Dumitrascu, Oana

Introduction: Embolic stroke of undetermined source (ESUS) is a clinical construct encompassing heterogenous possible mechanisms of incident stroke, potentially with variable responsiveness to anticoagulation and antiplatelet treatment. This study aims to identify differences in recurrent stroke risk based on phenotypic clusters in an ESUS population, and whether some clusters may benefit relatively more from anticoagulation over antiplatelet therapy. Methods: We identified patient phenotypes from a multicenter, retrospective cohort study of 1909 ESUS patients by dividing them into groups using Partitioning Around Medoids (PAM) with correlation-weighted Gower distance over 23 baseline demographic, clinical, laboratory, radiographic, and cardiac features. We confirmed optimal clustering at 3 groups. We assessed cluster associations with time to recurrent stroke using Kaplan-Meier survival analysis. We then employed a causal survival forest to estimate conditional average treatment effects (CATE) of anticoagulation versus antiplatelet therapy using the same baseline features as predictors with a 365-day horizon for restricted mean survival time differences. Finally, we used best linear projection to identify baseline features predictive of treatment effect and assessed whether effects differed significantly by cluster. Results: Cluster 1 (n=542) identified a low-risk, younger sample with minimal baseline disability and comorbidity burden. Cluster 2 (n=743) comprised a moderate-risk phenotype with intermediate comorbidity. Cluster 3 (n=626) represented the oldest and highest-risk phenotype. Kaplan-Meier analysis demonstrated significant differences in stroke-free survival across patient clusters (p < 0.001), where Cluster 1 experienced the lowest recurrent stroke rate and Cluster 3 had the highest. The clustering algorithm successfully identified clinically meaningful phenotypes with distinct risk profiles. While CATE varied across clusters, the differences were not statistically significant. Conclusion: In a multicenter ESUS population, we identified 3 distinct phenotypic clusters, each comprising nearly one-third of the sample and with a differential risk of recurrent stroke. Although cluster was not a significant effect modifier, substantial CATE variability by cluster was observed. Future clinical trials may consider evaluating secondary stroke prevention therapies among phenotypically similar patients who may respond differentially to novel therapies.

Background: In younger patients (<60 years) with cryptogenic stroke presumed to be patent foramen ovale (PFO)-related, the standard approach involves transcatheter PFO closure combined with antithrombotic therapy (ATA). However, due to their exclusion from randomized clinical trials, no formal recommendations exist for patients ≥60 years. This study investigates whether PFO closure benefits patients ≥60 years with prior cryptogenic stroke or if ATA remains the preferred option. Methods: We searched the PubMed, Embase, Web of Science, and ScienceDirect databases to obtain articles in all languages from January 2004 until July 2025. The primary outcome was a risk of recurrent stroke during follow-up and secondary outcomes were risk of new-onset atrial fibrillation (AF), all-cause mortality and in-hospital complications. PROSPERO registration ID: CRD420250652870. Results: One post hoc evaluation of the DEFENSE-PFO trial and eleven observational studies were included. Compared to ATA, PFO closure was associated with a reduced risk of recurrent stroke (HR=0.60; 95% CI: 0.45 to 0.80, p<.001) and mortality (HR=0.41; 95% CI: 0.19 to 0.90, p=.02; I2 = 43.8%) with no difference in risk of new-onset AF (HR=1.13, 95%CI: 0.53 to 2.44, p=.74). When compared with patients <60 years, individuals ≥60 years had a higher risk of recurrent stroke (HR = 2.68; 95% CI 1.40–5.13; p=.002), new-onset AF (HR = 4.12; 95% CI 1.90–8.95; p<0.001) and mortality during follow-up (HR = 8.24; 95% CI 3.49–19.46; p<.0001). In-hospital complications after PFO closure were comparable between two age groups. Conclusion: While PFO closure may reduce ischemic stroke risk in older patients with cryptogenic stroke, this benefit is offset by higher absolute risks for recurrent stroke, new-onset AF, and mortality. Therefore, highly individualized patient selection and age-specific risk tools are crucial. Further long-term randomized trials are essential to optimize PFO closure in this population.

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.

Introduction: Emerging evidence highlights the increased white matter hyperintensity (WMH) burden in APOE4 homozygotes, the greatest genetic risk factor for late-onset Alzheimer's disease (AD). The link between WMH and cerebral amyloid-beta (Aβ) accumulation remains unclear, especially in presymptomatic AD phases. We aimed to determine whether WMH burden (global or regional) mediates the association between APOE4 homozygosity and amyloid-PET Aβ deposition in a population of subjects with intact cognition. Methods: WMH were segmented using a deep learning model applied to T1 and T2-FLAIR MRI scans from 49 cognitively intact individuals older than 50. The global and regional (periventricular, lobar, basal ganglia, infratentorial) WMH volumes were adjusted for total intracranial volume and log-transformed to normalize distribution. Amyloid-PET cerebral Aβ burden was quantified in centiloid units; individuals with centiloid > 20 were classified as Aβ-positive. To examine our mediation hypothesis, we tested three pathways using logistic and linear regression models: 1) Path a, the association between APOE4 and global or regional WMH volumes (outcome); 2) Path b, the association between WMH volumes and Aβ positivity (outcome); 3) Path c (total) and c' (direct) effects of APOE4on Aβ positivity (outcome), before and after adjusting for WMH volumes. All models incorporated age and vascular risk factors (hypertension, diabetes, hypercholesterolemia, cigarette smoking). Results: We included 11 APOE4 homozygotes, of whom 7 were Aβ-positive and 38 non-carriers (35 3/3 and 3 3/2) (6 Aβ-positive). Compared to APOE4 non-carriers, APOE4 homozygotes had significantly greater WMH volumes in the posterior periventricular region only (p= 0.0453) (path a). Homozygotes were significantly more likely to be Aβ-positive compared to non-carriers (total effect, path c p=0.0019). This association remained significant after adjusting for WMH (direct effect, path c'= 0.0027). However, neither global (p=0.72) nor posterior periventricular (p=0.84) WMH volumes predicted Aβ positivity (path b) (Figure). Conclusions: In our cohort of cognitively normal individuals including preclinical AD, neither global nor regional WMH burden mediated the relationship between APOE4 homozygosity and Aβ positivity. Larger studies are needed to further evaluate the mechanistic relationship between WMH and neurodegeneration in APOE4 carriers.

Objective: To assess the link between retinal vascular health and cognitive performance in a diverse population, using a novel mobile laboratory platform and portable color fundus photography. Background: The retina is an accessible window into brain health. Studies that had highlighted the link between retinal vasculature and cognition included clinical populations or narrowly defined research cohorts, with limited generalizability. To address the need to expand this research to demographic and geographic diverse communities, we launched a mobile laboratory platform across rural and urban Arizona zip codes. Methods: 240 subjects were recruited in our prospective community-based study. We assessed cognition using the MindCrowd web-based testing platform and analyzed verbal paired associates (VPA) task, a validated measure of verbal associative memory sensitive to age-related cognitive decline. Non-mydriatic color fundus photographs were obtained using the portable hand-held Aurora camera (Optomed), two images per eye (disc- and macula-centered). Image processing and vascular feature quantification were automatically conducted using Automorph software. Linear regression models examined the associations between retinal vascular metrics and VPA, adjusting for age, sex, education attainment, and risk factors. Results: Our cohort’s mean age was 45 +/-16.7 years, 32.9% were male and 39.5% had a college degree. In disc-centered fundus images, fractal dimension strongly associated with chronological age (p = 1.04E-10). Greater artery tortuosity in the retinal zones B and C was associated with lower VPA (p = 0.02 and p = 0.004, respectively). In macula-centered images, fractal dimension showed the strongest association with age (p = 4.31E-11), reinforcing its utility as a robust biomarker of vascular aging. Males had wider average artery caliber in zone B (p=0.02). Zone B vein fractal dimension (p=0.002) and vein vessel density (p=0.006) were the strongest predictors of VPA. Conclusions: This study demonstrates the safety, feasibility, and utility of a mobile laboratory to collect high-quality non-mydriatic color photos and cognitive data across a geographically diverse cohort. Arterial tortuosity and venous fractal dimension and density, particularly in retinal zone B, were predictive of cognitive performance, after adjusting for vascular health covariates. Retina may become a scalable and accessible platform for studying brain aging in the general population.

Background: Studies have suggested that administering antithrombotics—oral anticoagulants (OACs) and antiplatelets (APLT)—after acute ischemic stroke(AIS) with hemorrhagic transformation (HT) is safe and can reduce ischemic recurrence. However, the safety of their early initiation after HT remains unclear. Method: This study utilized data from nine centers across several countries. The study population included patients with AIS who subsequently experienced HT. Patients with a specific HT type—hemorrhagic infarction(HI) or parenchymal hematoma(PH)—were categorized based on the time between HT and antithrombotic initiation, and their outcomes were compared. Outcomes included 30-day HT exacerbation and composite outcomes of recurrent stroke and systemic emboli, as well as 90-day vascular death and functional outcome. Results: Of 748 patients,496 received APLT, and 252 were prescribed OACs after HT. The median HT-to-APLT time was significantly shorter among HI patients than PH patients(1[IQR:0-2] vs. 3[IQR:1-5] days,p<0.001). The rates of 30-day HT exacerbation and composite outcomes, as well as 90-day vascular death and unfavorable functional outcomes, did not significantly differ between patients who received same-day, early (HI:<1day;PH:<3days), or late (HI:>1day;PH:>3days) APLTs after either HI or PH. Among patients who received OACs, those with HI had a significantly shorter median HT-to-OAC time than PH (7[IQR:2-15] vs. 15[IQR:7-32] days,p<0.001). However, 30-day HT exacerbation rates were comparable between early (HI:<7days;PH:<15days) and late (HI:>7days;PH:>15days) OAC initiation among patients with either HI or PH, late initiation among patients with PH was associated with higher rates of 30-day composite outcomes than early initiation(20.7% vs. 3%,p=0.044). Based on regression models adjusted for NIHSS and stroke severity, early initiation of APLTs or OACs was not associated with increased risk of HT exacerbation. Conclusion: Findings suggest that the same-day initiation of APLTs after HI or PH-1, and within 1-3days following PH-2, might not be associated with HT exacerbation or worsening outcomes. Similarly, OACs initiated 2-7days after HI and 7-15days after PH may not be associated with worsened patients' outcomes, whereas delays beyond these timeframes can be associated with higher thromboembolic risk.

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.