Nature Reviews Neurology最新文献

{"title":"Lysosomal dysfunction in neurodegenerative disease.","authors":"Sarah M Brooker, Robert Coukos, Dimitri Krainc","doi":"10.1038/s41582-026-01262-3","DOIUrl":"10.1038/s41582-026-01262-3","url":null,"abstract":"<p><p>Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"712-730"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081722","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 lesions in multiple sclerosis: 25 years of progress, remaining challenges and future directions.","authors":"Massimiliano Calabrese, Roberta Magliozzi, Agnese Tamanti, Stefano Ziccardi, Chiara Eccher, Pietro Biasi, Francesca Benedetta Pizzini, Damiano Marastoni","doi":"10.1038/s41582-026-01263-2","DOIUrl":"10.1038/s41582-026-01263-2","url":null,"abstract":"<p><p>Cortical lesions have evolved from a largely overlooked pathological feature to a central component of multiple sclerosis pathophysiology, yet their biology, clinical relevance and response to treatment remain incompletely understood. In this Review, we trace how pathological studies established the frequency and heterogeneity of cortical demyelination, with particular attention to subpial lesions and inflammation at the brain-cerebrospinal fluid interface. We examine the neuropathological and imaging evidence linking cortical pathology to meningeal inflammation, neuroaxonal injury and progression independent of relapse activity, and assess how emerging magnetic resonance imaging approaches for detecting and monitoring cortical lesions contribute to diagnosis and prognosis across the multiple sclerosis spectrum. Last, we discuss the sensitivity limits of imaging, the effects of disease-modifying therapies on this compartmentalized damage, and how quantitative magnetic resonance imaging, fluid biomarkers and artificial intelligence could help define biologically meaningful cortical endotypes and guide future therapeutic development.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"667-681"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906908","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":"Symptomatic treatment for Alzheimer disease: current evidence and future directions.","authors":"Clive Ballard, Pat Doherty, Zahinoor Ismail, Anne Corbett, Jeffrey L Cummings","doi":"10.1038/s41582-026-01260-5","DOIUrl":"10.1038/s41582-026-01260-5","url":null,"abstract":"<p><p>Symptomatic treatment remains central to the clinical management of Alzheimer disease (AD), even as disease-targeted therapies emerge. This Review synthesizes current evidence for pharmacological and non-pharmacological symptomatic therapies targeting cognition, function and neuropsychiatric symptoms in AD. Non-pharmacological interventions, including cognitive training, physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes, show small-to-moderate benefits, particularly in mild cognitive impairment, although implementation challenges persist. Established pharmacological treatments, notably cholinesterase inhibitors and memantine, deliver modest but significant benefits, with biomarker-stratified analyses suggesting the greatest benefit in individuals with confirmed AD pathology. Advances in muscarinic agonists, multitarget agents, neurotrophic modulators and repurposed drugs highlight emerging opportunities for broader symptomatic benefit. Neuropsychiatric symptoms remain highly prevalent and burdensome; personalized psychosocial interventions demonstrate meaningful reductions in agitation and depression, whereas atypical antipsychotics offer only modest efficacy with substantial safety concerns. Newer agents, including brexpiprazole for agitation and pimavanserin for psychosis, show promise but require careful interpretation of effect size and safety. Future progress will depend on biomarker-informed patient selection, integration of circuit-level measures, rational combination strategies spanning pharmacological and non-pharmacological modalities, and adoption of patient-centred outcomes. Symptomatic therapies will remain essential for improving quality of life in people with AD, even as disease-targeted therapies reshape disease trajectories.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"682-694"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875446","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":"Menopause-associated proteomic changes link to brain ageing and dementia risk.","authors":"Lisa Kiani","doi":"10.1038/s41582-026-01278-9","DOIUrl":"10.1038/s41582-026-01278-9","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"664"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148379","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":"Deeper versus broader B cell depletion in neuromyelitis optica spectrum disorder.","authors":"Ichiro Nakashima","doi":"10.1038/s41582-026-01269-w","DOIUrl":"10.1038/s41582-026-01269-w","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"665-666"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920742","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":"Role of complement and complement-targeted therapeutics in neurological diseases.","authors":"Marinos C Dalakas, Jan D Lünemann","doi":"10.1038/s41582-026-01261-4","DOIUrl":"10.1038/s41582-026-01261-4","url":null,"abstract":"<p><p>Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"695-711"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888277","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":"EBV reactivation precedes multiple sclerosis relapse.","authors":"Lisa Kiani","doi":"10.1038/s41582-026-01280-1","DOIUrl":"10.1038/s41582-026-01280-1","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"664"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148075","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":"Astrocytes support glioblastoma cells via tunnelling nanotubes.","authors":"Ian Fyfe","doi":"10.1038/s41582-026-01281-0","DOIUrl":"10.1038/s41582-026-01281-0","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"663"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149285","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":"Progressive sleep abnormalities precede ALS clinical onset.","authors":"Lisa Kiani","doi":"10.1038/s41582-026-01279-8","DOIUrl":"10.1038/s41582-026-01279-8","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":"664"},"PeriodicalIF":31.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148035","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":"Use of animal models to understand CNS neuroimmunology - guidance from the International Society for Neuroimmunology White Paper Task Force.","authors":"Jennifer L Gommerman, Katerina Akassoglou, Sergio E Baranzini, Burkhard Becher, Fabienne Brilot, Gonçalo Castelo-Branco, Shannon E Dunn, Maryam Faiz, Alexander Flügel, Nader Ghasemlou, Erin M Gibson, Judith M Greer, Denis Gris, Cole A Harrington, Steffen Jung, Lorraine V Kalia, Thomas Korn, Gurumoorthy Krishnamoorthy, Roland S Liblau, Francesca Odoardi, Laura Piccio, Anne-Katrin Pröbstel, Francisco J Quintana, Valeria Ramaglia, Manu Rangachari, Olga L Rojas, Marc J Ruitenberg, Scott Russo, Dorothy P Schafer, Benjamin M Segal, Jana Vukovic, Chao Wang, Michael A Wheeler, Heinz Wiendl, V Wee Yong, Frauke Zipp, Veronique E Miron","doi":"10.1038/s41582-026-01272-1","DOIUrl":"https://doi.org/10.1038/s41582-026-01272-1","url":null,"abstract":"<p><p>Neuroimmunology is a rapidly expanding field in which many breakthroughs have been fuelled by studies in animal models that capture aspects of human neurological disease. However, the variety of animal models available, with their relative merits and drawbacks, is not well documented in the literature, posing a hurdle for scientists who are venturing into the world of neuroimmunology. Moreover, nuances between animal models, their utility for studying neuroimmunological processes and the variables that affect their associated clinical and pathological outcomes can affect the reproducibility and clinical relevance of findings at the preclinical stage. In this Review, the International Society of Neuroimmunology White Paper Task Force describes animal models that can be used to study neuroimmunological aspects of neurological disease and the intrinsic and extrinsic factors that affect readouts from these models. We provide guidance on how to manipulate these factors to gain insight into neuroimmunology and to control them for improved reproducibility. We also consider the advantages and limitations of available tools, including robust genetic systems, neuroimmunological imaging, functional readouts and omics-based cell profiling. Finally, we discuss how animal models have advanced drug development to treat neuroimmunological diseases and how the same principles can provide insight into a variety of neurological disorders. We aim to provide guidance on how to optimize the use of animal models to gain insight into neuroimmunological mechanisms and support the preclinical drug discovery pipeline.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":""},"PeriodicalIF":31.2,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271285","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}