BACKGROUND:Despite increasing incidence of stroke among younger adults, the associations of social determinants of health (SDOH) and stroke among younger adults are not well known. This study investigates the associations between SDOH from early adulthood and stroke in a prospective longitudinal cohort. METHODS:We studied participants enrolled in the CARDIA study (Coronary Artery Risk Development in Young Adults). Participants aged 18 to 30 years were enrolled in 1985 and followed through 2022. We investigated longitudinal, time-varying measures of SDOH classified into 5 distinct domains: economic (6 measures), education (1 measure), healthcare (4 measures), neighborhood (2 measures), and social/community (5 measures). The outcome was incident stroke or transient ischemic attack. We evaluated associations between individual SDOH and stroke using unadjusted Cox models. We then evaluated whether a greater cumulative number of adverse SDOH domains (each represented by 1 exposure selected by empirical techniques) was associated with stroke risk after adjustment for demographics. RESULTS:Among the 5114 participants (54.5% were female; baseline age, 25 years; and median follow-up, 37.9 years), 146 individuals experienced stroke or transient ischemic attack, all of which occurred <65 years. Household income (hazard ratio [HR], 1.24 per $10 000 lower [95% CI, 1.11-1.39]), education (HR, 0.93 per greater year [95% CI, 0.87-0.99]), neighborhood deprivation (HR, 1.21 [95% CI, 1.02-1.43]), and lacking health insurance (HR, 1.49 [95% CI, 1.05-2.11]) were associated with stroke risk. Those experiencing 2 adverse SDOH domains (HR, 1.65 [95% CI, 0.91-2.97]) or ≥3 adverse domains (HR, 2.00 [95% CI, 1.09-3.66]) had progressively higher stroke risk (Ptrend=0.005). In interaction analyses, the association between income and stroke appeared stronger in Black participants (Pinteraction=0.02) and women (Pinteraction=0.02). CONCLUSIONS:In this young cohort followed through midlife, SDOH spanning several domains were associated with stroke risk. We also observed a dose-dependent response with the number of adverse SDOH domains experienced. Our results suggest that SDOH experienced throughout adulthood are relevant to future stroke risk.
The utility-weighted approach to analyzing the modified Rankin Scale (mRS) is increasingly being utilized in acute stroke clinical trials. This analytic approach assigns a patient-centered utility weight—the desirability or value of a health state to patients—to each level of the mRS. The utility-weighted-mRS analysis converts the mRS from a scale reflecting only the rank order of functional outcome after stroke into one that quantifies the value of each poststroke mRS health state from patients’ perspectives. The ability of the utility-weighted-mRS analysis to capture the unequal difference in patient health-related quality of life between each level of the mRS makes it an appealing patient-centered end point for acute stroke clinical trials. However, several concerns have historically raised skepticism regarding its value as a trial end point. Unfamiliarity with how utility weights are derived and used poses challenges to its use for shared decision-making between patients and clinicians. There are valid concerns that social, geographic, and demographic factors that differ between countries influence the mRS utility weights, so that use of uniform weights across all settings mildly reduces the precision of utility quantification, particularly in multinational stroke clinical trials. This narrative review aims to provide the clinical and research stroke community with a practical overview of key methodology in the utility-weighted-mRS analysis to aid in its interpretation, considers the advantages and challenges of using the utility-weighted-mRS analysis, and suggests future areas of study.
BACKGROUND:The meningeal lymphatic system contributes to hematoma resolution and neurological recovery after intracerebral hemorrhage (ICH). We previously demonstrated that intraperitoneal cilostazol administration promotes dural lymphatic growth and enhances clearance of intracerebrally injected red blood cells; however, the antiplatelet effects of cilostazol raise safety concerns in ICH, potentially limiting clinical translation. Here, we evaluated whether oral cilostazol at clinical-equivalent doses in mice enhances dural lymphatic function and improves outcomes after ICH. METHODS:ICH was induced by collagenase injection to model microvascular rupture. Cilostazol was orally administered to ICH mice at clinically equivalent doses, given at different time points and for varying durations. Prolymphangiogenic effects of cilostazol were examined in healthy in vivo and ex vivo meninges. Flow cytometry and immunofluorescence were performed to assess lymphatic endothelial cell proliferation and dural lymphatic remodeling. Lymphatic function was evaluated by in vivo live imaging and histological analysis of fluorescent tracer drainage. Short- and long-term histopathologic and behavioral outcomes were also evaluated. RESULTS:Oral cilostazol treatment initiated either 3 hours or 3 days after ICH enhanced dural lymphatic coverage and function, accompanied by reduced hematoma volume, neuronal injury, synapse loss, and long-term neurological deficits. Cilostazol increased CD31+PDPN+ lymphatic endothelial cells in ex vivo meninges, induced dural lymphatic hyperplasia, and enhanced lymphatic drainage in healthy mice. Both pretreatment and delayed treatment of cilostazol did not increase hematoma volume but rather improved ICH outcomes. CONCLUSIONS:By promoting dural lymphatic remodeling and drainage, cilostazol facilitates hematoma resolution and neurological recovery after ICH. Cilostazol treatment does not exacerbate initial bleeding or provoke hematoma expansion in the experimental ICH. These findings support clinical translation and provide mechanistic and dosing rationale for an ongoing phase II randomized trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT06504576).
Implementation science plays a pivotal role in advancing organizational change within stroke healthcare settings by systematically evaluating and facilitating the adoption of evidence-based practices. This topical review examines the use of key trial designs relevant to implementation science research that aim to change organizational practice, highlighting their unique design features and methodological considerations. It also provides case studies of stroke research that have used each of the methods discussed demonstrating the practical applications in real-world environments. This overview aims to guide researchers and clinicians in selecting appropriate trial designs to optimize the translation of research into sustainable organizational systems and processes.
BACKGROUND:Whether diffusion‑weighted imaging infarction patterns influence the efficacy and safety of early oral ticagrelor‑aspirin with intravenous thrombolysis in moderate acute ischemic stroke is uncertain. We assessed treatment effects by infarction pattern in this thrombolysis setting. METHODS:This was a subgroup analysis of the TAPIS trial (Ticagrelor With Aspirin Dual Antiplatelet Therapy Combined With Intravenous Thrombolysis in Patients With Ischemic Stroke), a 60-center, randomized, double‑blind trial in China. Patients aged 18 to 80 years with noncardioembolic stroke (National Institutes of Health Stroke Scale score 4-10) who received intravenous thrombolysis within 4.5 hours of onset were randomized within 6 hours to ticagrelor‑aspirin or placebo. Diffusion‑weighted imaging patterns were centrally adjudicated as multiple acute infarcts (MAIs; ≥2 lesions) or non‑MAIs (single infarction or diffusion‑weighted imaging-negative). The primary efficacy outcome was modified Rankin Scale score of 0 to 1 at 90 days; safety outcome was symptomatic intracranial hemorrhage. Treatment‑by‑pattern interaction was assessed. RESULTS:Among 1307 patients (94.6% of full analysis set; median age, 65.5 years; 71.2% male; median National Institutes of Health Stroke Scale score, 6.0), 409 (31.3%) had MAIs and 898 (68.7%) non‑MAIs (20.8% diffusion‑weighted imaging-negative, 79.2% single infarction). MAIs were associated with poorer prognosis than non‑MAIs (excellent outcome: 58.9% versus 69.2%; adjusted risk ratio, 0.92 [95% CI, 0.84-1.00]). Ticagrelor‑aspirin was associated with a higher likelihood of excellent outcome versus placebo in MAIs (64.4% versus 53.4%; risk ratio, 1.21 [95% CI, 1.02-1.42]), whereas no significant benefit was observed in non‑MAIs (71.2% versus 67.1%; risk ratio, 1.06 [95% CI, 0.97-1.16]; Pinteraction=0.18). Early neurological improvement showed significant heterogeneity by infarction pattern (Pinteraction=0.02); the treatment‑by‑pattern interaction for the primary outcome was nominally significant after adjusting for rescue tirofiban use (P=0.04). Symptomatic intracranial hemorrhage occurred in MAIs: 1 of 205 (0.5%) versus 2 of 204 (1.0%); non‑MAIs: 1 of 448 (0.2%) versus 1 of 450 (0.2%). CONCLUSIONS:In thrombolyzed patients with moderate noncardioembolic stroke, MAIs were associated with poorer functional outcomes. Early ticagrelor‑aspirin showed directionally consistent benefits without excess bleeding in patients with MAIs, though the primary interaction was not significant. These hypothesis‑generating findings may inform future trials of diffusion‑weighted imaging infarction pattern as an imaging biomarker to guide antiplatelet therapy in early reperfusion. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06316570.
Stroke prevention requires that patients follow recommended health behaviors. However, few stroke behavioral interventions have been shown to produce clinically significant behavior change in clinical trials, likely thwarted in the design process by limited application of behavioral theoretical models and insight into mechanistic underpinnings during intervention testing. The National Institutes of Health Stage Model for Behavioral Intervention Development provides a systematic, nonlinear, iterative framework for advancing behavioral interventions from theory to practice. Here, we provide an overview of methods from behavioral medicine research that can be applied to improve the development of successful stroke preventive behavioral interventions. Behavioral change theories can provide a conceptual basis for theoretical frameworks for behavioral interventions as they identify individual-level influences on health behaviors using specified constructs tied to underlying psychosocial mechanisms. For example, interventions targeting self-efficacy behaviors for self-management after stroke may be guided by Social Cognitive Theory to deliver patient-centered care. Mixed methods that integrate qualitative and quantitative findings can be useful for identifying key patient barriers to target while designing behavioral interventions, and for evaluating intervention effects, including the extent to which they target putative behavioral mechanisms. Adaptive clinical trial methods such as SMART (Sequential Multiple Assignment Randomized Trials) for identifying optimal intervention sequences and JITAI (Just-in-Time Adaptive Interventions) that leverage real-time contextual data to tailor components can improve potency and personalization of theoretically supported behavioral interventions. Overall, in accordance with the National Institutes of Health Stage Model, successful behavioral trials to advance stroke prevention should be grounded in behavioral theory for intervention development, informed by design methods that enable assessment of behavioral mechanistic targets, and conducted with adaptive clinical trial methodologies to tailor interventions.
BACKGROUND:The role of immune checkpoint B7-H3 in acute ischemic stroke prognosis and poststroke immunosuppression remains uninvestigated, despite the clinical significance of immune checkpoints with inflammaging and poststroke infections. In this study, we investigated the effect of regulating cerebral induction of B7-H3 after acute ischemic stroke and evaluated its longitudinal impact on brain damage, neuroinflammation, vascular integrity, host defense gene regulation, and functional outcomes. METHODS:C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (intravenously) with either B7-H3 small interfering RNA or a negative (nontargeting) small interfering RNA at 5 minutes after reperfusion. On poststroke days 1, 3, and 7, magnetic resonance imaging of the mouse brain was performed using a 9.4-T scanner to assess brain damage (T2, apparent diffusion coefficient, and kurtosis) and blood-brain barrier integrity (T1 with contrast). Real-time qPCR and NanoString nCounter neuroinflammation panels were used to determine acute changes in overall neuroinflammatory functions mediated by B7-H3. Motor function was assessed between days 1 and 7 of reperfusion. RESULTS:Early inhibition of B7-H3 after stroke significantly reduced blood-brain barrier disruption and brain damage and promoted functional outcomes. Poststroke neuroinflammation was reprogrammed with B7-H3 inhibition to balance neuroprotective anti-inflammatory mechanisms without compromising the immune response, which is crucial for preventing poststroke infections. CONCLUSIONS:The longitudinal assessment of blood-brain barrier, infarction, and proinflammatory cytokines demonstrates that B7-H3 induction during the acute period after stroke mediates poststroke neuroinflammation and secondary brain damage.
Suboptimal clinical outcomes are common after ischemic stroke with large vessel occlusion despite current reperfusion treatment with intravenous thrombolysis and mechanical thrombectomy. Targeting residual distal arterial and microvascular occlusions with intraarterial thrombolysis has recently gained substantial interest as an adjunct to improve cerebral tissue perfusion. While recent trials provide promise in selected patients with anterior-circulation stroke, further high-quality, large-scale studies and pooled individual-patient analyses are needed. This review summarizes the evolving role of intraarterial thrombolysis over the past 3 decades and projects potential developments.
BACKGROUND:In acute ischemic stroke due to medium vessel occlusion, the relative effectiveness of intravenous thrombolysis (IVT) and endovascular therapy (EVT) remains controversial, and treatment benefits may vary across patients. We evaluated the interaction between thrombus perviousness and treatment modality on 90-day functional outcome in patients with medium vessel occlusion. METHODS:This single-center retrospective cohort study analyzed 255 patients with imaging-confirmed medium vessel occlusion treated at a stroke center in China between 2018 and 2024 (154 IVT and 101 EVT with or without prior IVT). Thrombus perviousness was quantified using the thrombus perviousness index (TPI) from noncontrast computed tomography and computed tomography angiography. Multivariable logistic regression and inverse probability of treatment weighting evaluated the TPI-by-treatment interaction for 90-day functional independence (modified Rankin Scale score ≤2). Sensitivity analyses used alternative weighting strategies and a surrogate thrombus perviousness measure. RESULTS:The 90-day functional independence rate was similar between the IVT and EVT groups (51.9% versus 51.5%; P=0.96), and TPI was not independently associated with outcome. In the inverse probability of treatment weighting-weighted model, a significant interaction between TPI and treatment modality was observed (interaction odds ratio, 0.37 [95% CI, 0.24-0.56]; P<0.001). Higher TPI was associated with a greater likelihood of functional independence in IVT-treated patients (odds ratio per 0.05-unit increase, 1.73 [95% CI, 1.19-2.53]; P=0.005), but lower odds in EVT-treated patients (odds ratio, 0.65 [95% CI, 0.49-0.87]; P=0.003). Exploratory analyses in the IVT subgroup revealed a continuous increase in functional independence as TPI increased, without a stable cutoff. Rates of symptomatic intracranial hemorrhage and 90-day mortality did not differ between groups, and TPI was not associated with hemorrhage risk. CONCLUSIONS:In medium vessel occlusion, thrombus perviousness was associated with treatment outcomes, with higher perviousness favoring IVT-related benefits, whereas the use of EVT may be relatively advantageous in patients with low-perviousness thrombi.
BACKGROUND:There is a need for novel treatments that lower the risk of major adverse cardiovascular events and secondary inflammatory brain injury after an intracerebral hemorrhage (ICH). METHODS:We performed a double-blind, placebo-controlled, pilot randomized clinical trial at 11 centers across Canada to determine the feasibility of testing colchicine after an acute ICH. We recruited adults presenting within 48 hours of ICH onset with vascular neuroimaging evidence or risk factors for atherosclerosis. Participants were randomized to oral colchicine 0.5 mg daily or placebo and followed to a common study termination date. The primary feasibility outcome was the recruitment rate (participants/center per year). Secondary feasibility outcomes included retention of participants at 6 months and medication adherence at 12 months. This trial is registered (ClinicalTrials.gov ID: REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05159219). RESULTS:Between August 2022 and March 2024, 52 participants were allocated to colchicine 0.5 mg daily and 48 participants to placebo daily. Participants were, on average, 68 years old, and 60% were male. The mean time from ICH onset to randomization was 35 hours. The average recruitment rate was 8.9 participants/site per year. Retention at 6 months was 92% (colchicine 91% versus placebo 93%). Following randomization, 14 participants (27%) in the colchicine group and 13 participants (27%) in the placebo group permanently discontinued the study drug. Excluding participants who died or permanently discontinued the study intervention, 12-month medication adherence was 97%, with similar rates between the colchicine and placebo groups (100% versus 93%). We detected no difference in predefined exploratory efficacy or safety end points between the 2 groups over the median follow-up time of 364 days. CONCLUSIONS:It is feasible to test low-dose colchicine after an acute ICH. Future randomized clinical trials should account for the high rates of early permanent study drug discontinuation in this patient population. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05159219.
BACKGROUND:Raised inflammatory biomarkers predict an increased short-term risk of recurrent vascular events after stroke or transient ischemic attack, but it is uncertain whether the hazard is maintained thereafter. In the absence of previous population-based studies, we aimed to determine the predictive value of biomarkers for the long-term risk of recurrent stroke in intensively treated patients following transient ischemic attack or stroke. METHODS:We studied 12 blood biomarkers related to inflammation, neuronal cell damage, and thrombosis soon after transient ischemic attack or stroke in a population-based study (OXVASC [Oxford Vascular Study]; 2002-2011) with follow-up to 2025. We used Cox and negative binomial regressions to assess associations between each log-transformed biomarker (per SD increase) and recurrent stroke (first event and total number), adjusted for age, sex, and baseline vascular risk factors. RESULTS:Of 1292 consecutive patients (mean/SD age, 73.1/13.2 years; 47.8% male), 365 recurrent strokes occurred in 280 patients during 11 336 patient-years. All inflammatory biomarkers were associated with 10-year risk of recurrence, with little impact of adjustment for other risk factors (adjusted incidence rate ratio: IL-6 [interleukin-6], 1.21 [95% CI, 1.04-1.42]; CRP [C-reactive protein], 1.29 [95% CI, 1.11-1.49]; TNFR-1 [tumor necrosis factor receptor-1], 1.24 [95% CI, 1.05-1.46]; and NGAL [neutrophil gelatinase-associated lipocalin], 1.15 [95% CI, 0.99-1.33]). Moreover, number of elevated (top quartile) inflammatory markers was associated with higher burden of recurrence (incidence rate ratio, 1.31 [95% CI, 1.15-1.50]; P<0.001), with no diminution over time (90 days: hazard ratio, 1.24 [95% CI, 0.98-1.57]; 90 days-1 year: 1.24 [95% CI, 0.95-1.62]; 1-5 years: 1.22 [95% CI, 1.01-1.47]; and 5-10 years: 1.34 [95% CI, 1.06-1.68]), and similar associations for transient ischemic attack and minor stroke. Biomarkers related to neuronal cell damage or thrombosis were generally less predictive of recurrent stroke. CONCLUSIONS:Inflammatory biomarkers were more predictive of long-term recurrent stroke than neuronal or thrombotic biomarkers, particularly when several inflammatory markers were raised. Predictive value was independent of other vascular risk factors and did not diminish with duration of follow-up, supporting trials of anti-inflammatory strategies for long-term secondary prevention.
BACKGROUND:Spinal cord infarction (SCI) is a rare stroke subtype with no established acute treatment guidelines. Thrombolytic therapy has been used empirically based on extrapolation from cerebral stroke protocols, but comparative effectiveness data are lacking. We compared outcomes between standard care and thrombolysis in acute spontaneous SCI. METHODS:This retrospective cohort study used data from the TriNetX Global Collaborative Network. Adult patients with acute SCI (International Classification of Diseases, Tenth Revision, Clinical Modification code G95.11) were divided into the standard care group (antiplatelet therapy within 48 hours) or the thrombolysis group (alteplase or tenecteplase). Patients who underwent aortic repair procedures were excluded. Propensity score matching (1:1) balanced 68 covariates. The prespecified primary outcome was all-cause mortality; readmission and rehabilitation utilization at 180 days were secondary exploratory outcomes. E values were calculated for the significant association. RESULTS:Of the 965 patients in the standard care cohort and 103 in the thrombolysis cohort, 96 patients in each cohort remained after matching. Standard care was associated with significantly lower mortality (13.5% versus 29.2%; hazard ratio, 0.423 [95% CI, 0.219-0.817]; P=0.008); 180-day survival was 84.27% versus 68.69% (log-rank P=0.008), with an E value of 4.16. Readmission (14.6% versus 16.7%; P=0.669) and rehabilitation utilization (43.8% versus 49.0%; P=0.507) did not differ. The mortality association was consistent in direction across 3 sensitivity analyses. CONCLUSIONS:In spontaneous SCI, standard care was associated with significantly lower mortality than thrombolysis, without significant differences in readmission rates or rehabilitation utilization. These hypothesis-generating findings raise concerns about off-label thrombolytic use in SCI and support consideration of conservative management until higher-quality evidence emerges.
BACKGROUND:White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. METHODS:We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50-101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 fluid-attenuated inversion recovery-MRI and diffusion MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). RESULTS:The study population had a mean age of 78 years, 47% were women, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for fluid-attenuated inversion recovery-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Female participants showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas male participants exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. CONCLUSIONS:Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.
BACKGROUND:The effect of postthrombectomy blood pressure (BP) management on the development of acute kidney injury (AKI) in patients with acute ischemic stroke remains largely unexplored. METHODS:This secondary analysis of the OPTIMAL-BP trial (Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control) included patients with acute ischemic stroke due to large-vessel occlusion who achieved successful endovascular thrombectomy and had a systolic BP ≥140 mm Hg. Patients were randomized to intensive (target systolic BP <140 mm Hg) or conventional (target systolic BP 140-180 mm Hg) BP management for 24 hours. The outcomes were AKI within 7 days and within 2 days, defined according to the Kidney Disease: Improving Global Outcomes criteria. In addition, we examined the associations between AKI and functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Multivariable logistic regression analyses were performed with adjustment for age, sex, time from stroke onset to enrollment, baseline National Institutes of Health Stroke Scale score, and baseline estimated glomerular filtration rate. RESULTS:Of 306 patients, 19 were excluded, and 287 patients were included in this analysis (mean age, 73.2 years; 117 [40.8%] women). AKI within 7 days occurred more frequently in the intensive management group than in the conventional group (20/147 [13.6%] versus 9/140 [6.4%]; adjusted odds ratio, 2.54 [95% CI, 1.10-6.35]). Most AKI events were stage 1 (20/29 [69.0%]). Early AKI within 2 days was also more common with intensive BP management. Patients with AKI had significantly lower rates of functional independence (4/29 [13.8%] versus 126/257 [49.0%]; adjusted odds ratio, 0.19 [95% CI, 0.05-0.55]) and higher stroke-related mortality at 3 months (11/29 [37.9%] versus 8/257 [3.1%]; adjusted odds ratio, 13.8 [95% CI, 4.14-49.64]). In a sensitivity analysis with equal creatinine ascertainment, the association with 48-hour AKI did not reach statistical significance (7/76 [9.2%] versus 2/66 [3.0%]; adjusted odds ratio, 4.20 [95% CI, 0.83-32.6]), although the absolute risk difference remained directionally consistent. CONCLUSIONS:Intensive BP lowering after successful endovascular thrombectomy was associated with a higher risk of AKI, even when kidney injury was predominantly mild. In addition, AKI was associated with worse neurological outcomes. These findings suggest that AKI is an important marker of systemic hemodynamic vulnerability after aggressive postendovascular thrombectomy BP lowering. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04205305.
BACKGROUND:Leptomeningeal collaterals form a critical vascular network that enlarges to support retrograde reperfusion after ischemic stroke, yet the cellular mechanisms governing their structural plasticity remain poorly defined. Here we identify an immune-responsive vascular niche and uncover a central role for bone marrow-derived monocytes in regulating collateral remodeling. METHODS:GFP (green fluorescent protein)+ bone marrow chimeric mice and inducible monocyte-specific Ccr2-CreERT2/EphA4f/f and Ccr2-CreERT2/EphA4f/f/Tie2f/f mice underwent permanent middle cerebral artery occlusion to assess monocyte recruitment, collateral remodeling, cerebral blood flow, infarct volume, and functional recovery. Mechanistic studies evaluated EphA4 (ephrin receptor A4)/Tie2-PI3K (phosphatidylinositol 3-kinase) α signaling in macrophages, while serum sTie2 (soluble Tie2) levels and immune transcriptomic profiles were analyzed in patients with acute large vessel occlusion and correlated with angiographic collateral grade. RESULTS:We observed rapid recruitment of EphA4-expressing monocytes to pial collateral vessels after permanent middle cerebral artery occlusion. EphA4 knockout chimeric mice show a marked increase in monocyte recruitment, enhanced collateral diameters, improved cerebral blood flow, reduced infarct volume, and accelerated motor recovery. EphA4-null macrophages exhibited elevated Tie2, p-Akt, and PI3Kα, a phenotype reversed by PI3Kα inhibition or sTie2. We further show enhanced permanent middle cerebral artery occlusion-induced collateral enlargement, neuroprotection, and monocyte recruitment using Ccr2-CreERT2/EphA4f/f mice, which is attenuated in Ccr2-CreERT2/EphA4f/f/Tie2f/f double-knockout mice. Notably, we find that serum sTie2 levels are elevated in human patients with large vessel occlusion, and these levels correlate with improved digital subtraction angiography collateral scoring and key immune-specific bulk transcriptomic changes. CONCLUSIONS:Together, these findings establish immune cell-intrinsic EphA4/Tie2 signaling as a key regulator of leptomeningeal collateral enlargement and reveal a therapeutic axis for augmenting perfusion after stroke.
Older randomized trials have shown modest benefit for carotid endarterectomy for selected patients with asymptomatic carotid stenosis compared with medical treatment. However, improvements in contemporary medical therapy may have negated the benefit of carotid endarterectomy, and no large randomized trials comparing stenting with modern medical treatment have been completed. The recently reported CREST-2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trials) addressed these evidence gaps. We describe the main results of CREST-2 and our interpretation of the findings for clinical practice.
BACKGROUND:Children with Down syndrome (DS) are at high risk for moyamoya syndrome (MMS) and ischemic stroke, yet early detection strategies remain poorly defined despite the condition being surgically treatable. METHODS:We conducted a multicenter retrospective cohort study comparing children with Down syndrome-associated moyamoya syndrome (DS-MMS) and MMS without DS (MMS). The primary outcome was stroke as the primary presenting symptom. Secondary outcomes included diagnostic delays, angiographic features, prediagnostic systolic blood pressure percentiles, and 1-year neurological outcomes. Multivariable models adjusted for demographic and access-related covariates. RESULTS:In total, 271 patients were identified; 198 (73.1%) met inclusion criteria and comprised the analytic cohort. Among 198 patients (77 DS-MMS; 121 MMS), DS-MMS mean age was 9.5±5.2 years (50.6% female patients), and MMS mean age was 7.4±3.0 years (54.5% female patients). Stroke at presentation was more common in DS-MMS (71.4% versus 20.7%; absolute difference, 50.8%), corresponding to an adjusted odds ratio of 14.50 ([95% CI, 6.65-31.60]; P<0.001). Children with DS-MMS experienced longer delays from symptom onset to presentation and from presentation to diagnostic confirmation (both P<0.001). Posterior circulation involvement was more frequent in DS-MMS (adjusted odds ratio, 2.18 [95% CI, 1.09-4.37]; P=0.03), whereas angiographic severity was similar between groups. In the prediagnostic period, DS-MMS demonstrated a progressive rise in systolic blood pressure percentiles, exceeding the MMS cohort by 6 months (P<0.001). At 1 year, DS-MMS was associated with greater disability (adjusted odds ratio, 2.58 [95% CI, 1.45-4.57]; P<0.001) and spasticity (adjusted odds ratio, 6.33 [95% CI, 3.12-12.83]; P<0.001). CONCLUSIONS:DS-MMS represents a high-risk cerebrovascular phenotype characterized by delayed recognition and a markedly increased likelihood of stroke at presentation. Rising blood pressure percentiles preceding diagnosis may serve as an early physiological signal. These findings support targeted early detection strategies and a lower threshold for vascular imaging in symptomatic patients.
BACKGROUND:Health-related quality of life is a key secondary end point in stroke trials. Differential item functioning (DIF) occurs when individuals with the same underlying health-related quality of life interpret and respond differently to questionnaire items, potentially biasing treatment comparisons. This study evaluates DIF in the patient-reported 5-level EuroQOL questionnaire among patients with acute ischemic stroke across age, sex, and treatment groups. METHODS:Data were from the AcT trial (Alteplase Compared to Tenecteplase), a registry-based randomized comparison of alteplase and tenecteplase conducted at 22 stroke centers across Canada (December 2019-January 2022). Patients with acute ischemic stroke presenting within 4.5 hours of symptom onset and eligible for thrombolysis completed the 5-level EuroQOL questionnaire at 90 days poststroke. DIF was assessed using multigroup graded response models with the Wald-based sweep procedure, which accounts for between-group differences in latent trait distributions. We quantified effect sizes using signed weighted area between curves (sWABC); |sWABC| <0.10=negligible. RESULTS:Of 1577 patients enrolled in the trial, 1264 survived to 90 days with complete 5-level EuroQOL questionnaire data (51.2% tenecteplase; 46.5% female; 30.1% aged ≥80). Omnibus testing revealed significant DIF only for age (χ2=86.9, P<0.001); neither sex (χ2=31.7, P=0.063) nor treatment (χ2=22.4, P=0.379) showed evidence of DIF. Four items flagged for age-related DIF: self-care, usual activities, pain/discomfort, and anxiety/depression. However, only self-care (sWABC=-0.46) and usual activities (sWABC=-0.34) showed moderate effects, while pain/discomfort (sWABC=-0.002) and anxiety/depression (sWABC=0.09) were negligible. Importantly, factor scores from models with and without DIF adjustment correlated (correlation coefficient=0.98). CONCLUSIONS:The 5-level EuroQOL questionnaire appears to function equivalently across sex and treatment groups in this stroke population. Age-related DIF, though statistically detectable in physical functioning items, had little practical consequence for individual scores, supporting the instrument's use for health-related quality of life comparisons in stroke trials. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.
