34, p = 0.036), independent of age and education. The composite CSVD captures the additive impact of vascular injury, glymphatic dysfunction, and structural atrophy on recovery in a way that individual measures do not. cCSVD accounts for shared variance across these domains, reflecting a patient's latent capacity for cognitive recovery, where relative integrity in one CSVD domain may mitigate effects of another. This automated, T1-based framework offers a scalable tool for predicting post-stroke recovery.

Stroke is the third leading cause of death and disability combined worldwide and often results in hemiparesis. Functional magnetic resonance imaging (fMRI) is a non-invasive technique used to investigate changes in brain activations during tasks aimed at restoring the lost motor function. Participants with chronic stroke and residual hemiparesis in the upper extremity were recruited for a clinical intervention that included neurofeedback training and fMRI sessions with motor-execution and motor-imagery tasks. The present study provides a baseline characterization of brain activations prior to neurofeedback training. Since lesion site and volume varied across participants, two fMRI preprocessing pipelines were applied. The first one was used for twelve participants with lesions restricted to a single hemisphere and for one participant with small secondary lesions in the contralesional hemisphere, whereas the second one was used for two participants with large bilateral lesions. These were followed by quality control measures and statistical analysis. First-level (i.e., single-participant) analysis returned the strongest and most extensive activation across participants during motor-execution tasks, with clusters identified in the ipsilesional parietal lobe, bilateral occipital lobes, and cerebellum after Family-Wise Error correction. Second-level (i.e., group-level) analysis involving participants who underwent the first fMRI preprocessing pipeline revealed a significant cluster in the cerebellum after False Discovery Rate correction. These results are consistent with previous studies involving participants with chronic stroke performing motor-tasks. Cerebellar recruitment observed consistently across participants could reflect compensatory mechanisms supporting motor control after stroke.

Abstract Background: Acute ischemic stroke (AIS) remains a significant cause of disability worldwide. Current treatments, primarily intravenous thrombolysis (IVT), are limited by narrow time windows and reperfusion injury, leading to suboptimal outcomes for many patients. Chuanzhi Tongluo (CZTL), a traditional Chinese medicine, has been preliminarily recognized as a novel cerebral protection agent in animal models. Objectives: This trial investigates the efficacy and safety of CZTL capsule in patients with AIS who are not eligible for IVT or who experience early neurological deterioration after IVT. Methods and design: The CONCERN trial is an investigator-initiated, prospective, multicenter, double-blind, parallel-control, randomized clinical study in China. An estimated 1,208 eligible participants will be consecutively randomized to receive CZTL capsule therapy or placebo in 1:1 ratio across approximately 70 stroke centers in China. All enrolled patients are orally administered 2 capsules of CZTL or placebo 3 times a day together with antiplatelet agents for 3 months. Outcomes: The primary endpoint is an excellent functional outcome, defined as a score of 0 or 1 on the mRS at 90 days. Lead safety endpoints included 90-day mortality and symptomatic intracranial hemorrhage within 48 hours. Conclusions: Results of CONCERN trial will determine the clinical efficacy and safety of the traditional Chinese medicine CZTL capsule in the treatment of AIS patients. Trial registry number: ChiCTR2300074147 (www.chictr.org.cn).

BackgroundNeurodevelopmental impairment remains common in neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with the standard of care, therapeutic hypothermia (TH). The complement response activates at reperfusion and is known to exacerbate neuroinflammation and injury, though its full role and interaction with hypothermia are incompletely defined. We hypothesized that modulating the complement response could improve structural and functional outcomes in HIE, and tested a novel complement therapy (CT), consisting of C3a peptides and the C5a-receptor antagonist PMX205, as both a stand-alone treatment and as an adjuvant to TH. MethodsWistar rat pups were randomized to the following treatment groups: Sham (uninjured control), NT (uninjured, normothermia/not treated control), or injured and treated with either TH, CT, or CT+TH. At term-equivalence, mild-moderate hypoxic-ischemic injury was induced by Vannuccis method. To capture the short and long-term effects of the treatments, cohorts were harvested 3 or 66-72 days post-injury, respectively. Cerebral injury was measured by quantifying levels of inflammatory markers and cerebral tissue loss, and functional outcomes were assessed in a series of behavioral tests. The data were stratified to detect sexual dimorphisms. ResultsCT and TH treatments demonstrated test and sex-dependent differences in improvement compared to untreated, injured rats. In male rats, TH treatment worsened long-term hippocampal and thalamic brain injury and functional measures of ataxia and attention. CT-treatment worsened long-term thalamic loss in females. Combining the two treatments (CT+TH) demonstrated additive improvement in both sexes, including short and long-term cortical loss and ataxia. ConclusionsComplement modulation enhances the neuroprotective effects of TH after neonatal hypoxic-ischemic injury, with sex-specific effects on inflammation and behavior. Combining complement modulation with the standard of care often demonstrated synergistic improvement in both sexes, supporting complement-targeted therapy as a promising adjunct to hypothermia in neonatal HIE. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/717097v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1025d1forg.highwire.dtl.DTLVardef@2fa4e5org.highwire.dtl.DTLVardef@1f2c1c4org.highwire.dtl.DTLVardef@8f3410_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender. Saadat, A. (2026) https://BioRender.com/siwm825.

Stroke-associated pneumonia (SAP) is a common, severe complication in acute ischemic stroke (AIS) patients receiving bridging therapy (intravenous thrombolysis + mechanical thrombectomy), worsening prognosis and increasing mortality. Current SAP prediction models rely heavily on subjective clinical factors, limiting accuracy. This study developed an interpretable machine learning (ML) model combining inflammatory biomarkers to stratify SAP risk in AIS patients undergoing bridging therapy. We retrospectively enrolled AIS patients who received bridging therapy, collected baseline clinical data and inflammatory biomarkers, and constructed ML models (including XGBoost, random forest) with SHAP analysis for interpretability. The model integrating inflammatory biomarkers achieved excellent predictive performance (AUC=0.XX, 95%CI: XX-XX), outperforming traditional clinical models. SHAP analysis identified key biomarkers driving SAP risk, enhancing model transparency. This interpretable ML model provides an objective, accurate tool for SAP risk stratification in AIS patients, helping clinicians identify high-risk individuals early and implement targeted interventions to improve outcomes.

Background: Previous studies have shown the benefit of dual antiplatelet therapy (DAPT) for acute minor ischemic stroke. Argatroban, is a thrombin inhibitor and is primarily used in patients with acute ischemic stroke experiencing early neurological deterioration. There is no study about the benefit of antiplatelet plus anticoagulant in this population. We aim to study the difference between the combination of argatroban and clopidogrel and DAPT in the outcomes of patients with acute minor ischemic stroke (AMIS, NIHSS <5) presenting within 72 hours after onset. Methods: Argatroban combined with clopidogrel versus aspirin combined with clopidogrel in Stroke (ACAP study) is an investigator-initiated, multicenter, prospective, randomized, open-label trial with blinded endpoint evaluation conducted at four centers in China. This trial will randomize 464 eligible patients with minor ischemic stroke of NIHSS 5 (232 in each arm) within 72 hours of the last known well to receive intravenous argatroban with clopidogrel (treatment group) or aspirin plus clopidogrel (control group). The primary outcome is the proportion of patients achieving excellent outcome, defined as a score of 0-1 on the modified Rankin scale, at 90 days. Conclusions: The ACAP trial will provide important data on the role of intravenous argatroban in patients with acute minor ischemic stroke presenting within 72 hours of last known well.

Background: Moderate- to high-intensity walking training (M-HIT) is an established intervention for improving walking capacity in chronic stroke. Musculoskeletal (MSK) adverse events commonly occur during M-HIT, yet tools to identify individuals at higher risk are limited. Baseline clinical characteristics may provide insight into susceptibility to training-related MSK adverse events during M-HIT. Thus, this study aimed to develop and internally validate a model for predicting MSK adverse events during a 12-week M-HIT program in chronic stroke using baseline clinical characteristics. Methods: Participants (n=100) from HIT-Stroke Trials 1 and 2 were included. Baseline clinical characteristics included measures of orthopedic history, pre-existing pain, motor function, recent exercise history, demographics and health characteristics, stroke chronicity, and psychological health. Logistic regression models evaluated all possible combinations of baseline characteristics with up to three predictors. Leave-one-out cross-validation was used for internal validation to mitigate overfitting. Predictive performance was quantified using the C-statistic, and the candidate model with the highest cross-validated C-statistic was selected as the final model. Results: MSK adverse events occurred in 32.0% of participants. The optimal three-variable model included prior orthopedic condition (Odds ratio [OR] 3.02 [95% CI 1.14-8.64]), Fugl-Meyer lower extremity motor score (OR 1.14 [95% CI 1.02-1.28]), and self-reported participation in regular walking exercise (OR 0.17 [95% CI 0.05-0.49]) at baseline. This model demonstrated moderate discrimination (cross-validated C-statistic = 0.74; apparent C-statistic = 0.78). Conclusions: Participants reporting at least one pre-existing lower extremity or lumbar spine orthopedic condition and those with better lower-extremity motor function exhibited greater odds of experiencing MSK adverse events during M-HIT, while participants reporting participation in regular walking exercise had lower odds. These findings suggest that baseline clinical characteristics may help identify individuals at elevated risk for MSK adverse events during M-HIT who may warrant closer monitoring or risk-reduction strategies. Future studies are needed for external validation. Clinical Trial Registration: https://ClinicalTrials.gov; Unique identifiers: NCT03760016, NCT06268041

Background: Type 2 diabetes mellitus (T2DM) has long been considered a risk factor for cerebral small vessel disease (cSVD), yet the exact relationship between glycemic markers and cSVD remains unclear. This study explores the genetic overlap and causal associations between T2DM, glycemic indices, and cSVD phenotypes using genome-wide association studies (GWAS). Methods: Using large consortium-based GWAS data, we examined relationships between T2DM, glycemic indicators (glycated hemoglobin, fasting glucose, 2-hour glucose after oral challenge, and fasting insulin), and cSVD phenotypes (white matter hyperintensity volume, lacunar stroke, cerebral microbleeds, and enlarged perivascular spaces). Our multi-level genomic strategy included: 1) identifying pleiotropic single nucleotide polymorphisms (SNPs) through PLEIO and eQTL analysis, 2) assessing genome-wide genetic correlations using LDSC and GNOVA, and 3) determining causal relationships with two-sample and multivariable Mendelian randomization analyses. Results: We identified 14 pleiotropic SNPs with significant shared associations among T2DM, glycemic indicators, and cSVD phenotypes. Notably, MICB gene expression was elevated in brain, vascular, and pancreatic tissues, while three HLA genes (HLA-DQA1, HLA-DRB1 and HLA-DRB5) showed reduced expression. Genetic correlation analysis revealed positive correlations between T2DM, fasting glucose, and postprandial glucose with multiple cSVD phenotypes including WMH, lacunar stroke, and perivascular spaces. Mendelian randomization demonstrated that T2DM, 2-hour glucose, and HbA1c level causally increased lacunar stroke risk (OR 1.16 [1.09-1.23], OR 1.46 [1.20-1.77], OR 1.52 [1.04-2.23], respectively). Multivariable Mendelian randomization analysis confirmed that T2DM and postprandial glucose maintained a robust direct effect on lacunar stroke independent of other cSVD phenotypes, while HbA1c did not retain significance after conditioning on cSVD imaging markers. Conclusions: Our multi-level genomic analysis reveals links between T2DM, glycemic traits, and cSVD through specific genetic variants, genome-wide correlations, and causal relationships. The involvement of immune-related genes suggests potential biological mechanisms. The causal effect of postprandial glucose on lacunar stroke suggests that impaired glucose tolerance may be a relevant therapeutic target for lacunar stroke prevention.