Lancet Neurology最新文献

{"title":"Plasma phosphorylated tau 217 concentrations, APOE genotype, and timing of cognitive impairment in individuals across diverse racial and ethnic groups: a pooled analysis of prospective cohort studies.","authors":"Yuexuan Xu, Tamil Iniyan Gunasekaran, Yian Gu, Dolly Reyes-Dumeyer, Angel Piriz, Danurys Sanchez, Diones Rivera Mejia, Martin Medrano, Rafael A Lantigua, Lawrence Honig, Rachael Wilson, Ramiro Eduardo Rea Reyes, Jennifer J Manly, Adam M Brickman, Corinne D Engelman, Sterling Johnson, Sanjay Asthana, David A Bennett, Melissa Petersen, Sid O'Bryant, Badri N Vardarajan, Richard Mayeux","doi":"10.1016/S1474-4422(26)00313-3","DOIUrl":"10.1016/S1474-4422(26)00313-3","url":null,"abstract":"<p><strong>Background: </strong>Plasma tau phosphorylated at threonine 217 (p-tau217), a biomarker of Alzheimer's disease neuropathological changes, can increase before overt symptoms occur. However, individuals with similar p-tau217 concentrations but different genetic backgrounds might differ in their risk or timing of cognitive decline. We aimed to determine whether APOE genotype provides additional prognostic information beyond plasma p-tau217 concentration for estimating the risk and timing of cognitive impairment.</p><p><strong>Methods: </strong>We did a pooled analysis of participant-level data from seven multi-ethnic prospective cohorts of older adults, including individuals with no cognitive impairment at increased risk of dementia and individuals with mild cognitive impairment or dementia, recruited through academic research centres and community-based settings in Canada, Dominican Republic, and USA. Data were collected from 1992 to 2025. This study included data from participants with plasma p-tau217 measurements, clinical cognitive status, APOE genotype, and complete covariate data. The primary outcome was cognitive impairment, defined as mild cognitive impairment or dementia. Baseline analyses included all eligible participants; longitudinal analyses were restricted to participants with no cognitive impairment at baseline and with at least one follow-up clinical assessment. We evaluated whether APOE-ε4 carrier status modified the risk and timing of cognitive impairment associated with plasma p-tau217 concentration modelled as a continuous variable. Associations of baseline p-tau217 concentration with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by APOE-ε4 and with interaction terms. Timing and prognostic performance were evaluated using survival analyses, discrimination measures, and random survival forests.</p><p><strong>Findings: </strong>Among 8873 participants with available plasma p-tau217 concentration and clinical data who were examined for eligibility, 8582 participants (5652 [65·9%] female and 2930 [34·1%] male) were included in the baseline analysis. Mean age was 70 years (SD 10), and 1380 (16·1%) were Black, 4056 (47·3%) were non-Hispanic White, and 3146 (36·7%) were of Hispanic or other ethnic origin. 4569 (53·2%) participants had no cognitive impairment at baseline and were included in the longitudinal analysis. At baseline, higher p-tau217 concentrations were associated with cognitive impairment (odds ratio 1·77, 95% CI 1·42-2·20) and this association was stronger in APOE-ε4 carriers (2·25, 1·52-3·34) than in non-carriers (1·52, 1·35-1·72). Higher p-tau217 concentrations at baseline were also associated with incident cognitive impairment (hazard ratio 1·41, 95% CI 1·22-1·64; for 1-SD increase of p-tau217 levels), with a stronger association in APOE-ε4 carriers (1·76, 1·36-2·26) than in non-carriers (1·26, 1·12-1·42). Each 1-SD increase in p-tau217 concent","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1010-1024"},"PeriodicalIF":54.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of blood biomarkers to understand responses to lecanemab treatment.","authors":"Natalie S Ryan","doi":"10.1016/S1474-4422(26)00359-5","DOIUrl":"10.1016/S1474-4422(26)00359-5","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"967-969"},"PeriodicalIF":54.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic changes in plasma biomarkers of Alzheimer's disease in patients treated with lecanemab: a longitudinal cohort study.","authors":"Rui Mu, Anna Hofmann, Katherine Gong, Menghan Liu, Alex Roussak, Joseph Lowery, Yike Chen, Madeline Paczynski, Zachary Posey, Yuchen Cheng, Ying Xu, Yunchang Xie, William J B Powell, Inez Oh, Aditi Gupta, Nicholas Sykora, John Budde, Steven Funk, Tammie L S Benzinger, David M Holtzman, John C Morris, B Joy Snider, Randall J Bateman, Suzanne E Schindler, Carlos Cruchaga","doi":"10.1016/S1474-4422(26)00284-X","DOIUrl":"10.1016/S1474-4422(26)00284-X","url":null,"abstract":"<p><strong>Background: </strong>Anti-amyloid antibodies slow cognitive and functional decline in individuals with early symptomatic Alzheimer's disease, but few studies have examined changes associated with these treatments in plasma biomarkers linked to neurodegeneration. We analysed changes in a panel of 130 plasma proteins and their associations with conversion to amyloid PET negative status and cognitive changes in patients receiving lecanemab infusions as part of their clinical care.</p><p><strong>Methods: </strong>This longitudinal cohort study included patients with early symptomatic Alzheimer's disease and positive amyloid biomarkers who were identified as candidates for biweekly lecanemab infusions based on the US Food and Drug Administration label and consented to blood collection at the Washington University Memory Diagnostic Center (St Louis, MO, USA) between July 17, 2023, and Oct 10, 2025. Lecanemab was administered as a 10 mg/kg intravenous infusion every 2 weeks. Patients underwent clinical assessments and blood draws approximately every 6 months over up to 2 years. Research participants enrolled at the Knight Alzheimer Disease Research Center (Knight ADRC; St Louis, MO, USA) between May 3, 1996, and Feb 27, 2025, and who did not receive anti-amyloid antibodies, were included as control groups (an amyloid β-negative [Aβ-] group without cognitive impairment and an untreated group with cognitive impairment). The primary outcome was change in plasma concentrations of protein biomarkers associated with Alzheimer's disease pathology with lecanemab treatment. Associations between plasma biomarker changes and number of lecanemab infusions were examined using regression and mixed-effects models, with adjustment for demographics.</p><p><strong>Findings: </strong>The study included 197 patients in whom lecanemab infusions had been started (lecanemab group), as well as 173 patients in whom lecanemab had been ordered but not yet started, who were combined with 1139 research participants with cognitive impairment from the Knight ADRC cohort to form the untreated control group with cognitive impairment (n=1312). An additional 458 research participants formed the Aβ- control group without cognitive impairment. In the lecanemab group, the median patient age was 73 years (IQR 69-77); 104 (53%) were female and 93 (47%) were male; and most participants were White (187 [98%] of 190 with available data) and non-Hispanic (183 [97%] of 188 with available data). 130 biomarkers were classified into four distinct trajectories, with 34 showing significant changes (false discovery rate <0·05) in the lecanemab group. The trajectories were: normalising, with biomarkers shifting towards concentrations found in Aβ-individuals without cognitive impairment (eg, phosphorylated tau [p-tau]217, MAPT, and GFAP); overcorrecting, with biomarkers shifting towards and then beyond concentrations found in Aβ- individuals without cognitive impairment (eg, amyloid β peptides)","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"997-1009"},"PeriodicalIF":54.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical relevance of multiple sclerosis genetics: from susceptibility to disease severity and progression.","authors":"Lise Torp Jensen, Ralf Gold, Gil McVean, Kathrine E Attfield, Lars Fugger","doi":"10.1016/S1474-4422(26)00356-X","DOIUrl":"https://doi.org/10.1016/S1474-4422(26)00356-X","url":null,"abstract":"<p><p>Large-scale genome-wide association studies have identified hundreds of multiple sclerosis risk loci, most of which implicate immune pathways and establish multiple sclerosis as a highly polygenic, immune-mediated disease. These findings help explain why immune-modifying therapies suppress relapses and new lesion formation. However, susceptibility genetics does not adequately explain disability accumulation, variation in disease course, or treatment response. Evidence from rare-variant studies, genetic studies of disease severity and disability progression, epigenetic analyses, gene-environment studies, and Epstein-Barr virus research is beginning to extend this genetic framework from susceptibility to disease expression. Still, the direct clinical relevance of this research remains constrained by modest individual-level predictive value, underpowered studies of genetic determinants of disease severity and disability progression, complex regulatory mechanisms linking variants to function, and restricted generalisability across populations. At present, multiple sclerosis genetics is most useful for interpreting mechanisms, prioritising therapeutic targets, supporting causal inference, informing biomarker discovery, and enriching research cohorts. Future clinical value will likely depend on integrating genetic architecture with longitudinal clinical, imaging, biomarker, and multi-omic data to identify the contexts in which prevention or treatment is most likely to succeed.</p>","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":""},"PeriodicalIF":54.6,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Degenerative cervical myelopathy: early detection and the potential for preventing disability.","authors":"Carl M Zipser, Markus Hupp, Gergely David, Jan Valošek, Najmeh Kheram, Maryam Seif, Michèle Hubli, Paulina S Scheuren, Jan Rosner, Martin Schubert, Reto Sutter, Michael G Fehlings, Lindsay Tetreault, Allan R Martin, Benjamin Davies, Mark Kotter, José Miguel Spirig, Alan J Thompson, Armin Curt, Mazda Farshad, Patrick Freund","doi":"10.1016/S1474-4422(26)00314-5","DOIUrl":"https://doi.org/10.1016/S1474-4422(26)00314-5","url":null,"abstract":"<p><p>Degenerative cervical myelopathy (DCM), the most common non-traumatic spinal cord injury, is a prevalent, progressive, and highly disabling neurological disease, causing heterogeneous impairment ranging from sensory loss and impaired hand dexterity to gait, balance, and autonomic dysfunction. Disability often persists despite surgical decompression, and untreated disease can progress to irreversible neurological injury, including tetraplegia. Current clinical management is largely reactive, with diagnosis and intervention typically only after neurological deterioration has become clinically apparent and radiographic evidence of cervical myelopathy is established. Advances in multimodal diagnostics over the past 5 years are now enabling the detection of subtle spinal cord injury, biological disease activity, and subclinical neurodegeneration before overt clinical disability. Quantitative spinal cord MRI, advanced neurophysiological assessments, dynamic biomechanical metrics, and sensitive functional testing provide complementary tools for early detection, risk stratification, and prognostication. Together, these approaches are redefining DCM as a disease that should be managed proactively. Evidence supports decompressive surgery in patients with moderate-to-severe disease, whereas in milder disease or in spinal stenosis that might develop into DCM, the management of patients should be interdisciplinary, with active surveillance to detect early deterioration or decompressive surgery in selected cases. Improved prediction of disease trajectories and clearer evidence on long-term outcomes could enable selective earlier intervention and help to prevent neurological disability.</p>","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":""},"PeriodicalIF":54.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.","authors":"Giuseppe Plazzi, Ronald R Grunstein, Emmanuel Mignot, Gert Jan Lammers, David T Plante, Erik Buntinx, Rafael Del Río Villegas, Hailu Chen, Alexandra Lovett, Michael J Doane, Craig Hopkinson, Bhaskar Rege, Julie Himes, Yves Dauvilliers","doi":"10.1016/S1474-4422(26)00278-4","DOIUrl":"10.1016/S1474-4422(26)00278-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p&lt;0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sle","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"889-899"},"PeriodicalIF":54.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting orexin signalling in narcolepsy.","authors":"Jeongyeon Hwang, Thomas E Scammell","doi":"10.1016/S1474-4422(26)00316-9","DOIUrl":"10.1016/S1474-4422(26)00316-9","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"874-875"},"PeriodicalIF":54.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Finding more intracranial aneurysms that will never rupture.","authors":"Kaiwen Wang, Qian Zhang, Zheng Wen, Chengcheng Zhu, Xiaolin Chen, Shuo Wang, Qingyuan Liu","doi":"10.1016/S1474-4422(26)00315-7","DOIUrl":"10.1016/S1474-4422(26)00315-7","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"877-878"},"PeriodicalIF":54.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of unruptured intracranial aneurysms according to comorbidities, risk factors, country, and time period: a systematic review and meta-analysis.","authors":"Judith Dremel, Viktoria Rücker, Camilo Badel, Andreas Ziebart, Monique Vlak, Svetlana Hetjens, Amr Abdulazim, Steffi Jírů-Hillmann, Peter Heuschmann, Gabriel J E Rinkel, Nima Etminan","doi":"10.1016/S1474-4422(26)00276-0","DOIUrl":"10.1016/S1474-4422(26)00276-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The incidence of aneurysmal subarachnoid haemorrhage declined between 1980 and 2010, which coincided with a decline in smoking and prevalence of hypertension. We aimed to investigate whether the decrease in subarachnoid haemorrhage incidence is paralleled by declines in unruptured intracranial aneurysm (UIA) prevalence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;For this systematic review and meta-analysis, we searched Embase, PubMed, and Web of Science for articles published in any language from Jan 1, 2011 to Dec 31, 2025, and reassessed 68 articles published before March 1, 2011 from a 2011 systematic review and meta-analysis. Articles were eligible for inclusion if they used a cross-sectional or case-control design and provided the crude number of participants and those with UIA. We only included studies reporting numbers of UIA separately from ruptured aneurysms and with ten or more patients. Summary data were independently extracted by JD with AZ or CB and conflicts were resolved by GJER. The primary outcome was proportion of participants with UIA. Relative to a hypothetical reference population (mean age 50 years, 50% women, and no comorbidities), age and/or sex-adjusted prevalence ratios (PRs) for regions, comorbidities, and risk ratios (RRs) for female sex, smoking, and hypertension were estimated using generalised linear mixed models. A time trend analysis was done by binomial meta regression using the mid-year of data acquisition. We assessed the certainty of evidence using GRADE. The study was registered with PROSPERO, number CRD420261296728.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Our search screened 4708 studies. 67 reassessed and 95 newly identified articles, reporting on 316 131 participants and 11 822 people with UIAs, were included in our meta-analysis. In the reference population, the estimated prevalence of UIAs was 3·9% (95% CI 3·0-5·1). The prevalence of UIAs in individuals with atherosclerosis was 5·5% (4·7-6·4; 2229 of 40970 participants) and the adjusted PR was 1·3 (95% CI 0·8-2·0) compared with the reference population. For positive family history of aneurysmal subarachnoid haemorrhage (aSAH) or UIA, the UIA prevalence was 7·9% (5·6-11·1; 412 of 4252 participants) and the adjusted PR was 2·4 (0·5-11·2). For connective-tissue disorder, the UIA prevalence was 10·3% (6·5-16·0; 94 of 879 participants) and the adjusted PR was 3·9 (2·0-7·6). For autosomal dominant polycystic kidney disease (ADPKD), the UIA prevalence was 12·8% (9·2-17·6; 293 of 1990 participants) and the adjusted PR was 4·4 (1·5-12·6). RRs were for current smoking 1·4 (1·2-1·6; 798 of 27911 participants), for having hypertension 1·6 (1·5-1·7, 4043 of 83053 participants), and for female sex 1·9 (1·8-2·0; 3415 of 65020 women and 2122 of 76130 men). In studies on healthy individuals with MR angiography or CT angiography as imaging modality, the prevalence in 2016-2022 was 6·6% (6·3-6·8; 2904 of 41191 participants). The adjusted PR was 1·8 (1·1-2·8) ","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"911-925"},"PeriodicalIF":54.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tolerability, safety, and efficacy of atogepant versus topiramate in adults with migraine (TEMPLE): a randomised, head-to-head, phase 3b trial.","authors":"Uwe Reuter, Annelies Van Dycke, Jan Versijpt, Dagny Holle-Lee, Mark Kristof Farkas, Stewart J Tepper, Giovanna Forero, Lei Luo, Hua Guo, Eric Cohen, Brett Dabruzzo, Pranav Gandhi, Krisztian Nagy","doi":"10.1016/S1474-4422(26)00214-0","DOIUrl":"10.1016/S1474-4422(26)00214-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Oral calcitonin gene-related peptide (CGRP) receptor antagonists such as atogepant have been approved for preventive treatment of migraine but have not been compared directly with conventional oral non-specific preventive treatments. Topiramate is a widely used conventional oral non-migraine-specific preventive treatment for migraine but its use is often limited by poor tolerability. We aimed to evaluate the tolerability, safety, and efficacy of atogepant versus topiramate in adults with migraine, to provide direct comparative evidence to help inform treatment selection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;TEMPLE was a phase 3b, randomised, double-dummy, active-controlled trial with a 24-week double-blind treatment period and a 52-week open-label treatment period, done in sites with experience in diagnosing and treating migraine across 12 countries (Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Portugal, and the UK). Participants had a history of migraine and at least 4 migraine days per month on average across the 3 months before screening and during the combined screening and baseline period. Participants were randomly assigned 1:1 to atogepant (60 mg once daily) or topiramate (highest tolerated dose of 50 mg/day, 75 mg/day, or 100 mg/day) using interactive response technology. The primary endpoint assessed tolerability by measuring treatment discontinuation owing to treatment-emergent adverse events during the double-blind period in the safety population (all participants who received ≥1 dose of the study treatment during the double-blind period). Secondary efficacy endpoints related to clinical efficacy were at least 50% reduction from baseline in mean monthly migraine days and change from baseline in mean monthly migraine days during months 4-6 in the modified intention-to-treat population (all randomised participants who received ≥1 dose of study treatment, had an evaluable baseline period of eDiary data, and had ≥1 evaluable postbaseline 4-week [1 month] period of eDiary data within 24 weeks after first dose of study medication [month 1 to month 6], regardless of whether on study treatment or off study treatment). TEMPLE is registered with ClinicalTrials.gov (NCT05748483) and EU Clinical Trials Register (2022-501172-25-00); the double-blind period is completed and the open-label period is ongoing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Between Oct 7, 2023, and April 28, 2025, 730 participants were screened, 545 were randomly assigned, and 540 (479 [89%] female and 61 [11%] male, 517 [96%] White) were included in the safety population (atogepant n=273; topiramate n=267). Discontinuation due to treatment-emergent adverse events across the 24-week double-blind period was lower in the atogepant group (33 [12%] of 273) compared with the topiramate group (79 [30%] of 267; relative risk [RR] 0·4, 95% CI 0·3 to 0·6; p&lt;0·0001). Treatment-related adverse events were reported by 153 (56%) of","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"806-817"},"PeriodicalIF":54.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}