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Background: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) can be misdiagnosed as multiple sclerosis (MS). This study aims to contrast demographic, clinical, neuroimaging, and genetic features of CADASIL patients with vs. without prior MS misdiagnosis. Methods: We conducted a retrospective cohort study to compare genetically or histopathologically confirmed CADASIL patients with and without a prior MS misdiagnosis across Mayo Clinic. Patients were classified into high-, medium-, low-, or unknown-risk by location of NOTCH3 mutation. Disease severity was assessed using NOTCH3 Small-Vessel Disease (N3SVD) scale. Between-group comparisons used independent t-test for age, chi-square or Fisher’s exact test for categorical variables, and Mann–Whitney U test for quantitative variables. Within the misdiagnosed subgroup, neuroimaging changes between MS to CADASIL diagnosis were assessed using Wilcoxon signed-rank test for quantitative data and Stuart–Maxwell test for categorical data. Significance was set at p<0.05 (two-sided). Results: Among 107 patients (mean age 57.5±13.4 yrs) with CADASIL, 12 (11.2%) had a prior MS misdiagnosis (Table 1). Compared to patients without misdiagnosis (n=95), those misdiagnosed were younger, more frequently Asian, more likely to undergo lumbar puncture (83.3% vs 26.3%, p <0.001), and less likely to have had stroke (33.3% vs 65.3%, p =0.031). There were no significant differences in deep white matter hyperintensity scores or lacune counts. However, the misdiagnosed group had a higher median modified Rankin Scale ( p =0.008) and a different distribution of N3SVD stages ( p =0.017), with a higher proportion in stage 3A (33.3% vs 5.3%). There was no significant difference in genetic risk categories (Figure), but 5 of 12 misdiagnosed cases clustered in the medium risk EGFR 13, 13.5, and 14 domains. Among the misdiagnosed, 41.7% received MS-specific treatment during a median of 10.2 months (range 0.4–138.1) before diagnostic correction (Table 2). Over this period, there were no significant changes in DWMH score, lacune count, mRS, or N3SVD stage (all p >0.05). Conclusions: About one in nine CADASIL patients had a prior MS diagnosis. Atypical presentations in younger individuals without a clear stroke history may prompt consideration of MS over CADASIL, leading to diagnostic delays and unnecessary treatments. EGFR domain risk category did not correlate with misdiagnosis.

Objective: Epidemiological data have suggested that late-life depression (LLD) occurs as a consequence of cerebrovascular and neurodegenerative disorders, but there is also some evidence suggesting that the relationship may occur in the other direction, namely that LLD may be a risk factor for cerebrovascular and neurodegenerative disorders. However, the neurobiological basis of these associations remain unclear. This study investigated the associations of LLD with markers of cerebrovascular pathology, brain volumes, and cortical thickness from 3-Tesla brain magnetic resonance imaging (MRI). Methods: Participants from the Atherosclerosis Risk in Communities Study received brain MRI scans in late-life (ages 67-90). The following neuroimaging outcomes were assessed: cortical infarcts, lacunar infarcts, any microhemorrhages, lobar microhemorrhages, subcortical microhemorrhages, white matter hyperintensity volume, total and regional brain volumes (z-scores), and total average and regional cortical thickness (z-scores). At the same visit, LLD was evaluated with the 11-item Center for Epidemiological Studies Depression Scale (CES-D) and defined as CES-D score≥9. Associations between LLD and neuroimaging outcomes were examined using logistic and linear regression models, and were adjusted for age, race-center, sex, education level, vascular risk factors, stroke, cognitive status, APOE e4 carrier status, and total intracranial volume when assessing volumes. Results: Among 1,857 participants, the median age was 76 years, 59.5% were female, 28.3% were Black, and 6.8% had LLD. LLD was not associated with infarcts or microhemorrhages. There was no evidence of an association between LLD and total white matter hyperintensity volume or total average cortical thickness. However, LLD was independently associated with smaller volume (SD) of the rostral anterior cingulate (b 1 : -0.18; 95% CI: -0.33, -0.04) and greater cortical thickness (SD) in the medial orbitofrontal cortex (b 1 : 0.19; 95% CI: 0.01, 0.38), though effect sizes were small and did not survive correction for multiple comparisons. Conclusion: Findings from this study suggest LLD is not cross-sectionally associated with neuroimaging markers of cerebrovascular disease. While LLD may be linked to subtle volume and cortical thickness changes in specific regions of interest, future longitudinal research is warranted to validate and clarify these associations and explore their potentially bidirectional relationship.

Background: Stroke is a leading cause of death and disability despite advances in risk factor management. Many risk factors for stroke have also been implicated as risk factors for mild cognitive impairment (MCI) and dementia. Given these shared risk factors, cognitive impairment (CI) may represent an accumulation of neurological injury that is associated with an elevated risk of stroke. In ARIC-NCS, we aimed to 1) understand the independent relationship between pre-stroke CI (MCI or Dementia) and incident stroke; 2) explore mortality differences in stroke patients with vs without pre-stroke CI; and 3) evaluate modifiers of these relationships. Methods: 5434 stroke-free participants were evaluated for cognitive status at an in-person visit in 2011-13 (visit 5; ages 66-90), based on cognitive testing and informant interviews. Incident definite or probable strokes (ischemic or hemorrhagic) from visit 5 through 2022 were identified via ongoing surveillance (semi-annual telephone calls, with expert classification). Using Cox proportional hazards regression models adjusted for demographics and vascular risk factors, we evaluated associations between CI (MCI or dementia) and incident stroke, and between CI and death among individuals with stroke. Finally, we tested effect modification by age at visit 5, sex, education, and race, via stratified models and formal interaction terms. Results: Compared to those without CI, individuals with CI (23%) were older (77 vs 75 years, p<0.001), and more frequently male (48% vs 40%). Over 10+ years, CI was independently associated with an increased risk of incident stroke (HR:1.52, 95% CI:1.18-1.96). Among individuals with stroke, risk of death was also higher in CI vs non-CI patients (HR 1.78, 95% CI 1.27-2.50). In stratified analysis, we found a significant interaction by sex (p-interaction=0.04): in males, CI was associated with elevated stroke risk (HR:2.01, 95% CI:1.39-2.91) without a similar risk in females (HR:1.22, 95% CI:0.85-1.75). Interactions by race, age, and educational level were not statistically significant, but effect sizes were qualitatively larger in White participants and individuals with more education. Conclusion: CI is associated with incident stroke independent of shared risk factors, especially in men. This work adds to our understanding of populations at risk for stroke, thus aiding efforts to optimize stroke prevention in at-risk populations.

Background: Cervical artery dissection (CeAD) accounts for nearly 25% of all ischemic strokes in young adults. CeAD can lead to the development of dissecting aneurysms (DA). However, the incidence, risk factors and outcomes of CeAD patients with DA is not well established. This study aims to identify risk factors for developing DA, subsequent growth, and impact on patient outcomes. Methods: This is a secondary analysis of the Antithrombotics for Stroke Prevention in Cervical Artery Dissection (STOP-CAD), a multicenter cross-sectional international retrospective study. CeAD patients were stratified for the presence of DA. We used multivariable regression to identify factors associated with DA. Patients with DA were further analyzed for DA growth. The primary outcome was ischemic stroke after CeAD+DA diagnosis. Secondary outcomes included ischemic stroke after CeAD+DA with DA growth. Multivariable logistic regression analysis was used to assess the association between DA and risk factors. We also performed univariate Cox regression and generated Kaplan-Meier survival curves comparing study outcomes based on presence of DA and subsequent growth. Results: Of the 4023 patients included in the STOP-CAD study, 4008 were included in this analysis and 767 (19%) patients had DA (546 with DA on initial presentation). Patients with DA had a mean age of 46 [IQR 37-55] years and 50% (383) were women. In combined adjusted analyses, DA patients were more often non-Hispanic (aOR 0.63, 95% CI 0.41-0.94, p<0.02), more commonly had a history of migraine (aOR 1.27, 95% CI 1.01-1.59, p=0.037), connective tissue disorder (aOR 2.02, 95% CI 1.22-3.36, p=0.007), minor neck trauma (aOR 1.70, 95% CI 1.29-2.26, p<0.001) and were more likely to present with ischemic stroke (aOR 1.73, 95% CI 1.05-2.87, p=0.031). DA growth was noted in 55 out of 546 (10%) patients with DA on presentation. There was no significant difference in the risk of ischemic stroke by day 180 in patients with DA (hazard ratio [HR] 0.92 [95% CI, 0.65-1.30]; P =0.63) or DA growth (HR 2.40, [95% CI, 0.79-7.24]; P =0.12). Conclusion: In this subanalysis of STOP-CAD, nearly one in five patients with CeAD developed a DA. Factors associated with a higher likelihood of DA included non-Hispanic ethnicity, history of migraine, connective tissue disorder, minor neck trauma, and ischemic stroke at presentation. DA diagnosis and DA growth did not impact the risk of subsequent ischemic stroke at 6 months.

Introduction: Optimizing patient selection and time-to-intervention will be crucial to the success of future clinical trials seeking to implement therapies and improve intracerebral hemorrhage (ICH) patient outcomes. Automated and accurate ICH and perihematomal edema (PHE) volumetry carries significant potential to strengthen trials targeting ICH and PHE expansion. Aims: The Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage (QUANTUM) trial was designed with aims of (1) validating a fully automated artificial intelligence (AI) method for supratentorial, spontaneous ICH and PHE volumetry against the manual and semiautomated quantification methods and (2) establishing a model framework for the translation of AI technology through conduct of a clinical trial under the equivalence hypothesis paradigm. Methods: This trial was a prospective, randomized, clinical study with blinded outcome assessment. Six independent raters were randomized in a 1:1 ratio to ICH and PHE volumetry from non-contrast CT scans in the Virtual International Stroke Trials Archive with either the semiautomated or manual quantification method. The primary outcomes were equivalence between (1)ICH volume measurements on admission (<24h from symptom onset) for the manual versus the fully automated or the sem-automated quantification methods, and (2)PHE volume measurements on day 3 (72±12h from symptom onset) for the manual versus the fully automated or the semiautomated quantification methods. The required sample size was 126 ICH and 126 PHE measurements, based upon a significance level of 0.025 to account for the two equivalence tests. Results: The geometric mean relative discrepancies between the fully automated and the manual ICH and PHE volume measurements did not cross the pre-specified 10% equivalence margin. The geometric mean relative discrepancies between the semiautomated and the manual ICH and PHE volume measurements did cross the pre-specified 10% equivalence margin. The fully automated method (mean 10.0±2.7s/scan) was significantly faster than the manual (mean 189±199 s/scan; P <0.001) and semiautomated (mean 79±68s/scan; P <0.001) methods. Conclusions: ICH and PHE volumes quantified by AI could replace clinician measurements within a 10% error margin and with substantially greater efficiency. The semiautomated method could not replace manual measurements. This trial demonstrated feasibility of the equivalence hypothesis framework for AI validation studies.

Introduction: Studies suggest that stroke and hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real-world populations. Hypothesis: We hypothesized that HF subtypes are differentially associated with cognitive impairment and that lower left ventricular ejection fraction (LVEF) correlates with poorer cognitive performance. Methods: We conducted a cross-sectional study of patients aged ≥18 years seen at a Heath System in 2022 who underwent both echocardiogram and cognitive assessment within one year. HF was classified into four groups based on 2022 American Heart Association HF guideline: No heart failure, HFpEF (HF with preserved LVEF), HFmrEF (HF with mid-range LVEF), and HFrEF (HF with reduced LVEF). Cognitive impairment was categorized using the Montreal Cognitive Assessment (MOCA) as normal (≥26), mild (18–25), moderate (10–17), and severe (<10). Multivariable linear regression assessed the correlation between EF and MoCA, and logistic regression evaluated the association between HF subtypes and severity of cognitive loss, adjusting for age, sex, race, hypertension, diabetes, dyslipidemia, chronic kidney disease, stroke. Results: A total of 1,695 patients were included in the study (mean age, 75.3±14 years; 48.3% female). 82.0% had HFpEF; 7.1%, HFmrEF; 7.9%, HFrEF, and 3.0% no HF. LVEF was positively associated with MoCA score (β=0.028, p=0.032). Patients with LVEF ≤40% had lower MoCA scores (17.7 ± 6.2 vs. 19.1 ± 5.9, p=0.008) and higher adjusted odds of moderate/severe cognitive impairment (aOR 2.49, 95%CI 1.20-5.15, p=0.014), compared to those with LVEF >40%. Adjusted odds of moderate to severe cognitive impairment were 1.14 for HFpEF, 0.99 for HFmrEF, and 2.81 for HFrEF compared to patients with no heart failure (trend-P=0.031, Table). Conclusions: Lower LVEF was independently associated with worse cognitive performance. Patients with HFrEF had a 2.5-fold higher risk of moderate to severe cognitive impairment. This association was not observed in patients with HFpEF or HFmrEF, suggesting differential cognitive effects across HF subtypes. Further studies are warranted to confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

Background: The clinical characteristics and complications associated with de novo pseudoaneurysm formation beyond the acute phase of cervical artery dissection remain poorly defined. In this study, we examined the incidence, risk factors, and related ischemic and hemorrhagic events of post-acute de novo pseudoaneurysm formation. Methods: We analyzed data from the STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection). A de novo pseudoaneurysm was defined as a new (not present on initial imaging) focal enlargement in the diameter of the artery, greater than the native lumen. The incidence of de novo pseudoaneurysm was assessed at 90 days, 180 days, and beyond 180 days of follow-up. Univariate and multivariate regression analyses were conducted to identify risk factors for post-acute de novo pseudoaneurysm formation. Kaplan-Meier survival estimates were used to compare ischemic and hemorrhagic events between patients with and without de novo pseudoaneurysms. Results: Among 4008 patients, 546 were excluded as they had dissecting pseudoaneursyms on initial presentation. Therefore, 3,462 patients were included in this analysis of whom 220 patients (6.35%) developed a de novo pseudoaneurysm over a maximum follow-up of 4.4 years. Of these, 127 (57.72%) were detected within the first 90 days, and 172 (78.18%) within the first 180 days. In multivariate regression analyses, in addition to hypertension, active smoking and Hispanic ethnicity, fibromuscular dysplasia (FMD) was an independent risk factor for post-acute de novo pseudoaneurysm formation (adjusted OR: 2.160; 95% CI: 1.408–3.315; p < 0.001). Notably, the presence of a de novo pseudoaneurysm was not associated with a significant increase in ischemic (hazard ratio [HR] 1.43 [95% CI, 0.89–2.30]; P=0.14) or hemorrhagic events (hazard ratio [HR] 1.42 [95% CI, 0.43–4.69]; P=0.57). Conclusion: De novo pseudoaneurysm formation following a diagnosis of a cervical artery dissection is not uncommon and most frequently occurs within the first 180 days. FMD was independently associated with this complication. The development of a de novo pseudoaneurysm did not significantly increase the risk of subsequent ischemic or hemorrhagic events.

Background: There is much interest in drug development to prevent rebleeding after symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCM) and its neurologic sequelae. A recent randomized prospective controlled trial (AT CASH EPOC clinicaltrials.gov NCT02603328) demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter CCM iron deposition or SH rates. However, the consequences of discontinuing atorvastatin in CCM patients remain unknown. Given reports of rebound effects with discontinuation of statins, we here hypothesize that SH recurs more frequently in hemorrhagic CCMs after discontinuation of atorvastatin than placebo. Methods: We conducted 12-month (±1 month) post-treatment follow-up of all 80 patients randomized in the AT CASH EPOC trial (41 atorvastatin, 39 placebo) to identify potential recurrent SH from the date of trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded for < 90% compliance with study drug or its discontinuation <3 months during the trial, and for lack of follow-up. Cases were censored during follow-up upon CCM resection/radiation or atorvastatin initiation/re-initiation. Results: Follow-up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin.During follow-up, 4 SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and only 1 SH 395 days after discontinuing placebo. Kaplan–Meier curves demonstrated significantly lower symptomatic hemorrhage-free survival in the atorvastatin-discontinuation group (log-rank chi=4.136, p=0.042). The Gehan–Breslow–Wilcoxon test (chi=4.080, p=0.043) highlighted early divergence in recurrent SH risk. The hazard ratio was 0.162 (95% CI 0.027–0.977) for placebo vs. atorvastatin discontinuation. Conclusion: While there was no difference in SH rates during 2 years of treatment with atorvastatin versus placebo in randomized clinical trial, discontinuation of atorvastatin was associated with a significantly higher and earlier risk of recurrent SH compared with placebo discontinuation. This raises concern for a rebound effect during the year after statin withdrawal in hemorrhagic CCM patients, potentially mediated by reactivation of Rho-associated kinase. Additional studies are warranted to confirm these observations and to assess whether statin tapering or maintenance therapy can mitigate the risk of discontinuation in hemorrhagic CCM.

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.