Approximately 450,000 Veterans are living with Alzheimer disease and related dementias (ADRD), and the high prevalence of ADRD represents a major public health challenge for the Veterans Health Administration. While advancing age and genetic predisposition are well-established ADRD risk factors, growing evidence suggests that additional modifiable factors may also play an important role. This study leveraged data from the VA Million Veteran Program (MVP) to (1) estimate 10-year incidence of ADRD and (2) evaluate associations between a broad range of individual-level risk and resilience factors and incident ADRD in a large, nationally representative sample of Veterans. This retrospective cohort study included Veterans aged ≥65 years at MVP enrollment who completed the MVP Baseline Survey and had VA electronic health record (EHR) data available. Individual-level variables including sociodemographic factors, military-specific characteristics, military environmental exposures (MEEs), health conditions, and health behaviors were characterized using MVP Baseline Survey data and supplemented with EHR data as available. The primary outcome was ADRD, which was determined using a validated algorithm based on International Classification of Diseases diagnosis codes extracted from the EHR. Associations between each risk/resilience factor and incident ADRD were examined using separate Cox regression models adjusted for age, sex, and education. The sample included 245,949 Veterans (age: mean 73.16, SD 6.84 years; 2.59% female). Approximately 4.56% (n = 11,216) of the sample developed ADRD over 10 years. History of traumatic brain injury (TBI; hazard ratio [HR] 2.96, 95% CI 2.76-3.17), depression (HR 2.93, 95% CI 2.82-3.04), and alcohol use disorder (AUD; HR 2.35, 95% CI 2.19-2.53) were the health factors most strongly associated with ADRD. ADRD risk was also elevated among Veterans with a history of exposure to Agent Orange (HR 1.09, 95% CI 1.03-1.14), chemical/biological warfare agents (HR 1.31, 95% CI 1.23-1.39), and pyridostigmine bromide tablets (HR 1.67, 95% CI 1.44-1.93). Findings identified TBI, depression, AUD, and MEEs as key variables associated with ADRD in Veterans. These factors may represent important targets for prevention and intervention efforts aimed at improving the long-term health of aging Veterans. Additional work is needed to clarify the mechanisms through which these factors influence ADRD risk and to establish whether observed associations are causal.

Nonstenotic (<50%) carotid plaques (NSCPs) are increasingly recognized as potential embolic sources in embolic stroke of undetermined source (ESUS), but their etiologic role remains uncertain because of limited data and the lack of standardized definition of high-risk plaque. We evaluated the clinical applicability and reliability of a modified CT angiography (CTA)-based Plaque-Reporting and Data System (RADS) classification for characterizing NSCPs in ESUS and examined the association between high-risk NSCPs and stroke laterality, the coexistence of competing stroke mechanisms, and the risk of stroke recurrence. We conducted a single-center cohort study (January 2016-June 2025) including consecutive ESUS patients with unilateral anterior circulation stroke and neck CTA, retrospectively and prospectively enrolled. NSCPs were classified using a modified CTA-based Plaque-RADS: (1) normal vessel wall; (2) maximum wall thickness (MWT) <3 mm; (3) MWT ≥3 mm (3ab) or ulceration (3c); (4) intraplaque hemorrhage (4a) or intraluminal thrombus (4c). Patients were stratified according to the presence of ipsilateral high-risk Plaque-RADS (categories 3-4) vs ipsilateral low-risk Plaque-RADS (categories 1-2). Inter-rater agreement for CTA-based Plaque-RADS was assessed, and associations between high-risk Plaque-RADS and stroke side, competing embolic sources, and recurrent ischemic events were evaluated with multivariable regression and survival analyses. Among 512 patients (median age 70 years, 47.8% women), 109 (21.3%) had ipsilateral high-risk and 403 (78.7%) had low-risk Plaque-RADS scores. Inter-rater agreement was excellent (Cohen κ = 0.83, p < 0.001). High-risk Plaque-RADS scores were more frequent ipsilaterally than contralaterally (21.3% vs 11.9%; adjusted odds ratio [aOR] 2.65, 95% CI 1.73-4.06, p < 0.001). Ipsilateral high-risk Plaque-RADS scores were inversely associated with cardioembolic sources, including atrial cardiopathy (34.9% vs 39.2%; aOR 0.59, 95% CI 0.36-0.96, p = 0.036), high-risk patent foramen ovale (2.7% vs 21.8%; aOR 0.14, 95% CI 0.03-0.60, p = 0.008), and atrial fibrillation detected after stroke (8.4% vs 17.5%; adjusted subdistribution hazard ratio [aSHR] 0.46, 95% CI 0.23-0.95, p = 0.037). During follow-up, overall stroke recurrence did not significantly differ, but ipsilateral high-risk Plaque-RADS scores were significantly associated with an increased risk of ipsilateral stroke recurrence (11.2% vs 3.0%; aSHR 3.19, 95% CI 1.15-8.83, p = 0.026). CTA-based Plaque-RADS can be reliably applied in routine clinical practice to categorize NSCPs in ESUS. Ipsilateral high-risk NSCPs are strongly associated with the index stroke side, lower prevalence of competing cardioembolic sources, and increased ipsilateral recurrence, supporting their role as a distinct causal mechanism within ESUS and underscoring the need for randomized trials on secondary prevention.

Sport-related head exposure characteristics (i.e., concussion history, sport contact classification, and total years of sport participation) are suggested to be associated with short-term and long-term health outcomes in competitive athletes. However, their relationship with intermediate health outcomes (specifically within 5 years of collegiate sport retirement) remains unknown. Therefore, we examined associations between sport-related head exposure characteristics and physical, mental, cognitive, and behavioral health measures among former collegiate athletes. Former collegiate athletes who completed a baseline evaluation between 2018 and 2021 and were evaluated within 5 years of collegiate graduation were included. Primary predictors included lifetime concussion history (0 [referent], 1-2, 3+), sport contact classification (unexposed [ref.], low, high), and total years of sport participation (continuous). Outcome measures collected included the Alcohol Use Disorders Identification Test, Brief Symptom Inventory-18 (BSI-18), Neuro-Quality of Life cognitive domain (Neuro-QoL), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Sport Concussion Assessment Tool (SCAT) symptom inventory, 12-Item Short Form Survey (SF-12), and Satisfaction with Life Scale. Twelve multivariable linear regression models with bootstrapping were constructed, with adjusted unstandardized beta coefficients (BAdj) and standard errors (SEs) estimated. Overall, 3,910 former collegiate student-athletes were examined; 48.6% were female, 73.0% attended a Division I school, 36.2% self-reported ≥1 lifetime diagnosed concussion, 38.1% participated in a high-exposure sport, and the median years since college graduation to assessment was 5.0. Independently, scores of BSI anxiety (BAdj = 1.24, SE = 0.36), BSI depression (BAdj = 0.88, SE = 0.37), global severity index [GSI] (BAdj = 2.66, SE = 0.91), PHQ-9 (BAdj = 1.34, SE = 0.40), PSQI (BAdj = 0.69, SE = 0.29), SCAT total symptom severity (BAdj = 5.14, SE = 1.31), and SF-12 mental composite score (BAdj = -3.39, SE = 0.83) were worse in athletes with 3+ concussions compared with athletes without a history of concussion. Athletes with 1-2 concussions vs no concussion history similarly had worse scores independently for BSI-18 GSI (BAdj = 0.88, SE = 0.35), anxiety (BAdj = 0.40, SE = 0.15), Neuro-QoL (BAdj = -0.97, SE = 0.36), PHQ-9 (BAdj = 0.77, SE = 0.19), PSQI (BAdj = 0.27, SE = 0.13), SCAT total symptom severity (BAdj = 2.13, SE = 0.55), and SF-12 mental composite score (BAdj = -1.80, SE = 0.41). Lifetime concussion history was the most common predictor of adverse self-reported health outcomes compared with other exposure characteristics, within 5 years of collegiate sport retirement. Despite the associations, most former athletes remained within normal clinical levels during this early postretirement period.

Status epilepticus (SE) is a neurologic emergency with possible long-term sequelae, including the development of epilepsy. We aimed to determine whether peri-ictal MRI abnormalities (PMA) are associated with unprovoked seizures after de novo SE. Adults without epilepsy and a first nonhypoxic SE were included from a prospective database of the Christian Doppler University Hospital, Salzburg, Austria. MRI scans performed within 48 hours of SE diagnosis were evaluated for PMA on diffusion-weighted imaging (DWI), T2-weighted fluid-attenuated inversion recovery (FLAIR), and arterial spin labeling (ASL). The outcome was unprovoked seizures, assessed by retrospective review of hospital records and telephone interviews. Cumulative risk of seizures stratified by PMA occurrence (PMA on DWI/FLAIR, hyperperfusion on ASL, no PMA) was evaluated through survival analysis. Multivariable analysis using logistic regression was conducted to assess the influence of PMA, etiology, semiology, and ictal EEG patterns on seizure occurrence. Among 135 patients included (median age 70 [interquartile range (IQR) 58-80] years and 55% female), 43 (32%) experienced seizures during a median follow-up of 23 (IQR 9-39) months. The cumulative seizure probability at 1 and 4 years was 34% (95% CI 17-47) and 61% (95% CI 37-75) in patients with PMA on DWI/FLAIR; 0% and 13% (95% CI 0-29) in patients with hyperperfusion on ASL; and 25% (95% CI 14-34) and 36% (95% CI 19-49) in those without PMA. Other SE features associated with higher seizure risk were treatment refractoriness (odds ratio [OR] 2.93, 95% CI 1.23-6.98, p = 0.02), longer SE duration (OR 1.003, 95% CI 1.001-1.004, p = 0.02), and lateralized periodic discharges on ictal EEG (OR 3.59, 95% CI 1.37-9.83, p = 0.005). In multivariable analysis, PMA on DWI/FLAIR (log-odds 1.23, 95% CI 0.13-2.33, p = 0.03) and remote etiology (log-odds 1.85, 95% CI 0.45-3.25, p = 0.009) were independently associated with increased seizure probability. PMA on DWI or FLAIR were independently linked to a cumulative seizure risk exceeding 60% after de novo SE, consistent with a diagnosis of epilepsy. The findings of our study may help guide long-term treatment decisions in patients with de novo SE.

Although diabetes mellitus (DM) is a well-established determinant of dementia risk, most studies have evaluated type 2 DM (T2DM) or any DM. The influence of type 1 DM (T1DM) on dementia risk remains unclear. We evaluated associations of T1DM and T2DM, separately, with incident dementia using linked electronic health records (EHRs). This prospective cohort study used previously collected survey and EHR data from the All of Us (AoU) cohort, a convenience sample of US adults. Eligible participants were 50 years or older and completed baseline surveys. Enrollment began in 2017, with data available through October 2023, along with records before enrollment. Mean follow-up from baseline was 2.4 years. We developed an algorithm to distinguish DM type based on count of T1DM encounters. This algorithm was validated against 2 reference measures: self-reported diabetes type and C-peptide values. Using AoU data, we classified participants as having no DM, T1DM, or T2DM. We ascertained incident dementia using ICD-9, ICD-10, and Systematized Nomenclature of Medicine codes in participants' EHRs. We estimated hazard ratios (HRs) and 95% CIs for the association of diabetes type with incident dementia using Cox proportional hazards models. Among 283,772 participants (mean [SD] age 64.62 [8.96] years; 56.7% women), 60.3% identified as non-Hispanic White and 13.3% as Hispanic/Latino. Optimal DM classification algorithm cutoffs varied by reference standard: self-reported diabetes: ≥1 T1DM EHR encounter (sensitivity: 0.59; specificity: 0.90) and C-peptide: ≥3 T1DM EHR encounters (sensitivity: 0.76; specificity: 0.79). Defining T1DM as having ≥1 T1DM encounter, 5,442 participants had T1DM. Compared with those without DM, participants with T1DM had higher dementia incidence (sociodemographic-adjusted HR 2.82; 95% CI 2.28-3.48) and those with T2DM also had elevated risk (sociodemographic-adjusted HR 2.08; 95% CI 2.87-2.31). Results were similar across sex, race, and ethnicity strata. In AoU, DM was associated with elevated dementia risk, with the highest risk among those with T1DM. These findings highlight the need to better understand mechanisms tying T1DM to dementia.

The aquaporin-4 (AQP4) water channel plays an integral role in clearing brain waste. However, little is known about whether variations in the AQP4 gene contributes to brain health or dementia risk. We aimed to determine whether a functional AQP4 haplotype was associated with cognition, brain volumes, or incident dementia. This study included participants from 2 prospective cohort studies. First, participants from the original, offspring, new offspring spouse, and generation 3 cohorts from the Framingham Heart Study (FHS; enrolled 1948-2005) were included with dementia follow-up until 2022. Original FHS participants were from Framingham, Massachusetts at the time of enrollment. Analyses were replicated for brain MRI outcomes and incident dementia with UK Biobank participants (enrolled 2006-2010) who were followed until 2022. All participants were dementia-free at the time of cognitive assessment, brain MRI, and commencement of dementia follow-up. Linear regression models were conducted to analyze the associations between AQP4 and the cognitive and brain MRI outcomes. Cox proportional hazard regression models were conducted to analyze the association between AQP4 and incident all-cause dementia risk. Data analysis spanned February 2023 to July 2025. The FHS sample comprised 3,847 participants (65% homozygote major, 31% heterozygote, 4% homozygote minor) with cognitive testing (mean age 61 ± 11 years; 54% women); 3,332 had brain MRI. Heterozygotes displayed better verbal episodic memory (β = 0.32, 95% CI 0.09-0.55, p = 0.007, N = 1,201) and larger hippocampal volumes (β = 0.09, 95% CI 0.02-0.16, p = 0.012, N = 1,052) compared with homozygote majors. Similar findings were observed in the UK Biobank; homozygote minors displayed larger hippocampal volumes (β = 0.05, 95% CI < 0.01-0.11, p = 0.035, N = 32,219) and lower amounts of diffusion tensor imaging measured free water (β = -0.09, 95% CI -0.16 to -0.03, p = 0.005, N = 31,807) compared with homozygote majors. Heterozygotes displayed a statistically significant lower rate of incident all-cause dementia (hazard ratio 0.93, 95% CI 0.88-0.98, p = 0.012, N = 114,868, incident cases = 5,625) compared with homozygote majors. Carrying at least 1 minor allele at an AQP4 haplotype (homozygote minors or heterozygotes) was linked to better verbal episodic memory, larger hippocampal volumes, lower amounts of free water, and lower dementia risk. Further studies are required to replicate these results among diverse samples.

To provide the clinically validated, nationwide estimates of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in Korea, and to describe their relative proportions. From January to March 2025, 47 referral hospitals participating in a nationwide hospital-based registry identified actively followed patients with MS, NMOSD, or MOGAD. Diagnoses followed international criteria, and antibody status was confirmed using validated CBAs. Actively followed patients had ≥1 outpatient visit in the prior 6 months. Centers provided demographics, treatments, and Expanded Disability Status Scale. Prevalence used national population data. A total of 4,196 patients were identified, 1,799 MS, 1,616 NMOSD, and 781 MOGAD (ratio 2.3:2.1:1). Mean age at onset was 33.4 ± 12.0 years for MS, 42.7 ± 14.7 for NMOSD, and 41.7 ± 17.8 for MOGAD, and the female-to-male ratios were 2.2:1 for MS, 5.1:1 for NMOSD (6.5:1 in aquaporin-4-IgG positive cases), and 1.5:1 for MOGAD. Crude prevalence estimates were 3.48, 3.13, and 1.51 per 100,000, respectively. This nationwide registry demonstrates a distinctive Korean CNS inflammatory demyelinating disease profile, with a relatively higher proportion of NMOSD and MOGAD reflecting the low prevalence of MS in East Asia.

Recent revisions to multiple sclerosis (MS) diagnostic criteria include the optic nerve as a site of dissemination in space, enabling this diagnosis in patients with acute optic neuritis (ON) and a single additional MS-typical location on MRI if dissemination in time (DIT) is demonstrated. We aimed to assess the frequency of non-MS diagnoses in this context. We retrospectively analyzed consecutive patients with inaugural acute ON and at least 1 MS-typical lesion in a single brain location on baseline MRI across 3 French centers. All patients met DIT criteria and underwent aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing. Final diagnoses were based on clinical, radiologic, and follow-up data. Among 96 patients (mean age 35.8 years; 70.8% female), 73 (76.0%) were diagnosed with MS and 23 (24.0%) with MOG antibody-associated disease (n = 18) or neuromyelitis optica spectrum disorder. Longitudinally extensive lesions, bilateral involvement, chiasmal enhancement, or optic perineuritis were observed in 100% of non-MS patients and 24.6% of patients with MS (difference 75.4%, 95% CI: 64.3-86.6; p < 0.001). All patients without these patterns were ultimately diagnosed with MS. AQP4 and MOG antibody testing, along with careful orbital MRI interpretation, is recommended in patients with ON meeting minimal new MS criteria.