Background Patients with acute ischemic stroke (AIS) attributable to symptomatic intracranial atherosclerotic disease (sICAD) remain at substantial risk of early neurological deterioration (END) despite standard medical treatment. Aim To determine whether early addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy reduces END in patients with AIS attributable to sICAD within 48 hours of symptom onset. Design The study of Combined Therapy with PCSK9 Inhibitor and Statin in Acute Ischemic Stroke (CAPTAIN) is a multicenter, prospective, randomized, open-label, blinded-endpoint trial conducted in China, with a planned sample size of 416 patients. Eligible patients will be randomized in a 1:1 ratio to receive either early evolocumab plus standard-dose statin or standard-dose statin therapy. Outcomes The primary efficacy outcome is the occurrence of END within 3 days after randomization, defined as an increase in the National Institutes of Health Stroke Scale score of at least 2 points from baseline. Secondary efficacy outcomes include neurological improvement, changes in National Institutes of Health Stroke Scale (NIHSS) score, shift in the 90-day modified Rankin Scale score distribution, recurrent stroke, and changes in lipid parameters. The primary safety outcome is the incidence of moderate-to-severe systemic bleeding within 3 days after randomization, as defined by the GUSTO criteria. Conclusions This study is expected to provide evidence on the efficacy and safety of the early addition of a PCSK9 inhibitor to statin therapy in patients with AIS attributable to sICAD. Trial registration number [NCT06696820][1] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT06696820 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study involves human participants and was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (IRB approval number: 2024-S151). Written informed consent must be obtained from all patients or their legal representatives. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available upon reasonable request. High-Quality Clinical Research Fund of Tongji Hospital, 2024TJCR013 Integrated Chinese and Western Medicine Project for Chronic Disease Management, CXZH2024014 Chutian Talent Programme—Science and Technology Innovation Team [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06696820&atom=%2Fmedrxiv%2Fearly%2F2026%2F07%2F28%2F2026.07.27.26358990.atom

Ischemic cerebrovascular disease involves complex interactions between metabolic reprogramming and epigenetic regulation. Recent studies indicate that enhanced glycolysis and lactate accumulation under hypoxic conditions not only maintain cell viability by supplying energy but also participate in disease regulation through lactylation. Lactylation regulates gene expression, immune polarization, metabolic enzyme activity, and angiogenesis through epigenetic remodeling. In ischemic cerebrovascular disease, lactylation exerts dual roles: on one hand, it can induce neuronal death, exacerbate neuroinflammation, and form a vicious metabolic cycle; on the other hand, it can influence immune cell function and gene expression, thereby exerting neuroprotective effects. Accordingly, targeting lactate metabolism or lactylation-modifying enzymes holds considerable therapeutic potential. Nevertheless, the spatiotemporal regulation, synergistic effects, and broader physiopathological implications of lactylation warrant further in-depth investigation. This review systematically summarizes the role of the "glycolysis-lactate-lactylation" axis in the pathogenesis of ischemic cerebrovascular disease, and discusses its potential as a therapeutic target.

Objective: Intracranial aneurysm (IA) is a serious cerebrovascular disease. This study aimed to investigate the clinical characteristics and plasma biomarkers associated with IA. Methods: A total of 207 participants were enrolled: 45 with unruptured IA, 95 with ruptured IA, and 67 controls. Clinical characteristics, plasma biomarkers, peripheral blood macrophage subsets, and inflammatory cytokines in arterial wall tissue (from six ruptured IA patients and controls) were analyzed. Results: Compared to controls, ruptured IA patients exhibited elevated D-dimer, high-sensitivity Creactive protein and glucose, while unruptured IA patients showed increased platelet count and plateletcrit. Compared to unruptured cases, ruptured IA patients demonstrated higher glucose and D-dimer levels, but lower prothrombin activity and activated partial thromboplastin time. Logistic regression identified association between elevated epithelial neutrophil-activating peptide 78 (ENA78) and platelet with unruptured IA, whereas elevated glucose, D-dimer and matrix metalloproteinase-9 (MMP-9) were associated with ruptured IA. Arterial wall analysis showed upregulation of MMP-9, intercellular adhesion molecule-1, and ENA78 in IA patients. Ruptured IA patients exhibited an altered peripheral blood profile characterized by higher CD14-CD16* cell proportion and decreased CD14*CD16- cells compared to controls. Conclusion: Both inflammatory cytokines and coagulation parameters are implicated in IA pathogenesis, suggesting their potential roles in the development and rupture of IA. (c) 2026 International Hemorrhagic Stroke Association. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PURPOSE:To evaluate the independent and interaction effects of prophylactic intra-arterial nitroglycerin-verapamil versus saline and a 6 Fr Glidesheath Slender versus a conventional 6 Fr sheath on clinical radial artery spasm during diagnostic transradial cerebral angiography. MATERIALS AND METHODS:In this prospective, single-center, 2 × 2 factorial randomized trial, 255 patients undergoing diagnostic TRCA were assigned to prophylactic intra-arterial NV or saline and radial access with either GSS or conventional 6 Fr sheath (CS). The primary outcome was clinical RAS. Secondary outcomes included radial artery occlusion (RAO) and procedural outcomes. RESULTS:Clinical RAS occurred more frequently with GSS than with CS (33.9% vs 18.8%, P = .003). NV did not significantly reduce RAS compared with saline (29.7% vs 21.7%, P = .149). RAO was also higher with GSS (23.6% vs 11.7%, P = .022). After adjustment for prespecified covariates, GSS use remained associated with clinical RAS. CONCLUSION:In this exploratory randomized trial, prophylactic intra-arterial NV did not significantly reduce clinical RAS during diagnostic TRCA. GSS use was associated with higher rates of clinical RAS and RAO under the evaluated procedural conditions. These findings should be interpreted cautiously and require validation in future studies.

Achieving accurate monitoring of electrophysiological activity from the brain cortex is critical for preventing postoperative neurological deficits during craniotomy. However, current technologies face profound challenges in enabling consistent high-quality neural signal acquisition due to complex intracranial environments (e.g., wet/fragile brain surfaces and surgical instrument interference). Here, we develop a soft electrode array with reconfigurable hydrogel interfaces for sustainable high-fidelity monitoring of electrophysiological states from the functional brain cortex throughout neurosurgical procedures. Specifically, we propose a solution-triggered reconfiguration strategy to implement the repeated disassembly/replacement of hydrogel interface layers on electrodes, ensuring consistently superior recording and stimulation properties. Furthermore, through modification with cationic hydrogel microspheres, the hydrogel interface demonstrates strengthened wet adhesion and antiswelling performances, creating robust hydrogel/brain coupling to minimize motion artifacts. In craniotomy of animal models, the electrode array maintains low impedance and high signal-to-noise ratio during repeated repositioning tests through hydrogel interface reconfiguration. In traumatic brain injury models, the electrode array can record consistent high-quality somatosensory evoked potential with dynamic tracking of potential amplitude and latency changes in sensory areas. Quantitative assessments in nerve block experiments verify that the soft electrode array can efficiently elicit motor evoked potentials in motor areas with low stimulation currents. The proposed soft electrode array represents a promising platform for sustainable high-fidelity electrophysiological monitoring. The hydrogel interface design strategy provides an effective approach for developing reconfigurable devices in biomedical applications.

Abstract Background and aims Successful recanalization without functional independence is common after endovascular thrombectomy in stroke. The effect of tirofiban, a glycoprotein IIb/IIIa receptor antagonist, after successful endovascular treatment is unclear. Methods In this multicenter, double-blind, randomized trial at 82 centers in China, patients with anterior-circulation large vessel occlusion stroke achieving successful recanalization (modified Thrombolysis In Cerebral Infarction score 2b-3) after endovascular treatment were assigned to receive tirofiban (intra-arterial bolus, 5 μg/kg, followed by intravenous infusion at 0.1 μg/kg/min for 24 hours) or placebo. The primary efficacy outcome was functional independence, defined as modified Rankin scale (mRS) score of 0–2 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage within 48 hours and death at 90 days. Results A total of 689 patients were assigned to the tirofiban group and 691 to the placebo group. The percentage of patients with a mRS score of 0–2 at 90 days was 49.4% in the tirofiban group and 43.3% in the placebo group (unadjusted risk ratio, 1.14 [95% CI, 1.02-1.28]; P=0.02; adjusted risk ratio, 1.15 [95% CI, 1.03-1.27]; P=0.01). Symptomatic intracranial hemorrhage occurred in 11.9% with tirofiban and 9.4% with placebo (adjusted risk ratio, 1.24 [95% CI, 0.91-1.68]; P=0.17); 90-day mortality was 18.3% and 19.0%, respectively (adjusted hazard ratio, 0.96 [95% CI, 0.75-1.22]; P=0.72). Conclusions In patients with acute anterior-circulation large vessel occlusion stroke achieving successful recanalization, adjunct tirofiban increased the likelihood of functional independence at 90 days without increasing the risk of symptomatic intracranial hemorrhage or mortality. (ClinicalTrials.gov number, NCT06265051.) Conflict of interest

BACKGROUND:Successful reperfusion after endovascular thrombectomy does not consistently result in functional independence in acute ischaemic stroke. We aimed to assess the efficacy and safety of tirofiban, a glycoprotein IIb/IIIa receptor antagonist, given to patients with acute ischaemic stroke who had had a successful endovascular reperfusion. METHODS:This multicentre, double-blind, randomised controlled trial at 82 hospitals in China included patients with acute ischaemic stroke due to anterior-circulation large-vessel occlusion who had had a successful reperfusion after thrombectomy. Eligible patients were randomly assigned (1:1) to receive either tirofiban (intra-arterial bolus 5 μg/kg followed by intravenous infusion 0·1 μg/kg per min for 24 h) or placebo (administered with the same volume and according to the same bolus and infusion procedures as tirofiban), using computer-generated randomisation with fixed blocks stratified by study site. Patients, treating clinicians, investigators, and outcome assessors were masked to group assignments. The primary efficacy outcome was functional independence at 90 days (with a modified Rankin Scale score of 0-2), assessed in all randomly assigned participants (intention-to-treat population). Safety outcomes were symptomatic intracranial haemorrhage within 48 h, any evidence of intracranial haemorrhage on imaging within 48 h, and death within 90 days, and they were assessed in patients having received the study treatment with at least one safety evaluation. The Adjunct Tirofiban Treatment after Successful Endovascular Thrombectomy Recanalisation in Acute Anterior Circulation Ischaemic Stroke (ATTRACTION) trial is registered with ClinicalTrials.gov, NCT06265051 and is now completed. FINDINGS:Of 1686 patients assessed, 1380 were randomly assigned to either the tirofiban group (689 patients) or the placebo group (691 patients) between April 9, 2024, and Sept 29, 2025. Median age was 71 years (IQR 62-77), 591 (43%) patients were female and 789 (57%) were male, and 1367 (99%) were of Han Chinese ethnicity. No patients were lost to follow-up at 90 days. Functional independence at 90 days was recorded in 340 (49%) of 689 patients in the tirofiban group and 299 (43%) of 691 patients in the placebo group (unadjusted absolute risk difference 6·1 percentage points, 95% CI 0·8-11·3, p=0·023; adjusted risk ratio 1·15, 95% CI 1·03-1·27, p=0·0092). There was no significant difference between study groups in the proportion of patients with symptomatic intracranial haemorrhage within 48 h (82 [12%] of 687 patients in the tirofiban group vs 65 [9%] of 691 patients in the placebo group), the proportion with any intracranial haemorrhage within 48 h (235 [34%] patients vs 219 [32%] patients), and 90-day mortality (126 [18%] patients vs 131 [19%] patients). INTERPRETATION:In patients with acute ischaemic stroke due to anterior-circulation large-vessel occlusion achieving successful reperfusion, adjunctive tirofiban increased the likelihood of functional independence compared with placebo. Although symptomatic intracranial haemorrhage occurred numerically more often with tirofiban, the between-group difference was not significant, and this finding warrants caution when weighing potential benefit against bleeding risk. FUNDING:Tongji Hospital Clinical Research Fund.

Background Silent cerebral embolization frequently occurs after transradial cerebral angiography and is commonly detected on diffusion‐weighted imaging (DWI). However, the distribution patterns, burden, and procedural determinants of embolic lesions remain incompletely understood. Methods This prespecified secondary analysis of a randomized controlled trial evaluated embolic lesion patterns following transradial cerebral angiography under different heparin strategies. Patients with postoperative DWI were included. Lesion patterns were characterized by multiplicity, laterality, size, and overall burden. Multivariable Poisson regression identified factors associated with DWI‐positive lesions and lesion distribution patterns. Results Among 456 patients with evaluable postoperative DWI, embolic lesions were detected in 77 (16.9%). Most lesions were small (<5 mm [62.3%]) and cortical (61.0%), whereas 29.9% had multiple lesions and 22.1% had bilateral involvement. Fazekas grade ≥2 (adjusted risk ratio [RR], 2.38 [95% CI, 1.60–3.53]; P<0.001) and longer procedure duration (adjusted RR, 1.05 [95% CI, 1.02–1.08] per minute; P<0.001) were significantly associated with DWI‐positive lesions. Heparin strategy was not associated with overall lesion incidence. However, heparinization combined with continuous heparinized saline flush was significantly associated with multiple lesions (adjusted RR, 1.52 [95% CI, 1.01–2.28]; P=0.044), bilateral involvement (adjusted RR, 1.21 [95% CI, 1.04–1.42]; P=0.015), and high lesion load (adjusted RR, 2.86 [95% CI, 1.02–8.01]; P=0.045). Conclusions Embolic lesions after transradial cerebral angiography show heterogeneous distribution patterns beyond incidence alone. Characterization of lesion multiplicity, laterality, and burden provides a more nuanced assessment of embolic injury. Continuous pressurized heparinized saline flush is associated with more diffuse lesion patterns, highlighting procedural and technical influences on embolic risk. Registration URL: chictr.org.cn; Unique Identifier: ChiCTR2400080902.

Disorders of the central nervous system (CNS) are intricate and often resistant conditions that create a significant global impact, affecting millions of individuals each year. The blood-brain barrier (BBB) acts as a protective mechanism for the brain against external substances, but it also prevents most therapeutic agents from entering the CNS, leading to inadequate drug absorption and reduced effectiveness after diagnosis. Nasal drug delivery has emerged as a viable approach to bypass the BBB, facilitating direct access to the brain through the olfactory and trigeminal nerve routes. Although considerable research focuses on innovative nasal formulations with proven clinical promise, a critical gap persists: a systematic framework that bridges laboratory breakthroughs with clinical implementation. This review addresses this unmet need by integrating recent basic research advances with practical clinical requirements. We summarize nasal transport pathways, targeted design strategies, formulation optimization, and device engineering. Crucially, we propose a structured clinical evaluation framework built upon five essential pillars: targeting precision, pharmacokinetic performance, multi-organ safety profiling, device-drug clinical compatibility, and anatomical translation from animal models to humans. By mapping current research capabilities against clinical readiness criteria, this framework identifies translational bottlenecks and provides actionable guidance to accelerate the bench-to-bedside transition of intranasal drug delivery systems for CNS disorders.

The focus of this study is to investigate the role of diffusion tensor imaging along the perivascular space (DTI-ALPS) index in brain aging. To address this, we first examined the association of DTI-ALPS with aging hallmarks among 40,488 UK Biobank (UKB) participants. Next, we developed normative brain age models incorporating the DTI-ALPS index from 12,401 healthy UKB adults and validated in UKB-ADNI and UKB-TALENT datasets. Finally, we explored the relationship between brain age gap (BAG) with peripheral organ function, chronic diseases, proteomics, and genetics, while identifying modifiable factors in a longitudinal cohort. The findings revealed that DTI-ALPS index correlated with chronological age, telomere length, brain structure, and cognition. A brain age model integrating the DTI-ALPS index achieved good accuracy in the UKB (r = 0.756) and replicated well in two independent datasets (UKB-ADNI: r = 0.766; UKB-TALENT: r = 0.724), with choroid plexus volume emerging as an additional contributor. Musculoskeletal health was a key driver for brain aging in females, while pulmonary metrics prevailed in males. Neurodegenerative and metabolic disorders increased BAGs, imparting increased mortality risk. Protein-wide and genome-wide analysis identified 154 BAG-related proteins and 11 loci. Modifiable factors, particularly systolic blood pressure below 120 mmHg, were strongly associated with reduced BAGs. Overall, the DTI-ALPS index is a promising brain aging biomarker, offering insights into links between brain and peripheral health, and highlighting sex-stratified therapeutic strategies. Aggressive blood pressure control may mitigate brain aging and promote long-term brain health.

Background The optimal management of acute ischemic stroke caused by medium vessel occlusion (MeVO) remains uncertain. Recent randomized trials have failed to demonstrate a clear benefit of endovascular therapy in this population, whereas intra–arterial thrombolysis (IAT) has emerged as a biologically plausible alternative. However, prospective evidence supporting IAT in MeVO is lacking, and the optimal dosing strategy for stand–alone IAT remains undefined. Aim To preliminarily evaluate the efficacy and safety of intra–arterial tenecteplase (IA–TNK) plus standard medical therapy (SMT) compared with SMT alone in patients with acute MeVO stroke, and to explore a stepwise IA–TNK dosing strategy. Design The MeVO–TNK trial is a multicenter, prospective, randomized, open–label, blinded–endpoint (PROBE), exploratory phase II study. A total of 60 participants with imaging–confirmed MeVO will be randomized 1:1 to receive either IA–TNK plus SMT or SMT alone. Participants presenting beyond 6 hours from symptom onset must demonstrate salvageable penumbral tissue on advanced imaging. Those assigned to the intervention group will receive up to two intra–arterial boluses of tenecteplase (0.0625 mg/kg per bolus), with the second bolus administered based on angiographic assessment of reperfusion and safety. Outcomes The primary efficacy outcome is final infarct volume measured at 72±24 hours after randomization. Secondary efficacy outcomes include the proportions of patients achieving modified Rankin Scale (mRS) scores of 0–1, 0–2 and 0–3 at 90 days, a shift analysis of the mRS distribution at 90 days, early neurological deterioration, and National Institutes of Health Stroke Scale score at 7 days or discharge. The primary safety outcome is symptomatic intracranial hemorrhage within 24 hours. Conclusions This trial will provide preliminary evidence on the biological efficacy, reperfusion potential and safety of stand–alone IA–TNK for acute MeVO stroke, helping to address an important evidence gap and inform the design of future confirmatory studies. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Chinese Clinical Trial Registry, ChiCTR2400091249. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study involves human participants and was approved by the ethics committee of Tongji Medical College, Huazhong University of Science and Technology (IRB approval number: 2024-S053). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors National Natural Science Foundation of China, 82171385 High-Quality Clinical Research Fund of Tongji Hospital, 2024TJCR013 Hubei Provincial Natural Science Foundation of China, 2025AFB718

Background Transradial access has become an increasingly preferred approach for cerebral angiography. However, embolic events, often clinically silent, remain a frequent concern. Despite routine use, the efficacy and safety of heparin strategies in this setting lack randomised clinical trial evidence.Methods In this investigator-initiated, single-centre, prospective, open-label, outcome-blinded randomised clinical trial, adult patients undergoing transradial cerebral angiography with a negative diffusion-weighted imaging (DWI) scan within the past month were enrolled. Participants were randomised (1:1:1) to receive no heparin (heparin-free), systemic heparinisation alone or systemic heparinisation followed by continuous heparinised saline flush. A follow-up DWI was performed within 24 hours postprocedure to identify new ischaemic lesions. The primary efficacy outcome was the incidence of new embolic events. Safety outcomes included bleeding and other procedure-related adverse events.Results Between March and December 2024, 472 patients were randomised. Embolic events were detected in 24 of 158 patients (15.2%) in the heparin-free group, 24 of 157 patients (15.3%) in the heparinisation group (adjusted risk ratio (RR) 0.93; 95% CI 0.54 to 1.61; p=0.802) and 35 of 157 patients (22.3%) in the heparinisation followed by heparinised saline flush group (adjusted RR 1.22; 95% CI 0.74 to 2.03; p=0.437). Bleeding complications occurred in one (0.6%) patient in the heparin-free group, three (1.9%) patients in the heparinisation group and nine (5.7%) patients in the heparinisation followed by heparinised saline flush group (p=0.02). Overall adverse events were reported in two (1.3%), four (2.5%) and 11 (7.0%) patients across the respective groups (p=0.018).Conclusions Systemic heparinisation did not reduce embolic events, while continuous heparinised saline flush increased bleeding and adverse events without added benefit. These findings suggest that routine use of heparinised flush warrants reconsideration, emphasising the need to balance procedural anticoagulation strategies against safety risks in clinical practice.Trial registration number ChiCTR2400080902.

BACKGROUND:Obesity is a risk factor for white matter hyperintensities (WMH) and cognitive decline, but underlying mechanisms regarding sex differences, obesity metrics, and the glymphatic system remain unclear. METHODS:Using data from the UK Biobank, we performed sex-stratified analyses. Our approach integrated obesity trajectory modeling (over a mean 9-year period), genome-wide association studies, and 2-sample Mendelian randomization. We examined associations of body mass index, waist-hip ratio, and body fat percentage with glymphatic system function assessed via the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, WMH volume, and cognitive performance. Models were adjusted for age, education, socioeconomic status, vascular risk factors, and intracranial volume, and a sensitivity check was conducted. RESULTS:In 37 684 middle-aged and aging participants (mean age 63.9±7.6 years), significant sex-by-obesity interactions were observed (Pinter<0.05). Men showed consistently greater effects for obesity-related declines in total DTI-ALPS index, total WMH burden, and symbol digit substitution test compared with women (all P<0.001). Trajectory analysis identified waist-hip ratio as the primary driver for men, specifically for deep WMH, middle DTI-ALPS index (all P<0.001), whereas body mass index/body fat percentage predominated in women. Sex-stratified genome-wide association studies confirmed divergent genetic architectures supporting these phenotypes. MR validated stronger causal effects of waist-hip ratio on deep WMH in men than in women (P<0.001). Crucially, mediation analyses demonstrated a significant role of the DTI-ALPS index in women. The effect of body fat percentage on periventricular WMH was primarily explained by an indirect pathway via total DTI-ALPS index (indirect effect, β=0.037 [95% CI, 0.032-0.042]; P<0.001), with a nonsignificant direct effect (β=-0.002 [95% CI, -0.016 to 0.011]; P=0.806), indicating full mediation. CONCLUSIONS:Obesity impacts WMH burden or cognition via sex-divergent pathways, with central adiposity (waist-hip ratio) more detrimental in men and general adiposity (body mass index/body fat percentage) acting through DTI-ALPS index in women. These findings advocate for sex-tailored interventions to control weight, thereby protecting the glymphatic system and reducing the risk of brain injury.

Background Gait speed is a core marker of physical function in older adults. This study aimed to examine the longitudinal associations of nocturnal sleep duration and sleep quality with incident slow gait in Chinese community-dwelling older adults. Methods We analyzed data from the China Health and Retirement Longitudinal Study (CHARLS) 2011 baseline and 2015 follow-up. Participants aged ≥ 60 years with normal gait speed at baseline were included. Sleep duration was categorized as short (< 6 h), normal (6–8 h), or long (> 8 h). Sleep quality was classified as good/fair or poor based on self-report. Incident slow gait was defined as gait speed falling below one sex- and age-group-specific standard deviation of the mean at follow-up. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results Of 3,195 participants, 441 (13.8%) developed incident slow gait over 4 years. Compared with normal sleep duration, short sleep was associated with an increased risk of incident slow gait in the fully adjusted model (OR = 1.25, 95% CI: 1.01–1.55, P = 0.044). Long sleep duration and poor sleep quality showed no significant association with incident slow gait in the fully adjusted model. Subgroup analyses revealed no significant effect modification by sex, age, education, marital status, or residence. Conclusion Short nocturnal sleep duration (< 6 hours) was independently associated with incident slow gait in Chinese older adults. These findings suggest that short sleep may represent a potential target for preserving physical function in aging populations.

BACKGROUND:Successful recanalisation without functional independence is a frequent phenomenon following endovascular thrombectomy (EVT) for large vessel occlusion (LVO) stroke. AIM:To demonstrate the safety and efficacy of adjunct tirofiban therapy after EVT in patients with anterior circulation LVO stroke achieving successful recanalisation, defined as modified Thrombolysis In Cerebral Infarction 2b-3. DESIGN:The study of adjunct tirofiban treatment after successful EVT recanalisation (ATTRACTION: Adjunct Tirofiban Treatment after Successful Endovascular Thrombectomy Recanalisation in Acute Anterior Circulation Ischaemic Stroke) is a multicentre, prospective, double-blinded, randomised trial enrolling 1360 patients in China. Eligible patients will be randomised 1:1 to either the tirofiban or placebo group. OUTCOME:The primary efficacy outcome is assessed as the proportion of participants with a modified Rankin Scale score of 0-2 at 90 days, and the primary safety outcome is symptomatic intracranial haemorrhage within 48 hours from randomisation. CONCLUSIONS:This study will provide evidence on the efficacy and safety of sequential tirofiban therapy after successful recanalisation in patients with anterior circulation LVO stroke. TRIAL REGISTRATION NUMBER:NCT06265051.

White matter hyperintensities (WMH) are key markers of cerebral small vessel disease (CSVD) linked to increased risks of stroke, dementia, and cognitive decline. Physical activity (PA) has been hypothesized to reduce WMH burden and preserve brain health, yet findings across studies remain mixed. This study examines the association between PA and WMH burden, as well as white matter integrity using diffusion tensor imaging (DTI) metrics, in a cohort of 10,868 participants from the UK Biobank. Participants were categorized into low, intermediate, and high PA tertiles based on accelerometer data. WMH volumes, normalized for head size, were classified into quintiles. Multilevel ordered logistic regression models revealed that high PA levels were significantly associated with reduced WMH burden (OR = 0.956, p = 0.026), while low PA levels increased the likelihood of higher WMH burden (OR = 1.148, p < 0.001). Subtype analyses indicated stronger associations between PA and periventricular WMH compared to deep WMH. Furthermore, DTI metrics demonstrated that higher PA levels were correlated with improved fractional anisotropy (FA) and reduced mean diffusivity (MD) in key white matter tracts, such as the corpus callosum and fornix, suggesting better white matter integrity. Our findings emphasize the potential neuroprotective effects of PA, particularly in mitigating WMH progression and preserving cognitive and motor functions. These results underscore the importance of promoting PA, especially in older adults, as a strategy to reduce the burden of CSVD and support brain health. Future longitudinal studies are needed to confirm causality and elucidate underlying mechanisms.

Late-life depression (LLD) is commonly observed in elderly individuals with cerebral small vessel disease (CSVD). Structural or functional injury of brain parenchyma can affect vascular physiology and lead to CSVD. To date, accumulating evidence has indicated that advanced age and persistent hypertension may damage the regulation of cerebral blood flow (CBF) in response to hemodynamic changes. CBF abnormalities have been associated with endothelial damage followed by blood-brain barrier (BBB) disruption, and together they injure brain parenchyma. Consequently, ischemic neuroimaging markers are manifested in the form of lacunar strokes, cerebral microbleeds, enlarged perivascular spaces, subcortical infarcts, and particularly white matter hyperintensity. According to statistical analyses, CSVD-related hallmarks are associated with depression, especially in late life, as has been suggested by the well-known vascular depression hypothesis. Dysfunctional coordination, involving limbic-cortical pathways from fronto-subcortical circuits, is now drawing more attention. In the elder individuals with depression, the implicit role of numerous CSVD abnormalities have yet been sorted and elucidated exclusively. Connections between neuroimaging findings and clinical pathology are not clarified. This review summarized a possible association between CSVD and LLD to gain insights into the mechanism of LLD's development.

BACKGROUND:The long-term benefits of bailout intracranial angioplasty or stenting (BAOS) after thrombectomy in patients with acute large vessel occlusion remain unclear. This study compared BAOS with standard therapy in patients with large vessel occlusion with unsuccessful recanalization (expanded Thrombolysis In Cerebral Infarction score 0-2a) or >70% residual stenosis after thrombectomy. METHODS:ANGEL-REBOOT (Randomized Study of Bailout Intracranial Angioplasty Following Thrombectomy for Acute Large Vessel Occlusion) was a multicenter, open-label, blinded-end point, randomized trial conducted across 36 Chinese hospitals. Patients ≥18 years of age with anterior or posterior circulation large vessel occlusion within 24 hours of stroke onset were enrolled. After identification of thrombectomy failure or high-grade residual stenosis, patients were randomly assigned to the BAOS group (intervention) or the standard therapy group (control), in which thrombectomy was continued or terminated. The use of tirofiban was permitted in both groups during and after the procedure. In the intention-to-treat population, the primary outcome was analyzed using an assumption-free ordinal analysis (Wilcoxon-Mann-Whitney test) to compare the modified Rankin Scale scores (ordinal variable ranging from 0 to 6) between groups at 1-year follow-up, from which the generalized odds ratio was derived. Secondary outcomes included stroke recurrence in the treated artery and all-cause mortality within 1 year, analyzed using Cox proportional hazards models. RESULTS:A total of 348 patients were randomly assigned (176 to the BAOS group and 172 to the standard therapy group) and followed for 90 days, from December 19, 2021, to June 2, 2023. Of these, 326 patients (166 in the BAOS group and 160 in the standard therapy group) completed the 1-year follow-up. Compared with standard therapy, BAOS significantly improved the 1-year modified Rankin Scale score distribution (generalized odds ratio, 1.34 [95% CI, 1.05-1.73]; P=0.02). Fewer stroke recurrences in the treated artery occurred in the BAOS group than in the standard therapy group (7 of 166 [4%] versus 21 of 160 [13%]; hazard ratio, 0.30 [95% CI, 0.13-0.71]; P=0.006). One-year mortality rates were similar between groups (25 of 166 [15%] versus 27 of 160 [17%]; hazard ratio, 0.87 [95% CI, 0.50-1.50]). CONCLUSIONS:Among Chinese patients with large vessel occlusion with unsuccessful recanalization or high-grade residual stenosis after thrombectomy, BAOS was associated with reduced disability and stroke recurrence after 1 year compared with standard therapy. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05122286.

Spinal cord injury (SCI) is a debilitating neurological condition characterized by permanent sensory and motor dysfunction. While clearance of tissue debris represents a critical step in establishing a regenerative microenvironment after SCI, the underlying mechanisms remain incompletely understood. Regulatory T cells (Tregs) have emerged as critical immunomodulators in neurological diseases, with prior studies demonstrating their neuroprotective effects mediated through microglial regulation. As resident macrophages in the central nervous system (CNS), microglia play essential roles in debris clearance after SCI. Moreover, microglia-mediated synaptic elimination is crucial for maintaining tissue integrity and neural circuit function in neurological pathologies. However, it remains unclear whether and how Tregs influence microglial phagocytic activity, particularly synaptic engulfment post-SCI. In this study, we observed robust infiltration of Tregs into the injured spinal cords of both SCI patients and mouse models. Selective depletion of Tregs impaired the microglial phagocytosis of synaptic debris and reduced synapse density in mice post-SCI. Single-cell RNA sequencing and flow cytometry analyses revealed that microglial Cd74 expression was significantly upregulated following Tregs depletion. Remarkably, genetic ablation of Cd74 rescued the phagocytic deficits and mitigates reductions in synaptic density observed in Treg-deficient SCI mice. Osteopontin (OPN), a multifunctional cytokine implicated in regulating neuroinflammation, has previously been shown to mediate Treg-microglia interactions in stroke. Here, we demonstrated that Treg-derived OPN suppressed microglial CD74 expression, enhanced synaptic engulfment, and improved neurological outcomes after SCI. Collectively, our findings highlight a novel OPN-CD74 regulatory axis through which Tregs modulate microglial phagocytic function, offering new translational targets for SCI treatment.