BACKGROUND:Antithrombotic agents are essential for preventing cerebrovascular and cardiovascular diseases; however, bleeding complications remain a major concern, particularly among elderly patients and those receiving combination therapy. AIMS:We designed the Bleeding with Antithrombotic Therapy 2 (BAT2) Study, a prospective multicenter registry involving hospitals from a clinical research network in Japan, to clarify the risk of bleeding events in patients taking antithrombotic agents for cerebrovascular and cardiovascular diseases in recent clinical settings. METHODS:This prospective, multicenter, observational study followed bleeding and ischemic events for up to 2 years in patients with cerebrovascular and cardiovascular diseases. The primary outcome was major bleeding, and secondary outcomes included intracranial hemorrhage (ICH). RESULTS:The 5250 patients enrolled comprised 3134 (70 ± 11 years; male, 66.6%; HASBLED ⩾ 3, 32.8%) treated with single antiplatelet therapy (SAPT), 551 (71 ± 11 years; 25.8%; 40.8%, respectively) with dual antiplatelet therapy (DAPT), 870 (75 ± 10 years; 37.1%; 39.8%, respectively) with direct oral anticoagulant (DOAC) alone, 433 (72 ± 12 years; 34.2%; 41.4%, respectively) with warfarin alone, 143 (76 ± 8 years; 16.8%; 42.7%, respectively) with DOAC plus antiplatelet agents (AP), and 119 (73 ± 12 years; 18.5%; 47.5%, respectively) with warfarin plus AP. During follow-up (median, 1.98 years), 93 patients experienced major bleeding, and 55 developed ICH. Compared with the SAPT group (37 events, 0.63%/year), the DOAC (18 events, 1.12%/year; adjusted hazard ratio (aHR) = 1.94, 95% confidence interval (CI) = 1.09-3.46), warfarin (16 events, 2.02%/year; 3.44, 1.90-6.23), and DOAC plus AP groups (six events, 2.24%/year; 3.07, 1.28-7.35) exhibited significantly higher risks of major bleeding after multivariable adjustment. DAPT (aHR 2.47, 95% CI = 1.11-5.48), warfarin (5.38, 2.65-10.92), and DOAC plus AP (3.86, 1.30-11.47) had significantly higher risks of ICH than SAPT. The DAPT (2.28, 95% CI = 1.65-3.14), DOAC plus AP (1.96, 1.08-3.56), and warfarin plus AP (2.83, 1.62-4.92) groups showed significantly higher risks of ischemic events than the SAPT group. CONCLUSION:Oral anticoagulant alone and DOAC with antiplatelet therapy were associated with higher risks of major bleeding events than SAPT in long-term follow-up for patients with stroke and cardiovascular disease.

Asymptomatic carotid or intracranial arterial stenosis, silent brain infarction, cerebral white matter lesions, and cerebral microbleeds are well-established predictors of stroke. When these findings are detected through brain screening programs ("brain dock"), aggressive management of vascular risk factors is warranted. In cases of severe carotid stenosis, revascularization procedures such as carotid endarterectomy or carotid artery stenting may be considered. In East Asia, including Japan, genetic predisposition appears to play a significant role. The moyamoya disease-related RNF213 p.R4810K variant has been linked to intracranial arterial stenosis, and NOTCH3 variants are associated with an increased burden of white matter disease. Closer integration of screening programs and routine clinical care is expected to further enhance the value of brain dock.

A 66-year-old man with a history of left parietal lobe hemorrhage presented with impaired consciousness, right-ward conjugate eye deviation, and trembling movements of right fingers. While initial motor signs resolved with antiseizure medication, impaired consciousness persisted and was subsequently accompanied by colonic dilatation and mucous diarrhea for several days. Five days after the first episode resolved, a second similar episode occurred. During the second episode, scalp electroencephalogram showed an evolving seizure pattern, and I-N-isopropyl-iodoamphetamine single photon emission computed tomography revealed hyperperfusion in the left parietal, insular, and temporal cortices. While ictal colonic dilatation has been reported, mucous diarrhea as a seizure symptom is unprecedented. The reproducibility of abdominal signs suggests mucous diarrhea and colonic dilatation as ictal symptoms of post-stroke epilepsy.

Background: Diabetes mellitus induces a prothrombotic state through mechanisms including platelet activation, leading to reduced responsiveness to antithrombotic therapy. However, the clinical consequences of diabetes, glycemic control, and diabetic nephropathy on the risk of ischemic and bleeding events under antithrombotic therapy have not been fully investigated. Methods: This was a prospective, multicenter observational study, enrolling patients receiving oral antiplatelets or anticoagulants. Baseline brain MRI was performed to assess small vessel disease (SVD): white matter hyperintensity, cerebral microbleed, lacune, enlarged perivascular space, with central reading. The SVD burden was defined as SVD score >2 (range, 0–4). Cox regression models were used to evaluate the associations of diabetes, hemoglobin A1c (HbA1c) categories (<6, 6–7, ≥7 %), and diabetes with macroalbuminuria (≥300 mg/gCr) with the risks of ischemic events, ischemic stroke, major bleeding, intracranial hemorrhage, and mortality. The covariate included conventional vascular risk factors and the SVD burden. Results: Of the analyzed 5,249 patients (median age 73 [IQR 66–79] years), diabetes was present in 1,460 (28%), and the median HbA1c level was 5.9 (IQR 5.6–6.4) %. The SVD burden was observed in 1,400 (27%). During a median of 2 (IQR1.8–2.0) years, 278 ischemic events, 197 ischemic strokes, 93 major bleedings, 55 intracranial hemorrhages, and 217 deaths were observed. Diabetes was associated with an increased risk of ischemic events and ischemic stroke (adjusted hazard ratio [aHR]: 1.62, 95%CI: 1.25–2.1; aHR: 1.41 [1.03–1.94], respectively). A higher HbA1c level (≥7.0%) was also associated with an increased risk of ischemic events and ischemic stroke (aHR: 1.76 [1.24–2.5]; aHR: 1.55, [1.02–2.38], respectively). Diabetes and HbA1c categories were not associated with major bleeding, intracranial hemorrhage, or mortality. Macroalbuminuria was observed in 230 of 3,114 (7.4%). Patients with diabetes and macroalbuminuria had an increased risk of major bleeding (aHR: 2.67 [1.11–6.34]), compared to those without diabetes and macroalbuminuria. Conclusions: Diabetes and poor glycemic control remain independent risk factors for ischemic events in patients with antithrombotic therapy. In addition, diabetes with macroalbuminuria was associated with a significantly higher risk of major bleeding, highlighting implications for clinical decision making in long-term antithrombotic therapy.

Abstract Background and aims Asians have a higher incidence of intracerebral hemorrhage than non-Asians. We aimed to evaluate whether early versus late initiation of direct oral anticoagulation (DOAC) after acute ischemic stroke (AIS) yields different safety and efficacy outcomes in Asian versus non-Asian patients. Methods We analyzed ELAN trial data from 2,013 AIS patients with atrial fibrillation (AF) randomized to early (≤48 hours for minor/moderate stroke; 6–7 days for major stroke) or late DOAC initiation. Patients were categorized as Asian or non-Asian by region. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage (SICH), or vascular death at 30 days. Results Among 1,975 patients with complete data, 245 were Asian and 1,730 non-Asian. Asian patients had more severe strokes and worse functional outcomes. The primary outcome occurred in 6.5% of Asian patients (4.8% early vs 8.3% late) and 3.1% of non-Asian patients (2.7% vs 3.6%) (P < 0.01). Higher rates of recurrent ischemic stroke (4.1% [2.4% vs 5.8%] vs. 1.7% [1.3% vs 2.1%], P = 0.02) and systemic embolism (2.0% [0.8% vs 3.3%] vs 0.5% [0.4% vs 0.6%], P = 0.02) accounted for this difference. No significant group differences were found in major extracranial bleeding, SICH, or vascular death. No significant interaction between region and treatment allocation. Conclusions Although Asian patients had worse baseline profiles and outcomes, treatment effects did not differ by region. These findings support the generalizability of early DOAC initiation in Asian AIS patients without requiring region-specific timing modifications. Conflict of interest Takeshi Yoshimoto: nothing to disclosure.

Background and Purpose We aimed to evaluate whether early versus late initiation of direct oral anticoagulant (DOAC) after acute ischemic stroke (AIS) yields different safety and efficacy outcomes in Asian versus non-Asian patients. Methods We analyzed Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN (ELAN) trial data from 2,013 AIS patients with atrial fibrillation (AF) randomized to early (≤48 hours for minor/moderate stroke, 6–7 days for major stroke) or late DOAC initiation (3–4 days for minor ischemic stroke, 6–7 days for moderate ischemic stroke, 12–14 days for major ischemic stroke). Patients were categorized by region as Asian (Japan and India) or non-Asian. The primary outcome was a composite of major extracranial bleeding, symptomatic intracranial hemorrhage (SICH), recurrent ischemic stroke, systemic embolism (SE), or vascular death at 30 days (trial registration: ClinicalTrials.gov number, NCT03148457). Results Among 1,975 patients, 245 were Asian (192 from Japan and 53 from India) and 1,730 were non-Asian. The primary outcome occurred in 6.5% of Asian patients (4.8% early vs. 8.3% late) and 3.1% of non-Asian patients (2.7% vs. 3.6%) (P<0.01). Higher rates of recurrent ischemic stroke (4.1% [2.4% vs. 5.8%] vs. 1.7% [1.3% vs. 2.1%], P=0.02) and SE (2.0% [0.8% vs. 3.3%] vs. 0.5% [0.4% vs. 0.6%], P=0.02) accounted for this difference. No significant differences were observed in major extracranial bleeding, SICH, recurrent ischemic stroke, SE, or vascular death. No significant interaction was observed between region and treatment allocation. Conclusions Although Asian patients had worse baseline profiles and outcomes, treatment effects did not differ by region, supporting the generalizability of early DOAC initiation in Asian AIS patients without region-specific timing modifications.

INTRODUCTION:To investigate the association of intracranial atherosclerotic disease (ICAD), alone and comorbid with cerebral small vessel disease (SVD), with ischemic or hemorrhagic events in patients receiving antithrombotic therapy. PATIENTS AND METHODS:In this prospective, multicenter, observational study, baseline brain MRI was performed to assess SVD (white matter hyperintensities, cerebral microbleeds, lacunes, enlarged perivascular spaces [PVS]), nonlacunar infarcts, and ICAD. SVD burden was defined as SVD score > 2. ICAD was classified as normal-to-mild, moderate, and severe stenosis-to-occlusion. The outcomes were any ischemic event, ischemic stroke, major bleeding, intracranial hemorrhage, and all-cause mortality. We assessed associations of ICAD with outcomes via Cox regression and mediation analyses, adjusting for SVD burden. RESULTS:Among 5250 patients (mean age: 71 ± 11 years, 33% women), 3947 (75%) received antiplatelets and 1304 (25%) anticoagulants at baseline. ICAD was normal-to-mild in 3781 (72%), moderate in 571 (11%), and severe-to-occluded in 894 (17%). SVD burden was observed in 1400 (27%). ICAD was associated with a higher frequency of non-lacunar infarcts and a lower frequency of PVS. There was no graded association between ICAD severity and SVD burden. During a median follow-up of 2 years, 278 ischemic events, 197 ischemic strokes, 97 major bleedings, 55 intracranial hemorrhages, and 217 deaths occurred. Severe-to-occluded ICAD independently increased the risk of any ischemic event (adjusted hazard ratio: 1.39 [1.03-1.86]) and mortality (2.01 [1.48-2.74]); coexisting SVD burden further increased the risk of all outcomes. ICAD directly affected ischemic events, while mortality was mainly driven by its additive interaction with SVD. CONCLUSIONS:ICAD increases the risk of any ischemic events and, with comorbid SVD, contributes to hemorrhagic events and excess mortality.

Abstract Background and aims Nonvalvular atrial fibrillation (NVAF) and Atherosclerotic cardiovascular disease (ASCVD) often coexist, yet whether clinical outcomes differ by sex in this population remains unclear. We evaluated sex differences in a post hoc analysis of ATIS-NVAF (Optimal Antithrombotic Therapy in Ischemic Stroke patients with Nonvalvular Atrial Fibrillation and atherothrombosis), a randomized trial of patients with recent ischemic stroke or transient ischemic attack (TIA), NVAF, and concomitant ASCVD. Methods We compared baseline characteristics and clinical outcomes by sex in a post hoc analysis of ATIS-NVAF. The primary outcome was the composite of cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, urgent revascularization for ischemia, or major bleeding within 2 years. Secondary outcomes were ischemic cardiovascular events; safety outcomes were major and clinically relevant non-major bleeding. We constructed a logistic regression model to estimate adjusted odds ratios (aORs) for women versus men. Results Of 222 patients, most were men (74.8%). Women were significantly older than men (median age, 79 [IQR 73.3–84] vs. 77 [71–81]; P=0.01). Regarding atherosclerotic disease, carotid artery stenosis was significantly less common in women (5/56 (8.9%) vs. 43/166 (25.9%); P=0.008), whereas intracranial artery stenosis was more frequent (24/56 (42.9%) vs. 47/166 (28.3%); P=0.04). The primary outcome was not significantly different between women and men (16.1% vs. 21.1%; aOR, 0.42; 95% CI, 0.16–1.10). There were no statistically significant differences in secondary outcomes or in safety outcomes. Conclusions There were no significant sex differences in the 2-year composite of cardiovascular and bleeding events. Conflict of interest Dr Uchida reports lecture fees from Daiichi Sankyo, Johnson & Johnson, Kaneka, Medtronic, Stryker, and Tokai Medical Products outside the submitted work. Dr. Yoshimura reports grants from Medico’s Hirata, Medtronic, and Terumo and lecture fees from Medtronic, Kaneka, Stryker, Daiichi Sankyo, Bristol-Meyers Squibb, and Johnson & Johnson outside the submitted work. Dr Koga reports lecture fees from Bayer Yakuhin, Boehringer Ingelheim, and Daiichi Sankyo and research funding from Boehringer Ingelheim and Daiichi Sankyo outside the submitted work. Dr Ihara reports lecturer fees from Daiichi Sankyo and Eisai and grant support from Panasonic, GE Precision Healthcare LLC, Bristol-Myers Squibb, and Shimadzu Corporation. Dr Yoshimoto reports personal fees from Eli Lilly, Daiichi Sankyo, Medico’s Hirata, Nippon Boehringer Ingelheim, Stryker, Takeda Pharmaceutical, and Tonbridge Medical. Dr Hirano reports lecture fees from Daiichi Sankyo and honoraria from Bayer Yakuhin outside the submitted work. Dr Toyoda reports personal fees from Janssen Pharmaceuticals, Otsuka Pharmaceutical, and SoftBank group outside the submitted work. Dr Sakai reports personal fees from Asahi Intecc, Kaneka, Medtronic, Stryker, and Terumo outside the submitted work. Dr Yamagami reported grants from Bristol Myers Squibb during the conduct of the study; lecture fees from Abbott Medical Japan, Boston Scientific Japan, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Otsuka Pharmaceutical, and Stryker outside the submitted work. No other disclosures were reported. Funding: Bristol Myers Squibb

Abstract Background and aims In patients with embolic stroke of undetermined source (ESUS), identification of atrial fibrillation (AF) is essential for secondary prevention. Although implantable loop recorders (ILRs) improve AF detection, real-world data regarding subsequent treatment decisions and stroke recurrence remain limited. Methods We retrospectively analyzed patients diagnosed with ESUS who underwent ILR implantation at a single comprehensive stroke center between 2016 and 2024 and were followed for at least 1 year. We evaluated AF detection rate and time to detection, antithrombotic therapy at implantation, treatment modifications after AF detection, and characteristics of recurrent ischemic stroke during follow-up Results A total of 190 patients were included (median age 72 years; 36.8% female). AF was detected in 59 patients (31.1%), with a median time to detection of 104 days. At the time of ILR implantation, 144 patients (76.8%) were receiving antiplatelet therapy and 41 (21.4%) anticoagulation. After AF detection, anticoagulation was initiated in all patients (direct oral anticoagulants in 98.3%), and catheter ablation was performed in 8 patients (13.6%). During follow-up, 13 patients (6.8%) experienced recurrent ischemic stroke (median NIHSS score at recurrence, 4); AF had not been detected in 11 of these cases. 2 patients without AF presented with large vessel occlusion. Anticoagulation, mainly warfarin, was newly initiated in 6 patients at recurrence. Conclusions ILR-guided monitoring contributed to AF identification and therapeutic decision-making in patients with ESUS. However, recurrent stroke often occurred in the absence of detected AF, highlighting the need for continuous etiological reassessment beyond AF surveillance alone. Conflict of interest Takafusa Ando: nothing to disclose. Naruhiko Kamogawa: nothing to disclose. Junpei Koge: nothing to disclose. Masayuki Shiozawa: nothing to disclose. Sohei Yoshimura: nothing to disclose. Eriko Yamaguchi: nothing to disclose. Masafumi Ihara: nothing to disclose. Kazunori Toyoda reports honoraria from Janssen Pharmaceuticals and Daiichi Sankyo. Masatoshi Koga reports honoraria from Daiichi Sankyo and research funding from Boston Scientific and Daiichi Sankyo.

Importance Tenecteplase has advantages over standard-dose alteplase for acute ischemic stroke. A low-dose alteplase regimen (0.6 mg/kg) remains the standard in Japan and is commonly used in several Asian countries. Objective To determine whether standard-dose tenecteplase at 0.25 mg/kg achieves a higher rate of recanalization on the initial angiogram than low-dose alteplase at 0.6 mg/kg in patients scheduled for mechanical thrombectomy. It is inevitable to generate evidence required to support potential regulatory approval of tenecteplase in Japan. Design, Setting, and Participants This investigator-initiated, multicenter, randomized, controlled, open-label, superiority trial was conducted from August 19, 2022, through March 13, 2025, with 3-month follow-up and was the first ever to compare tenecteplase (0.25 mg/kg) with alteplase (0.6 mg/kg) for acute ischemic stroke. Participants included patients with large-vessel-occlusion stroke eligible for intravenous thrombolysis within 4.5 hours of symptom onset followed by mechanical thrombectomy. A total of 221 patients were randomized and 218 who received trial drugs were included in the full analysis set (107 tenecteplase; 111 alteplase). These data were analyzed from July 2025 to December 2025. Interventions Patients were randomly assigned in a 1:1 ratio to receive either intravenous tenecteplase or alteplase. Main outcomes and measures The primary outcome was substantial reperfusion (modified Treatment in Cerebral Ischemia grade 2b to 3 or no retrievable thrombus) on the initial angiogram. Secondary outcomes included the 90-day modified Rankin Scale. Safety outcomes were symptomatic intracranial hemorrhage within 24 to 36 hours and mortality at 90 days. Results A total of 218 patients (mean [SD] age, 77.1 [12.0] years; 92 female and 126 male) who received trial drugs were included in the full analysis set (107 tenecteplase; 111 alteplase). Substantial reperfusion occurred in 10.3% of the standard-dose tenecteplase group vs 3.6% of the low-dose alteplase group (absolute difference, 6.5 percentage points; 90% CI, 0.89-12.1), meeting the prespecified success criterion. The estimated common odds ratio for a shift toward better 90-day functional outcome with tenecteplase was 1.47 (95% CI, 0.92-2.35). Rates of symptomatic intracranial hemorrhage (2.8% vs 1.8%) and mortality (6.5% vs 9.9%) were similar between tenecteplase and alteplase groups. Conclusions and relevance In this study, standard-dose tenecteplase (0.25 mg/kg) prior to thrombectomy resulted in a higher rate of early substantial reperfusion compared with low-dose alteplase (0.6 mg/kg), with comparable functional and safety outcomes. Standard-dose tenecteplase is a promising thrombolytic option in regions where low-dose alteplase is currently the standard of care. Trial Registration Japan Registry of Clinical Trials Identifier: 051210055

BACKGROUND AND OBJECTIVES:Stroke is one of the most common causes of adult-onset epilepsy. We aimed to develop a model to predict poststroke epilepsy (PSE) after a first-ever ischemic stroke, incorporating neuroimaging features of incident stroke. METHODS:We analyzed clinical and neuroimaging features of patients with first-ever acute ischemic stroke consecutively admitted to Massachusetts General Hospital, United States. We performed competing risk regression with all-cause mortality as a competing event and derived the final multivariable model using backward stepwise elimination by the Akaike Information Criterion. We externally validated the model in 3 international cohorts in Hong Kong (Queen Mary Hospital [HK-QMH], Ruttonjee Hospital [HK-RH]) and Japan (National Cerebral and Cardiovascular Center) by discrimination and calibration and compared its performance with the SeLECT and SeLECT2.0 scores. RESULTS:We included a final derivative cohort of 1,436 patients with a mean age of 67.4 years and a slight male predominance (54.7%), along with a total of 2,534 patients in the validation cohorts. PSE, defined as the occurrence or recurrence of unprovoked seizure >7 days after stroke, occurred in 5.5% of the overall study population. Six variables (infarct size [Is], cortical involvement [C], hemorrhagic transformation [H], early seizures [E], MCA involvement [Mi], and age younger than 65 [A]) were independent predictors included in the final model and formed the IsCHEMiA score. Model discrimination was consistent across all cohorts, with c-statistics of 0.870 (United States), 0.852 (HK-QMH), 0.857 (HK-RH), and 0.826 (Japan). The model was well calibrated at 1 and 3 years after stroke in the overall validation cohort. The IsCHEMiA score improved the prediction of PSE compared with SeLECT in all cohorts and the overall study population (c-statistic 0.848 vs 0.782, z = 5.170, p < 0.0001). For example, an IsCHEMiA score of 3 predicts a low risk of PSE at 1 year (2%) and 5 years (6%) while an IsCHEMiA score ≥8 predicts a high risk at 1 year (67%) and 5 years (78%). DISCUSSION:The IsCHEMiA score is an improved and readily applicable predictive model developed and validated using international stroke cohorts in the modern era of reperfusion therapies. It serves as a foundation for personalized management and may guide future clinical trials on antiepileptogenic therapies in acute ischemic stroke.

Background: The ATIS-NVAF trial evaluated antithrombotic strategies in patients with nonvalvular atrial fibrillation (NVAF) and atherosclerotic cardiovascular disease (ASCVD) with prior ischemic stroke or transient ischemic attack (TIA). Whether adding an antiplatelet agent to oral anticoagulation (OAC) yields net clinical benefit may differ by atrial fibrillation (AF) type. Methods: In the ATIS-NVAF trial, patients with NVAF, ASCVD and prior stroke/TIA were randomized to either OAC monotherapy or OAC plus single antiplatelet therapy. The primary outcome was the 2-year composite of ischemic cardiovascular events and major bleeding. Secondary outcomes included individual ischemic events; safety outcomes included major and clinically relevant nonmajor (CRNM) bleeding. This prespecified subanalysis compared outcomes between OAC monotherapy and combination therapy, stratified by AF type (paroxysmal [PAF] vs persistent [PeAF]). Cumulative incidence rate was estimated by Kaplan–Meier method. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with Firth’s penalized. A treatment-by-AF-type interaction term was tested. Results: The PAF subgroup included 163 patients, and the PeAF subgroup included 152 patients. In the PAF subgroup, the 2-year cumulative incidence of the primary outcome was 16.3% with combination therapy and 14.3% in the OAC monotherapy (HR [combination vs monotherapy] 1.19, 95%CI 0.55-2.64, P=0.65). The incidence of major/CRNM bleeding was higher with combination therapy in PAF (20.9% vs 9.1%, HR 2.53, 95% CI 1.12-6.33, p=0.02). In the PeAF subgroup, neither the primary outcome (15.1% vs 20.3% with monotherapy; HR, 0.76; 95% CI, 0.35–1.61; p=0.48) nor bleeding differed between treatment groups. Ischemic event rates were similar between regimens regardless of AF type. No significant treatment by AF type interaction was detected. Conclusions: In patients with NVAF, ASCVD and prior ischemic stroke/TIA, adding an antiplatelet agent to OAC increased bleeding in PAF without reducing ischemic events and no advantage of combination therapy was observed in PeAF. OAC monotherapy may therefore be the safer option for patients with PAF in the absence of a clear ischemic benefit.

BACKGROUND:Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. AIMS AND METHODS:In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. RESULTS:We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. CONCLUSION:The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities.Data Access Statement:no original data are presented in this document.

Background: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors and has been available in Japan since May 2022. Data on the efficacy and safety of andexanet alfa in patients with intracerebral hemorrhage (ICH) taking factor Xa inhibitors (FXaI) is limited, especially regarding the association with time metrics. Objective: To evaluate the efficacy of Andexanet alfa in ICH patients taking FXaI. Methods: Patients taking FXaI within 24 hours of the ICH onset were included from our single-center prospective registry. We compared consecutive patients treated with andexanet alfa from May 2022 to March 2025 with a consecutive historical cohort managed without andexanet alfa from January 2019 to May 2022. Patients who were directly transferred to the operating room from the emergency department for emergent hematoma removal or ventriculostomy were excluded. We calculated hematoma volume on baseline and 24-hour non-contrast CT and evaluated hematoma expansion, defined as a 33% or 6.0mL or more increase from baseline. Functional outcome was assessed at 90 days, and the favorable outcome was defined as mRS score of 0-3 or the same as before onset. We collected data on time metrics and examined the association between the hematoma expansion or the favorable outcome and the onset-to-door (OTD) time. Results: A total of 72 patients (median age, 80 years; female, 27; median NIHSS score, 14) were included. Andexanet alfa was administered in 40 (56%) patients with the median door-to-needle time of 52 minutes. The median OTD time was shorter in the andexanet alfa group (112 vs 301 minutes, p=0.04)(Table). The initial hematoma volume does not differ between the two groups (11 vs 19 mL), but the hematoma expansion was significantly less observed in the andexanet alfa group adjusted by age and NIHSS score (28% vs 75%, adjusted odds ratio 0.12; 95%CI 0.04 – 0.37). This association tended to be consistent regardless of OTD time but was more pronounced in the patients with a shorter OTD time (Figure). The rate of favorable outcome was numerically higher in the andexanet alfa group but did not differ significantly between the two groups (53% vs 38%, adjusted odds ratio 2.45; 95%CI 0.89-6.72). Conclusions: Early administration of andexanet alfa inhibits hematoma expansion and might contribute to improved functional outcome in intracerebral hemorrhage patients associated with factor Xa inhibitors.

Background: The optimal antithrombotic strategy after ischemic stroke or TIA in patients with nonvalvular atrial fibrillation (NVAF) and atherosclerotic cardiovascular disease (ASCVD) remains uncertain. We tested whether baseline systolic blood pressure (SBP) modifies the net clinical effect of intensified therapy. Methods: The ATIS–NVAF trial randomized patients with ischemic stroke/TIA, NVAF, and ASCVD to oral anticoagulant (OAC) monotherapy or OAC plus single antiplatelet therapy. In this subanalysis of participants with baseline SBP data, patients were stratified by SBP <130 (low SBP) vs ≥130 mmHg (high SBP). The primary endpoint was a composite of ischemic events (stroke, myocardial infarction, systemic embolism, or cardiovascular death) and major bleeding. Secondary endpoints included all–cause mortality, any ischemic events, and recurrent ischemic stroke. Safety endpoints included major bleeding and major or clinically relevant non-major (CRNM) bleeding. Cox models estimated adjusted hazard ratios (HRs) within strata and tested treatment–by–SBP interaction. Results: Of the 314 patients (median age: 78 years; 225 men), 116 were in the low SBP stratum and 198 were in the high SBP stratum. The adjusted HRs of the combination therapy compared to the monotherapy for the incidence of primary outcome were 0.34 (95 % confidence interval [CI]: 0.12–0.96) for the low SBP stratum and 1.70 (95 % CI: 0.82–3.55) for the high SBP stratum (interaction p = 0.018). As for secondary endpoints, any ischemic events (interaction p = 0.065) and recurrent ischemic stroke (interaction p = 0.073) favored combination therapy in the low–SBP stratum. No significant interaction was observed for major bleeding (interaction p = 0.120); however, in the high–SBP stratum, combination therapy increased major/CRNM bleeding (HR 2.91, 95% CI 1.15–7.33). Kaplan–Meier curves mirrored these findings. Conclusions: Baseline SBP appears to modify the benefit–risk profile of combination antithrombotic therapy in post–stroke/TIA patients with NVAF and ASCVD. In those with SBP <130 mmHg, combination therapy reduced ischemic events without excess major bleeding, supporting SBP-guided individualization of antithrombotic therapy.

Purpose of reviewThis review highlights three of the most promising mouse models of vascular cognitive impairment and dementia (VCID) that recapitulate chronic cerebral hypoperfusion. It also discusses therapeutic candidates evaluated using these models.Recent findingsThe three mouse models of chronic cerebral hypoperfusion induced by carotid artery manipulations are bilateral common carotid artery stenosis (BCAS), asymmetric common carotid artery surgery (ACAS), and gradual common carotid artery stenosis (GCAS). Altogether, these models reproduce white matter lesions and executive dysfunction. Notably, ACAS and GCAS exhibit gradual cerebral blood flow (CBF) reduction and motor impairments, addressing key limitations of BCAS, which induces abrupt CBF decrease and no motor deficits. Furthermore, ACAS uniquely demonstrates subcortical small infarcts, a hallmark feature of clinical VCID. These models have greatly contributed to elucidating VCID pathophysiology, including abnormal oligodendrocyte maturation, astrocytic dysfunction, and neuroinflammation. Several therapeutic strategies developed using these models - such as adrenomedullin and SIRT1 activator - are currently under investigation in clinical trials.SummaryThe three models are robust and complementary tools for exploring the VCID mechanisms. They have been instrumental in advancing our understanding of VCID pathogenesis and in facilitating the development of novel therapeutic approaches.

Background: The Thrombolysis in Cerebral Infarction scale is the most widely used scale to evaluate reperfusion after mechanical thrombectomy (MT), defined according to the percentage of reperfusion in downstream arterial branches. A limitation of this volume-based score is that it does not account for the varying eloquences of different arterial territories. Understanding territorial reperfusion patterns may advance the knowledge of incomplete reperfusion and more granular outcome prediction after MT. We therefore aimed to classify the territorial reperfusion patterns of cortical branches of the middle cerebral artery (MCA) after MT and to evaluate their impact on clinical outcomes. Methods: This single-center observational study included patients who underwent MT for internal carotid artery (ICA) or MCA M1 occlusion between January 2014 and May 2025. Patients with concomitant anterior cerebral artery occlusion were excluded. Reperfusion status of the twelve MCA branches was evaluated on final angiography and subsequently subjected to latent class analysis (LCA) to identify distinct reperfusion patterns. The primary outcome was achievement of modified Rankin Scale 0–2 or returning to baseline at 90 days. Multivariable logistic regression was performed to compare outcomes across classes. Results: A total of 473 patients (median age 78 [IQR 70–85] years; 222 female [47%]) were analyzed. The LCA model identified five classes of reperfusion patterns (Figure 1); class 1: good reperfusion in all territory (n=326), class 2: poor reperfusion in the parietal and the occipital lobe (n=41), class 3: poor reperfusion in the frontal lobe (n=52), class 4: reperfusion limited to the temporal lobe (n=13), class 5: poor reperfusion in all territory (n=45). In multivariable analysis, the likelihood of achieving the primary outcome was significantly higher in class 1 (61.0%, adjusted odds ratio [aOR] 15.1, 95% confidence interval [CI] 5.9–46.4), class 2 (56.1%, aOR 9.9, 95% CI 3.2–35.5), class 3 (53.8%, aOR 9.9, 95% CI 3.3–33.9), but not in class 4 (30.8%, aOR 4.4 95% CI 0.8–22.0) compared with class 5 (14.6%) (Figure 2,3). Conclusion: LCA identified five territorial reperfusion patterns of MCA cortical branches after MT. These patterns may provide insights into the characterization of incomplete reperfusion, but further studies are needed for validation.