Adult-onset seizure reflects the burden of acquired brain insults, but established disease-modifying preventive strategies are limited. We evaluated whether semaglutide initiation is associated with a lower incidence of adult-onset seizure compared with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs) in adults with type 2 diabetes. Using the All of Us Research Program, we emulated a population-based target trial in new-user, active-comparator cohorts from January 2018 to October 2023. We compared semaglutide vs other GLDs and semaglutide vs SGLT2i. Incident epilepsy or seizure was identified from diagnostic codes. Effects were estimated using inverse probability of treatment weighting with weighted Cox models and targeted maximum likelihood estimation (TMLE). Subgroup and sensitivity analyses with multiple outcome definitions and analytic approaches were conducted to assess the robustness of findings. We evaluated mediation through hemoglobin A1c (HbA1c) and body mass index (BMI) using the longitudinal Vansteelandt framework. We analyzed 10,213 patients in the semaglutide (n = 2,586, mean age, 60.1 years; 56.8% female) vs other GLDs cohort (n = 7,627, mean age, 63.7 years; 54.2% female) and 8,605 patients in the semaglutide (n = 2,814, mean age, 60.5 years; 66.2% female) vs SGLT2i cohort (n = 5,791, mean age, 64.4 years; 47.3% female). Semaglutide was associated with a lower risk of adult-onset seizure compared with other GLDs (weighted HR 0.44 [95% CI 0.25-0.79]; 4-year risk difference -1.78% [95% CI -2.58 to -0.98]) and SGLT2i (weighted HR 0.48 [95% CI 0.27-0.85]; 4-year risk difference -1.46% [95% CI -2.41 to -0.51]). TMLE estimated risk differences per 1,000 persons of -14.20 (95% CI -18.33 to -10.07) vs other GLDs and -7.62 (95% CI -11.65 to -3.60) vs SGLT2i, corresponding to numbers needed to treat of 70 and 131, respectively. Mediation was minimal for HbA1c (2.4% vs other GLDs; 6.5% vs SGLT2i) and BMI (0% vs other GLDs; 0.7% vs SGLT2i). Semaglutide initiation was associated with a lower risk of adult-onset seizure compared with SGLT2i and other GLDs in patients with type 2 diabetes, independent of glycemic and weight effects. Residual confounding, low event counts, and shorter follow-up limit causal interpretation. This study provides Class II evidence that semaglutide use was associated with a lower risk of adult-onset seizures compared with other GLDs and SGLT2i.

Disorders of arousal (DOAs) and sleep-related hypermotor epilepsy (SHE) share overlapping clinical features, making differential diagnosis challenging. Although video polysomnography remains the gold standard, EEG patterns to distinguish these conditions are not yet well defined. Slow-wave sleep (SWS) fragmentation is a key marker of DOA, but its characteristics in SHE remain unexplored. The aim of this study was to assess SWS fragmentation in DOAs and SHE, its potential diagnostic value, and overnight dynamics. Eighty-seven patients with DOAs (n = 47; mean age 23.90 ± 13.10 years; 44.7% children) or SHE (n = 40; mean age 25.11 ± 13.08 years; 27.5% children) underwent overnight polysomnography with blinded scoring. SWS fragmentation was quantified, distinguishing fast, mixed, and slow arousals, and its overnight evolution was evaluated. Groups were compared and diagnostic SWS fragmentation cutoff values were defined using receiver-operating characteristic curves. Total sleep time and sleep efficiency did not differ between groups. N2 sleep percentage was significantly lower in DOAs than in SHE (p = 0.008), whereas REM sleep percentage was higher in DOAs (p = 0.008). SWS percentage was comparable between groups (DOA: 23.50% ± 6.01; SHE: 21.11% ± 6.78). SWS fragmentation was significantly higher in DOAs than SHE (p < 0.001), particularly in slow and mixed components (p < 0.001), whereas SHE showed more fast interruptions (p = 0.006). Regarding overnight dynamics, linear mixed models revealed significant group × period interactions for SWS fragmentation index and slow/mixed arousal index, indicating distinct overnight patterns, with DOAs showing a marked reduction at the end of the night. In adults, the highest area under the curve (AUC) values were obtained for SWS Fragmentation and slow/mixed arousal indices with satisfactory classification performances (AUC 0.81 and 0.84, respectively). The SWS Fragmentation Index cutoff value of 6.64/h and slow/mixed arousal index cutoff of 2.40/h reached a sensitivity of 80.8% and specificity of 86.2%. In children, SWS Fragmentation Index ≥5.06/h achieved 76.2% sensitivity and 90.9% specificity (AUC 0.84) while slow/mixed arousal index showed excellent discriminative performance (AUC 0.96) with a cutoff of 2.10/h reaching 95.2% sensitivity and 90.9% specificity. SWS fragmentation, especially mixed and slow arousals, represents a supportive neurophysiologic marker that may assist the differential diagnostic process between DOAs and SHE. Quantitative SWS microstructure parameters may improve diagnosis and provide insight into pathophysiologic mechanisms.

The contribution of late-life vascular risk factors to dementia risk remains controversial. Because low blood pressure (BP) has been associated with worse clinical outcomes in frail individuals, we hypothesized hypertension, but not diabetes or smoking, is associated with higher dementia risk in robust than in frail older adults. We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) over 11 years (2011-2022). We included all community-living White and Black participants aged 67-89 years without dementia at baseline visit 5 (2011-2013) from ARIC-NCS field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; Minneapolis suburbs, Minnesota). The primary vascular risk factors measured at baseline included elevated BP (systolic BP 120-129 mm Hg and diastolic BP < 80 mm Hg), hypertension (systolic BP ≥ 130 mm Hg, diastolic BP ≥ 80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician's diagnosis, or use of diabetes medication), and former and current smoking (self-reported). We defined frailty status using the Fried criteria (5 components that include low energy, low physical activity, slowness, weakness, and weight loss). We estimated cause-specific hazard ratios (HRs) of incident dementia (ascertained from in-person neuropsychological assessments, semiannual participant or informant report, or surveillance of claims from hospitalizations and death certificates) with Cox proportional hazards models including a multiplicative interaction between vascular factors and frailty. HRs of dementia were then stratified by frailty (robust [no frailty components present] vs prefrail/frail [at least 1 frailty component present]). There were 377 (15.8%) dementia cases in robust participants (n = 2,383; mean age, 74.2 years; 55.4% female) and 812 (30.0%) in prefrail/frail participants (n = 2,710; mean age 76.4 years; 61.3% female). There was a significant interaction between BP and frailty on dementia risk (p = 0.026). For robust participants, HRs were 1.03 (95% CI 0.65-1.64) for elevated BP and 1.39 (95% CI 1.00-1.94) for hypertension relative to normal BP. For prefrail/frail participants, HRs were 0.68 (95% CI 0.49-0.95) and 0.82 (95% CI 0.66-1.01), respectively. Diabetes and current smoking were associated with higher dementia risk in both robust and prefrail/frail individuals. Late-life hypertension was associated with a lower relative risk of dementia in prefrail/frail participants, but the association was positive in robust participants. BP interpretation and management to support brain health in older adults could consider age-related functional status.

REM sleep behavior disorder (RBD) is characterized by loss of REM sleep atonia leading to dream enactment behavior. Isolated RBD (iRBD) is a known prodrome of alpha-synuclein pathology including Parkinson disease (PD) and dementia with Lewy bodies (DLB). Depression is also a common prodromal symptom of PD/DLB, and death by suicide is greater among individuals with PD. Patients with RBD are at greater risk of comorbid depression, but the prevalence of suicidal ideation in this population is unknown. We aim to assess the frequency of suicidal ideation and whether it is associated with autonomic, motor, and cognitive dysfunction in the North American Prodromal Synucleinopathy 2 (NAPS2) consortium. NAPS2 is a longitudinal study that includes measurements of autonomic function (SCOPA-AUT, orthostatic blood pressure), motor function (UPDRS), cognition (MoCA), and suicidal ideation (PHQ-9). We used a linear mixed-effects model, adjusting for age, sex, impulsivity, current carbidopa/levodopa use, and PHQ-9 score, to compare those who endorsed recent suicidal ideation with those who did not. Of 489 total participants, 40 endorsed suicidal ideation at the first visit (22.5% female, mean age 61.5) and 449 denied suicidal ideation (19.4% female, mean age 64.6). Higher PHQ-9 scores were significantly associated with higher SCOPA-AUT scores (+0.566; SE = 0.045; p < 2 × 10-16), higher UPDRS II scores (+0.372; SE = 0.03; p < 2 × 10-16), higher UPDRS III scores (+0.265; SE = 0.057; p = 3.80 × 10-6), and lower MoCA scores (-0.078; SE = 0.021; p = 3 × 10-4). The PHQ-9 score was not significantly associated with orthostatic blood pressure drops. Recent suicidal ideation occurred in approximately 1 of 12 patients with iRBD, a prodromal syndrome of PD with an increased risk of death by suicide. Individuals with iRBD who scored higher on PHQ-9 had on average greater autonomic dysfunction on SCOPA-AUT, more motor findings, and greater cognitive deficits. This study establishes that suicidal ideation is common in iRBD and suggests an iRBD phenotype that identifies individuals at high risk of depression and suicide. Future studies should expand on these findings and target interventions to decrease mortality and self-harm.

The brain-predicted age difference (brain-PAD) is considered a marker of neurodegeneration in people with multiple sclerosis (pwMS) and is associated with greater disability and cognitive impairment. However, the impact of disease-modifying factors (DMFs) on brain-PAD remains unknown, as does the extent to which their effect on disability and cognition is mediated through brain-PAD. The goal of this study was to investigate this in pwMS using a same-age cohort to eliminate calendar age as a confounding factor. Brain age was determined using brainageR from 3-dimensional T1-weighted MRI scans, and brain-PAD was calculated as the difference between predicted and chronological age. Disability was evaluated with the Expanded Disability Status Scale (EDSS), the 9-hole peg test (9HPT), and timed 25-foot walk test (T25FWT). Cognitive function was assessed using the Minimal Assessment of Cognitive Function in MS battery and converted to Z-scores. DMFs included lifetime smoking, alcohol consumption, physical activity, diet, leisure, and educational level, as well as body mass index (BMI) at 18 years. The effect of DMFs on brain-PAD was examined using linear regression, adjusting for sex. Mediation analyses were performed to investigate to what extent brain-PAD is a mediator of DMF effects on disability and cognition. The study included 117 healthy controls (mean age 52.8 ± 1.1 years, 74.3% female) and 242 pwMS (mean age 52.8 ± 0.9 years, 70.6% female), with a median disease duration of 15.2 years (interquartile range [IQR] 8.2-24.5) and a median EDSS score of 3.5 (IQR 2.5-4.0). Smoking (β = 0.20, p = 0.002), alcohol consumption (β = 0.18, p = 0.007), and BMI at 18 years (β = 0.15, p = 0.021) were associated with a higher brain-PAD, whereas higher physical activity (β = -0.13, p = 0.041) was linked to a lower brain-PAD. Mediation analysis demonstrated an indirect effect of smoking and alcohol on EDSS score (β = 0.039, p = 0.003; β = 0.039, p = 0.009), 9HPT (β = 0.057, p < 0.0001; β = 0.055, p = 0.004), T25FWT score (β = 0.045, p = 0.009; β = 0.044, p = 0.013), and cognitive performance (β = -0.066, p = 0.0004; β = -0.060, p = 0.016). Physical activity demonstrated an indirect effect of better performance on EDSS score (β = -0.027, p = 0.032) and cognitive performance (β = 0.042, p = 0.034). DMFs unrelated to MS, particularly smoking, alcohol use, and BMI at 18 years, accelerate brain aging. Brain-PAD mediates these effects and contributes to worsening disability and cognition, underscoring the potential of lifestyle interventions to mitigate neurodegeneration and preserve function in pwMS.

Adults with unexplained neurologic presentations often undergo extensive evaluations without timely diagnosis. Evidence supporting the clinical utility of rapid whole-genome sequencing (rWGS) in hospitalized adult populations remains limited. We evaluated the diagnostic yield of rWGS in adults hospitalized for unexplained neurologic manifestations and assessed clinical predictors of a phenotype-concordant genetic diagnosis. We performed a retrospective cohort analysis of adult inpatients (≥18 years) undergoing rWGS as part of a structured inpatient clinical genomics implementation at Mayo Clinic between June 2022 and September 2025. Testing was performed after primary team consultation and subsequent assessment by a clinical geneticist. We prespecified a neurologic cohort restricted to patients admitted to the neurology inpatient service in whom presenting neurologic phenotypes were the primary indication for hospitalization and genomics consultation. Patients with non-neurologic primary indications were excluded from this study. The primary outcome was a phenotype-concordant genetic diagnosis on rWGS determined by genotype-phenotype assessment. Analytic objectives included identification of clinical predictors of a phenotype-concordant genetic diagnosis, and a secondary outcome was rWGS-attributable changes in clinical management. Patients with and without phenotype-concordant diagnoses were compared using univariable logistic regression for categorical candidate predictors (odds ratios [ORs] with 95% CIs) and the t test for age. Among 96 adults who completed rWGS, 57 (59.4%) met criteria for the neurologic cohort (mean age 53.0 ± 18.0 years; 35.1% female). Thirteen of 57 (22.8%) received a phenotype-concordant genetic diagnosis involving IFIH1, CNBP, NOTCH1, C9orf72, FGF14, HUWE1, NLRP12, CCM2, PTPN11, FLNA, HEXA, PRNP, and ATXN8OS. Factors associated with a phenotype-concordant diagnosis included a family history of similar neurologic symptoms in first-degree or second-degree relatives (OR 7.4; 95% CI 1.9-31.5), multisystem involvement (OR 6.9; 95% CI 1.6-29.8), refractory psychiatric symptoms (OR 6.1; 95% CI 1.1-35.7), and unexplained ataxia (OR 4.0; 95% CI 1.1-15.1). rWGS directly altered clinical management in 2 cases, including initiation of immunotherapy for an NLRP12-associated autoinflammatory disorder and enrollment in a gene-therapy trial for adult-onset Tay-Sachs disease. In this tertiary-care inpatient cohort, rWGS identified a phenotype-concordant genetic diagnosis in nearly one-quarter of adults. Limitations include single-center design and preselection through specialized consultation, which may limit generalizability.

Recent randomized trials reported no overall functional benefit of endovascular treatment (EVT) for distal medium-vessel occlusion (DMVO) and did not identify consistent effect modifiers to guide patient selection. Consequently, the role of EVT-particularly for M2 occlusions-remains controversial. We investigated whether baseline clinical severity modifies the association between successful recanalization and 90-day outcome in patients with M2 occlusion. Multicenter retrospective cohort study at 2 tertiary stroke centers including consecutive adults with acute ischemic stroke due to M2 occlusion (January 2015-January 2023) triaged by multimodal CT and treated with EVT. The primary end point was functional independence (modified Rankin Scale [mRS] ≤ 2) at 90 days. Secondary end points included symptomatic intracerebral hemorrhage (sICH), mRS 0-1, and penumbra salvage volume (PSV). The primary analysis used multivariable logistic regression with baseline National Institutes of Health Stroke Scale (NIHSS) modeled linearly and an NIHSS×recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] ≥2b) interaction term. Johnson-Neyman probing and inverse probability weighting (IPW) were applied; a supplementary restricted cubic spline analysis was performed to explore potential nonlinearity. Among 147 patients, 85 (58%) achieved successful recanalization. The mean age was 74 years (SD 13), and 47% were female. Higher baseline NIHSS (adjusted odds ratio [aOR] 0.83 per point, 95% CI 0.73-0.94) and older age (aOR 0.96 per year, 95% CI 0.94-0.99) were associated with lower odds of functional independence. NIHSS significantly modified the association between recanalization and outcome (interaction p = 0.03). The magnitude of the association between successful recanalization and functional independence was larger at higher NIHSS. Model-based estimates suggested a descriptive crossover around NIHSS 10, whereas statistical evidence of benefit emerged only at higher NIHSS values. Successful recanalization was associated with greater PSV (+33 mL, p = 0.01). In the PSV interaction model, onset-to-imaging time differed by recanalization status (p < 0.01): time was positively associated with PSV in the mTICI ≤2a group, but near zero in mTICI ≥2b. IPW analyses were concordant. sICH occurred in 8.2% vs 4.8% (p = 0.42). In M2 occlusions, the magnitude of the association between successful recanalization and functional independence was larger at higher NIHSS and not reliably demonstrable at lower NIHSS. These findings support a severity-informed, individualized EVT approach while remaining hypothesis-generating rather than prescriptive for specific NIHSS thresholds. Major limitations include the retrospective observational design and potential residual confounding.

Epidemiologic studies exploring the effect of parity on Alzheimer disease (AD) yield mixed results, and little is known about how parity may modify the impact of AD pathology on brain and cognitive aging. We examined the effect of parity and AD pathology on hippocampal volume (HV) and cognitive changes in cognitively unimpaired (CU) postmenopausal women. Analysis was performed on CU postmenopausal women from the ALFA+ observational cohort based in the BarcelonaBeta Brain research center, who completed 1 or 2 visits spaced by ∼3 years (mean = 3.38, SD = 0.55) with reproductive data, cognitive testing (modified Preclinical Alzheimer's Cognitive Composite), CSF biomarkers (Aβ42 and Aβ40), and structural MRI. We used linear mixed-effects models to investigate the interactive effects of parity, time, and Aβ status (based on CSF Aβ42/Aβ40) on cognition and HV. APOE-ε4 status, age, and total intracranial volume were included as covariates. A total of 254 women were included in our analyses ranging from 49.2 to 73.4 years (mean age = 61.2) at visit 1. A significant interaction between parity and Aβ status was observed for cognitive decline and HV. In women with positive amyloid status, higher parity was associated with steeper cognitive decline (β = -0.035, 95% CI -0.068 to -0.003, p = 0.033) and lower HV across time points (β = -0.134, 95% CI -0.263 to -0.005, p = 0.036). In CU postmenopausal women, higher parity interacts with AD pathology to influence cognitive decline and HV reductions. These findings suggest that parity may affect resilience to AD pathology in preclinical AD stages.

Late-life dementia has a strong heritable component. While the APOE ɛ4 allele is the strongest genetic risk factor of Alzheimer disease (AD), polygenic risk factors also play a significant role. Cardiometabolic diseases (CMDs) and their risk factors predict dementia in many cohorts, but how genetic predictors of CMD influence dementia-related outcomes remains unclear. In this study, we examined the associations of polygenic risk scores (PRSs) for major CMDs and the established APOE risk alleles with dementia-related outcomes in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is enriched for Black participants underrepresented in late-life dementia research. We constructed PRSs for AD and related dementias (ADRDs) and CMDs, including stroke, coronary artery disease, venous thromboembolism, type 2 diabetes, atrial fibrillation, blood pressure (systolic blood pressure, diastolic blood pressure, and pulse pressure), and circulating lipid levels (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), using lead genome-wide significant genetic variants from the latest genome-wide association studies. We evaluated the predictive performance of each PRS on their primary end point and tested their associations with incident cognitive impairment (ICI), assessed using the 6-item screener and enhanced cognitive battery, and dementia as a contributing cause of death (DCCD). In addition, we explored the impact of APOE variants and, based on previous reports, local genetic ancestry at the APOE locus on these dementia-related outcomes. Up to 8,818 participants were analyzed (mean age 63.7 years; 58.9% female; 83.3% Black). For CMD PRS, we identified a significant association between PRS for pulse pressure and DCCD (hazard ratio [HR] 1.16, 95% CI 1.06-1.28, p < 1.76 × 10-3). We observed that the PRS for ADRD was associated nominally with DCCD (HR 1.12, 95% CI 1.00-1.25), but not with ICI among REGARDS participants, suggesting heterogeneity in associations across different cognitive-related end points. Furthermore, we identified a nominally significant (p < 0.1) attenuated effect of APOE risk alleles on ICI among those with African ancestry at the APOE locus, similar to previous reports. Higher PRS for pulse pressure was associated with increased DCCD risk, supporting shared genetic underpinnings between CMD and dementia.

Calcitonin gene-related peptide (CGRP) plays a central mechanistic role in migraine and is an established drug target. However, it remains unclear whether peripheral plasma CGRP levels meaningfully reflect disease activity. We investigated whether circulating plasma CGRP differs between individuals with migraine and healthy controls and whether concentrations vary across migraine subtypes, clinical status, and preventive treatment use. This cross-sectional observational study enrolled adults (≥18 years) with migraine with aura, migraine without aura, or chronic migraine primarily from specialized care. Healthy controls without personal or first-degree family history of primary headache disorders were mainly recruited through web-based advertisement. Venous blood was obtained by antecubital phlebotomy, and plasma CGRP was quantified in duplicate using a validated high-affinity radioimmunoassay. Controls were matched 1:4 to participants with migraine on age, sex, body mass index, and storage duration. The primary outcome was between-group difference in plasma CGRP concentrations. Group comparisons were performed using Mann-Whitney U tests. Regression models were performed to assess associations with clinical variables. A total of 588 participants with migraine and 147 matched controls were analyzed (mean age 43.1 ± 11.9 vs 41.5 ± 11.5 years; 88.8% vs 85.7% female). The median (interquartile range) plasma CGRP concentrations were lower in participants with migraine compared with controls (125 [68-173] vs 151 [118-199] pmol/L; p < 0.001). Subgroup analyses revealed no significant differences across subtypes (episodic vs chronic, with aura vs without aura), ictal vs interictal status, or preventive medication use (all p > 0.05). Sensitivity analyses restricted to headache-free participants confirmed the principal findings, demonstrating lower plasma CGRP concentrations across all migraine subgroups compared with controls (all p < 0.001). Multivariable models identified no clinical predictors of plasma CGRP levels. Sample storage duration did not correlate with measured levels (Spearman ρ = -0.032; p = 0.37). Plasma CGRP concentrations were modestly lower in migraine and did not vary by clinical subtype or disease state. These findings challenge the assumption that migraine is characterized by elevated circulating CGRP and suggest limited utility of plasma CGRP as a disease biomarker.

Alzheimer disease (AD) is increasingly viewed as a clinical-biological continuum, but the utility of biomarkers in individuals aged ≥80 years, the so-called "very old," remains uncertain, because of concerns about its clinical usefulness. This study aimed to determine the clinical impact and prognostic value of AD biomarkers in very old individuals. We performed a retrospective longitudinal cohort study within the Sant Pau Initiative on Neurodegeneration (SPIN, Barcelona, Spain), a memory clinic-based research cohort. Patients were referred from primary care physicians or community neurologists for evaluation within a public universal health care catchment area. We included SPIN participants evaluated between October 2013 and May 2024 who were aged ≥80 years and had mild cognitive impairment (MCI) at the baseline visit. Participants underwent standardized clinical and neuropsychological assessments and had CSF and plasma biomarker measurements available. AD biology was defined by the CSF phosphorylated tau at threonine 181/amyloid-β 42 ratio. Plasma phosphorylated tau at threonine 217 (p-Tau217) was evaluated for (1) diagnostic accuracy for AD biology and (2) prognostic associations with longitudinal cognitive change (Mini-Mental State Examination [MMSE]) and progression to dementia. Analyses used linear mixed-effects models for MMSE trajectories and Cox regression for dementia conversion. A total of 167 participants were included (mean age 82.3 years, 59% women) with a mean follow-up of 35.8 months; the ones with AD biology (n = 116, 69%) had worse baseline cognitive performance, particularly in memory, compared with those without (Cohen d = 0.34, p = 0.03). Plasma p-Tau217 showed excellent diagnostic accuracy for detecting AD biology (0.93, 95% CI 0.88-0.98; cutoff 0.19 pg/mL; sensitivity 94.5%; specificity 84%). Over time, participants with AD biology declined faster on the MMSE than those without (-0.47 vs -0.18 points per year; p < 0.01). Cox models showed an increased risk of progression to a dementia stage among individuals with higher plasma p-Tau217 concentrations (hazard ratio 1.49, 95% CI 1.05-2.13, p = 0.026). In very old individuals with MCI, AD biology (CSF) and plasma p-Tau217 identify individuals at higher risk of faster cognitive decline and progression to dementia. Limitations of this study include the single-center design and the modest sample size.

The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort. We analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline. Among 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of ≥1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by ≥ 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by ≥ 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35-62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E ε4 status, and baseline CDR-SB performance. Futility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.

The mechanisms underlying racial/ethnic differences in dementia incidence and pathology are multifactorial, and hypertension represents an actionable target for reducing these differences. We aimed to estimate the extent to which controlling for hypertension mediates racial/ethnic inequities in neuroimaging markers of brain aging. The Health and Aging Brain Study-Health Disparities cohort is a highly phenotyped, racially and ethnically diverse cohort of cognitive aging. We used marginal structural models with inverse probability weights to estimate total and controlled direct effects of race/ethnicity, hypertension, and systolic blood pressure (SBP) at baseline, with neuroimaging markers measured on average 2 years later. Neuroimaging markers of brain aging were measured at the 2-year follow-up. Among Black and Hispanic participants with any neuroimaging data at the second visit (overall N = 1,347), 68% and 71% were women, 75% and 67% had hypertension, and the mean age was 61 and 63 years, respectively. Black and Hispanic participants had greater white matter hyperintensity volume (WMHV) compared with non-Hispanic White (NHW) participants (n = 1,333, β [95% CI]: Black 2.08 [1.68-2.59], Hispanic 0.99 [0.91-1.08]). After analytically setting hypertension status to absent, Black-NHW inequities in WMHV were attenuated (β [95% CI]: 1.3 [1.01-1.65]). Black participants had lower amyloid deposition compared with NHW participants (n = 679, β [95% CI]: -0.29 [-0.46 to -0.12]), but analytically controlling for hypertension did not appreciably change estimates. Compared with NHW participants, Hispanic participants had lower Alzheimer disease meta-region of interest cortical thickness (n = 1,005, β [95% CI]: -0.20 [-0.34 to -0.07]), but neither hypertension nor SBP significantly mediated this difference. Medial temporal lobe tau-PET standardized uptake value ratio did not significantly differ in Black or Hispanic participants compared with NHW participants (n = 408). Black-NHW inequities in subclinical cerebral small vessel disease may be mitigated by population-level efforts to reduce hypertension prevalence. Future studies should extend this work to examine clinical outcomes.

Neurologic outcomes after pediatric large vessel occlusion (LVO) stroke are poor. In the absence of a pediatric randomized clinical trial, cohort and registry studies have demonstrated improved outcomes with thrombectomy compared with medical management alone. However, the benefit of thrombectomy in children with LVO and mild presenting symptoms remains uncertain. Our objective was to determine if thrombectomy is associated with superior functional outcomes compared with medical management alone in pediatric patients with acute LVO stroke and mild presenting symptoms. We undertook a case-control study pooling individual patient data from 4 published cohort studies on pediatric LVO stroke (Save ChildS, Save ChildS Pro, KidClot, Pediatric LVO Stroke Study), with patients treated at 75 centers across Europe, North America, and Australia between 2000 and 2023. Patients ≤18 years of age with acute LVO stroke on imaging and pediatric NIH Stroke Scale score ≤5 on admission were included. Patients treated with endovascular thrombectomy were compared with those treated with medical management alone. The primary clinical outcome was the functional status at 3 months after stroke, measured using the pediatric modified Rankin Scale and compared between groups using ordinal regression analysis. The primary safety outcome was the rate of symptomatic intracerebral hemorrhage. Pooled data identified 63 pediatric patients (female: n = 21, 33.3%; mean age 9.6 years, SD 5.1, range 0.5-18.0) who met the inclusion criteria. The cohorts were well balanced for IV thrombolysis status, age, sex, site and side of occlusion, ASPECTS, and stroke etiology. Thrombectomy treated patients (n = 25) had significantly better pediatric modified Rankin Scale scores at 3 months than medically managed patients (n = 38; odds ratio 5.5 [95% CI 1.22-24.81]; p = 0.027). In the medical management group, n = 13 (34.2%) of patients had early neurologic deterioration in the first 24 hours, compared with only one patient in the thrombectomy group (4%, p = 0.005). No symptomatic intracerebral hemorrhages occurred in either group. Thrombectomy in pediatric LVO stroke with mild presenting symptoms results in improved clinical outcomes compared with medical management alone and may prevent early neurologic deterioration. These findings can assist treating teams with acute clinical decision making in this complex clinical situation. This study provides Class III evidence that in pediatric patients with acute LVO stroke and mild presenting symptoms, thrombectomy results in better functional outcomes compared with medical management alone.

The association between breast cancer diagnosis and treatment and the risk of incident ischemic stroke remains unclear. We investigated ischemic stroke risk among breast cancer survivors and evaluated associations by age, follow-up duration, and type of cancer treatment. We conducted a nationwide, retrospective, matched cohort study using the Korean National Health Insurance Service database. Women aged 18 years and older with newly diagnosed breast cancer who underwent breast cancer surgery between January 2010 and December 2016 and had no prior stroke were identified. Each was matched 1:3 by birth year to cancer-free women. The primary outcome was first ischemic stroke, defined as hospitalization with International Classification of Disease, Tenth Revision codes I63/I64 plus inpatient brain CT or MRI. Subdistribution hazard ratios (sHRs) and 95% CIs were estimated using Fine-Gray models that accounted for death as a competing risk and adjusted for sociodemographic factors and cardiovascular and non-CV comorbidities. We analyzed 107,606 breast cancer surgery survivors (mean age, 50.0 years) and 322,818 matched cancer-free women. Over a mean 7.2-year follow-up, ischemic stroke occurred in 1,155 survivors (1.07%). Stroke risk was elevated shortly after breast cancer diagnosis (1-year sHR 1.59; 95% CI 1.34-1.89; 3-year sHR 1.17; 95% CI 1.05-1.30) compared with cancer-free women, with stronger associations at 3 and 6 months after diagnosis across all age groups. Over the long term, survivors had a slightly lower risk of stroke (sHR 0.94; 95% CI 0.88-1.00), and in a 1-year landmark analysis including only event-free individuals, the risk was lower (sHR 0.87, 95% CI 0.81-0.93). Among survivors, anthracycline use (sHR 1.25) and combined tamoxifen-aromatase inhibitor therapy (sHR 1.49) were associated with increased risk of stroke, whereas radiation therapy was associated with decreased risk (sHR 0.84). These associations attenuated and became nonsignificant beyond 1 year. Stroke risk was also higher among survivors with low income, hypertension, diabetes, or current smoking. The association between breast cancer and ischemic stroke risk is time dependent, with a short-term increase after diagnosis and treatment followed by a gradual decline over time. These findings highlight the need for proactive stroke risk management, including early CV assessment and ongoing monitoring for thromboembolic events during survivorship.

Continuation of antiseizure medication (ASM) during pregnancy is essential for seizure control in most women with epilepsy, yet few studies have characterized the neurocognitive phenotypes associated with prenatal ASM exposure, with limited data on newer agents. The aim of this study was to determine whether in utero exposure to specific types of ASM monotherapies is associated with poorer neurocognitive outcomes compared with ASM-unexposed children. This semiprospective cohort study included children aged 3-18 years born to women enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs. Children without major congenital anomalies who were exposed prenatally to carbamazepine (n = 20), lamotrigine (n = 23), levetiracetam (n = 20), valproate (n = 19), or topiramate (n = 11) monotherapy, or who were unexposed to ASMs (n = 19), were followed from birth and underwent standardized neuropsychological assessment by a neuropsychologist blinded to prenatal ASM exposure status. Primary outcomes included Full-Scale IQ (FSIQ) and index scores from the Wechsler Intelligence Scales; secondary outcomes assessed academic skills, memory, language, and executive functions. Generalized linear mixed-effects models were used to estimate associations between prenatal ASM exposure and cognitive outcomes, adjusting for maternal IQ, epilepsy characteristics, and relevant perinatal factors. Of 110 children assessed (mean age 9.6 years; 51% female), 91 were exposed to ASM monotherapy in utero and 19 were unexposed. Children exposed to valproate, levetiracetam, topiramate, or carbamazepine scored lower across multiple cognitive domains, including processing speed, verbal comprehension, visuospatial reasoning, and academic skills (Cohen d range = -0.8 to -1.0). The largest FSIQ differences were observed for topiramate (b = -17.4, 95% CI -30.6 to -6.1) and levetiracetam (b = -13.9, 95% CI -24.5 to -3.8). Lamotrigine-exposed children showed performance comparable to unexposed peers. Cognitive outcomes did not vary by ASM dose, likely because of smaller sample sizes. Prenatal exposure to topiramate, levetiracetam, valproate, and carbamazepine was associated with domain-specific cognitive vulnerabilities, particularly in IQ, processing speed, and academic functioning. Topiramate and levetiracetam exposure were linked to the largest IQ differences compared with unexposed children. While valproate is typically associated with the greatest risk, its impact seemed attenuated in this cohort. By contrast, cognitive performance in lamotrigine-exposed children was comparable to unexposed peers, suggesting that it may be comparatively safer with respect to cognitive outcomes. This study provides Class II evidence that in utero exposure to valproate, levetiracetam, topiramate, and carbamazepine, but not to lamotrigine, is associated with worse neurocognitive outcomes in children compared with unexposed children.

The efficacy of endovascular treatment for acute large vessel occlusion strokes has been demonstrated, but whether it can improve functional outcomes in patients with acute ischemic stroke (AIS) who only present with severe large vessel stenosis without occlusion has not yet been studied. This study investigates the effectiveness of immediate angioplasty or stenting on functional outcomes in AIS patients with severe intracranial stenosis without occlusion. We retrospectively included patients with AIS with symptom onset within 24 hours and imaging-confirmed severe intracranial stenosis (70%-99%, Warfarin Asprin Symptomatic Intracranial Disease criteria) of the culprit vessel from 7 centers in China between January 1, 2020, and December 31, 2024. We compared patients undergoing immediate angioplasty or stenting with those receiving standard medical treatment (SMT) alone. The primary outcome was the distribution of modified Rankin Scale (mRS) scores at 90 days. The treatment effect was estimated through multivariable adjusted models and inverse probability of treatment weighting (IPTW). Safety outcomes included symptomatic intracranial hemorrhage (sICH) within 24 hours and mortality within 90 days. A total of 242 patients were included, with a mean age of 65.7 years, and 86 patients (35.5%) were female. Ninety-six (39.7%) patients underwent immediate angioplasty or stenting, and 146 (60.3%) received SMT. The median 90-day mRS score was 1 (interquartile range 0-3) in the immediate angioplasty or stenting group and 1 (interquartile range 1-3) in the SMT group. The immediate angioplasty or stenting group showed a shift toward better functional outcomes on the mRS scores (adjusted common odds ratio [OR] 2.73 [95% CI 1.49-5.00], p = 0.001; after IPTW, OR 2.50 [95% CI 1.72-3.63], p < 0.001). There was no significant difference in the incidence of sICH (1.0% vs 1.4%; adjusted risk ratio 0.36 [95% CI 0.02-5.35], p = 0.46) or mortality (2.1% vs 1.4%; adjusted hazard ratio 1.01 [95% CI 0.92-1.11], p = 0.93). Among patients with AIS with severe intracranial stenosis without occlusion, immediate angioplasty or stenting was associated with improved 90-day functional outcomes compared with SMT alone. No significant difference was observed in the incidence of sICH or mortality. This study provides Class III evidence that in AIS patients with severe intracranial stenosis, immediate angioplasty or stenting was associated with improved 90-day functional outcomes compared with SMT.

Clinical trials in REM sleep behavior disorder (RBD) to delay or prevent the development of Parkinson disease (PD), dementia with Lewy bodies (DLBs), and multiple system atrophy (MSA) will soon begin. The Prodromal Synucleinopathy Rating Scale (PSRS) was developed to capture the breadth and severity of clinical burden of prodromal disease. We analyzed the clinicometric properties and reliability of the PSRS in the North American Prodromal Synucleinopathy (NAPS) cohort. PSRS ratings were examined for visits conducted from August 2022-June 2025 on participants who did not have overt PD, DLB, or MSA (n = 348). Clinician raters used clinical judgement to evaluate signs and symptoms within each domain. Scores range from 0 (none) to a maximum of 2-4 points per domain, with a total maximum score of 25. The domains include cognitive (COG), behavioral/psychiatric (PSY), motor-axial (MAX), motor-appendicular (MAP), autonomic (AUT), sleep (SLP), and sensory (SEN). Spearman correlations were generated between ratings for each domain, the total sum score (SUM), and with independent measures of similar constructs. Test-retest reliability for 20 case examples protocols among 20 different raters was quantified using Bayesian generalized linear mixed-effects model. Participants were 79% male with a mean age of 65.4 ± 10.4 years. The following correlations were statistically significant at p < 0.0001: COG with Montreal Cognitive Assessment (r = -0.42) and Clinical Dementia Rating-Sum of Boxes (r = 0.77); PSY with Neuropsychiatric Inventory-Questionnaire (r = 0.38); MAX and MAP with the Movement Disorders Society-Unified Parkinson Disease Rating Scale Motor (r = 0.65 and 0.75, respectively); AUT with Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (r = 0.39); SLP with Epworth Sleepiness Scale (r = 0.23); and SEN with Brief Smell Identification Test (r = -0.66). The PSRS SUM was correlated with the Functional Assessment Scale (r = 0.47), Schwab and England Activities of Daily Living (r = -0.58), and Clinician Global Impression of Severity (r = 0.29, p < 0.0001 for each). The inter-rater and intrarater reliability means ranged from 0.76 to 0.98. In this large multicenter RBD cohort, moderate to strong correlations were observed between PSRS domains and multiple independent measures of clinical burden. Reliability data were good to excellent. These findings demonstrate preliminary validity for the PSRS for measuring synucleinopathy clinical burden in those with RBD. NCT05826457 NAPS Consortium Website: naps-rbd.org/.

Parkinson disease (PD) is a progressive neurodegenerative disorder increasingly linked to gut microbiota dysbiosis, which may influence disease mechanisms and symptom expression. Fecal microbiota transplantation (FMT) targets the gut-brain axis, but clinical evidence remains inconsistent. This study aimed to evaluate the efficacy and safety of FMT in PD. We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with protocol registration in International Prospective Register of Systematic Reviews (CRD420251142846). MEDLINE, Embase, and the Cochrane Library were searched from inception through September 2025. Randomized controlled trials (RCTs) and observational studies enrolling adults with mild-to-moderate PD who received FMT through any administration route were eligible. The primary outcome was motor function assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) part III. Secondary outcomes included UPDRS part II, quality of life (Parkinson's Disease Questionnaire-39 [PDQ-39]), constipation severity (Wexner score), and adverse events. Random-effects models pooled effect estimates with 95% CIs, and exploratory meta-regression assessed follow-up duration, publication year, and sample size. Eight studies (5 RCTs and 3 observational studies) including 220 participants were analyzed. The mean age ranged from approximately 60 to 70 years, and women comprised about 40% of participants. FMT was associated with significant improvement in motor function (UPDRS part III: mean difference [MD] -9.67, 95% CI -16.81 to -2.53) and constipation severity (Wexner score: MD -3.91, 95% CI -7.68 to -0.13). Improvements in UPDRS part II and PDQ-39 were observed at 12 weeks but not sustained at 24 weeks. In RCT-only analyses, UPDRS part III improvement remained significant (MD -6.82, 95% CI -11.23 to -2.40), whereas other outcomes were not consistently significant. Meta-regression indicated that longer follow-up was associated with greater improvement in UPDRS part II (p = 0.043). FMT was generally well tolerated; however, gastrointestinal adverse events were more frequent in the FMT group (risk ratio 3.12, 95% CI 1.14-8.53), predominantly mild to moderate. FMT may provide short-term improvements in motor and gastrointestinal symptoms in PD, but effects appear transient. Small sample sizes, heterogeneity, and limited follow-up restrict conclusions, underscoring the need for larger randomized trials. Pooled estimates reflected evidence from observational studies and should be interpreted cautiously.

Recent enough to matter: Perceived temporal proximity, anxiety, and COVID-19 vaccine intent.