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Background A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. Methods We conducted a 12‐month posttreatment follow‐up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow‐up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow‐up. Cases were censored during follow‐up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. Results Follow‐up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage‐free survival in the atorvastatin‐discontinuation group (log‐rank χ 2 =4.136, P =0.042). The hazard ratio was 0.162 (95% CI, 0.027–0.977) for placebo versus atorvastatin discontinuation. Conclusions Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis‐generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603328.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Background and Objectives: Cervical artery dissection (CeAD) is a leading cause of ischemic stroke in younger adults, yet sex-specific variations in its clinical presentation, imaging characteristics, and outcomes remain underexplored. We aimed to evaluate these differences using data from a large, multicenter registry. Methods: We analyzed data from the STOP-CAD registry, which includes patients with radiologically confirmed non-traumatic CeAD enrolled between 2015 and 2021 across multiple centers. Clinical and imaging characteristics were compared between men and women using multivariable logistic regression. Outcomes assessed included ischemic stroke recurrence at 180 days, excellent functional outcome (modified Rankin Scale [mRS] 0–1) at 90 days, symptomatic intracerebral hemorrhage (sICH), and mortality. Results: Among 4,023 patients with CeAD, 1,783 (44.6%) were women. Compared to men, women were younger (median age: 42 vs 50 years), more likely to have a history of migraine (26.9% vs 8.3%) and connective tissue disorders (14.3% vs 5.8%), and presented more frequently with non-ischemic symptoms such as headache, neck pain, or tinnitus (adjusted OR [aOR] 2.0; 95% CI, 1.8–2.3; p<0.001). Women had significantly higher odds of vertebral artery dissection (OR, 1.3; 95% CI, 1.2-1.5; p<0.001), multivessel involvement (OR, 2.1; 95% CI, 1.7-2.5; p<0.001), and pseudoaneurysm formation (OR, 1.3; 95% CI, 1.1-1.6; p=0.003). Despite these differences, there was no significant sex-based difference in key clinical outcomes: excellent functional recovery at 90 days (OR 0.94; 95% CI 0.76-1.15 p=0.542), ischemic stroke recurrence at 180 days (OR 0.56 CI 0.23-1.3 p=0.213), or mortality (OR 0.83; 95% CI 0.47-1.48, p=0.529). Conclusion: In this large international cohort, we observed women with CeAD were younger, more likely to present with non-ischemic symptoms with distinct imaging features. These underscore the need for heightened clinical suspicion of CeAD in women presenting with atypical symptoms, even in the absence of ischemic deficits or conventional vascular risk factors, and suggest that sex-specific phenotyping may enhance diagnostic accuracy and early management.

Background: The management of asymptomatic high-grade carotid stenosis remains challenging, particularly in identifying individuals at highest risk for hypoperfusion-related stroke. Impaired cerebrovascular reactivity (CVR) has emerged as a potential predictor of future cerebrovascular events. Objective: To perform a systematic review and meta-analysis to quantify the association between impaired CVR and the risk of ipsilateral ischemic stroke or TIA in patients with asymptomatic high-grade carotid stenosis/occlusion. Methods: A systematic literature search of PubMed, Embase and Scopus was conducted from inception till July 2025. Eligible studies included asymptomatic patients with ≥70% carotid stenosis or occlusion who underwent CVR assessment and reported ipsilateral ischemic stroke or TIA outcomes. Pooled relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Forest plots were generated, and heterogeneity was assessed using the chi-square test and the I 2 statistic. Results: Six prospective observational studies including a total of 361 patients with asymptomatic high-grade carotid stenosis/occlusion (mean age 70.4 years; 73.6% male; 71.2% with hypertension; 28.6% with diabetes; 29.6% current or former smokers) were included in the analysis. Of these, 120 patients had impaired CVR and 241 had preserved CVR. Transcranial Doppler (TCD) was the most frequently used modality to assess CVR, with acetazolamide or CO 2 as the vasodilatory stimulus. Following CVR assessment, patients were monitored for a weighted mean follow-up of 26.2 months (range: 21.5 to 42.5 months). The incidence of ipsilateral ischemic stroke or TIA was 14.2% in patients with impaired CVR versus 2.1% in those with preserved CVR (RR 3.98; 95% CI 1.62–9.76; P = 0.003; Figure 1). When limited to ipsilateral ischemic stroke alone, the incidence was 21.4% in the impaired CVR group compared to 4.3% in the preserved CVR group (RR 3.35; 95% CI 1.54–7.25; P = 0.002; Figure 2). Conclusions: Impaired CVR is associated with a 3- to 4-fold increased risk of ipsilateral ischemic stroke or TIA in patients with high-grade carotid stenosis/occlusion. CVR assessment may help stratify risk and guide individualized management in this population.

Background: Patients with cervical artery dissection (CAD) have a higher prevalence of cerebral aneurysms, likely due to underlying vasculopathies. Understanding risk factors and outcomes in this population may inform screening and management strategies. Methods: We conducted a post-hoc analysis of the STOP-CAD study, a multicenter international registry of patients with non-major trauma-related CAD across 63 centers. Cerebral aneurysms were identified based on medical history and intracranial vascular imaging obtained for dissection diagnosis. We compared demographic, clinical, laboratory, and imaging characteristics between patients with and without aneurysms. Variables with p<0.05 in univariate analysis were entered into a multivariable binary logistic regression to identify independent predictors. Clinical outcomes including ischemic stroke and symptomatic intracranial hemorrhage at follow-up were compared between both groups. Results: Out of 4023 patients included in the STOP-CAD study, 116 (2.9%) had at least one incidental cerebral aneurysm. In adjusted binary logistic regression, patients with cerebral aneurysm were more likely to have a history of migraine (aOR 1.78 95% CI 1.15-2.75, p=0.009), history of hypertension (aOR 1.65 95% CI 1.12-2.43, p = 0.010), known connective tissue disorder (aOR 3.47 95% CI 1.71-7.03), history of dissection (aOR 2.63 95% CI 1.31-5.28, p = 0.007), and a dissecting aneurysm at the site of the dissection (aOR 1.94 95% CI 1.25-3.01, p = 0.003). At follow-up, the presence of a cerebral aneurysm was not associated with ischemic stroke (7.8% vs. 5.6% p>0.1), but with a trend towards increased odds of symptomatic intracranial hemorrhage (3.4% vs. 1.2%, p = 0.062). Conclusions: Patients with CAD and concurrent incidental cerebral aneurysm were more likely to have a history of migraine headaches and markers of underlying vasculopathy and had a non-significantly increased risk of intracranial hemorrhage at follow-up. Further studies are needed to identify best practices for surveillance and risk stratification in this subgroup.

Introduction: AI-driven software has been recommended as a means of triaging suspected large vessel occlusions (LVOs) on CT angiography (CTA), and different solutions are now commercially available. This study compared the performance of two software packages, Brainomix 360 Triage LVO and Rapid LVO, in prospective, real-world use. Methods: Consecutive patients scanned for suspected stroke at 3 comprehensive stroke centres from May to July 2024 (3 months) were included in the study. CTA, where available, was processed in real time by both Rapid and Brainomix software. Ground truth on vessel occlusion was ascertained using clinical review of electronic medical records. Occlusion location was coded as intracranial internal carotid artery terminus (ICA-T), middle cerebral artery (MCA) M1 or MCA M2. If more than one occlusion was observed, the most proximal of these was taken as the primary vessel affected. Results: There were 561 suspected stroke patients scanned during the study period across the three sites. Of these, CTA was sent for processing by both Rapid LVO and Brainomix 360 Triage LVO for 359 cases. Cases were excluded if no contrast was detected (n=17), leaving 342 cases (Table 1). Of these, proximal LVO (ICA-T or MCA M1) was confirmed in 14 cases and MCA M2 occlusions were present in 6 cases. Table 2 shows the LVO detection results for all cases from the two software packages. For both devices, sensitivity was higher when considering only proximal occlusions (ICA-T or M1). Performance was similar overall, but there was a trend towards differing sensitivity for more distal occlusions. As a composite measure, area under the curve (AUC) was higher for Brainomix than Rapid (Figure 1) but this difference was not significant. The positive predictive value (PPV) was low for both software packages due to the low incidence of LVO in the patient population. Conclusions: This study demonstrated consistent performance of two AI software devices, Brainomix 360 Triage LVO and Rapid LVO, for detection of LVO on CTA imaging, in prospective, real-world use. The low number of positive cases in the dataset (N=21) is a limitation of the study. There was a trend towards different performance for more distal vessel occlusion locations. Overall, the sensitivity observed in this dataset was in line with reports from previous retrospective studies for both software packages and underlines the importance of prospective evaluation to understand real-world performance.

Background: The optimal role of advanced cardiac imaging in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that advanced imaging would provide greater diagnostic utility than transthoracic echocardiography with bubble study (bTTE). Methods: We retrospectively analyzed adults ≥18 years admitted with ESUS/cryptogenic stroke or recurrent embolic stroke with known atrial fibrillation (Aug 2024–Aug 2025). Patients with incomplete workup or known stroke mechanism prior to advanced imaging were excluded. Transesophageal echocardiography (TEE), cardiac MRI (CMRI), or CT heart morphology (CTH) were considered diagnostic if thrombus, patent foramen ovale (PFO), aortic plaque, or valvular pathology was detected. Outcomes included (1) etiology determination, (2) management change, and (3) diagnostic yield comparison between bTTE and advanced imaging. Results: Of 588 ischemic strokes, 178 met inclusion criteria; 48 were excluded for incomplete workup. Among 130 eligible patients, 65 (50%) underwent advanced imaging (40 TEE, 19 CTH, 6 CMRI). Etiology was identified in 41.5% (95% CI 30–54%), and management was changed in 40.0% (95% CI 29–52%). Compared with bTTE alone (14.6% yield), advanced imaging identified additional etiologies in 42.9% (McNemar p<0.001). Advanced imaging was more frequently performed in younger patients (mean 59.6 vs 69.2 years, p<0.001), while posterior circulation strokes were associated with higher odds of positive findings (OR 5.25, 95% CI 1.01–27.2). Conclusions: Advanced cardiac imaging identified a potential etiology and changed management in ~40% of ESUS/cryptogenic strokes, significantly outperforming bTTE. Although younger patients more often underwent advanced imaging in this cohort, only posterior circulation strokes predicted clinically actionable findings. Routine incorporation of advanced cardiac imaging into ESUS evaluation may improve diagnostic accuracy and treatment decisions.

Background: Previous studies have reported the mean difference in homocysteine level in patients with and without silent brain infarction. However, evidence regarding the rate of silent brain infarcts in the presence versus absence of hyperhomocysteinemia remains limited. Objective: We aim to perform a systematic review and meta-analysis to compare the rate of silent brain infarcts in patients with hyperhomocysteinemia compared with patients with normal or low homocysteine levels. Methods: A systematic search of PubMed, Embase, Web of Science, Scopus were searched from inception to June 18, 2025. Eligible studies compared the rate of image-confirmed silent brain infarcts in patients with hyperhomocysteinemia versus those with normal homocysteine levels. The primary outcome was the rate of silent brain infarcts; the secondary outcome was cognition assessed by the Mini-Mental State Examination (MMSE). Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model, and heterogeneity was assessed using I 2 statistics. Subgroup analyses were performed according to increasing hyperhomocysteinemia cutoffs (>12 μmol/L and 9–12 μmol/L) as defined in the included the studies. Results: Four observational studies involving 2331 patients were included (mean age was 58.0±6.4 years, 45.8% women). Of these, 1087 had hyperhomocysteinemia and 1244 had normal levels. The rate of silent brain infarcts was 23.3% (253/1087) in patients with hyperhomocysteinemia versus 22.8% (284/1244) in controls (OR 1.82; 95% CI 1.11-3.00; P = 0.02, Figure 1A). The association was higher in studies using a > 12 µmol/L cutoff (OR 3.08; 95% CI 1.85-5.11; P < 0.0001, Figure 1B). Patients with hyperhomocystinemia had lower MMSE score compared with controls (mean difference of -1.55; 95% CI -3.60-0.50; P = 0.14, Figure 2). Conclusions: Hyperhomocysteinemia is associated with increased risk of silent brain infarcts and numerically lower cognitive performance. Findings suggest a possible dose-dependent relationship between homocysteine level and silent stroke risk. Prospective studies are needed to determine whether homocysteine is a modifable therapeutic tharget for reducing silent infarcts and cognitive decline.

Objective: Patent foramen ovale (PFO) closure is recommended for patients younger than 60 years with embolic stroke of undetermined source (ESUS) or cryptogenic stroke, but it’s role in patients older than 60 years remains unclear. We aim to investigate the benefit of closure in patients older than 60 with ESUS or cryptogenic stroke. Methods: Patients older than 60 years with ESUS or cryptogenic stroke from several large tertiary hospitals were recruited, who received a PFO closure after multidisciplinary brain-heart case conference, compared to age-matched cohort patients with ESUS or cryptogenic stroke. The primary outcome included recurrent ischemic stroke that occurred up to a median follow up of 5 years following PFO closure between two groups. The safety outcome was the occurrence of any complications after PFO closure, including new onset atrial fibrillation (AF). Results: A total of 102 patients (Table 1) were included (mean age 66±4), 56 male (55%), who received a PFO closure. Procedure-related complications, including new onset transient AF were low (1%). After following patients up to 5 years, patients with PFO closure demonstrated a relatively low incidence of recurrent ischemic stroke (3.9%, 4/102), compared to age-matched control cohort with a total of 97 patients (mean age 67±4), which had higher incidence of stroke recurrency (8.2%, 8/97) (Table 2). Kaplan-Meier event curve (Figure 1) reveals a trend of reducing recurrent stroke in patients with PFO closure but not achieved statistical significance. Conclusions: In patients with cryptogenic stroke or ESUS who are older than 60 years, PFO closure demonstrated safety profiles with a noticeable trend of reducing recurrent ischemic stroke compared to their age-matched counterparts. Prospective randomized trials are warranted in this young-older population.

Introduction: Plasma biomarkers of Alzheimer’s disease (AD), including amyloid-β (Aβ42/Aβ40), phosphorylated tau (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) have shown strong reliability in predicting dementia risk. White matter hyperintensities (WMH) represent a major vascular contributor to dementia. We investigated how plasma biomarkers of AD interact with WMH on MRI to influence incident dementia risk. Methods: We included dementia-free participants from the Atherosclerosis Risk in Communities (ARIC) Study who underwent MRI and plasma biomarker assessment at Visit 5 (2011–2013). WMH was quantified and considered continuously (log-transformed and standardized), and in tertiles. Plasma biomarkers were log-base-2-transformed. Cox proportional hazards models were used to estimate dementia risk over 10 years associated with plasma biomarkers and WMH, independently and multiplicatively. Models were adjusted for demographic variables (age, sex, race, and education), vascular risk factors (hypertension, diabetes, smoking status, body mass index, and estimated glomerular filtration rate), and APOE ε4 status. Results: Among 1,538 participants (aged 67- 90 years, 29% Black), 30% ( N = 462) developed dementia over the 10-year follow-up period. For every doubling of plasma Aβ42/Aβ40 , indicating lower amyloid burden, dementia risk decreased, while doubling of p-tau 181 , NfL, and GFAP were each associated with increased dementia risk, in separate models; each of these associations was independent of WMH (Table 1). Additionally, dementia risk increased per SD increase in WMH, independent of each plasma biomarker. Although no multiplicative interaction terms reached statistical significance (p<0.05), there was suggestive evidence that Aβ42/Aβ40 and GFAP have smaller effect sizes on dementia risk in subgroups at the highest WMH tertile (p-interactions<0.10; see Table 2). Discussion: Plasma biomarkers and WMH independently predict dementia risk over 10 years, though there remained limited evidence of multiplicative effects. Plasma biomarkers may be less important for dementia risk in individuals who also have extensive WMH. These findings emphasize the importance of incorporating both AD-specific plasma markers as well as indicators of cerebral small vessel disease, such as WMH, into dementia risk profiling.