Stroke

BackgroundMinor ischemic stroke is heterogeneous, and low NIHSS does not reliably identify patients at risk of deterioration or disability. We investigated whether integrating CT perfusion and angiographic vessel status identifies prognostically distinct phenotypes in a consecutive stroke-code cohort. MethodsWe analyzed consecutive adults with ischemic stroke, baseline NIHSS 0-5, prestroke modified Rankin Scale (mRS) [&le;]2, presentation within 24 hours of symptom onset or last known well, and emergency multiparametric CT. Patients were classified as no perfusion deficit/no vessel occlusion (PF-/VO-), perfusion deficit without visible occlusion (PF+/VO-), or perfusion deficit with vessel occlusion (PF+/VO+). The primary outcome was mRS [&ge;]3 at 90 days; early neurological deterioration (END), defined as an NIHSS increase [&ge;]2 points by 24 hours, was secondary. Multivariable logistic regression adjusted for prespecified covariates and additional variables associated with each outcome in univariable analysis. ResultsOf 2211 patients evaluated through the stroke-code pathway, 534 met inclusion criteria; 391 (73.2%) were PF-/VO-, 61 (11.4%) PF+/VO-, and 82 (15.4%) PF+/VO+. END occurred in 8.1% and mRS [&ge;]3 at 90 days in 17.6%. END occurred in 6.6%, 4.9%, and 17.1% of PF-/VO-, PF+/VO-, and PF+/VO+ patients, respectively (P=0.004), whereas mRS [&ge;]3 occurred in 13.3%, 34.4%, and 25.6%, respectively (P<0.001). Compared with PF-/VO-, PF+/VO+ was independently associated with END (adjusted odds ratio [aOR], 2.50 [95% CI, 1.03-6.06]), whereas PF+/VO- was independently associated with mRS [&ge;]3 at 90 days (aOR, 3.36 [95% CI, 1.67-6.73]). Findings were consistent across definitions of disabling versus nondisabling stroke and after exclusion of lacunar stroke. ConclusionsMultiparametric CT identified distinct risk phenotypes in minor ischemic stroke. Perfusion deficit without visible vessel occlusion was associated with 90-day disability, whereas combined perfusion deficit and vessel occlusion identified patients at increased risk of END. Tissue perfusion and vessel status may provide complementary information for acute risk stratification and future trial enrichment.

Background: Immunothrombosis is increasingly recognized in large-vessel-occlusion acute ischemic stroke (LVO-AIS), yet most biomarker studies infer thrombus biology from circulating neutrophil extracellular trap (NET) markers or from pre-defined thrombus subtypes. We prospectively studied 160 patients with anterior-circulation LVO-AIS treated with mechanical thrombectomy to determine whether intrathrombus NETosis markers identify thrombus phenotypes with distinct clinical trajectories, and whether plasma NETosis biomarkers reflect the molecular composition of thrombi. Methods: Thrombi underwent quantitative histopathology and immunohistochemistry for citrullinated histone H3 (CitH3), neutrophil elastase (NE) and CD61. Thrombi were analyzed without prior etiological or histological stratification, and intrathrombus markers were dichotomized at cohort medians (CitH3 6.62%, NE 3.95%, CD61 23.09%) to define internally standardized candidate phenotypes. Associations with thrombus composition, collateral circulation (Tan 2-3), 3-month functional independence (modified Rankin Scale 2 or less) and long-term mortality were assessed by correlation analyses and progressively adjusted multivariable models, with cross-compartment correlations corrected by the Benjamini-Hochberg false discovery rate (FDR). Results: Intrathrombus markers defined prognostically distinct phenotypes: CD61 tracked functional recovery, NE preserved collateral circulation and CitH3 long-term survival, each remaining significant after multivariable adjustment. Circulating NE, myeloperoxidase and leukocyte count instead tracked the macroscopic red-blood-cell-fibrin composition of retrieved thrombi. Cross-compartment concordance was limited: after FDR correction the only significant plasma-thrombus association was an inverse correlation between plasma cell-free DNA and intrathrombus NE, and no intrathrombus marker correlated positively with its circulating counterpart. Conclusions: Local immunothrombotic signatures therefore provide clinically relevant information not captured by plasma markers, and median-defined intrathrombus thresholds represent hypothesis-generating cutoffs for external validation and NET-targeted treatment stratification.

Introduction Mechanical thrombectomy has been well-established as the standard of care treatment for patients with moderate to severe acute ischaemic stroke secondary to large vessel occlusion. However, the clinical value of endovascular treatment (EVT) in patients presenting with minor stroke and low baseline National Institutes of Health Stroke Scale scores remains incompletely defined, with limited high-quality clinical evidence. This protocol outlines the methodology of a randomized trial designed to evaluate whether EVT combined with best medical therapy (BMT) achieves superior functional outcomes relative to BMT alone among patients with minor stroke. Methods and analysis Eligible patients with acute minor anterior circulation ischaemic stroke and confirmed large vessel occlusion (n=264) will be randomized via a computer generated block randomization sequence to receive either EVT plus BMT (intervention arm) or BMT alone (control arm). The primary efficacy outcome is the proportion of participants achieving excellent functional recovery, defined as a modified Rankin Scale score of 0 or 1 at 90 days. Primary safety outcomes comprise symptomatic intracranial haemorrhage within 48 hours after randomization (classified according to Heidelberg criteria) and all cause mortality at 90 days. Participants will be considered eligible if they satisfy all of the following inclusion criteria: (1) enrolment within 24 hours of stroke symptom onset or time last known well; (2) baseline NIHSS score of 2 - 5 accompanied by at least one focal neurological deficit (including altered consciousness, facial palsy, limb weakness, aphasia or hemispatial neglect); (3) angiographically confirmed acute occlusion of the intracranial internal carotid artery, the M1 segment of the middle cerebral artery, or a dominant M2 branch; (4) a hypoperfusion volume (Tmax >6s) [&ge;] 50mL on computed tomography or magnetic resonance perfusion imaging. Both intention to treat and per protocol analyses will be undertaken, and potential sources of heterogeneity in treatment effect magnitude will be explored. Ethics and Dissemination This study was approved by the ethnic committee from the First Affiliated Hospital of Wannan Medical University (2023-IRB90). The findings of this study will be disseminated through publication in peer-reviewed journals. Registration URL:https://www.clinicaltrial.gov; Unique identifier: NCT06143488.

Abstract Background: Despite the high stroke burden in the elderly, their thrombolysis utilization is suboptimal partly due to heightened hemorrhagic risk. Observational data suggest that low-dose thrombolysis may offer comparable efficacy to standard-dose with a trend toward reduced symptomatic intracranial hemorrhage (sICH), yet high-level evidence for low-dose thrombolysis in this broad population remains absent. Objective: To evaluate the safety and efficacy of low-dose intravenous tenecteplase thrombolysis in elderly stroke patients within 4.5 hours of ischaemic stroke onset. Methods and design: The DATE-AGING trial is a multicenter, prospective, randomized, open-label, blinded-end point (PROBE) non-inferiority study. Eligible participants are elderly patients (aged [&ge;]70 years)with acute ischemic stroke who meet current guideline recommendations for intravenous thrombolysis within 4.5 hours of symptom onset will be randomly assigned to Low-dose Tenecteplase group (0.175 mg/kg, max 17.5 mg) or Standard-dose Tenecteplase group (0.25 mg/kg, max 25 mg). The primary outcome was excellent functional outcome, defined as a mRS 0-1 assessed at 90-day post-randomization. Safety outcomes included sICH within 36 hours and mortality at 90 days. Discussions: The DATE-AGING trial is intended to provide high-quality evidence for low-dose tenecteplase intravenous thrombolysis in elderly patients with acute ischemic stroke. Trial registry number: NCT07294209(https://clinicaltrials.gov/study/07294209). Keywords: elderly patients, acute ischemic stroke, intravenous thrombolysis, low-dose tenecteplase

Background: Excessive inflammation in early phases post-ischemic stroke is associated with poor long-term outcome and increased stroke recurrence. Interventions capable of downregulating persistent states of inflammation could improve recovery and prevent secondary stroke. Cardiovascular exercise (CE) has well-established anti-inflammatory effects but its capacity to attenuate the exaggerated inflammatory response triggered by ischemic stroke is unclear. Methods: We investigated the impact of eight weeks of CE on the serum concentration of inflammatory mediators in the early subacute phase post-stroke. Seventy-one patients with firstever ischemic stroke were randomly assigned to moderate-to-vigorous CE (n=45) or standard care (SC) (n=26). Concentrations of CRP, IL-6, IL-8, IL-10, TNF- and IL-1{beta} were measured at baseline and after the interventions. Differences between groups were analyzed with linear mixed models adjusted for age and sex. Results: Compared with the CE group, the SC group showed significant increases in IL-6 ({beta}=0.585, 95% CI=0.164-1.006, p=0.0073), IL-8 ({beta}=0.160, 95% CI=0.004-0.317, p=0.0447), and TNF- ({beta}=0.0845, 95% CI=0.0137-0.1553, p=0.0206). The SC group also showed greater increases in CRP ({beta}=0.250, 95% CI=-0.407, 0.906, p=0.4499) and IL-10 ({beta}=0.251, 95% CI=-0.024, 0.527, p=0.0729) but group differences were not significant. IL-1{beta} levels remained stable and differences between groups were not significant ({beta}=-0.008, 95% CI=-0.058, 0.042, p=0.7618). Conclusions: When introduced in the early subacute phase of stroke recovery, moderate-tovigorous CE mitigates increases in inflammation, but the effect differs across mediators. To what extent reducing the inflammatory response in the early stages post-stroke with CE can impact longterm recovery and stroke recurrence needs to be determined.

BACKGROUND: Existing models for discharge to long-term institutional care after stroke are developed within single health systems and pool to an area under the curve near 0.80, but none is accompanied by an estimate of how much of the outcome is a property of the health system rather than the patient. METHODS: Secondary analysis of the International Stroke Trial, a randomised trial in 19,435 patients with suspected acute ischaemic stroke recruited in 1991-1996 across 36 countries. Among 14,885 survivors to six months with residence recorded, we developed and internally validated a logistic prognostic model for residential or nursing-home residence using 17 admission-day terms, and compared it against a pre-specified benchmark of age and stroke syndrome alone. Between-country variation was estimated by a method-of-moments decomposition with a cluster bootstrap. RESULTS: Institutional residence was recorded for 1,984 of 14,885 survivors (13.3%); the model was fitted on 14,121 patients containing 1,935 events. In 10-fold cross-validation with the whole procedure refitted per fold, the out-of-fold c-statistic was 0.789, calibration slope 0.987, calibration-in-the-large 0.1371 predicted against 0.1370 observed, and Brier score 0.1013. A benchmark of age and stroke syndrome alone reached an optimism-corrected 0.774 against 0.790 for the full model, a corrected difference of 0.0160. Between-country variation gave an intraclass correlation of 0.0409 (0.0191 to 0.0673), and in leave-one-country-out validation the c-statistic ranged from 0.635 to 0.823 across the 14 countries with enough events to estimate it. CONCLUSIONS: Institutional residence after stroke can be stratified at admission with discrimination comparable to existing models and calibration that holds in unseen patients, but almost all of the signal is carried by age and stroke syndrome. Performance varies substantially between countries, pointing to placement systems as the limit on what a pooled model can do.

Background Accurate prediction of 90-day outcomes following ischemic stroke is crucial for optimizing clinical strategies. This study aimed to systematically review and meta-analyze studies using deep learning (DL) and hand-crafted radiomics (HCR) models for predicting 90-day modified Rankin Scale (mRS) outcomes after ischemic stroke. Methods We followed the PRISMA guidelines for systematic reviews. Four databases (PubMed, Embase, Web of Science, and Cochrane Library) were searched comprehensively for studies published up to September 2025. Inclusion criteria encompassed original research focusing on ischemic stroke patients with mRS at 90 days as the primary outcome and predictive models utilizing imaging biomarkers from CT or MRI. Quality assessment of the included studies was conducted using the PROBAST and and METhodological RadiomICs Score (METRICS) tools. Results Seventeen studies were included in the quantitative meta-analysis. Models demonstrated good prognostic performance for 90-day outcomes, with pooled AUCs of 0.85 (95% CI: 0.80-0.86) for internal and 0.74 (95% CI: 0.67-0.89) for external validation sets, with no significant difference (p=0.42). Deep learning and hand-crafted radiomics models showed comparable diagnostic accuracy in the primary analysis (p=0.667); a difference in sensitivity favouring hand-crafted radiomics emerged only in a post-hoc analysis after exclusion of one outlier study. Models incorporating clinical variables significantly outperformed imaging-only models (p<0.01). CT- and MRI-based models showed similar performance. Treatment-specific analyses revealed higher sensitivity for IVT-based models and higher specificity for combined MT+IVT models. Conclusions DL and HCR models demonstrate robust potential for predicting 90-day outcomes in ischemic stroke. Future research should focus on standardizing model evaluation metrics and incorporating explainable AI techniques to improve clinical applicability.

INTRODUCTION: Stroke, dementia, and late-life depression share overlapping vascular pathophysiology, yet simple markers of shared neurological vulnerability across these conditions remain limited. Most gait research has relied on usual walking speed (UWS) alone, leaving it unclear whether quick walking speed (QWS) and gait adaptability (QWS minus UWS), relate to these conditions in the same way. METHODS: We examined associations of UWS, QWS, and gait adaptability with executive function, verbal memory, depressive symptoms, and incident stroke and dementia in the Framingham Heart Study Offspring cohort. A larger sample (n=2,308; mean age 61.5 years [SD 9.2]; 54% women) was used for cross-sectional and stroke analyses, and a dementia-free sample of 1,148 participants aged 60 years or older (mean age 68.5 years [SD 5.8]; 53% women) was used for analyses of incident dementia. We estimated associations per SD slower walking or smaller adaptability using linear, logistic, and Cox regression (10-year follow-up), overall and in women and men. RESULTS: Slower QWS and UWS were each associated with worse executive function, higher odds of high depressive symptoms (QWS OR 1.24, 95% CI 1.07-1.45; UWS OR 1.26, 95% CI 1.09-1.46), and greater hazard of incident stroke (QWS HR 1.30, 95% CI 1.03-1.64; UWS HR 1.36, 95% CI 1.11-1.65). Executive function and stroke associations were observed primarily in men (stroke QWS HR 1.55, 95% CI 1.11-2.17). For incident dementia, slower QWS reached significance (HR 1.34, 95% CI 1.10-1.63), while UWS did not (HR 1.20, 95% CI 0.98-1.46). Lower gait adaptability was associated with worse executive function overall and in women and men, and with incident dementia in women (HR 1.35, 95% CI 1.04-1.76), but not with depressive symptoms or stroke. No gait measure was associated with delayed recall. CONCLUSION: Slower QWS was associated with incident dementia; UWS was not. Adding a brief quick walking trial to routine gait assessment may identify risk that habitual-pace screening overlooks.

Background: Dexmedetomidine (DEX) and midazolam (MDZ) are commonly used agents for conscious sedation in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT). While DEX offers superior sedation quality and potential neuroprotective effects, it is also associated with risk of hemodynamic instability. High-quality evidence directly comparing their impact on functional outcomes after EVT is lacking. This trial aims to determine whether conscious sedation with DEX, compared to MDZ, improves functional outcomes in patients with AIS due to anterior circulation large vessel occlusion (LVO) undergoing EVT. Methods: PEACE (Dexmedetomidine versus Midazolam for Conscious Sedation during Endovascular Stroke Thrombectomy) is a prospective, randomized, open label, blinded-endpoint, multicenter trial. Up to 810 patients with AIS due to LVO in the anterior circulation within 24 hours of last known well will be randomly assigned in a 1:1 ratio to receive either DEX or MDZ for conscious sedation during EVT across 30 centers in China. Results: The primary end point is the proportion of patients achieving a modified Rankin Scale (mRS) score 0-2 at 90 days, analyzed in the intention-to-treat population using a modified Poisson regression model, with results expressed as a risk ratio. Key secondary outcomes include the ordinal distribution of mRS scores at 90 days, and successful recanalization. Safety outcomes include symptomatic intracranial hemorrhage within 48 hours, and mortality at 90 days. Conclusion: The PEACE trial will provide definitive, high-level evidence on the comparative efficacy and safety of DEX versus MDZ for conscious sedation during EVT in patients with AIS due to LVO in the anterior circulation, with the goal of guiding clinical practice.

Background: Autophagy is a homeostatic pathway supporting stress adaptation and is dysregulated in atherosclerosis. Its potential as a biomarker or therapeutic target in atherosclerotic vascular disease (ASVD) remains incompletely defined. We measured autophagic flux in peripheral blood mononuclear cells (PBMCs) from patients with peripheral arterial disease (PAD) or carotid stenosis (CS), compared with healthy controls, and explored clinical outcome associations. Methods: Ninety-four patients with PAD or CS and 19 healthy controls were studied. Autophagic flux was quantified from fresh blood using a validated ex vivo chloroquine inhibition ELISA measuring LC3BII accumulation. Major adverse cardiovascular events (MACE) and major adverse limb events (MALE) were ascertained over a median follow up of 828 days. Results: The ASVD cohort comprised claudication (n = 16), chronic limb threatening ischemia (CLTI; n = 49), and CS (n = 29). Autophagic flux was higher in ASVD than controls (mean 281.4 vs. 182.3 ng LC3BII/mg protein/h; p < 0.0001) and remained independently associated after multivariable adjustment. Within CLTI, concurrent infection was associated with lower flux (p = 0.001), approaching control levels (p = 0.327). In CLTI, higher flux quartiles were associated with lower MACE risk, most strongly for quartile 3 (hazard ratio 0.07 vs. quartile 1, 95% CI 0.01 to 0.50; p = 0.009). Conclusion: Autophagic flux is elevated in PBMCs from ASVD patients, independent of age and sex. Attenuated flux in CLTI with concurrent infection may indicate autophagic exhaustion in advanced disease. The association between higher flux and lower MACE in CLTI suggests prognostic utility, warranting evaluation in larger prospective studies.

Background: Stroke imposes substantial mortality and socioeconomic burden in India, particularly among younger adults. However, prospective evidence on the prognostic value of baseline clinical and radiomics features for mortality prediction remains limited. Objective: To assess mortality at 28, 90, 180, and 365 days after stroke; characterize survival patterns across stroke subtypes and vascular territories; and identify baseline demographic, clinical, and radiomics predictors of mortality. Methods: This prospective cohort study recruited consecutive patients with stroke admitted to a tertiary care hospital in Mangalore, India. Demographic, clinical, laboratory, and radiomics features were collected at admission, and mortality was assessed at 28, 90, 180, and 365 days. Kaplan Meier analysis was used to compare survival across stroke subtypes and vascular territories, while Cox proportional hazards regression was used to identify independent baseline predictors of mortality. Results: Among 63 confirmed stroke cases, 38 (60%) had ischemic stroke (IS) and 25 (40%) had haemorrhagic stroke (HS). Within the middle cerebral artery (MCA) territory, HS patients demonstrated better survival than IS patients due to a greater burden of adverse baseline characteristics such as previous stroke, atrial fibrillation, and higher lesion volume in the IS-MCA subgroup. The combined clinical-radiomics model demonstrated superior prognostic performance than individual models, with higher concordance indices and consistently lower Akaike Information Criterion values. In the combined model, stroke severity (aHR = 2.35, 3.0, 2.93, 2.41) and DWI texture heterogeneity of lesion (aHR = 2.35, 2.11, 2.24, 2.10) were the strongest predictors of mortality across all time points. The CT attenuation heterogeneity (aHR = 1.81, 28 days; 1.76, 90 days; 1.80, 180 days) of lesion and age (aHR = 1.48, 365 days) were also significant predictors. Conclusion: The radiomics features provide critical complementary information to clinical parameters for predicting 28-day mortality, unlike during mid- to long-term follow-up where their incremental contribution appears to be limited. Our results may have important implications in resource-constrained settings for supporting personalized post-stroke management and rehabilitation.

Background/Aims: Pre-stroke depression has been shown to be associated with worse functional outcomes and depression after stroke. However, it is not currently well understood whether pre-stroke mood disorders (e.g., depression, anxiety, mood and psychotic disorders, substance use disorder) are associated with withdrawal of life-sustaining treatment (WOLST) after a severe stroke. Methods: This was a retrospective cohort study within the Tufts Vascular Neurology Registry of patients hospitalized with severe acute ischemic stroke (AIS, defined as NIHSS [&ge;]10) or severe nontraumatic intracerebral hemorrhage (ICH, defined as ICH score [&ge;]2) between 2018 and 2022. Multivariate logistic regression was performed to identify predictors of WOLST. Results: This study included 405 patients with severe stroke. Patients who opted for WOLST were more likely to be older, female, have AIS, and experience more severe strokes. In an adjusted analysis (basic demographics, stroke type), a pre-stroke mood disorder was associated with WOLST (OR 2.15, 95% CI 1.11-4.15). In models stratified by stroke type (AIS vs. ICH) and adjusted for stroke severity, WOLST was associated with age in both groups and with mood disorder in patients with ICH. The WOLST event rate was higher in the ICH group (19% vs 11%). Conclusion: Pre-stroke mood disorder was associated with increased rates of withdrawal of care after severe stroke in this patient population. Opportunities to actively treat depression may be useful to include in goals of care discussions to mitigate the potential impact of this factor in decision-making. Consistent with prior studies, we observed a higher proportion of WOLST in older, female, and ICH patients. Future studies regarding the quality and content of goals of care discussions may help elucidate the differing effects of pre-stroke mood disorders on WOLST by stroke type seen in this study.

Background. Prediction models after stroke increasingly add neuroimaging information to bedside data. Whether findings documented in radiology reports improve short term risk stratification beyond a patient's evolving physiological state is unknown. Methods. We studied 4,827 adults with acute ischaemic stroke, intracerebral haemorrhage or subarachnoid haemorrhage in MIMIC IV (2008 to 2019). At eight landmarks from 6 to 48 hours after ICU admission, models ranked patients by their risk of deterioration or death within 24 hours. The baseline model combined demographic and clinical characteristics, a previously validated dynamic ICU state representation, and the physiology, treatment and imaging status at each landmark. A locally run language model extracted imaging phenotypes from 6,992 head CT and MRI reports; three phenotypes and four location categories met a pre specified reliability criterion for automated extraction in independent validation and entered the model. The primary outcome was the difference in the proportion of events captured among the 10% of patients ranked highest at each landmark, in temporal validation (2017 to 2019; 8,923 patient landmarks, 666 events). Results. Among the highest ranked 10%, adding imaging phenotypes captured no additional event (348 of 666 with and without them): a difference of 0.00 percentage points (95% CI -2.20 to +2.01). Discrimination (AUROC 0.855 vs 0.849), calibration and net benefit were similar. No prespecified sensitivity analysis, stroke subtype or availability-adjusted analysis showed statistically supported incremental capture. In a post hoc redundancy analysis, imaging phenotypes improved capture when added to demographic and clinical characteristics alone (+12.91 points, 7.54 to 17.81), but this gain was no longer evident once the dynamic state representation was included. Conclusions. Neuroimaging phenotypes derived from routine radiology reports were associated with short-term deterioration, but we found no evidence that they added risk stratification value beyond the dynamic ICU state and contemporaneous physiology.

Background: Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cerebrovascular disease, but its effects on the cerebral microcirculation are poorly defined. We investigated whether LDL-C is associated with pericyte dysfunction in acute ischemic stroke (AIS) and explored underlying mechanisms. Methods: Serum soluble platelet-derived growth factor receptor-{beta} (sPDGFR{beta}) was measured in two independent AIS cohorts (n=97 and n=86). Cerebral pericyte transcriptional responses to LDL-C were analyzed by single-cell RNA sequencing in Apoe-knockout mice fed control or high-fat diet (n=4 [male/female: 2/2]/group), and cultured human brain pericytes were exposed to purified human LDL cholesterol with or without N-acetyl-L-cysteine. Results: Higher serum sPDGFR{beta} was associated with greater neurological deficit and circulating neurofilament light chain. LDL-C positively correlated with sPDGFR{beta} in both clinical cohorts. High-fat diet induced coordinated suppression of type-I interferon pathways, and a positive shift in reactive oxygen species-related transcriptional programs in mouse pericytes; exploratory sex-by-diet analyses suggested larger transcriptional responses in females. In cultured human pericytes, LDL-C induced oxidative-stress, lipid-handling, and ferroptosis-associated transcriptional programs while suppressing type-I interferon signaling. Cross-species enrichment analysis showed that LDL-C-induced and -repressed signatures in cultured pericytes aligned with the sex-by-diet interaction in Apoe-knockout mice. LDL-C also reduced cell-surface PDGFR{beta} and increased sPDGFR{beta} release in cultured pericytes, which were significantly attenuated by N-acetyl-L-cysteine, whereas LDH activity increased numerically but not significantly. Conclusions: Clinical and experimental findings support an LDL-pericyte axis linking atherogenic lipid stress to cerebral microvascular dysfunction, with possible sex-dependent modulation of oxidative stress and type-I interferon signaling as potential mechanisms.

Background Endovascular treatment of unruptured intracranial aneurysms (UIAs) often requires dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. Clopidogrel remains widely used, but variable bioactivation and high on-treatment platelet reactivity have prompted interest in alternatives such as prasugrel. We compared thromboembolic and hemorrhagic outcomes after clopidogrel versus prasugrel use in endovascular UIA treatment. Methods We queried the TriNetX Global Collaborative Network for adults with UIA who underwent endovascular treatment between 2016 and 2025 and received aspirin plus clopidogrel or prasugrel. Cohorts were matched 1:1 using propensity score matching based on demographics and comorbidities. Outcomes were assessed at 6 months and 1 year and reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results Among 15,496 adults, 711 matched pairs were included. At 6 months, no significant differences were observed for in-stent thrombosis (OR 0.77, 95% CI 0.38?1.57; p=0.47), cerebral infarction (OR 1.04, 95% CI 0.75?1.46; p=0.80), cerebral hemorrhage (OR 1.07, 95% CI 0.80?1.44; p=0.65), or gastrointestinal hemorrhage (OR 0.84, 95% CI 0.43?1.64; p=0.61). Findings remained nonsignificant at 1 year. Conclusions In this propensity-matched TriNetX analysis, clopidogrel and prasugrel were not associated with significant differences in thromboembolic or hemorrhagic outcomes after endovascular UIA treatment. Prasugrel may be a reasonable alternative P2Y12 inhibitor in selected patients, including those with suspected or documented clopidogrel non-response.

The gut-brain axis has emerged as a critical modulator in neurological diseases, including stroke. While acute post-stroke dysbiosis is well established, it remains unclear whether these alterations persist long-term and can be therapeutically modulated. This study addresses this gap through integrated metagenomic and metabolomic profiling in two independent clinical stroke cohorts, complemented by experimental models. Experimental stroke induced persistent changes in gut microbiota composition and altered short-chain fatty acid profiles. In patients, microbiota composition remained distinct from controls up to three months after ischemic stroke or transient ischemic attack (TIA), accompanied by persistent reductions in propionic and valeric acid and reduced abundance of Prevotella-associated microbial signatures. We performed a randomized, double-blind interventional trial (PRISE) testing a multispecies probiotic versus placebo, using household members as additional controls. Probiotic intervention led to microbiome compositional changes with increased abundance of beneficial taxa and significantly improved functional recovery. The tested probiotic strains showed anti-inflammatory and antioxidant effects in vitro. These findings suggest that targeted modulation of the microbiome represents a promising therapeutic avenue to improve chronic stroke recovery, warranting validation in larger Phase III clinical trials.

Arterial stiffness and endothelial dysfunction are non-traditional risk markers after stroke, yet reliability and minimal detectable change (MDC) of pulse wave velocity (PWV) and flow-mediated dilation (FMD) have not been established. We examined test-retest reliability and MDC of carotid-femoral (cfPWV), carotid-radial (crPWV), and femoral-dorsalis pedis PWV (ffPWV), and absolute and relative brachial artery FMD in people >12 months post-stroke. Seventeen individuals (n=4(24%) females; 63.9{+/-}8.6 years; 4.5{+/-}2.8 years post-stroke) completed two bilateral assessments of PWV via applanation tonometry and FMD via duplex ultrasound within one week. Intraclass correlation coefficients (ICC2,1) were calculated via two-way random-effects models, and MDC derived at 68%, 90%, and 95% confidence levels. We found good-to-excellent reliability for cfPWV in paretic (ICC2,1=0.85; 95%CI:0.59,0.95) and non-paretic (ICC2,1=0.94; 95%CI:0.82,0.98) limbs, with MDC95% values of 2.23 and 1.68 m/s, respectively. crPWV and ffPWV exhibited poor reliability bilaterally (ICC2,1=0.12-0.33). Relative FMD showed-moderate reliability for paretic (ICC2,1=0.50; 95%CI:-0.20,0.85) and non-paretic (ICC=0.59; 95%CI:0.04,0.84) limbs, with MDC95% values of 6.88% and 7.65%, respectively. Reliability for absolute FMD was poor (ICC2,1=0.11-0.44). These findings support cfPWV as a reliable vascular assessments in individuals >12 months post-stroke, and provide stroke-specific MDC values to guide interpretability in future trials.

Introduction: Hematoma expansion is a main cause of early worsening after spontaneous intracerebral hemorrhage (ICH). Many hospitals in low income countries have no invasive pressure monitoring and no automated pupillometer. Staff use the Glasgow Coma Scale (GCS) and a penlight to check the pupils, and pupil changes seen with a penlight usually come late. The speed of pupil constriction may change earlier, and smartphones record video fast enough to measure it. Methods and analysis: This will be a single-centre prospective cohort study of 120 adults with ICH on non-contrast computed tomography (NCCT) who arrive within 24 hours of symptom onset. At admission and every 6 hours until 48 hours, we will record a 6 second smartphone video of each eye reacting to a flash, using an eyecup that blocks ward light. Open-source software will measure the pupil diameter in every frame. The main measure is constriction velocity (CV). The primary outcome is hematoma expansion (an increase of more than 6 mL or more than 33%) on NCCT at 24 hours. Secondary outcomes are a fall of 2 or more GCS points within 48 hours and in-hospital death. The primary analysis estimates the area under the receiver operating characteristic curve for the percentage fall in CV from each patient's first recording. Ethics and dissemination: Patients or their legal representatives will give written consent. Results will be submitted to a peer-reviewed journal, and the analysis code will be made public.

Abstract Background: Chronic subdural hematoma (cSDH) remains a significant and increasingly prevalent cause of morbidity in older adults. Disease progression is sustained by de novo formed highly vascularized pseudomembranes and a persistent cycle of fluid accumulation and hematoma expansion. Although inflammatory and angiogenic pathways have been implicated in cSDH pathogenesis, the endothelial mechanisms underlying persistent vascular leak remain poorly understood. We investigated the cSDH vascular microenvironment in human patients and examined the role of vascular endothelial cadherin (VECAD) remodeling in cSDH endothelial dysfunction. Methods: Human cSDH membranes and fluid were evaluated by multiplex profiling, histology, immunofluorescence, immunoprecipitation, western blotting and exploratory bulk RNA sequencing. A human brain endothelial cell (HBEC) line was exposed to patient-derived cSDH fluid to assess VECAD remodeling, endothelial barrier permeability, and proliferation. Results: Multiplex profiling of patient-derived cSDH fluid detected mediators associated with endothelial cell (EC) activation, extracellular matrix remodeling, inflammation, and angiogenesis. In patient pseudomembranes, discontinuous VECAD coincided with erythrocyte extravasation. Two hyperdense (high-risk) specimens showed more extensive disruption than the hypodense (low-risk) specimen while vessel counts appeared similar. Bulk RNA sequencing identified an angiogenic environment and enrichment in cadherin regulation. A soluble VECAD (sVECAD) isoform was detected in cSDH fluid. Exposure of HBECs to patient-derived cSDH fluid increased EC proliferation, cytoplasmic VECAD (cVECAD) accumulation, and EC barrier permeability. Concurrent dexamethasone or minocycline treatment attenuated VECAD cleavage. Conclusions: VECAD disruption is a prominent feature of cSDH and is associated with EC barrier dysfunction. These findings support further evaluation of soluble VECAD as a candidate biomarker and of junction-preserving pathways as potential therapeutic targets.

BACKGROUND: White matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients. METHODS: RVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts. RESULTS: Approximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20-5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05-12.29]). CONCLUSIONS: RVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure-independent therapeutic target with corroborating clinical evidence.