BackgroundRemote ischemic conditioning (RIC), a low-cost, non-invasive therapy involving brief cycles of limb ischemia and reperfusion, may be a neuroprotective adjuvant or alternative to reperfusion therapies in acute ischemic stroke (AIS) and may also have therapeutic effects in hemorrhagic stroke (HS). This systematic review and meta-analysis evaluated the efficacy of RIC in AIS and HS.MethodsThis review was conducted in accordance with PRISMA guidelines and was registered in PROSPERO (CRD42024549594). Literature searches were conducted on MEDLINE, Embase, and Web of Science from inception to December 9, 2025. Randomized controlled trials (RCTs) involving adults with AIS or HS were included in the study. We focused on functional outcomes; secondary measures included cerebral hemodynamics and neuroimaging. Outcomes were analyzed using the DerSimonian-Laird model, while study heterogeneity was evaluated using Cochran's Q.ResultsOverall, 35 studies (6,304 patients) were included. Functional outcomes were significantly better in AIS patients who received RIC versus those who did not, as indicated by lower modified Ranking Scale (mRS) scores (SMD=-0.18, 95%CI -0.35 to -0.01, n=11 studies) and higher odds for favourable (OR=1.28, 95%CI 1.05 to 1.57, n=17 studies) and excellent (OR=1.27, 95%CI 1.06 to 1.51, n=12 studies) outcomes; furthermore, post-treatment stroke severity (indicated by NIHSS scores) was also lower in AIS patients receiving RIC (SMD=-0.64, 95%CI -0.96 to -0.31, n=16 studies). MRS scores and outcomes were better when RIC was initiated beyond 24 hours, and the protocol involved bilateral application and/or use beyond seven days. Favourable mRS outcomes were only better in patients receiving RIC without reperfusion.ConclusionRIC appears to improve functional and neurological outcomes in AIS patients. However, the quality of evidence is limited by regional generalizability (i.e, most studies came from China), small sample sizes, and methodological heterogeneity. We encourage future trials to include patients presenting beyond 4.5 hours and to incorporate bilateral RIC application and to extend RIC use beyond seven days. We also encourage studies to focus on patients who are not eligible for reperfusion therapy.
BACKGROUND:Patients with acute ischemic stroke (AIS) and active cancer (AC) face high risks of recurrent stroke and death. Evidence guiding antithrombotic selection remains limited. AIMS:To investigate post-AIS prescribing patterns of antiplatelet versus anticoagulant therapy in AIS patients with AC and their associated clinical characteristics and outcomes. METHODS:We retrospectively analyzed 2003-2024 data from the Acute-Stroke-Registry-and-Analysis-of-Lausanne (ASTRAL). We included patients with AC discharged after index AIS on antiplatelet therapy (single or dual) or anticoagulation (±antiplatelet therapy). We excluded patients with no or inactive cancer, missing data on discharge antithrombotics, cancer diagnosed after hospitalization, and those who died or entered palliative care before treatment decisions. The primary outcome was a recurrent ischemic cerebrovascular event within 12 months. Secondary outcomes included 3-month ischemic cerebrovascular recurrence, modified Rankin Scale (mRS) shift and all-cause mortality. The safety outcome was symptomatic intracranial hemorrhage (ICH) at 3 and 12 months. We used multivariable regression models adjusted for prognostic variables. RESULTS:Among 8,035 patients with AIS, 313 had AC and met eligibility criteria. Median age was 73 years (IQR 63-79), and 111 (35%) were women. At discharge, 178 (57%) received antiplatelet therapy and 135 (43%) anticoagulation. Patients previously naïve to antithrombotic therapy (n=150) more often received antiplatelet therapy (68% vs 32%, p<0.001). At 12 months, ischemic cerebrovascular recurrence occurred in 28/160 (18%) patients in the antiplatelet group and 33/118 (28%) in the anticoagulation group (subdistribution hazard ratio [sHR] 0.59, 95%CI 0.33-1.04). At 3 months, the antiplatelet group had lower risks of ischemic cerebrovascular recurrence (sHR 0.45, 95%CI 0.25-0.82) and all-cause mortality (adjusted hazard ratio [aHR] 0.61, 95%CI 0.41-0.90). Mortality at 12 months (aHR 1.16, 95%CI 0.62-2.16) and mRS shift at 3 months (adjusted odds ratio [aOR] 0.79, 95%CI 0.49-1.26) and 12 months (aOR 0.81, 95%CI 0.48-1.37) were similar between groups. No ICHs were recorded. CONCLUSION:In a registry spanning two decades, most patients with AC were discharged on antiplatelet therapy after AIS. Antiplatelet and anticoagulant groups showed similar long-term risks of ischemic cerebrovascular recurrence. Antiplatelet therapy was associated with reduced medium-term ischemic cerebrovascular recurrences and mortality, although between-group clinical differences may have contributed to these findings.Data access statement:Anonymized data are available from the corresponding author upon reasonable request and subject to a signed data transfer and use agreement.
BACKGROUND:Conventional MRI markers of cerebral small vessel disease (CSVD) capture accumulated structural injury but may not fully reflect ongoing physiological dysfunction associated with cognitive impairment. AIMS:We investigated whether MRI-derived oxygen extraction fraction (OEF), a non-invasive marker of cerebral oxygen extraction, is associated with cognitive impairment in CSVD beyond conventional structural MRI burden. METHODS:In this hospital-based observational study, 448 adults with CSVD underwent 3T multiecho gradient-echo MRI for whole-brain OEF mapping using a quantitative susceptibility mapping/quantitative blood oxygen level-dependent framework. Participants were classified as having mild cognitive impairment (MCI) or no MCI by a blinded clinical consensus panel. Whole-brain voxelwise analyses compared OEF between groups and examined associations with the composite cognitive score, Fazekas score, and total CSVD score; post hoc ROI-based analyses examined associations with conventional CSVD burden markers and a composite cognitive score. In an exploratory longitudinal subset of 82 participants, we assessed whether baseline OEF or within-subject OEF change was associated with cognitive change. RESULTS:Participants with CSVD-MCI showed higher OEF in distributed cortical-subcortical regions than cognitively preserved participants after adjustment for demographic, vascular, and conventional CSVD burden variables. The largest cross-sectional cluster showed higher OEF in the CSVD-MCI group than in the CSVD-no-MCI group (0.342±0.045 vs. 0.294±0.027). Complementary whole-brain analyses and post hoc analyses of the largest group-difference cluster showed that higher OEF was associated with lower composite cognitive scores after covariate adjustment, whereas no associations with Fazekas score or total CSVD score were identified. In the longitudinal subset, baseline OEF was not associated with follow-up composite cognitive score or cognitive change, whereas greater within-subject OEF increase was associated with greater cognitive decline (standardised β=-0.229, p=0.030). CONCLUSIONS:MRI-derived OEF was associated with cognitive impairment in CSVD independently of conventional structural MRI burden. These findings suggest that OEF may provide complementary physiological information for characterising cognitive vulnerability in CSVD. Larger multicentre longitudinal studies incorporating quantitative perfusion imaging and validated amyloid and tau biomarkers are warranted.
RATIONALE:The 2017 Stroke Recovery and Rehabilitation Roundtable (SRRR) consensus statement on biomarkers identified genetic and blood biomarkers as a developmental priority for stroke recovery and rehabilitation. While progress has been made, this nascent field still lags behind other medical disciplines. Further development is critical because molecular biomarkers hold great promise to provide key insights into the neurobiological mechanisms of both spontaneous and treatment-induced stroke recovery. Such insights could lead to effective recovery biotherapeutics and help optimize the timing and delivery of therapies.MethodsA multidisciplinary taskforce of international experts with expertise in omics and stroke recovery identified and prioritized key focus areas. Consensus opinion was developed across 15 virtual meetings, 2 rounds of anonymous polling and a 2-day in-person meeting. Key recommendations were iteratively refined until full consensus was achieved by all taskforce members.ResultsOur main recommendation is that there is a critical need for large-scale, multi-center, discovery-based omics studies to identify molecular targets in stroke recovery. To help achieve this goal we suggest ways to harmonize future studies including timepoints for data collection, outcome measures, and biospecimen selection. In addition, we address the limitations of current candidate biomarkers, translational challenges, emerging technologies, biomarker response to interventions, multi-site collaboration, and ethical concerns.ConclusionsThere is a great need for collaborative efforts by the international neurorehabilitation community to collect and harmonize molecular biomarker data. The resulting discoveries will be foundational to precision neurorehabilitation and the development of recovery biotherapeutics to enhance recovery for stroke survivors.
BACKGROUND:Perivascular spaces (PVSs) are markers of cerebral small vessel disease (cSVD). While some vascular risk factors are known, broader determinants of regional PVS burden and progression remain unclear. AIM:This study aimed to identify exposome-wide determinants of cross-sectional regional PVS burden in the basal ganglia (BG) and centrum semiovale (CSO) and examine associations of identified exposures with PVS progression. METHODS:We analyzed 44,938 UK Biobank participants (4568 with repeat imaging after 2.6 ± 1.0 years). Of 3767 candidate exposures across eight domains, 1289 were retained after preprocessing. The cross-sectional Exposome-Wide Association Study (ExWAS) used negative binomial regression with false discovery rate (FDR) correction. Surviving exposures were further examined with weighted quantile sum (WQS) regression to assess relative importance, Conway-Maxwell-Poisson longitudinal models, and structural equation modeling (SEM) linking exposures to cognition via PVS. RESULTS:ExWAS identified 80 exposures for BG-PVS and 89 for CSO-PVS (PFDR-corrected < 0.01). Higher diastolic blood pressure (BG: incident rate ratio (IRR) = 1.04, 95% confidence interval (CI) = 1.03-1.05; CSO: IRR = 1.07, 1.05-1.08) and greater left ventricular (LV) myocardial mass (BG: IRR = 1.05, 1.04-1.07; CSO: IRR = 1.09, 1.06-1.11) were associated with greater burden. WQS weights were dominated by cardiovascular exposures in BG (54.5%) but were more broadly distributed in CSO, including cardiovascular (31.9%), sociodemographic (20.9%), and environmental (12.7%). Longitudinally, cardiovascular and adiposity exposures were nominally associated with faster BG-PVS progression, with stronger effects in females. SEM demonstrated cardiovascular exposures linked to cognition through BG-PVS, but not CSO-PVS. DISCUSSION:Determinants of PVS burden and progression showed regional heterogeneity: BG-PVS is more strongly associated with cardiovascular exposures and cognition, while CSO-PVS shows a broader, more heterogeneous pattern. These findings support the importance of regional PVS assessment and suggest cardiovascular risk management may be particularly relevant to BG-PVS-related cSVD.
BACKGROUND AND AIM:Individuals without stenotic large-artery atherosclerosis (LAA) are an important subgroup of the patients who suffer transient ischemic attack (TIA) or ischemic stroke (IS), and they are commonly treated with dual antiplatelet therapy (DAPT). Stenotic LAA is a marker of higher vascular risk, and current guideline-defining trials did not prospectively evaluate if negative LAA status modifies the effect of DAPT. Moreover, platelet activation may not contribute as much toward future stroke risk after excluding stenotic LAA, leaving uncertainty regarding the applicability of this treatment among populations without this marker. We aimed to evaluate the efficacy and safety of DAPT compared with monotherapy for patients who suffered a TIA or IS without stenosis of 50% or more on vessel imaging. METHODS:We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to November 2025 for publications in English. We included randomized controlled trials comparing short-term (up to 90 days) DAPT to single antiplatelet therapy after a TIA or IS with outcome data available for the groups without 50% or more stenosis on vessel imaging. Data were pooled using random-effects for non-rare outcomes and Bayesian models for rare outcomes. The primary outcome was a new ischemic or hemorrhagic stroke. We also analyzed ischemic and hemorrhagic stroke individually, moderate and severe bleeding, any bleeding, all-cause death, functionality and a composite vascular outcome. RESULTS:Eight publications met the eligibility criteria. DAPT was associated with a reduction in new stroke, with a relative risk of 0.80 (95% CI 0.65 to 0.98; p = 0.04, I² = 25.5%). Trial sequential analysis showed a substantial risk of type I error, and a sensitivity analysis restricted to studies that included only high-risk TIA or mild IS found no significant benefit. There was an increase in moderate and severe bleeding (odds ratio of 2.70, 95% Bayesian Credible Interval 1.28 to 4.85) and no differences in functionality and mortality. Heterogeneity in trial methodology and populations may limit interpretation of our findings, but sensitivity analyses evaluating the impacts of DAPT duration and region of trial conduction on new stroke did not show significant effects, although they are hindered by the small number of studies. CONCLUSION:In patients with TIA or IS with a negative assessment of stenotic atherosclerosis on any vessel imaging, the benefit of DAPT is unclear, particularly for individuals with high-risk TIA and mild IS, while there is an increased risk of bleeding. Further trials are required to clarify if DAPT is truly beneficial for these patients.
BACKGROUND:The glymphatic system is a brain-wide perivascular clearance pathway that facilitates cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange and the removal of metabolic waste from the brain parenchyma. Increasing evidence indicates that glymphatic transport is critically dependent on the integrity and function of cerebral small vessels, suggesting a close link with cerebral small vessel disease (cSVD). Structural and functional alterations of small vessels may disrupt glymphatic flow, while impaired glymphatic clearance may in turn exacerbate small vessel-related brain injury, indicating a bidirectional interaction between these two processes. METHODS:In this review, we synthesize current evidence on the relationship between cSVD and glymphatic dysfunction, integrating findings from experimental models and in vivo human studies. We discuss shared pathophysiological mechanisms linking small vessel pathology to impaired perivascular fluid transport, summarize associations between glymphatic dysfunction and established cSVD imaging markers, and evaluate emerging therapeutic strategies aimed at restoring or enhancing glymphatic function. We highlight areas of convergence and inconsistency in the existing literature and identify key knowledge gaps that warrant further investigation. We also review potential therapeutic approaches, both behavioral and pharmacological to improve glymphatic function. CONCLUSION:Current evidence supports a close but incompletely understood bidirectional relationship between cSVD and glymphatic dysfunction. Targeting glymphatic function may represent a possible therapeutic strategy for cSVD and vascular cognitive impairment.
BACKGROUND:CT angiography (CTA) is a key investigation in cerebrovascular disease. However, CTA is not always available and it also requires intravenous injection of iodinated contrast agents. It is increasingly possible to derive additional information from standard imaging sequences using artificial intelligence techniques. We investigated whether CTA maps could be derived from non-contrast CT (NCCT). METHODS:We conducted a retrospective, multicenter study across five Chinese hospitals, enrolling 3709 patients who underwent head NCCT paired with CTA. The dataset encompassed three cerebrovascular conditions: intracranial aneurysms (IA), intracranial atherosclerotic stenosis (IAS), and normal intracranial arteries. We developed the Cerebrovascular CTA Generative Artificial Intelligence Model (CTA-GAI) to synthesize CTA images directly from NCCT head scans. Synthetic outputs were evaluated against five typical models using quantitative metrics and visual assessment by clinicians. We also assessed the potential clinical utility of synthetic CTA for preliminary screening and triage by evaluating its ability to distinguish diseased from normal intracranial arteries and to classify common cerebrovascular subtypes. RESULTS:CTA-GAI demonstrated consistent and robust performance across both the validation and test sets. In internal validation, synthetic CTA images achieved a mean absolute error (MAE) of 0.0416, mean squared error (MSE) of 0.0178, peak signal-to-noise ratio (PSNR) of 25.59 dB, and structural similarity index measure (SSIM) of 85.41%. Clinicians assigned an average visual quality score of 4.45 out of 5. These metrics reflect close approximation to real CTA images. Performance remained consistent across four external validation sets. In a test set of 110 patients, clinicians achieved an overall accuracy, precision, sensitivity, specificity, and F1 score of 92.7%, 97.7%, 86.0%, 98.3%, and 91.5%, in distinguishing diseased intracranial arteries. Differentiation between IA and IAS within diseased arteries reached 90.7% accuracy. CONCLUSION:CTA-GAI can synthesize CTA-like images from NCCT that show promising utility for preliminary assessment in clinical practice. These results support its potential role as a rapid, low-cost, and non-invasive tool for large-scale screening or triage of cerebrovascular diseases.
BACKGROUND:To determine whether computed tomography (CT) thrombus characteristics modify the effect of intravenous (IV) thrombolysis type (tenecteplase vs alteplase) on outcomes. METHODS:This is a secondary analysis of the Alteplase compared to Tenecteplase (AcT) trial. Patients with visible intracranial occlusions on thin-slice baseline imaging were included. Key thrombus characteristics assessed by CT imaging were hyperdense artery sign, thrombus length, residual flow, clot burden score, and occlusion site. Multivariable analyses were performed to test for interactions between thrombolysis type and thrombus characteristics on clinical and angiographic outcomes. RESULTS:Of 1577 patients, 939 met inclusion criteria; 479 (51.0%) received tenecteplase and 460 (49.0%) alteplase. Among the 498 patients (53.0%) treated with endovascular thrombectomy (EVT), angiographic outcomes were comparable between treatment groups. A significant interaction was observed between thrombolysis type and thrombus length; longer thrombi were associated with reduced likelihood of modified Rankin Scale (mRS) 0-1 with alteplase (adjusted odds ratio (aOR) per 1 mm increase, 0.97 (95% confidence interval (CI): 0.95-1.00)), but not with tenecteplase (aOR: 1.00 (95% CI: 0.98-1.02); interaction p = 0.04). Similarly, the presence of residual flow within the thrombus was associated with higher odds of mRS 0-2 in the alteplase group (aOR: 2.00 (95% CI: 1.25-3.20)), but had no significant effect in the tenecteplase group (aOR: 0.93 (95% CI: 0.62-1.41); interaction p = 0.01). No other significant interactions between thrombus characteristics and thrombolysis type were identified. CONCLUSION:In the AcT trial, alteplase appeared less effective with longer thrombi and those lacking residual flow, whereas IV tenecteplase showed more consistent effectiveness across thrombus characteristics. These findings require confirmation in future prospective studies.
BACKGROUND:Venous thrombosis and venous thromboembolism (VTE) are important causes and complications of stroke. They may complicate acute stroke as deep venous thrombosis or pulmonary embolism (DVT/PE), contribute causally to ischemic stroke through paradoxical embolism from a patent foramen ovale (PFO), or present directly as cerebral venous thrombosis (CVT). Despite shared pathophysiological features and overlapping antithrombotic strategies, these conditions are typically considered separately, fragmenting evidence and limiting the exchange of concepts. PURPOSE:We therefore convened experts across both stroke neurology and thrombosis medicine fields to examine these conditions under a unifying venous theme and define priorities for future clinical trials. METHODS:Thirty-two stroke and thrombosis clinicians and researchers identified research priorities across three domains: prevention of VTE after stroke, secondary prevention after PFO-related stroke, and acute and long-term management of CVT. Structured discussions were guided by the PICO (Population, Intervention, Comparison, Outcome) framework, followed by a Delphi survey to establish consensus. Priority questions centered on the balance between thrombosis prevention and bleeding risk and the optimal timing, duration, and choice of DVT/PE prophylaxis after stroke; the optimal antithrombotic strategy for patients awaiting or forgoing PFO closure; and, for CVT, the role of endovascular therapy in severe disease and the optimal duration of secondary prevention (Graphical Abstract). Across domains, the group prioritized pragmatic and platform trial designs, integration with international registries to address the rarity of CVT, and patient-oriented outcomes that extend beyond functional recovery. CONCLUSIONS:By considering these venous conditions together and bridging stroke and thrombosis disciplines, this work defines priority questions to address persistent evidence gaps, harmonize practice, and improve patient-centered outcomes.
BACKGROUND:Evidence is lacking on whether support and education programs, facilitated by mobile technology, benefit people with stroke. AIMS:The primary aim was to determine the effectiveness of a co-designed, eHealth self-management intervention for reducing unplanned hospital presentations. METHODS:Prospective, multicenter randomized controlled trial with blinded outcome assessment and intention-to-treat analysis. Randomization (1:1, stratified by age and level of disability at baseline) within 2 weeks of hospital discharge. Participants aged ⩾18 years with modified Rankin Scale (mRS) score 0-4 were recruited from 11 Australian hospitals. To maintain blinding, all participants co-developed three to five self-management goals with a trained clinician-researcher, using a standardized approach. Following randomization, participants were allocated to receive personalized, goal-centered electronic messages (intervention) or administrative messages (active control) over 12 weeks via text or email. The groups were not informed about the number of messages they would receive and were unaware that only the intervention group had their messages tailored to their goals. The primary outcome was unplanned hospital presentations (emergency department/admission) within 90 days post-randomization. Secondary outcomes included goal attainment, self-efficacy, and various health outcomes. We used generalized mixed-effects regression model with a logistic link for categorical outcomes and Cohen's d (0.2 considered small effect, 0.5 moderate-1.0 large) to assess within-group change. RESULTS:The trial was impacted by COVID-19 and ceased with 556/890 planned participants; 465 were randomized (n = 234 control, n = 231 experimental), a median of 10 days post-discharge (median age 67.2 years, 67.1% male, median 3 goals/participant). Primary outcome assessments for 222 control and 218 experimental participants showed no between-group differences for unplanned hospital presentations (odds ratio (OR): 1.32; 95% confidence interval (CI): 0.52-3.34). Compared to controls at 90 days, a larger proportion of the experimental group had >3 unmet needs and slight to severe disability (both <8% difference). Both groups showed non-significant improvements in goal attainment at 90 days post-randomization; overall attainment was stronger among intervention participants (within-group change Cohen's d intervention 0.76 vs 0.61). CONCLUSION:We found no evidence that tailored, electronic messaging over 12 weeks, in addition to structured goal-setting reduced unplanned hospital presentations. Future research is needed to understand the role of disability and unmet needs, and factors that influence goal attainment. TRIAL REGISTRATION:ACTRN12618001468213, U1111-1206-7237.
BACKGROUND:Randomized trials have demonstrated substantial benefit of mechanical-thrombectomy (MT) in selected patients treated 6 to 24 hours after stroke onset. However, these trials relied on advanced imaging not typically available in resource-constrained settings. The RESILIENT-Extend trial aims to evaluate the efficacy and safety of MT in the 8-24-hour window using a pragmatic imaging selection based on non-contrast CT and CT angiography alone. METHODS:RESILIENT-Extend is a multicenter, randomized, controlled, open-label, blinded-endpoint phase III trial conducted in Brazil. Patients presenting with anterior circulation LVO within 8-24 hours from time last known well will be randomized 1:1 to receive either MT plus best medical management (BMM) or BMM alone. The trial uses a minimization algorithm to balance prognostic variables including age, NIHSS, ASPECTS, occlusion site, time window, and clinical site. The primary outcome is the distribution of 90-day modified Rankin Scale scores assessed by blinded central adjudication. DISCUSSION:RESILIENT-Extend is the first randomized trial to assess MT in the extended time window using only widely available imaging modalities. The results will inform the generalizability of MT to real-world practice in low- and middle-income countries and resource-constrained settings. CLINICALTRIALS:govNCT04256096.
BACKGROUND:There is a well-established association between atrial fibrillation (AF) and an increased risk of ischemic stroke; new evidence, however, suggests that atrial high-rate episodes (AHREs), a subset of atrial tachycardia (AT), may also contribute to this risk. Through cardiac remodeling pathways and physiological changes, a multi-faceted risk of stroke exists. Our review suggests there is an increased risk of ischemic stroke in the presence of AHREs and, additionally, a greater risk of developing overt AF after these events. There are, however, many inconsistencies within the studies including ambiguity surrounding AHRE definitions and control for anticoagulation and concurrent AF episodes that are not often reported. Further research is warranted to better define atrial high-rate episodes and to further characterize this relationship. While there is clinical direction for anticoagulation in patients with AF, there are no standardized indications for intermediate durations of AHREs and oral anticoagulation is largely determined on an individual basis. Given this gap within clinical practice, we performed a review of the literature to explore if a relationship between episodes of AHREs and ischemic stroke exists, excluding those with a history of prior AF. AIMS:To systematically review and meta-analyze the association between device-detected AT/AHREs and (1) risk of ischemic stroke and (2) progression to clinical AF, excluding patients with a prior history of AF. SUMMARY OF REVIEW:A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (PROSPERO CRD42022337209). MEDLINE, EMBASE, and Cochrane databases were searched up to 10 March 2025. Nine studies (n = 5099 patients) met inclusion criteria. Overall, 33.7% experienced at least one AHRE, and 2.5% developed a thromboembolic event during follow-up. A meta-analysis of six studies demonstrated a 2.6-fold increased risk of ischemic stroke in patients with AHREs (pooled hazard ratio (HR) = 2.59, 95% confidence interval (CI) = 1.54-3.64; I2 = 0%). A second meta-analysis demonstrated a 4.5-fold increased risk of progression to AF (pooled effect size = 4.51, 95% CI = 1.50-7.51; I2 = 73.1%). Among the reviewed studies, definitions of AHRE duration and rate varied substantially. CONCLUSIONS:Device-detected AHREs are associated with a significantly increased risk of ischemic stroke and progression to clinical AF in patients without prior AF. While the magnitude of stroke risk is lower than that reported for overt AF, AHREs represent a clinically meaningful risk marker. Standardized definitions and burden thresholds are required to guide anticoagulation strategies and optimize stroke prevention.
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:Rehabilitation has been identified by the World Stroke Organization (WSO) as a key priority to reduce the global burden of stroke. Global access to rehabilitation is inconsistent and is particularly limited in low-and-middle-income countries. Progress in rehabilitation has not been as well evidenced as progress in acute care. The WSO certification program, which commenced in 2021, focuses on acute interventions. A rehabilitation certification program, applicable in both inpatient and outpatient rehabilitation settings, has been developed to complement the acute certification program to address global implementation of evidence-based stroke care. AIM:To develop globally applicable, evidence-based, stroke rehabilitation recommendations and performance metrics for use in a stroke rehabilitation certification program. METHODS:Strong recommendations were extracted from high-quality stroke rehabilitation Clinical Practice Guidelines, systematic reviews and syntheses of clinical practice guidelines, and from the defining criteria of the International Stroke Recovery and Rehabilitation Alliance (ISRRA) Centers of Clinical Excellence. The WSO Rehabilitation Implementation Committee led the development of the recommendations and invited input from three international, multidisciplinary consultation groups. Group 1 compared strong recommendations from the Australia/New Zealand Living Guidelines with other international guidelines to identify consistent, high-quality recommendations. Group 2 mapped recommendations from global guideline syntheses against the Australia/New Zealand Living Guidelines. Group 3 reviewed and adapted the ISRRA Center of Clinical Excellence recommendations. Recommendations were consolidated through consensus meetings involving representatives from each workgroup, including people from high, upper-middle, and lower-middle-income countries. Strong recommendations that were consistent across teams, alongside additional recommendations based on certainty of evidence, anticipated risk versus benefit, and relevance across settings, were included as patient-level recommendations in the implementation certification program. Service-level recommendations were generated through consensus or derived from existing guidelines. An implementation manual, outlining "what," "who," and "how," as well as indicators to demonstrate performance of each recommendation, was developed to support clinical implementation and to facilitate assessment for certification. The criteria were piloted between November 2024 and September 2025 at 15 centers in six upper- and lower-middle-income countries (three continents) and subsequently refined. Expectations (mandatory or recommended) for each level of certification (Minimal, Essential and Advanced) were set post-pilot through rating strength of evidence, a series of group discussions and review of pilot data.ResultsFifty-five recommendations were included. Nine recommendations address service-level indicators, and 46 address patient-level indicators. Service-level indicators address defining features of rehabilitation services that are not apparent in individual patient medical record audits. Patient-level indicators address management of swallowing impairment, nutrition and hydration, information provision and goal setting, amount and timing of rehabilitation, exercise and motor rehabilitation, visual function, communication, mood and cognition, management of complications, and discharge planning and support. An implementation manual complements the recommendations to guide clinical care and consistent assessment.ConclusionsThe WSO rehabilitation recommendations and performance metrics incorporate the most current evidence and have been refined following pilot-testing. The recommendations are globally relevant and support both resource-limited and high-income settings in participating in the rehabilitation certification program to advance international stroke rehabilitation delivery.
RATIONALE:There is a growing recognition of the importance of engaging with people with lived experience (PWLE) to support research relevance and impact. However, there is little specific guidance for stroke recovery and rehabilitation researchers about how best to engage with PWLE of stroke in research, who face additional barriers to engaging due to common post-stroke sequelae including communication and cognitive difficulties, sensory and perceptual impairments, emotional wellbeing, and fatigue. The aim of this roundtable was to develop recommendations to support researchers to engage with PWLE of stroke in primary and secondary research conducted in laboratory, clinical, health system, or community settings. METHODS:We convened an interdisciplinary, international taskforce comprising researchers and lived experience experts (n = 16) to create recommendations to support researchers to engage with PWLE of stroke meaningfully and respectfully. Guided by priorities and key gaps identified by taskforce members, and underpinned by gray and published literature, we formed discrete workgroups to develop consensus-based recommendations and guidance documents addressing common barriers to engagement in stroke research. The recommendations and guides were reviewed, and consensus was reached during a 2-day hybrid in-person/online meeting of the taskforce. These were further refined through consultation with international experts in research engagement. RESULTS:We created the EMBED (Engaging Meaningfully to Build research with people with lived experience to drive improvements in stroke research) framework, consisting of five consensus recommendations: Select the engagement approach; Identify people to engage with; Embed accessible and inclusive ways of working; Support and strengthen accessibility and inclusivity; and Report accessibility and inclusivity. Ten guidance documents provide practical support to researchers to engage with PWLE of stroke in all research settings. CONCLUSIONS:The EMBED framework provides researchers with pragmatic and structured support to engage with PWLE in stroke research.
BACKGROUND:Atrial fibrillation and atrial flutter (AF/AFL) are major contributors to ischemic stroke, heart failure, disability, and mortality worldwide. OBJECTIVE:To provide a descriptive global analysis of AF/AFL burden using Global Burden of Disease (GBD) 2023 estimates, with emphasis on incidence, prevalence, deaths, disability-adjusted life years (DALYs), and their distribution by sex, age, and socio-demographic index (SDI). METHODS:We performed a descriptive epidemiological analysis using direct extractions from the Institute for Health Metrics and Evaluation Global Burden of Disease 2023 Results Tool for the cause category "atrial fibrillation and atrial flutter." We assessed incidence, prevalence, deaths, DALYs, and selected rates globally and according to sex, quinquennial age group, and SDI. Temporal trends were examined using available historical series, and the 2023 burden was summarized across major demographic and SDI strata. RESULTS:In 2023, AF/AFL accounted globally for 5,021,980 incident cases, 59,045,058 prevalent cases, 9,265,726 DALYs, and 377,258 deaths. Compared with 1990, the global burden increased substantially in absolute terms. It was substantially higher in older adults, with the highest observed counts of incident and prevalent cases in the 70- to 74-year age group, the highest DALY counts in the 80- to 84-year age group, and the highest death counts in the 85- to 89-year age group. Men accounted for more incident and prevalent cases in absolute terms, whereas women accounted for more deaths and DALYs; age-standardized rates indicated higher male incidence, prevalence, and DALYs, but essentially equivalent mortality between sexes. High-SDI settings carried the largest absolute burden and the highest rates across all major metrics. Overall, the findings indicate a marked expansion in the global AF/AFL burden, with important heterogeneity by age, sex, and socio-demographic development. CONCLUSION:AF/AFL remains a major and growing global public health challenge. The burden is increasingly concentrated in older populations, shows persistent sex differences, and remains greater in high-SDI settings. These findings reinforce the relevance of AF/AFL to stroke prevention, health-system planning, and long-term cardiovascular care worldwide.
South Asians comprise one-quarter of the world’s population, yet likely account for over 40% of global stroke deaths. They experience earlier stroke onset than whites, a 1.5-fold higher stroke mortality than Europeans, and a higher risk relative to other Asian populations. However, most studies aggregate South Asians with other Asian populations or compare native South Asians with other immigrant groups. This review synthesizes current evidence on the burden of stroke, epidemiology, risk factors, clinical presentation, subtypes, mechanisms, and treatment in South Asians, with an emphasis on disparities compared to other ethnic groups. We discuss risk factors including distinct cardiometabolic profiles, genetic polymorphisms that affect homocysteine levels and drug metabolism, dietary patterns, and lifestyle factors. We review stroke subtypes in South Asians and explore treatment and prevention strategies. Finally, we offer recommendations to target the multifactorial origins of elevated stroke burden in South Asians, including improvements in screening, pharmacogenomic testing, and thresholds for intracranial vessel imaging. To address this disparity and reduce the high burden of stroke in these communities, it is important to develop tailored management strategies, increase clinical trial representation, and establish South Asian stroke registries.
BACKGROUND AND AIMS:The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS:In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS:Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS:The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.
