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Background: Embolic stroke of undetermined source (ESUS) comprises infarct mechanisms presumed to be embolic and non-lacunar. One explanation for the lack of superiority of anticoagulation over aspirin is the inclusion of subcortical infarcts with white matter disease (WMD), reflecting small vessel pathology. We hypothesized that WMD is associated with recurrent ischemic stroke (RIS) in ESUS and this risk is not lessened by anticoagulation. Methods: We conducted a secondary analysis of the multicenter Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) registry, including ESUS patients from 27 U.S. centers (2015–2024). WMD severity was graded using the Fazekas scale from MRI and dichotomized as mild (0–1) vs. moderate-to-severe (2–3). The primary outcome was RIS. Secondary outcomes were major bleeding and all-cause mortality. Inverse probability of treatment weighting (IPTW) adjusted for baseline differences. Cox proportional hazards models assessed associations between WMD and outcomes. Subgroup analyses explored effect modification by age, risk factors, and treatment type. Results: Among 1,890 ESUS patients with MRI data, 684 (36.2%) had Fazekas 2–3. These patients were older with more vascular risk factors, but IPTW achieved covariate balance. In the weighted cohort, RIS occurred more frequently in Fazekas 2–3 vs. 0–1 (7.1% vs. 4.6%/year; HR 1.56, 95% CI 1.10–2.22, p = 0.01). Major bleeding and mortality were similar (bleeding: 1.7% vs. 1.8%/yr, HR 0.96, p = 0.92; death: 7.0% vs. 6.7%/yr, HR 1.04, p = 0.81). Subgroup analyses showed no interaction between WMD and age, vascular risk factors, or treatment type (antiplatelet vs. anticoagulation), suggesting consistent RIS risk in those with higher WMD. Discussion: Moderate-to-severe WMD identifies ESUS patients at higher risk of ischemic stroke recurrence, with no mitigation by anticoagulation. These findings suggest that WMD may indicate non-embolic mechanisms and support the use of imaging-based risk stratification in ESUS.

Background and Objectives: Pregnancy and the postpartum period increase the risk of cervical artery dissection (CEAD), a notable cause of stroke in young women. We aimed to describe the clinical presentation, imaging findings, and outcomes of CEAD occurring during pregnancy or shortly after delivery. Methods: We analyzed data from the STOP-CAD registry, a large international multicenter study of patients treated with antithrombotic therapy for non-traumatic CEAD between 2015 and 2021. This sub-study focused on women who were pregnant or within 12 weeks postpartum at the time of symptom onset. We assessed baseline clinical features, imaging results, acute stroke treatments, and functional outcomes. Results: Among 1,783 women in the registry, 62 (3.5%) had pregnancy-associated CEAD, with a median age of 34 years (IQR, 30-38). One-third had a history of migraine (33.9%), one-fifth had hypertension (21.0%), while other vascular risk factors were rare. Recent minor neck trauma was reported in 17.7%. Ischemic stroke symptoms occurred in 25 (40.3%) patients, and 23 (37.1%) had acute infarcts on imaging. However, most (59.7%) presented with non-ischemic symptoms. Vertebral artery dissections were more common than carotid dissections (62.9% vs. 48.4%), and 33.9% had multivessel involvement. Among patients presenting with ischemic stroke symptoms, 4 received thrombolysis and 7 underwent thrombectomy. Remarkably, 92% had excellent functional recovery (modified Rankin Score 0–1) at 90 days, and there were no stroke recurrences at 180 days. Conclusion: Pregnancy- and postpartum-associated CEAD is uncommon and associated with ischemic stroke in nearly half of patients. A history of migraine and hypertension may be potential risk factors. Despite the severity of presentation, most patients had favorable outcomes with timely treatment.

Background: High-grade intracranial atherosclerosis (ICAS) is associated with an elevated risk of recurrent ischemic stroke, particularly in patients with severe stenosis (70–99%). Identifying predictors of early recurrence can inform risk stratification and guide treatment strategies. Methods: The Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) study is a multicenter, international, retrospective cohort analysis pooling data from 35 comprehensive stroke centers. We included hospitalized adult patients with symptomatic ICAS, defined as 50–99% stenosis of an intracranial artery (intracranial vertebral, basilar, distal ICA, or M1 MCA), confirmed by vascular imaging and associated with a qualifying ischemic event. Patients with only high-grade stenosis (70-99%) were included in this analysis. The primary outcome was to determine predictors of recurrent ischemic stroke in the territory of the symptomatic artery within 90 days of the index event. Baseline demographic, clinical, and imaging characteristics were recorded. Multivariable Cox proportional hazards regression with stepwise selection (p < 0.1) was used to identify independent predictors of recurrence; model discrimination was assessed using Harrell’s C-statistics. Results: Among 2,050 patients, 1,476 had high-grade (70-99%) symptomatic ICAS. The mean age was 67 ± 12.5 years, and 767 (55%) were male. Most patients were non-Hispanic (90.1%), taking dual antiplatelet therapy (77.8%), and statins (94.5%). Recurrent stroke occurred in 160 patients (10.8%) within 90 days. In multivariable Cox model, independent predictors of recurrence included atrial fibrillation (HR 2.05; 95% CI, 1.26–3.33; p = 0.004), hyperlipidemia (HR 1.57; 95% CI, 1.10–2.24; p = 0.014), diabetes mellitus (HR 1.36; 95% CI, 0.98–1.88; p = 0.064), and home use of dual antiplatelet therapy (HR 1.60; 95% CI, 1.01–2.54; p = 0.043)(Harrell’s C-statistic=0.62). In patients who underwent perfusion(n=402), mistmatch >10seconds were associated with increased recurrence (HR 1.80; 95% CI 0.95-3.38, p=0.07) and atrial fibrillation (HR 2.06: 95% CI 0.03-4.60, p=0.78) though did not reach statistical significance. Conclusion: In this population, diabetes, hyperlipidemia, atrial fibrillation, and prior use of dual antiplatelet therapy were associated with increased risk of 90-day recurrent ischemic stroke. Perfusion imaging may help identify high-risk patients who could benefit from intensified secondary prevention.

Introduction: Intracranial atherosclerosis (ICAS) is a leading cause of ischemic stroke (IS) worldwide and carries a high risk of recurrence. Current guidelines favor 90 days of dual antiplatelet therapy (DAPT) for severe symptomatic ICAS, but recurrence remain high. Limited data suggest possible benefit of single antiplatelet plus anticoagulation (SAPT+AC). We compared the effectiveness and safety of DAPT versus SAPT+AC. We hypothesized that DAPT would lower 90-day recurrent IS risk without significantly increasing bleeding. Methods: This substudy of the Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) included patients from 35 centers (Jan 2019–Jun 2024) with symptomatic 50–99% ICAS in the intracranial internal carotid, vertebral, basilar, or M1 segment of the MCA, presenting ≤72 hours from last known well. The primary efficacy outcome was recurrent IS in the same vascular territory at 90 days; the primary safety outcome was severe bleeding (symptomatic intracranial hemorrhage or major extracranial bleeding). Categorical variables were compared using χ 2 and continuous variables with the Student's t test; multivariable Cox regression adjusted for key covariates. Results: Of 2050 BIORISK-ICAS patients, 1658 met criteria (DAPT n=1499; SAPT+AC n=159). Mean age was 67 vs. 73 years, and 44% were women. At 90 days, recurrent IS occurred in 121 DAPT patients (8.07%) vs. 13 SAPT+AC patients (8.17%); unadjusted HR 0.83 (95% CI, 0.50–1.36; p=0.46). After adjustment for age, diabetes, coronary heart disease, atrial fibrillation, active smoking, and borderzone infarct, the adjusted HR was 0.99 (95% CI, 0.52–1.86; p=0.97). Severe bleeding occurred in 34 DAPT patients (2.26%) and 5 SAPT+AC patients (3.14%); unadjusted HR 0.79 (95% CI, 0.28–1.85; p=0.50), adjusted HR 0.66 (95% CI, 0.21–2.09; p=0.47). Conclusions: In patients with symptomatic ICAS, DAPT and SAPT+AC were associated with similar risks of 90-day recurrent ischemic stroke and severe bleeding. Well-powered randomized trials are needed to determine the optimal antithrombotic regimen in this high-risk population.

Background: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. Methods: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). Patients with ESUS were categorized into three groups: (1) established mechanism after further work up (ESUS-E), (2) patients who underwent a comprehensive diagnostic workup without an identified etiology (ESUS 2.0), and (3) no advanced workup (ESUS-NAW). The primary outcome of recurrent ischemic stroke was assessed by comparing ESUS 2.0 to both ESUS-E and ESUS-NAW groups using adjusted Cox proportional hazards models. Results: Of the 2,281 patients included, 694 (30%) were classified as ESUS-E, 344 (15%) as ESUS 2.0, and 1,443 (55%) as ESUS-NAW. The ESUS 2.0 group had a significantly lower annualized recurrence rate (1.98 per 100 person-years) compared to both the ESUS-NAW group (7.7 per 100 person-years; aHR 0.27, 95% CI: 0.11–0.62; p=0.002) and the ESUS-E group (6.10 per 100 person-years; aHR = 0.35; 95% CI 0.15–0.85, p=0.020). Within the ESUS-E group, cancer (aHR 5.33; 95% CI: 2.09–13.63; p < 0.001) and non-stenosing atherosclerotic disease or arch atheroma (aHR 3.40; 95% CI: 1.18–9.83; p = 0.023) were associated with significantly increased risk of recurrence when compared to ESUS 2.0. Conclusion: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0, diverging from the 5–6% annual recurrence rates observed in prior ESUS trials. These findings suggest that patients who receive comprehensive diagnostic evaluation without identification of a specific etiology have a lower risk of recurrent stroke, an important consideration for the design of future ESUS studies.

Background and Objectives: Cervical artery dissection (CeAD) is a common cause of ischemic stroke in young adults. We aim to identify age-based differences in clinical presentation, imaging findings, and outcomes after CeAD. Methods: This was a sub-study using the STOP-CAD registry, a multicenter cross-sectional international retrospective study of patients diagnosed with CeAD and treated with an antithrombotic from January 1, 2015 to December 31, 2021. Baseline clinical and imaging characteristics were compared between younger and older adults with CeAD (≤45 versus >45 years of age) using multivariable logistic regression. We chose this age cut off due to its frequent usage in stroke in the young literature. Multiple logistic regression models were used to determine association between young age and outcomes after CeAD (ischemic stroke at 180 days, excellent functional outcome with modified Rankin Scale of 0-1 at 90 days, and mortality) after adjusting for sex, vascular risk factors, CeAD characteristics, and NIHSS on presentation. Results: Among 4023 CeAD patients included in the study, 1901 (47.3%) were ≤45 years of age. Patients were followed for a median of 307 days (IQR 102-831). Young adults with CeAD were more likely to be women (Odds Ratio [OR], 2.4; 95% CI, 2.1-2.9; p<0.001), of Hispanic ethnicity (OR, 1.8; 95% CI 1.3-2.5; p<0.001), have a history of migraines (OR, 1.6; 95% CI, 1.3-2.0; p<0.001) and recent neck trauma (OR, 1.6; 95% CI, 1.3-1.9; p<0.001) while having fewer traditional vascular risk factors. Young adults with CeAD had higher odds of a non-ischemic presentation (OR, 1.3; 95% CI, 1.1-1.5; p=0.013), vertebral artery dissection (OR 2.5; 95% CI, 2.2-3.0; p<0.001), and multivessel involvement (OR 1.5; 95% CI, 1.1-1.9; p=0.004). In adjusted analysis, younger age was not associated with an increased risk of recurrent ischemic stroke (adjusted Hazard Ratio [HR], 0.48; 95% CI 0.2-1.2; p=0.119). Younger age was associated with significantly greater odds of excellent functional outcome at 90 days (aOR, 1.48; 1.20-1.84, p<0.001) and lower risk of death at follow up (aHR, 0.37; 95% CI, 0.17-0.81; p=0.012) after CeAD. Conclusion: In a large international cohort, young adults with CeAD had a distinct clinical phenotype with higher odds of non-ischemic presentation, vertebral artery dissection, and multivessel involvement while having fewer traditional vascular risk factors. Young adults had a decreased odds of disability and mortality after CeAD.

BACKGROUND: Cervical artery dissection (CeAD) may result in dissecting aneurysm (DA) formation. We aimed to characterize risk factors and clinical outcomes associated with DA in a large, international CeAD cohort. METHODS: We performed a secondary analysis of STOP-CAD (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection), an international, multicenter, retrospective cohort. Patients with spontaneous CeAD were assessed for DA at baseline and de novo DA formation. Significant covariates in univariable analysis were included in multivariable regression models aiming to identify factors associated with DA formation. Logistic regression and Cox proportional hazards models evaluated the association of DA with ischemic and hemorrhagic outcomes. RESULTS: Among 4008 patients with CeAD, 546 (13.6%) had a DA at baseline, and 221/2938 (7.5%) patients developed a de novo DA during follow-up, of which 172/221 (78.2%) were detected in the first 180 days. Patients with DA had a mean age of 47 years, and 383 (49.9%) were women. Baseline or de novo DA was associated with a history of connective tissue disorder (adjusted odds ratio [aOR], 2.02 [95% CI, 1.22–3.36]), fibromuscular dysplasia (aOR, 1.69 [95% CI, 1.28–2.25]), and multiple vessel dissection (aOR, 1.53 [95% CI, 1.19–1.98]). Lower odds of DA were seen in Hispanic ethnicity (aOR, 0.64 [95% CI, 0.43–0.97]) and ischemic stroke presentation (aOR, 0.41 [95% CI, 0.34–0.49]). Fibromuscular dysplasia was associated with de novo DA formation (aOR, 2.30 [95% CI, 1.52–3.49]). DA was not associated with ischemic stroke (hazard ratio, 0.71 [95% CI, 0.44–1.16]; P =0.173) or intracranial hemorrhage (HR, 1.09 [95% CI, 0.42–2.84]; P =0.86) by day 180. CONCLUSIONS: DAs are relatively common manifestations of CeAD, typically occurring within 6 months of CeAD diagnosis. DA was not associated with an increased risk of subsequent ischemic stroke or intracranial hemorrhage.

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.

Abstract Background Tau phosphorylation and aggregation are hallmark features of Alzheimer's disease pathology(AD). Previous studies have shown that plasma phosphorylated tau( p ‐tau) at threonine 217 can detect AD‐related tau tangle pathology. However, the head‐to‐head association between p ‐tau217 and different tau PET tracers remains unexplored. Here, we conducted a head‐to‐head comparison of the association between plasma p ‐tau217 and four distinct tau PET tracers[MK6240, Flortaucipir(FTP), PI2620, RO948]. Method We studied 338 individuals across the AD continuum from the HEAD study[190 cognitively unimpaired elderly(CU), 109 with mild cognitive impairment(MCI), and 39 with dementia] with available FTP, MK6240, and plasma p ‐tau217 measured by ALZpath assay. A subset of 64 individuals(28 CU, 25 MCI, and 11 dementia) also had PI2620 and RO948, and p ‐tau217 measured by Lumipulse. The strength of the association was determined using t‐value maps from regression models testing the association between each tau PET tracer and plasma p ‐tau217, and the extent was measured by the percentage of significant voxels(t‐value>3.2). R‐square metric was used to determine how much of the variance in tau PET tracer estimates was explained by plasma p ‐tau217 concentrations. Associations between p ‐tau217 with tau PET were evaluated using the Spearman test. Result We found that in CU, both the extent and magnitude of the association with plasma p ‐tau217 were higher for MK6240 compared to FTP (Figure 1A‐D). Plasma p ‐tau217 explained a greater proportion of the variance in MK6240 than in FTP (Figure 1E‐F). In CI, the extent and magnitude of the association were similar for MK6240 and FTP. Additionally, plasma p ‐tau217 explained a similar proportion of the variance in MK6240 and FTP. Using the subset of individuals who had all tau tracers, MK6240 showed a slightly higher extent of association with p ‐tau217, followed by FTP, PI2620, and RO948 (Figure 2A‐B). The magnitude of association was stronger for MK6240, followed by PI2620, RO948, and FTP (Figure 2C‐D). Plasma p ‐tau217 explained a greater proportion of the variance in MK6240, followed by FTP, RO948, and PI2620 (Figure 2E‐F). We compared the associations between different p ‐tau217 assays, and both assays presented similar associations with all tau PET tracers (Figure 3). Conclusion In summary, our results indicate that the four tau PET tracers exhibit robust associations with plasma p ‐tau217 in similar topographical regions.

Abstract Background The 2024 NIA‐AA criteria propose an Alzheimer's disease (AD) staging system based on medial temporal (MT) and neocortical tau burden. However, the optimal strategy to assess tau burden in these regions, which represent distinct phases of AD pathophysiology, remains unclear. Here, we compared tau load and spatial extent of tauopathy (SEOT) as markers of tau burden in participants scanned with [ 18 F]MK6240 and [ 18 F]FTP. We investigated the relationship between these metrics in MT and neocortical regions‐of‐interest (ROIs) and determined which better correlates with AD severity. Method A total of 257 cognitively unimpaired (CU) and 124 Aβ+ cognitively impaired participants (mean age 68.2 years; 58% female) from the HEAD study underwent tau‐PET imaging with both [ 18 F]MK6240 and [ 18 F]FTP. Tau load was quantified using regional SUVR, and SEOT was calculated as the proportion of abnormal voxels relative to young controls. Both metrics were derived from the MT and neocortical ROIs. Spearman's correlations were computed between SUVR and SEOT within the same tracer and across tracers in the same ROIs. We compared rho coefficients to assess whether one metric showed stronger concordance. Additionally, we compared the correlations of SEOT and SUVR with global cognition, cortical thickness, Aβ‐PET load, and plasma pTau‐217. Statistical comparisons were performed using the R package cocor . Result SUVR and SEOT exhibited non‐linear correlations in both MT and neocortical ROIs for both tracers, with SEOT enhancing the correlation between [ 18 F]MK6240 and [ 18 F]FTP in the neocortex ( p <.0001; Figure 1). Both metrics increased with AD severity, with MT SUVR outperforming SEOT in distinguishing Aβ‐ CU from Aβ+ CU individuals, and neocortical SEOT outperforming SUVR in distinguishing Aβ+ MCI from CU (Figure 2). Neocortical SEOT showed stronger correlations with AD severity markers than SUVR for both tracers. MT SEOT was comparable to SUVR, outperforming SUVR only in correlations with MMSE and Aβ‐PET for [ 18 F]FTP (Figure 3). Conclusion Tau extent improves the association of tau‐PET tracers with AD severity, particularly in the neocortex. These findings suggest that tau extent might be a more suitable surrogate marker of tau burden in neocortical regions, offering valuable insights for in vivo staging of tau pathology and clinical trials targeting late‐stage tau pathology.