Annals of Neurology最新文献

{"title":"Understanding the Pattern of Cognitive Decline in GBA1-Related Parkinson's Disease: An Exploratory Longitudinal Multi-Cohort Study.","authors":"Merle Bode, Claire Pauly, Sonja Rós Jónsdóttir, Claudia Schulte, Sara Becker, Isabel Wurster, Benjamin Roeben, Stefanie Lerche, Werner Poewe, Rejko Krüger, Inga Liepelt-Scarfone, Kathrin Brockmann","doi":"10.1002/ana.78362","DOIUrl":"https://doi.org/10.1002/ana.78362","url":null,"abstract":"<p><strong>Objective: </strong>People with Parkinson's disease (PD) who carry a pathogenic GBA1 variant (PD_GBA1) are at higher risk of cognitive impairment than those without the variant (PD_{GBA1_wildtype}). To date, little is known about the pattern and evolution of cognitive decline in PD_GBA1. This multicenter study characterized the cognitive profile of PD_GBA, focusing on the longitudinal trajectories and the group-specific onset times among cognitive functions, as well as their clinical relevance.</p><p><strong>Methods: </strong>In this exploratory longitudinal multicohort-study (Parkinson's Precision Medicine Initiative [PPMI], Amyloid-Beta in cerebrospinal spinal fluid as a risk factor for cognitive dysfunction in Parkinson's Disease [ABC-PD], and National Centre for Excellence in Research on Parkinson's disease [NCER-PD]), comprehensive neuropsychological assessments were standardized across 546 healthy controls (follow-up years = 2.9 ± 4.3), 903 PD_{GBA1_wildtype} (follow-up years = 4.4 ± 4.2), and 211 PD_GBA1 (follow-up years = 4.8 ± 3.4). We evaluated performance across age and disease duration using generalized linear mixed effects models (GLMMs) within each cognitive domain. An exploratory latent trajectory analysis was computed to identify potential cognitive subgroups. Time-to-first-event models, assessing risks of clinically relevant performance impairment (test score z ≤ -1.5, Montreal Cognitive Assessment [MoCA] < 26), and an expanding time-window approach identified the course of cognitive impairment.</p><p><strong>Results: </strong>PD_GBA1 performed worse in executive function, attention, visuocognitive skills, and memory than PD_{GBA1_wildtype} at baseline and exhibited a more rapid and widespread decline across these domains. The risk of developing clinically relevant cognitive impairment during the disease course was increased in PD_GBA1. Processing speed and visuoperceptual showed the earliest performance impairments in PD_GBA1, preceding PD_{GBA1_wildtype} by 1.2 and 2.5 disease years, respectively. Within the PD_GBA1 group, we identified a subgroup with rapidly declining cognition, who were more likely to be male patients, report depressive symptoms, and carry a severe GBA1 mutation.</p><p><strong>Interpretation: </strong>PD_GBA1 exhibits accelerated domain-generalized and more severe cognitive decline compared to PD_{GBA1_wildtype}. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316366","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":"Reply to \"CSF Amyloid-β Risk Stratification in CAA: A Missing Link for Anti-Amyloid Therapy Safety\".","authors":"Philipp Arndt, Stefanie Schreiber","doi":"10.1002/ana.78339","DOIUrl":"10.1002/ana.78339","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1118-1119"},"PeriodicalIF":7.5,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823509","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":"Degos Disease Presenting as a Hemorrhagic Brain Mass.","authors":"Junjiang Wu, Fan Lin","doi":"10.1002/ana.78338","DOIUrl":"10.1002/ana.78338","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1115-1117"},"PeriodicalIF":7.5,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838586","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 Amyloid-β Risk Stratification in Cerebral Amyloid Angiopathy: A Missing Link for Anti-Amyloid Therapy Safety.","authors":"Hajime Takase","doi":"10.1002/ana.78337","DOIUrl":"10.1002/ana.78337","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1118"},"PeriodicalIF":7.5,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823504","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":"Cortical Thickness and White Matter Surface Morphology in Tourette Syndrome: A Cohort Study.","authors":"Sahar Delavari, Adam C Frank, Ravi Bansal, Flora M Vaccarino, Robert A King, Paul Lombroso, Lawrence Scahill, James F Leckman, Bradley S Peterson","doi":"10.1002/ana.78340","DOIUrl":"10.1002/ana.78340","url":null,"abstract":"<p><strong>Objective: </strong>To examine cortical thickness and white matter surface morphology in a large sample of individuals with Tourette syndrome (TS) and neurotypical controls across the lifespan, and to assess associations with symptom severity, comorbidities, and medication use.</p><p><strong>Methods: </strong>Cross-sectional neuroimaging cohort study utilizing high-resolution, T1-weighted magnetic resonance imaging scans obtained in 264 participants (151 TS, 113 neurotypical controls), aged 6-63 years. Image processing included rigorous quality control and deformation-based morphometry. Voxel-wise measures of cortical thickness and white matter surface displacement from a template brain were calculated. General linear models applied voxel-wise tested group differences adjusted for age, sex, and socioeconomic status. Additional covariates in sensitivity analyses included full-scale IQ, comorbid illnesses, and medication use. Interactions of group with age and sex, as well as associations with symptom severity, were also evaluated.</p><p><strong>Results: </strong>Compared with controls, TS participants showed extensive cortical thinning in precentral and postcentral gyri, inferior and middle frontal gyri, and inferior parietal lobule, as well as white matter surface displacement in overlapping regions. These effects remained significant after covarying for IQ, comorbidity, and medication use. Neither age nor sex significantly moderated these group differences. Attention deficit hyperactivity disorder symptom severity was associated with additional frontoparietal cortical thinning; obsessive-compulsive disorder severity showed no effect. Tic symptom severity did not associate significantly with brain measures anywhere.</p><p><strong>Interpretation: </strong>These findings suggest that cortical thinning and associated white matter reductions in TS reflect stable neurodevelopmental traits rather than transient symptom states. These cortical portions of cortico-striato-thalamo-cortical circuits may serve as targets for future therapeutic interventions. ANN NEUROL 2026;100:1104-1114.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1104-1114"},"PeriodicalIF":7.5,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811650","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":"Cerebrospinal Fluid Cytokine Expression and Relationships With Neurological Measures in Virologically Controlled People With HIV.","authors":"Jack Peterson, Clarissa Xia, Govind Nair, Joseph Snow, Julia Stone, Gina Norato, Brandon Do, Samuel Darko, Kory Johnson, Swati Shah, Amanda Wiebold, Melina Jones, Avindra Nath, Darshan Pandya","doi":"10.1002/ana.78405","DOIUrl":"https://doi.org/10.1002/ana.78405","url":null,"abstract":"<p><strong>Objective: </strong>Quantify cytokines in cerebrospinal fluid (CSF) of virologically suppressed people with HIV (PWH) and people without HIV (PWoH) and correlate these with neuroimaging, neuropsychometric (NP), and neurodegenerative measurements.</p><p><strong>Methods: </strong>CSF samples were collected from virologically suppressed PWH and demographically matched PWoH under a natural history protocol. Participants underwent annual lumbar puncture, magnetic resonance imaging (MRI) brain scans, and NP testing at the National Institutes of Health (NIH). Using a magnetic bead assay, concentrations of 30 cytokines were measured in 136 PWH and 30 PWoH CSF samples, from 82 PWH and 25 unique PWoH participants.</p><p><strong>Results: </strong>Thirteen cytokines - IP-10/CXCL10, G-CSF, GM-CSF, IL-7, IL-1ra, IL-1α, MIP-1β/CCL4, IL-15, TNF-α, IFN-α2, IL-10, IL-8/CXCL8, and IL-β - were significantly higher (p < 0.05) in the CSF of PWH compared to PWoH. Five others were elevated, and one decreased, in PWH (p = 0.05-0.10). Seven cytokines (EGF, IL-15, IL-6, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, and TNF-α) positively correlated with white matter lesion burden and 4 (eotaxin/CCL11, G-CSF, GM-CSF, and IL-1ra) with white matter volume in PWH. Significant positive correlations were seen between cytokines, including IP-10/CXCL10, MIP-1α/CCL3, MIP-1β/CCL4, IL-15, IL-6, and TNF-α, and NP scores. IL-10, IL-15, IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, and VEGF positively correlated with CSF total tau and neurofilament light levels. Principal component analysis revealed discrete subsets of PWH. Demographics and comorbidities did not significantly impact differences between PWH and PWoH.</p><p><strong>Interpretation: </strong>Elevated expression of several cytokines in the CSF of virologically suppressed PWH indicates persistent immune activity and supports the existence of a central nervous system (CNS) reservoir. Numerous cytokines showed favorable associations with NP data, including \"proinflammatory\" cytokines such as IL-6 and TNF-α and several chemotactic cytokines, whereas some \"anti-inflammatory\" cytokines such as IL-10 correlated positively with unfavorable neurodegenerative markers. Our findings suggest that cytokine functions in the CNS of PWH vary from the periphery, are pleiotropic and potentially protective, and evolve over time. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316365","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":"Prediction of First and Recurrent Falls in Parkinson's Disease.","authors":"Joaquin A Vizcarra, Kat Hefter, Michael Tran Duong, Ashkan Ertefaie, Umberto Tachinardi, Christopher A Olm, Hamsanandini Radhakrishnan, Corey T McMillan, David Irwin, Daniel Weintraub, Brian Litt, Dani S Bassett, Andrew Siderowf","doi":"10.1002/ana.78400","DOIUrl":"https://doi.org/10.1002/ana.78400","url":null,"abstract":"<p><strong>Objective: </strong>To develop and externally validate prediction models for next-year falls in Parkinson's disease (PD), and to evaluate the incremental value of imaging and fluid biomarkers.</p><p><strong>Methods: </strong>We developed models in Parkinson's Progression Markers Initiative (PPMI) to predict next-year falls with external validation in University of Pennsylvania (UPenn) cohorts. We evaluated incident falls among visits without current or prior falls and recurrent falls among visits with current falls. We calculated area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), and development-derived risk strata.</p><p><strong>Results: </strong>The incident model, comprising Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III, Montreal Cognitive Assessment, and Geriatric Depression Scale (GDS), was developed in 773 visit-pairs and validated in 589 visit-pairs. AUROC was 0.704 (95% confidence interval [CI] = 0.653-0.750) in PPMI and 0.630 (95% CI = 0.564-0.687) in UPenn. Incident fall risk increased from 7.1 to 18.5% across low- to high-risk groups in UPenn. The recurrent model, comprising Hoehn and Yahr (H&Y), GDS, and Symbol Digit Modalities Test, was developed in 302 visit-pairs and validated in 137 visit-pairs. AUROC was 0.683 (95% CI = 0.623-0.753) in PPMI and 0.641 (95% CI = 0.538-0.732) in UPenn. Recurrent fall rates increased from 22.2 to 65.0% across low- to high-risk groups in UPenn. Exploratory biomarker augmentation modestly improved discrimination beyond clinical models in PPMI, but not in external validation, where estimates were imprecise.</p><p><strong>Interpretation: </strong>Clinical measures may identify next-year fall risk in PD with moderate discrimination, although performance attenuated in external validation. Exploratory biomarkers provided modest incremental value in development but not in external validation. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293396","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":"Rate and Shape of Functional Decline in Amyotrophic Lateral Sclerosis Identify Clinically Distinct Amyotrophic Lateral Sclerosis Phenotypes.","authors":"Andrea Calvo, Cristina Moglia, Antonio Canosa, Umberto Manera, Elisabetta Zucchi, Giulia Gianferrari, Ilaria Martinelli, Gabriele Mora, Sara Cabras, Francesca Palumbo, Enrico Matteoni, Giorgio Pellegrino, Emilio Minerva, Daniela Pascariu, Stefano Callegaro, Fabrizio D'Ovidio, Rosario Vasta, Letizia Mazzini, Fabiola De Marchi, Jessica Mandrioli, Adriano Chiò","doi":"10.1002/ana.78394","DOIUrl":"https://doi.org/10.1002/ana.78394","url":null,"abstract":"<p><strong>Objective: </strong>The ALS Functional Rating Scale-Revised decline rate compresses trajectory shape into a single number, potentially missing distinct phenotypes. We tested whether shape identifies phenotypes that rate does not distinguish, and whether post-hoc analysis recovers a hidden ultrarapid subgroup.</p><p><strong>Methods: </strong>From the Piemonte and Valle d'Aosta register (2000-2022), we applied 2 models to 1,686 amyotrophic lateral sclerosis patients: a Gaussian mixture model (GMM; rate axis) and a latent-class mixed model (LCMM) with cubic splines (shape axis). Concordance, prognostic performance, calibration, and clinical utility were assessed at 24 months. External validation used the Emilia-Romagna register.</p><p><strong>Results: </strong>The rate model identified 4 classes (GMM-Slow 31%, GMM-Inter-slow 46%, GMM-Inter-fast 17%, GMM-Catastrophic 6%; slopes -0.44 to -3.52 points/month); the shape model 4 (LCMM-SlowLinear 46%, LCMM-PlateauFall 23%, LCMM-LateDecline 15%, LCMM-RapidEarly 16%). Concordance was modest (kappa = 0.273). Adding shape to rate changed discrimination negligibly (C-index 0.761 vs 0.755), but separated subgroups within rate classes (within GMM-Catastrophic, 30.1 vs 12.0 months). LCMM-LateDecline combined moderate early decline with reduced respiratory reserve (median forced vital capacity 83.5%) and 22.7-month median survival. The combined model gave the greatest net benefit for the composite outcome. Of 945 patients excluded for sparse sampling, 367 were ultrarapid progressors with shorter survival than LCMM-RapidEarly; findings replicated in the Emilia-Romagna register.</p><p><strong>Interpretation: </strong>Rate and shape describe partially overlapping aspects of the disease. LCMM-LateDecline, with moderate early decline yet occult respiratory compromise, is clinically challenging, and the 3-visit criterion hides over half of ultrarapid patients. Rate predicts the overall burden of progression, whereas shape predicts the timing of deterioration. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259899","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":"Tornado-Like Enhancement in Primary Central Nervous System Lymphoma.","authors":"Daihui Zhang, Hongrui Zhang, Yuan Li, Sha Liu","doi":"10.1002/ana.78402","DOIUrl":"https://doi.org/10.1002/ana.78402","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149242112","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":"Ambulatory Episodic Hypertension in Parkinson's Disease With Orthostatic Hypotension.","authors":"Heba A Deraz, Alok K Dwivedi, Kevin R Duque, Aaron Bloemer, Luca Marsili, Jesus Abanto, Nathaly Chinchihualpa Paredes, Andrea Herrera Gorriti, Emily J Hill, Andrew P Duker, Abhimanyu Mahajan, Alberto J Espay","doi":"10.1002/ana.78393","DOIUrl":"https://doi.org/10.1002/ana.78393","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to determine whether ambulatory hypertensive episodes are associated with clinical outcomes in patients with Parkinson's disease (PD) with neurogenic versus non-neurogenic orthostatic hypotension.</p><p><strong>Methods: </strong>Consecutive patients with PD with suspected orthostatic hypotension (OH) underwent 24-hour ambulatory blood pressure monitoring in the home setting. The primary exposure was the number of hypertensive episodes across 24 hours. Neurogenic OH was defined by a heart rate response to orthostatic systolic blood pressure reduction of <0.5 beats/min/mmHg during standardized 3-minute orthostatic testing. The primary outcome was quality of life measured by the Parkinson's Disease Questionnaire-39 Summary Index (PDQ-39 SI). Secondary outcomes included orthostatic symptom burden and motor severity. Multivariable linear regression models with interaction terms were adjusted for age, sex, disease duration, and levodopa equivalent daily dose, with robustness assessed through multiple sensitivity analyses.</p><p><strong>Results: </strong>Fifty-nine patients with PD were included, 30 with neurogenic OH and 29 with non-neurogenic orthostatic hypotension. Among patients with neurogenic OH, a greater number of hypertensive episodes was associated with better quality of life, lower orthostatic symptom burden, and lower motor impairment scores. In patients with non-neurogenic OH, these associations were absent or occurred in the opposite direction. Associations were stronger during daytime than night-time periods and remained consistent in sensitivity analyses.</p><p><strong>Interpretation: </strong>In patients with PD and neurogenic OH, ambulatory hypertensive episodes were associated with better clinical outcomes, an association not observed in patients with non-neurogenic OH. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149242128","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}