Lammers GJ, Plazzi G, Mignot E
… +13 more, Pizza F, Dauvilliers Y, Barateau L, Maruff P, Scammell TE, Latzman RD, Naylor M, Olsson T, Stukalin E, Tanaka S, Volfson D, Khachadourian V, Harel BT
JAMA Neurol
· 2026 Feb · PMID 41359331
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IMPORTANCE: 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 sl...IMPORTANCE: 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. OBJECTIVE: To explore the effects of oveporexton, an oral OX2R-selective agonist, on cognition in people with NT1. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: In this secondary analysis of the TAK-861-2001 randomized clinial trial, the OX2R agonist oveporexton improved NT1-associated cognitive symptoms in adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05687903.
IMPORTANCE: Prior authorization (PA) is widely used by insurers to control health care costs and promote high-value care, but it can create significant barriers to accessing medications. This is particularly concerning i...IMPORTANCE: Prior authorization (PA) is widely used by insurers to control health care costs and promote high-value care, but it can create significant barriers to accessing medications. This is particularly concerning in neurology, where timely treatment is critical to avoid disease progression and optimize patient outcomes. OBJECTIVE: To assess the consequences, barriers, and facilitators of PA policies affecting access to pharmacologic treatment in 6 common neurologic conditions-Alzheimer disease, Parkinson disease, multiple sclerosis, migraine, cerebrovascular disease, and epilepsy-with focus on impacts on patients, clinicians, and administrators. EVIDENCE REVIEW: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines for scoping reviews were followed, and the study protocol was registered on Open Science Framework. MEDLINE and Embase were searched up to November 1, 2024, using Ovid for studies that assessed the role of PA as a primary or secondary outcome for the 6 included neurologic conditions, or for neurology broadly if strongly applicable to the study aim, after the signage of the Affordable Care Act in March 2010. Abstract screening and full-text review were done in duplicate. Key information was charted in extraction, including study characteristics, demographics, methods, results, and implications for relevant stakeholders. The results were aggregated and thematically analyzed. FINDINGS: A total of 364 studies were identified using our search strategy on Ovid, 278 records were screened, and 20 studies were included in this review. The most frequently identified consequences for patients were delays in care (60%) and increase in disease activity (25%). The most frequently identified consequence for clinicians (35%) and administrators (15%) was time burden. The most common facilitators were the use of clinical pharmacists or technicians (20%) and health system specialty pharmacies (15%). CONCLUSIONS AND RELEVANCE: According to the results of this scoping review, PA can contribute to significant access barriers for people with neurological conditions and is associated with burden for all stakeholders involved. Reforms to PA can work towards more equitable access to medications for patients.
Seners P, Nehme N, Ter Schiphorst A
… +37 more, Charbonneau F, Chausson N, Belley M, Wacongne A, Kaaouana O, Henry C, Girbovan A, Bennani ON, Maïer B, Dupin M, Gerschenfeld G, Lun F, Marc G, Dassa J, Benoit T, Sablot D, Loeillot J, Rigal J, Smadja D, Scarcia L, Caroff J, Pico F, Henon H, Skerlak S, Basille F, Ben Hassen W, Marnat G, Allard J, Legris L, Bourcier R, Forestier G, Chivot C, Albers GW, Lansberg MG, Turc G, Papassin J, OPEN-WINDOW collaborators
JAMA Neurol
· 2026 Jan · PMID 41324934
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IMPORTANCE: In patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO), the benefit of intravenous thrombolysis (IVT) administered beyond 4.5 hours from the last time known well before endovascular th...IMPORTANCE: In patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO), the benefit of intravenous thrombolysis (IVT) administered beyond 4.5 hours from the last time known well before endovascular therapy (EVT) is uncertain. Recently, the TIMELESS trial failed to demonstrate a benefit of IVT in this setting, but this trial focused on patients directly admitted to comprehensive stroke centers (CSCs) with fast access to EVT. OBJECTIVE: To assess the efficacy and safety of IVT initiated beyond 4.5 hours in patients with AIS-LVO initially admitted to primary stroke centers (PSCs) and subsequently transferred to a CSC for EVT, allowing substantial time for the IVT to take effect. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective cohort study was conducted between January 2020 and December 2024, with 3-month follow-up, at 20 French PSCs. All consecutive patients with AIS-LVO admitted beyond 4.5 hours from the last time they were known well in the PSC and subsequently transferred to a CSC for EVT, with or without IVT administered prior to transfer, were eligible for inclusion. Data analysis was performed between May 2025 and July 2025. MAIN OUTCOMES AND MEASURES: The primary outcome was the 3-month modified Rankin Scale score, analyzed in the ordinal approach. Propensity score with overlap weighting (PSOW) balanced covariates between patients treated with IVT vs those without. RESULTS: A total of 584 patients were included, among whom 309 patients (52.9%) were female. Median (IQR) age was 71 (61-81) years, median (IQR) baseline National Institutes of Health Stroke scale score was 15 (10-19), median (IQR) time from last known well to PSC imaging was 10.5 (6.9-14.0) hours, and 232 patients (39.7%) received IVT before transfer. Advanced brain imaging (magnetic resonance imaging or computed tomography [CT] with CT-perfusion) was performed at the PSC in 544 patients (93.2%). IVT use before transfer was independently associated with a shift toward better 3-month outcomes (PSOW-common odds ratio [OR], 1.97; 95% CI, 1.33-2.92; P = .001) and higher odds of recanalization during transfer (PSOW-OR, 8.69; 95% CI, 3.16-23.87; P < .001) compared with those without. The rate of any intracerebral hemorrhage and symptomatic intracerebral hemorrhage were similar between groups. CONCLUSIONS AND RELEVANCE: In this multicenter cohort study, IVT initiated beyond 4.5 hours prior to interhospital transfer for EVT was associated with higher rates of recanalization during transfer and improved 3-month functional outcomes, without safety concerns. These findings offer encouraging support for clinical trials evaluating IVT in the late time window before interhospital transfer.
Malek-Ahmadi M, Sharma S, Stipho F
… +4 more, Denkinger M, Singh A, Brum WS, Ashton NJ
JAMA Neurol
· 2026 Jan · PMID 41324928
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IMPORTANCE: 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, bot...IMPORTANCE: 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. OBJECTIVE: 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. DATA SOURCES: PubMed, Embase, and EBSCOhost databases from inception to September 1, 2025. STUDY SELECTION: 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. DATA EXTRACTION AND SYNTHESIS: 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. MAIN OUTCOME AND MEASURE: 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. RESULTS: 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). CONCLUSION AND RELEVANCE: 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.
Neilson LE, Montaño I, May JL
… +6 more, Sicard S, Cho Y, Iliff JJ, Elliott JE, Lim MM, Scott GD
JAMA Neurol
· 2026 Jan · PMID 41284280
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IMPORTANCE: Obstructive sleep apnea (OSA) is associated with many health conditions, including dementia and early mortality. Prior epidemiological studies linking OSA with Parkinson disease (PD) are conflicting, and no s...IMPORTANCE: Obstructive sleep apnea (OSA) is associated with many health conditions, including dementia and early mortality. Prior epidemiological studies linking OSA with Parkinson disease (PD) are conflicting, and no studies have examined the influence of continuous positive airway pressure (CPAP), the criterion standard treatment for OSA, on PD risk. OBJECTIVE: To examine the association between OSA with incident Parkinson disease among US veterans and risk modification by CPAP. DESIGN, SETTING, AND PARTICIPANTS: This electronic health record (EHR)-based cohort study was conducted among US veterans from January 1, 1999, to December 30, 2022, with mean (SD) follow-up of 4.9 (1.8) years. Veterans with PD at the time of exposure or incomplete records were excluded. Data analysis was completed from September 2024 to September 2025. EXPOSURE: OSA was defined by its appropriate administrative code; CPAP usage was extracted from a semistructured medical interview field in the EHR. MAIN OUTCOMES AND MEASURES: The primary outcome, cumulative incidence of PD, was calculated adjusting for competing risk of death after balancing for age, race, sex, and smoking status. RESULTS: A total of 13 737 081 US veterans were screened, and 11 310 411 veterans (1 109 543 female veterans [9.8%]) with mean (SD) age of 60.5 (14.7) years were included in analyses. Of included veterans, 1 552 505 (13.7%) had OSA. Veterans with OSA demonstrated 1.61 additional cases of PD (point estimate; 95% CI, 1.13-2.09) at 6 years from diagnosis per 1000 people compared to those without OSA. Results were confirmed when adjusting for body mass index, vascular comorbidities, psychiatric conditions, and relevant medications and were of greater magnitude in female veterans. Case numbers were significantly reduced when treated with CPAP early in the disease course. CONCLUSIONS AND RELEVANCE: In this EHR-based cohort study, OSA appeared to be an independent risk factor for the later development of PD and could be modified by early treatment with CPAP. Effective screening measures and protocols for consistent adherence to CPAP may have large impacts on brain health.
Wee LE, Tan WZ, Chow JY
… +9 more, Lim JT, Chiew C, Chia PY, Dickens B, Ng LC, Ong B, Leo YS, Lye DC, Tan KB
JAMA Neurol
· 2026 Feb · PMID 41284268
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IMPORTANCE: 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...IMPORTANCE: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURE: DENV infection recorded in the national registry. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.
Ney JP, Steinmetz JD, Anderson-Benge E
… +4 more, Gillespie CW, Becker A, Steele X, Esper GJ
JAMA Neurol
· 2026 Jan · PMID 41284264
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IMPORTANCE: Nervous system health is a major contributor to population health, which is directly affected by neurological conditions and other disorders where nervous system damage occurs. OBJECTIVE: To quantify aggregat...IMPORTANCE: Nervous system health is a major contributor to population health, which is directly affected by neurological conditions and other disorders where nervous system damage occurs. OBJECTIVE: To quantify aggregated health loss from diseases affecting the nervous system, including neurological disorders; neurodevelopmental disorders; congenital, neonatal, and systemic illnesses; and infectious diseases in the United States. DESIGN, SETTING, AND PARTICIPANTS: This is a cross-sectional study of the Global Burden of Disease 2021 study data for nervous system health loss confined to the United States from 1990 through 2021 among the entire US population. Data analysis was performed from December 2021 to January 2025. EXPOSURE: Thirty-six unique conditions that cause harm to the nervous system. MAIN OUTCOMES AND MEASURES: Totals and age-standardized estimates with 95% uncertainty intervals (UIs) for disability-adjusted life-years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), total attributable deaths (where applicable), and prevalence. RESULTS: In 2021, of the US population of 332.7 million, disorders affecting nervous system health impacted 180.3 million (95% UI, 170.7 million to 190.4 million) US individuals and were the top cause of disability, with 16.6 million (95% UI, 12.9 million to 20.9 million) DALYs. The most prevalent conditions were tension-type headache (121.9 million; 95% UI, 109.4 million to 135.1 million), migraine (57.7 million; 95% UI, 50.1 million to 66.1 million), and diabetic neuropathy (17.1 million; 95% UI, 14.4 million to 19.9 million). Conditions with the greatest collective disability were stroke (3.9 million DALYs; 95% UI, 3.5 million to 4.2 million DALYs), Alzheimer disease and other dementias (3.3 million DALYs; 95% UI, 1.6 million to 6.9 million DALYs), diabetic neuropathy (2.2 million DALYs; 95% UI, 1.5 million to 3.0 million DALYs), and migraine (2.1 million DALYs; 95% UI, 0.4 million to 4.6 million DALYs). Compared with age-standardized metrics in 1990, the prevalence of disorders affecting the nervous system was nearly identical (-0.2%; 95% UI, -1.5% to 1.9%), with decreased attributable deaths (-14.6%; 95% UI, -18.3% to -11.3%) but increased YLDs (9.8%; 95% UI, 4.6% to 16.6%). By state, Mississippi, Alabama, and Louisiana had the largest age-standardized DALY rates, while New York, Massachusetts, and New Jersey had the smallest. CONCLUSIONS AND RELEVANCE: Disorders affecting the nervous system are highly prevalent and cause disability for millions of US individuals, with reduced mortality leading to more YLDS. The United States should prioritize efforts to combat these conditions with development and implementation of new and effective prevention strategies, therapeutics, and focused rehabilitation.
Katsanos AH, Whitlock RP, Belley-Côté EP
… +18 more, Brady K, Wang A, Srivastava A, Jacquin G, Weiss V, Volný O, Sramek M, Peeters A, Marto JP, Wrona P, Tsolaki A, Li L, Nucera A, Mikulik R, Perera K, Catanese L, Shoamanesh A, Sharma M
JAMA Neurol
· 2026 Jan · PMID 41247709
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IMPORTANCE: In the Left Atrial Appendage Occlusion Study III (LAAOS III), surgical occlusion of the LAA during cardiac surgery for patients with known history of atrial fibrillation (AF) substantially reduced the risk of...IMPORTANCE: In the Left Atrial Appendage Occlusion Study III (LAAOS III), surgical occlusion of the LAA during cardiac surgery for patients with known history of atrial fibrillation (AF) substantially reduced the risk of stroke. OBJECTIVE: To assess the impact of LAAO on ischemic stroke subtype and outcome. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc exploratory analysis of the LAAOS III randomized clinical trial. Data were adjudicated from June 28, 2023, to November 29, 2023, and the main analyses took place from December 18, 2023, to April 29, 2024. The LAAOS III trial recruited participants from 105 centers in 27 countries between July 2012 and October 2018. Patients with AF and a CHA2DS2-VASc score of at least 2 undergoing cardiac surgery for other indications were included in the analysis. INTERVENTIONS: Surgical LAAO plus standard care vs standard care alone. MAIN OUTCOMES AND MEASURES: For strokes occurring during the trial, the functional outcome as measured by the modified Rankin Scale (mRS) score at day 7 or discharge, mortality, the presence of cortical infarcts, and the occurrence of infarcts of presumed cardioembolic origin were examined. RESULTS: Of 4811 participants in the LAAOS III trial followed up for 3.8 years, 273 had a first ischemic stroke. The mean (SD) age of participants at the time of the first ischemic stroke was 75 (7) years, 104 were female (38%), and 169 were male (62%). Participants allocated to receive LAAO had reduced (common odds ratio [OR], 0.80; 95% CI, 0.65-0.99) mRS scores at 7 days or discharge and a lower risk for mortality at 30 days (16.5% vs 20.1%; hazard ratio [HR], 0.55; 95% CI, 0.31-0.97) after a stroke event. Participants allocated to LAAO had fewer cortical infarcts on neuroimaging (46.2% vs 61.3%; difference in proportions: -15.2%; 95% CI, -26.7% to -3.7%), as well as a lower proportion of ischemic strokes of presumed cardioembolic etiology when compared with ischemic strokes in the no-LAAO group (42.9% vs 57.9%; difference in proportions: -15.1%; 95% CI, -26.5% to -3.7%). CONCLUSIONS AND RELEVANCE: This study found that LAAO in patients with AF undergoing cardiac surgery was associated with a decreased risk of presumed cardioembolic stroke, reduced disability, and mortality from stroke. These findings underscore the benefit of LAAO for patients with AF undergoing cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01561651.