Cognitive symptoms negatively impact people with narcolepsy type 1 (NT1). While the effects of orexin receptor 2 (OX2R) agonists have been explored on diagnostic features of the disorder (excessive daytime sleepiness and cataplexy), effects on cognitive symptoms are not characterized. To explore the effects of oveporexton, an oral OX2R-selective agonist, on cognition in people with NT1. This is a secondary analysis of the TAK-861-2001 phase 2, 8-week, parallel-group, double-blind, placebo-controlled randomized clinical trial, conducted from January 2023 to December 2023, with a 4-week follow-up period. TAK-861-2001 was a multicenter study conducted in clinical settings. Eligible participants were 18 to 70 years of age, with an International Classification of Sleep Disorders, Third Edition diagnosis of NT1. Data analysis was performed from July 2024 to July 2025. Participants were randomized 1:1:1:1:1 to twice-daily oral oveporexton or matching placebo, dosed 3 hours apart, in dose groups of 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo, or placebo/placebo, for 8 weeks. Cognitive symptoms were assessed using the Psychomotor Vigilance Task (PVT) for attention, the Continuous Paired Associate Learning (CPAL) test for memory, and the One Back (ONB) test and International Digit Symbol Substitution Test-symbols (IDSST-s) for executive function. Of 161 eligible individuals screened, 48 did not meet study inclusion criteria, 1 withdrew, and 112 were included in the study. Of 112 participants, mean (SD) age was 34.0 (11.5) years, and 58 participants (51.8%) were female. A total of 112 participants were randomized and received 1 or more doses of oveporexton (0.5/0.5 mg, n = 23; 2/2 mg, n = 21; 2/5 mg, n = 23; 7 mg, n = 23) or placebo (n = 22). Oveporexton improved attention, memory, and executive function over 8 weeks. Least-squares (LS) mean placebo-adjusted changes from baseline were -10.77 (95% CI, -16.74 to -4.79), -9.45 (95% CI, -15.66 to -3.24), -8.60 (95% CI, -14.84 to -2.36), and -8.69 (95% CI, -14.90 to -2.47) PVT lapses with 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo doses, respectively. LS mean placebo-adjusted changes were -22.52 (95% CI, -34.95 to -10.10), -16.92 (95% CI, -30.12 to -3.71), -15.51 (95% CI, -28.82 to -2.21), and -17.59 (95% CI, -30.50 to -4.68) for CPAL errors; -0.05 (95% CI, -0.10 to -0.01), -0.07 (95% CI, -0.12 to -0.02), -0.07 (95% CI, -0.12 to -0.02), and -0.05 (95% CI, -0.10 to 0.00) units for ONB log10-transformed performance speed; and 4.72 (95% CI, -1.38 to 10.83), 7.33 (95% CI, 1.06-13.61), 7.85 (95% CI, 1.75-13.95), and 11.82 (95% CI, 5.75-17.89) for IDSST-s correct responses. In this secondary analysis of the TAK-861-2001 randomized clinial trial, the OX2R agonist oveporexton improved NT1-associated cognitive symptoms in adults. ClinicalTrials.gov Identifier: NCT05687903.

This cross-sectional study assesses trends in annual out-of-pocket and total health care costs among commercially insured US individuals with multiple sclerosis younger than 65 years from 2002 to 2021.

Blood-based biomarkers (BBMs) demonstrate high accuracy in detecting Alzheimer disease (AD) pathological changes in symptomatic individuals. In autosomal dominant AD and in individuals with Down syndrome, both populations with near-universal development of AD pathology, elevations in BBMs are detectable years before clinical onset, supporting their utility for identifying preclinical disease in these cases. Among BBMs, plasma phosphorylated tau 217 (p-tau217) exhibits strong concordance with established in vivo markers of AD pathology. However, its ability to identify older adults without cognitive impairment who are amyloid-positive remains variable across studies and settings. To assess the standardized effect size of mean differences and classification accuracy of p-tau217 for published studies that compared amyloid-positive and amyloid-negative older adults without cognitive impairment. PubMed, Embase, and EBSCOhost databases from inception to September 1, 2025. Observational studies or randomized clinical trials with baseline data on individuals without cognitive impairment who were classified as either amyloid positive or amyloid negative and reported numeric data for p-tau217 levels. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline was used for this study. Two authors independently carried out literature searches to identify studies with older adults without cognitive impairment who were classified as either amyloid positive or amyloid negative where p-tau217 was quantified. The standardized mean difference (Hedges g) was used to characterize differences in mean p-tau217 levels. A pooled area under the curve (AUC) value was used to summarize the diagnostic accuracy of p-tau217 in identifying amyloid-positive individuals. Between-study heterogeneity was investigated using subgroup and sensitivity analyses. Publication bias was assessed using Egger tests. Data for 7834 participants (2533 amyloid positive, 5301 amyloid negative) from 18 publications were analyzed. A large effect size was observed for p-tau217 (Hedges g = 1.50; 95% CI, 1.33-1.68). Values for p-tau217 also demonstrated high accuracy for identifying amyloid-positive individuals without cognitive impairment (AUC = 0.87; 95% CI, 0.85-0.90). These findings demonstrate that plasma p-tau217 can reliably detect AD pathology in the preclinical stage. These findings support the clinical utility of plasma p-tau217 as a scalable, minimally invasive tool for early identification of AD, particularly in settings where timely intervention with disease-modifying therapies may offer the greatest benefit in slowing or preventing disease progression.

This case report describes a unique presentation of Kelch-like protein 11 antibody-associated paraneoplastic encephalitis in an 81-year-old woman with a high-grade neuroendocrine carcinoma consistent with metastatic Merkel cell carcinoma.

With increasing global incidence of acute dengue virus (DENV) infection, more accurate estimates of the burden of neurological events following infection are required; however, population-based estimates are lacking. To evaluate the risk and excess burden of neurological events in a cohort of DENV-infected adults in the acute postinfectious period vs population-based comparators without DENV infection. This was a retrospective, population-based cohort study in Singapore. National registries were used to construct a cohort of all adults (aged ≥18 years) infected with DENV from January 1, 2017, through December 31, 2023, for whom the index date (time 0 [T0]) was taken as the date of notification, and a cohort of uninfected population-based comparators, for whom T0 was randomly assigned to match T0 distribution in DENV-infected cases. As the period overlapped with the COVID-19 pandemic, individuals infected with SARS-CoV-2 within 30 days of T0 were additionally excluded, as were individuals who died before T0 and uninfected comparators with no prior health care contact. Data analysis was performed from January 1, 2017, through March 30, 2024. DENV infection recorded in the national registry. New-incident neurological events, including any neurological event, memory loss, movement disorders, and other neurological disorders (eg, fatigue or malaise, encephalitis or encephalopathy), following DENV infection were identified using national health care claims records, and risk was assessed over the acute follow-up period. Odds of new-incident neurological events in DENV-infected cases vs uninfected comparators were estimated using overlap-weighted logistic regression at 30 to 90 days after T0. A total of 65 207 confirmed DENV-infected cases (mean [SD] age, 48.4 [17.8] years; 34 876 [53.5%] male) were compared against 1 616 865 uninfected comparators (mean [SD] age, 54.8 [18.3] years; 730 702 [45.2%] male). At 30 days following DENV infection, individuals with DENV infection, compared with uninfected individuals, had elevated odds of any new-incident neurological event (adjusted odds ratio [aOR], 9.69; 95% CI, 6.59-14.90), memory loss (aOR, 3.19; 95% CI, 1.36-8.69), movement disorders (aOR, 7.10; 95% CI, 2.49-29.18), and other neurological events (aOR, 14.32; 95% CI, 8.61-26.04); risk trajectories diverged up to 90 days after infection. However, the overall excess burden was modest, with less than 1 excess event per 100 cases. The DENV-infected cases, compared with uninfected individuals, had increased odds of memory loss (aOR, 2.99; 95% CI, 1.30-7.87) and movement disorders (aOR, 6.38; 95% CI, 2.23-25.96) only among those aged 60 years or older and in cases infected during DENV serotype 3 transmission. DENV infection was associated with significantly higher odds of acute new-incident neurological events following infection, although the excess burden was modest. Older adults should be monitored for a wider spectrum of potential neurological complications following DENV infection.

This Viewpoint proposes 5 concrete steps to prevent neurological disorders.

This essay advocates for community-engaged research as a means to help overcome the delay in disseminating research findings among the general population.

Annual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions. To provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs. The Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM. Demographic, clinical, and angiographic characteristics. The primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort. A total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01). The annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.

This case report describes a case of iatrogenic cerebrospinal fluid–venous fistula as a previously unreported mechanism of cerebrospinal fluid leak following lumbar puncture.

This Viewpoint describes strategies to support involvement of primary care practitioners in neurological care.