Annals of Neurology最新文献

{"title":"AI-Driven Mapping of Seizure Spread Patterns.","authors":"Andrew Y Revell, Marc Jaskir, Akash R Pattnaik, William K S Ojemann, Erin Conrad, Nishant Sinha, Brittany H Scheid, Alfredo Lucas, John M Bernabei, John Beckerle, Joel M Stein, Sandhitsu R Das, Brian Litt, Kathryn A Davis","doi":"10.1002/ana.78203","DOIUrl":"https://doi.org/10.1002/ana.78203","url":null,"abstract":"<p><strong>Objective: </strong>The focus of epilepsy research has largely been on seizure onset; however, physicians typically examine the patterns of seizure spread past seizure onset as well. This study aims to align automated seizure analysis with clinical practice, leverage deep learning to standardize seizure annotations that varies among physicians, and understand common seizure spread patterns across patients.</p><p><strong>Methods: </strong>We developed deep learning algorithms on a small subset of patients to detect seizure activity and deployed these algorithms across 275 seizures in 71 patients to analyze the patterns of seizure spread (extent, timing, surgical outcomes, and common patterns) along with incorporating diffusion-weighted imaging to understand how these patterns relate to the structural connections of the brain.</p><p><strong>Results: </strong>Deep learning algorithms outperform single features (line length, absolute slope, and power) in ranking seizure onset contacts using physician annotations as a benchmark. We also find that poor outcome patients have more extensive brain regions involved in their seizures while also having more rapid spread between temporal lobes. Incorporating diffusion-weighted imaging, we find that an increase in structural connectivity between temporal lobes is associated with quicker seizure spread. Finally, we identify clusters of spread patterns common across patients based on spread timing, location, and extent.</p><p><strong>Interpretation: </strong>Analyzing seizure spread can reveal new insights into seizure evolution and its relationship with surgical outcomes in patients with epilepsy. The findings also suggest that focusing beyond seizure onset is crucial for understanding and treating epilepsy. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831273","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":"Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease.","authors":"Shannon Y Chiu, Wei-En Wang, Robin Chen, Jesse C DeSimone, Derek B Archer, Charles H Adler, Shyamal H Mehta, Sara R Dresler, Melissa J Armstrong, Nikolaus McFarland, Michael Okun, David E Vaillancourt","doi":"10.1002/ana.78252","DOIUrl":"https://doi.org/10.1002/ana.78252","url":null,"abstract":"<p><strong>Objective: </strong>Positive α-synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free-water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA- status.</p><p><strong>Methods: </strong>We studied patients with PD with baseline diffusion imaging and α-synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA_T), and clinical characteristics between SAA+ and SAA- groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status.</p><p><strong>Results: </strong>Among 462 participants (41 SAA- and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA- (pFDR < 0.05). No significant differences in FA_T were found between groups.</p><p><strong>Interpretation: </strong>Positive α-synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA_T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831336","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":"Pies in the Sky.","authors":"Shivangi D Pandya, Bernard P L Chan, Vijay K Sharma","doi":"10.1002/ana.78253","DOIUrl":"https://doi.org/10.1002/ana.78253","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831342","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":"How PPMI Enabled the First Interventional Platform Trial to Test Therapies in Participants With Early-Stage Neuronal Alpha-Synuclein Disease.","authors":"Tanya Simuni, Christopher S Coffey, Catherine M Kopil, Cora Allen-Savietta, Barbara Wendelberger, Amy Crawford, Ruth B Schneider, Andrew Siderowf, Karl Kieburtz, Caroline M Tanner, Thomas F Tropea, Heidi Whalen, Lianne Ramia, Cornelia Kamp, Cecilia Reyes, Kimberly Fabrizio, Tawny Willson, Erika Merriam, Maggie McGuire Kuhl, Sohini Chowdhury, Kenneth Marek","doi":"10.1002/ana.78250","DOIUrl":"https://doi.org/10.1002/ana.78250","url":null,"abstract":"<p><p>The Path to Prevention (P2P) platform trial is a multicenter, multi-regimen, proof of concept, phase 2A, randomized clinical trial evaluating the safety and early efficacy of investigational products for the treatment of early-stage Neuronal Alpha-Synuclein disease (NSD) populations. The P2P trial is nested within the Parkinson's Progression Markers Initiative (PPMI), which means that its conceptualization, design, and implementation are based on learnings from the PPMI study. P2P will recruit eligible participants from the PPMI cohort. P2P will also leverage PPMI infrastructure including PPMI study sites and PPMI study cores including the site management, data management, biorepository, imaging, statistical, and data science cores for study execution. This paper reviews the conceptual design of P2P focusing on its relationship with PPMI to demonstrate how the connectivity between PPMI and P2P is essential for the success of the P2P study. P2P is an important step forward in clarifying the clinical trial design and regulatory path for interventions in the early-stage NSD population. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831255","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":"Cerebrospinal Fluid-Mediated Dissemination in Balamuthia mandrillaris Amebic Encephalitis.","authors":"Shaoping Zhong, Jin Liu, Jianying Liu, Jing Ding","doi":"10.1002/ana.78255","DOIUrl":"https://doi.org/10.1002/ana.78255","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831295","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":"Biologic Frameworks for Synucleinopathies: Contributions of the Parkinson's Progression Markers Initiative.","authors":"Lana M Chahine, Roy N Alcalay, Ethan G Brown, Sohini Chowdhury, Christopher S Coffey, Tatiana Foroud, Mark Frasier, Douglas Galasko, Kalpana M Merchant, Brit Mollenhauer, Eduardo Tolosa, Nicola Pavese, Thomas F Tropea, Kenneth Marek, Tanya Simuni","doi":"10.1002/ana.78249","DOIUrl":"https://doi.org/10.1002/ana.78249","url":null,"abstract":"<p><p>A research biologic definition and staging of neuronal alpha-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, is critical toward improving clinical trial design and drug development. Neuronal synuclein disease, and the companion Integrated Staging System, are a biologic definition and staging system conceptualized by multiple stakeholders including academia, industry, advocacy organizations, and importantly, people with lived experiences. In large part, this was informed and enabled by the knowledge garnered from the Parkinson's Progression Markers Initiative. This review provides a historical perspective and details contributions from the Parkinson's Progression Markers Initiative, among others, that made this advancement possible. These include the key role it played in validation of an in vivo biomarker of neuronal alpha-synuclein, longitudinal characterization of dopaminergic dysfunction imaging, biospecimen collection and assays, comprehensive genetic characterization, and clinical phenotyping. In addition, the Parkinson's Progression Markers Initiative is generating and sharing data that will be used to address key gaps in knowledge, revisions, and future refinements of a biologic definition and staging of synucleinopathies. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831327","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":"Future Directions: The Parkinson's Precision Medicine Initiative.","authors":"Kenneth Marek, Thomas F Tropea","doi":"10.1002/ana.78244","DOIUrl":"https://doi.org/10.1002/ana.78244","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831292","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":"From Parkinson's Progression Markers Initiative to Parkinson's Precision Medicine Initiative: Still PPMI.","authors":"Kenneth Marek, Sohini Chowdhury, Thomas F Tropea","doi":"10.1002/ana.78242","DOIUrl":"https://doi.org/10.1002/ana.78242","url":null,"abstract":"<p><p>The Parkinson's Progression Marker Initiative (PPMI), sponsored by The Michael J. Fox Foundation for Parkinson's Research, is designed to develop disease biomarkers to accelerate Parkinson's disease (PD) therapeutics. During the past 15 years PPMI has acquired comprehensive clinical, imaging, biomarker and genetic data on thousands of participants that has guided clinical therapeutic studies for PD and related synucleinopathies. The study has established standardized strategies for acquisition and analysis of data and set a standard for data sharing and open-source publication. PPMI has by design consistently evolved to incorporate new knowledge and science. A key example is that PPMI data has enabled the transition from clinical to biologic definition of synucleinopathy. The study continues to expand our understanding of disease biology particularly in precise PD subsets in both in-clinic and a rapidly expanding remote participant cohort, using myPPMI, an online portal. This special issue reviews PPMI's continuing contribution to early detection, understanding disease biologic and staging, and innovative therapeutic strategies in PD and related synucleinopathies. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831286","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":"Multimorbidity and Associations with Cognition and Alzheimer's Disease Biomarkers.","authors":"Xiaqing Jiang, Sid E O'Bryant, Robert A Rissman, Leigh A Johnson, Meredith N Braskie, Kristine Yaffe","doi":"10.1002/ana.78238","DOIUrl":"https://doi.org/10.1002/ana.78238","url":null,"abstract":"<p><strong>Objective: </strong>Multimorbidity, the coexistence of 2 or more chronic conditions, has been linked to cognitive aging and Alzheimer's disease (AD) and AD-related dementias, yet the mechanisms remain unclear. We aimed to examine the associations of multimorbidity with cognition and biomarkers across multiple mechanistic pathways.</p><p><strong>Methods: </strong>We cross-sectionally analyzed 3,808 dementia-free participants (mean age 64.9 ± 8.5 years, 62% female) from the Health and Aging Brain Study: Health Disparities. Multimorbidity burden was assessed using a latent construct derived from chronic conditions identified through objective measures, medical history, and self-report. A latent factor score for cognition was estimated using confirmatory factor analysis and neuropsychological tests. Using linear and logistic regression, we examined the associations of multimorbidity burden with biomarkers of AD (positron emission tomography [PET] amyloid, plasma β-amyloid 42/40, and phosphorylated tau [p-tau] measures), neurodegeneration (cortical thickness, hippocampal volume, and plasma neurofilament light and total tau), and cerebral small vessel disease (SVD) (magnetic resonance imaging white matter hyperintensities, cerebral microbleeds, and lacunes).</p><p><strong>Results: </strong>Greater multimorbidity burden was associated with worse cognition and biomarkers of AD (PET amyloid standardized uptake value ratios and positivity, p-tau181, and p-tau217), neurodegeneration (neurofilament light, total tau, cortical thickness, and hippocampal volume), and SVD (white matter hyperintensity volume and presence of lacune and cerebral microbleeds).</p><p><strong>Interpretation: </strong>Among dementia-free individuals, higher multimorbidity burden was associated with biomarkers for greater AD pathology, neurodegeneration, and SVD. These findings support a more holistic approach to managing chronic disease burden, which has the potential to reduce overall pathophysiological burden and delay cognitive decline. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831304","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":"Pre-Diagnostic Plasma Carotenoids, Tocopherols and Retinol Levels, and Risk of Amyotrophic Lateral Sclerosis.","authors":"Éilis J O'Reilly, Kjetil Bjornevik, Jeremy D Furtado, Alpa V Patel, Ying Wang, Laurence N Kolonel, Loïc Le Marchand, Alberto Ascherio","doi":"10.1002/ana.78240","DOIUrl":"https://doi.org/10.1002/ana.78240","url":null,"abstract":"<p><strong>Objective: </strong>Our goal was to examine whether pre-diagnostic plasma carotenoids and tocopherols are associated with amyotrophic lateral sclerosis (ALS).</p><p><strong>Methods: </strong>A nested case-control study within 4 United States cohorts, where 154 participants with pre-diagnostic blood-draw, were diagnosed during follow-up with amyotrophic lateral sclerosis (ALS). Controls were randomly selected from participants alive on the date a case was diagnosed, matched 2:1 by cohort, sex, age, race/ethnicity, fasting-status, time of blood-draw. Carotenoid and tocopherol levels were quantified by high-performance liquid-chromatography with diode array-detector. ALS incidence or death rate ratios (RR) were estimated using conditional logistic regression adjusting for body mass index, smoking status, physical activity, cholesterol, and urate levels.</p><p><strong>Results: </strong>The association between beta-carotene and ALS varied by sex (p-for-interaction = 0.007). After matched- and multivariable-adjustment, women with higher cis-, trans- and total beta-carotene had lower incidence of ALS (RR for 1-standard deviation [SD] increase in total beta-carotene: 0.68; 95% CI: 0.48-0.98; p = 0.038), whereas a positive association was seen in men (1-SD increase: RR = 1.44; 95% CI: 1.03-2.01; p = 0.033). However, after further adjustment for other correlated carotenoids, the association in men was attenuated, whereas it remained significant in women. Women with higher beta-cryptoxanthin, but not men, had a lower risk of ALS (1-SD increase: RR = 0.67; 95% CI: 0.48-0.94; p = 0.02; p-for-interaction = 0.12). Alpha-carotene, lutein-zeaxanthin, lycopene, retinol, and tocopherols were not associated with ALS, except for a borderline inverse association of gamma-tocopherol in men (RR = 0.74; 95% CI: 0.54-1.01; p = 0.059).</p><p><strong>Interpretation: </strong>Higher pre-diagnostic plasma levels of beta-carotene and beta-cryptoxanthin in women and gamma-tocopherol in men were suggestively associated with lower ALS risk. Other carotenoids or tocopherols were not clearly associated with ALS. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831306","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}