Annals of Neurology最新文献

{"title":"Identification of New KCNT1-Epilepsy Drugs by In Silico, Cell, and Drosophila Modeling.","authors":"Michael G Ricos, Bethan A Cole, Rashid Hussain, Grigori Y Rychkov, Zeeshan Shaukat, Nadia Pilati, Stephen P Muench, Katie J Simmons, Leanne M Dibbens, Jonathan D Lippiat","doi":"10.1002/ana.78031","DOIUrl":"https://doi.org/10.1002/ana.78031","url":null,"abstract":"<p><strong>Objective: </strong>Hyperactive KCNT1 potassium channels, caused by gain-of-function mutations, are associated with a range of epilepsy disorders. Patients typically experience drug-resistant seizures and, in cases with infantile onset, developmental regression can follow. KCNT1-related disorders include epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. There are currently no effective treatments for KCNT1 epilepsies, but suppressing overactive channels poses a potential strategy.</p><p><strong>Methods: </strong>Using the KCNT1 channel structure we in silico screened a library of known drugs for those predicted to block the channel pore to inhibit channel activity. Cellular KCNT1 channel inhibition was analyzed using electrophysiology and Drosophila bang-sensitive assays were used to analyze seizure suppression. Brain penetration of one drug was analyzed using liquid chromatography-mass spectrometry in a mouse.</p><p><strong>Results: </strong>Eight known drugs were investigated in vitro for their effects on patient-specific mutant KCNT1 channels, with 4 drugs showing significant reduction of K⁺ current amplitudes. The action of the 4 drugs was then analyzed in vivo and 2 were found to reduce the seizure phenotype in humanized Drosophila KCNT1 epilepsy models. One drug, antrafenine, was shown to cross the blood-brain barrier in mice.</p><p><strong>Interpretation: </strong>This study identified a known drug, antrafenine, that reduces KCNT1 channel activity, reduces seizure activity in Drosophila, and crosses the blood-brain barrier in the mouse, suggesting its potential applicability as a new treatment for KCNT1 epilepsy. The sequential in silico, in vitro, and in vivo mechanism-based drug selection strategy used here may have broader application for other human disorders where a disease mechanism has been identified. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051438","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":"Predictive Value of Plasma Biomarkers in Tau-PET Transitions.","authors":"Jonathan Graff-Radford, Jeremy A Syrjanen, Prashanthi Vemuri, Val J Lowe, Christopher G Schwarz, Heather J Wiste, Walter K Kremers, Alicia Algeciras-Schimnich, Alexa Pichet Binette, Ruben Smith, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Erik Stomrud, David S Knopman, Petrice M Cogswell, Ronald C Petersen, Oskar Hansson, Clifford R Jack","doi":"10.1002/ana.78003","DOIUrl":"https://doi.org/10.1002/ana.78003","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to determine the predictive value of amyloid-positron emission tomography (PET) versus the plasma ratio of phosphorylated tau at threonine 217 (p-tau217) to non-phosphorylated tau217 (%p-tau217) for tau-PET transitions (T- to T+). The added value of combining plasma amyloid-β 42 and amyloid-β 40 (Aβ42/40) and %p-tau217 into an amyloid probability score (APS2) was also assessed.</p><p><strong>Methods: </strong>Mayo Clinic Study of Aging (MCSA) participants had plasma markers measured at via mass spectrometry (MS), an amyloid-PET scan, and a tau-PET (meta-temporal region of interest [ROI]) negative scan (standardized uptake value ratio [SUVR] <1.29) at the index (baseline) date, along with one or more follow-up tau-PET scans. The BioFINDER-2 cohort was used for validation. Cox proportional hazards models adjusted for age, sex, and apolipoprotein (APOE) ε4 were used to assess predictors, with scaling to the interquartile range (IQR) for comparability of hazard ratios (HR).</p><p><strong>Results: </strong>Among 255 tau-PET negative MCSA participants (median age: 71.9 years), 37 converted to tau-PET positive (median follow-up time: 3.81 years). Higher %p-tau217 (HR: 1.52 [95% CI: 1.28-1.80]), amyloid-PET centiloid (HR: 1.47 [95% CI: 1.20-1.79]), and APS2 (HR: 1.62 [95% CI: 1.22-2.16]) predicted tau-PET conversion. However, Aβ42/40 (HR: 0.94 [95% CI: 0.54-1.66]) was not associated with tau-PET conversion. In the BioFINDER-2 cohort (605 tau-negative, median age: 70.2), 33 converted to tau-positive (median follow-up time: 2 years), with higher %p-tau217 (HR: 1.80 [95% CI: 1.50-2.17]), amyloid-PET centiloid (HR: 2.29 [95% CI: 1.77-2.97]), and lower Aβ42/40 (HR: 2.38 [95% CI: 1.17-4.83]) predicting conversion.</p><p><strong>Interpretation: </strong>In two cohorts, %p-tau217 was associated with tau-PET conversion, comparable to amyloid-PET. APS2 also predicted conversion in the MCSA cohort, whereas Aβ42/40 predicted conversion in the BioFINDER-2 cohort, which had more individuals with cognitive impairment. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028619","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":"Cuneiform Nucleus Stimulation Can Assist Gait Training to Promote Locomotor Recovery in Individuals With Incomplete Tetraplegia.","authors":"Anna-Sophie Hofer, Lennart H Stieglitz, Marc Bolliger, Linard Filli, Adrian Cathomen, Romina Willi, Irina Lerch, Iris Krüsi, Melina Giagiozis, Christian Meyer, Martin Schubert, Michèle Hubli, Thomas M Kessler, László Demkó, Christian R Baumann, Lukas Imbach, Markus F Oertel, Andrea Prusse, Alina Kiseleva, Luca Regli, Martin E Schwab, Armin Curt","doi":"10.1002/ana.78026","DOIUrl":"https://doi.org/10.1002/ana.78026","url":null,"abstract":"<p><strong>Objective: </strong>Impaired ability to induce stepping after incomplete spinal cord injury (SCI) can limit the efficacy of locomotor training, often leaving patients wheelchair-bound. The cuneiform nucleus (CNF), a key mesencephalic locomotor control center, modulates the activity of spinal locomotor centers via the reticulospinal tract. Even with severe corticospinal damage, the widely distributed reticulospinal fibers frequently cross the lesion, and lumbosacral spinal locomotor centers remain responsive. Unilateral deep brain stimulation (DBS) of the CNF (CNF-DBS) can increase modulatory input to sublesional locomotor centers and was shown to induce stepping and promote locomotor recovery in rodent models of severe incomplete SCI. Given the evolutionarily conserved CNF-reticulospinal system, we hypothesize that CNF-DBS can augment training and improve gait in humans with incomplete SCI above the lumbosacral levels.</p><p><strong>Methods: </strong>Aiming at bench-to-bedside translation, we investigate CNF-DBS in non-ambulatory patients (clinicaltrials.gov, NCT03053791). Here, we present the first 2 individuals with chronic tetraplegia who underwent 6 months of locomotor training supported by unilateral CNF-DBS, with regular follow-up assessments of adverse and therapeutic effects performed without and with stimulation.</p><p><strong>Results: </strong>The walking distance covered during the 6-Minute Walking Test (6MWT) after 6 months compared to baseline served as the primary study end point, which was reached by patient 1 in the off-condition and by patient 2 in the off- and the on-condition. No serious adverse events occurred.</p><p><strong>Interpretation: </strong>We show that the CNF-DBS was well tolerated and had therapeutic potential in the first 2 patients, and discuss the lessons learnt with resulting implementations for the next patients. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028677","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":"150th Annual Meeting American Neurological Association","authors":"","doi":"10.1002/ana.78015","DOIUrl":"https://doi.org/10.1002/ana.78015","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 S34","pages":"S1-S358"},"PeriodicalIF":7.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012998","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":"Issue Information – TOC","authors":"","doi":"10.1002/ana.78027","DOIUrl":"https://doi.org/10.1002/ana.78027","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 S34","pages":"i-iii"},"PeriodicalIF":7.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012997","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":"Annals of Neurology: Volume 98, Number S34, September 2025","authors":"","doi":"10.1002/ana.78028","DOIUrl":"https://doi.org/10.1002/ana.78028","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 S34","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012996","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":"Comparative Safety Profiles of Ocrelizumab and Rituximab in Multiple Sclerosis Treatment Using Real-World Evidence.","authors":"Gabriel Cerono, Bruce A C Cree, Stephen L Hauser, Sergio E Baranzini","doi":"10.1002/ana.78033","DOIUrl":"https://doi.org/10.1002/ana.78033","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to compare the long-term safety profiles of ocrelizumab and rituximab in persons with multiple sclerosis (MS).</p><p><strong>Methods: </strong>Using retrospective data from the University of California (UC) Health System, we simulated a target clinical trial. The primary cohort from UC San Francisco (UCSF) and a validation cohort from 5 other UC Medical Centers were analyzed. After applying exclusion criteria and propensity score matching based on disease characteristics, demographics, and socioeconomic factors, we compared UCSF patients receiving ocrelizumab (n = 542) and rituximab (n = 271)and validated in the UC-wide MS population (n = 486 and n = 162 patients, respectively). The primary outcome was an all-cause hospitalization rate; secondary outcomes included hypogammaglobulinemia development and infection incidence.</p><p><strong>Results: </strong>Rituximab showed higher all-cause hospitalization rates compared to ocrelizumab in both UCSF (incidence rate ratio [IRR] = 2.29, 95% confidence interval [CI] = 1.37-3.82, p = 0.001) and UC-wide cohorts (IRR = 4.54, 95% CI = 4.30-7.61, p < 0.001). Cumulative hazard ratios (HRs) were similarly elevated with rituximab at UCSF (HR = 2.27, 95% CI = 1.37-3.75, p = 0.001) and UC-wide (HR = 4.01, 95% CI = 2.25-6.32, p < 0.001). The risk of developing hypogammaglobulinemia was higher with rituximab at both UCSF (HR = 2.72, 95% CI = 1.18-6.29, p = 0.003) and UC-wide (HR = 4.79, 95% CI = 2.04-11.25, p < 0.001).</p><p><strong>Interpretation: </strong>A more favorable safety profile was observed for ocrelizumab, with lower rates of hospitalization and hypogammaglobulinemia across 2 independent cohorts. These findings may help guide treatment strategies in persons with MS. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013491","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":"A Distinct Immunological Signature in Late-Onset Myasthenia Gravis: Insights from an Exploratory Proteomics Study.","authors":"Bhaskar Roy, Jiaxin Chen, Fatemeh Khani-Habibabadi, Nilay McLaren, Betty C Soliven, Vern C Juel, Kevin C O'Connor, Richard J Nowak, Linda L Kusner, Henry J Kaminski","doi":"10.1002/ana.78017","DOIUrl":"https://doi.org/10.1002/ana.78017","url":null,"abstract":"<p><strong>Objective: </strong>Approximately 80% of patients with myasthenia gravis (MG) have autoantibodies against acetylcholine receptor, and clinical characteristics may vary between early-onset (symptom onset age <50 years) and late-onset MG (EOMG and LOMG), but the pathophysiological differences between EOMG and LOMG are not well established.</p><p><strong>Methods: </strong>We performed an exploratory in-depth proteomics analysis examining 768 inflammatory proteins utilizing the baseline serum samples from the BeatMG study (NCT02110706). We performed pathway enrichment analysis to assess the pathways involved in LOMG. A total of 15 selected proteins from the initial analysis were further examined using the UK Biobank and further quantified in a separate validation cohort.</p><p><strong>Results: </strong>A total of 21 patients with EOMG (age 38.3 ± 12.1 years, 16 women [76.2%]) and 28 patients with LOMG (age 67.3 ± 8.6 years, 7 women [25%]) from the BeatMG study were included in the exploratory analysis. Several proteins involved in the regulation of leukocyte differentiation and myeloid leukocyte differentiation and migration pathways were more abundant in the LOMG group. Among them, 7 were significantly different in the UK Biobank cohort. A total of 80 participants (39 MG patients (age 54.33 ± 18.9 years, 17 women [43.6%]) and 41 healthy controls (age 49.56 ± 17.06 years, 21 women [66.1%]) were included in the validation cohort, and IL18R1, CXCL17, and CCL11 were validated to be specific for LOMG.</p><p><strong>Interpretation: </strong>Growing evidence supports that LOMG has a distinct immune pathomechanism. Further prospective studies are warranted to confirm the utility of these proteins as biomarkers of LOMG, and the feasibility of using them for more precise therapeutic targets to improve patient outcomes. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005631","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":"Happy 75th National Institute of Neurological Disorders and Stroke.","authors":"Walter J Koroshetz","doi":"10.1002/ana.78023","DOIUrl":"https://doi.org/10.1002/ana.78023","url":null,"abstract":"<p><p>For 75 years the National Institute of Neurological Disorders and Stroke has led neurological research in the US. Many thousands of people have volunteered in research and thousands of investigators devoted their careers to pursuing better treatments of neurological disorders. It's a time to reflect and to renew our collective resolve for future efforts. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937143","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":"Neurosyphilis.","authors":"Daniel J Minter, Felicia C Chow","doi":"10.1002/ana.78016","DOIUrl":"https://doi.org/10.1002/ana.78016","url":null,"abstract":"<p><p>Neurosyphilis remains an important and highly morbid neurologic infection. Recent years have seen a dramatic increase in the incidence of syphilis across a variety of populations, making recognition of the many neurologic complications of this infection still relevant for modern clinicians. As manifestations of neurosyphilis are famously varied, a high index of suspicion is essential, especially in the face of atypical presentations. In this review, we discuss updates to the epidemiology, range of clinical presentations, diagnosis, and management of neurosyphilis. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937168","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}