Nature Reviews Neurology最新文献

{"title":"Rethinking dementia prevention for a continuum of risk","authors":"Htet Lin Htun,Kaarin J. Anstey","doi":"10.1038/s41582-026-01273-0","DOIUrl":"https://doi.org/10.1038/s41582-026-01273-0","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"479 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022282","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 emerging role of microbiota in neuro-oncology.","authors":"Golnaz Morad, Rebecca A Soto, Nadim J Ajami, Sherise D Ferguson, Jennifer A Wargo","doi":"10.1038/s41582-026-01266-z","DOIUrl":"https://doi.org/10.1038/s41582-026-01266-z","url":null,"abstract":"<p><p>Primary and metastatic brain tumours are associated with poor clinical outcomes, largely owing to limited therapeutic advances and an incomplete understanding of brain tumour biology. Increasing evidence suggests that microbial communities play an important part in shaping systemic immunity and tumour biology. Microbes and microbial by-products from the gut and oral cavity can influence the central nervous system through the gut-oral-brain axis, providing potential mechanisms by which distant microbes shape the brain tumour microenvironment. A growing body of literature has identified distinct gut and oral microbial signatures associated with brain tumours and demonstrated that microbiota modulation can influence tumour growth and treatment response in preclinical models. In addition, emerging clinical data indicate that primary and metastatic brain tumours can harbour intracellular microbial elements. In this Review, we summarize current knowledge on the roles of the gut and oral microbiota and intratumoural microbial elements in brain tumour biology and treatment response. We present the technical challenges inherent to microbial studies in brain tumours due to low biomass and the high risk of contamination, and discuss key clinical, experimental and computational considerations needed for rigorous experimental design and standardized methodologies. Last, we discuss translational opportunities and future directions for moving the field towards clinical impact.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":""},"PeriodicalIF":31.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017374","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":"Atypical Alzheimer disease: a multi-axis framework toward defining heterogeneity.","authors":"Lea T Grinberg, Melissa E Murray","doi":"10.1038/s41582-026-01267-y","DOIUrl":"https://doi.org/10.1038/s41582-026-01267-y","url":null,"abstract":"<p><p>Alzheimer disease (AD) is defined biologically by the presence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain; however, these pathologies do not affect all brain regions equally. Typical AD usually presents with memory impairment, whereas atypical forms of AD, including posterior cortical atrophy, logopenic variant primary progressive aphasia, behavioural and dysexecutive AD, and corticobasal syndrome, manifest with prominent non-memory symptoms. Aβ biomarkers usually confirm that AD pathology is present, whereas regional tau, neurodegeneration and dysfunction more closely track the affected network and the presenting symptoms. The atypical variants, which tend to present at a younger age than typical AD, provide human models to study selective vulnerability of neurons and circuits. They also help us to test whether immune-glial, vascular, protein-handling, synaptic or genetic factors shape regional vulnerability and rate of progression beyond total Aβ and tau burden. In this Review, we integrate clinical, neuropathological, imaging, genetic and molecular evidence to describe atypical AD within the broader AD spectrum. We propose a practical multi-axis framework comprising clinical phenotype, AD biological context (AD pathology plus co-pathologies and molecular modifiers), network topography (regional patterns) and tempo (rate of clinical and biomarker progression). This framework could reduce diagnostic mismatches, make cohorts more comparable and support trials that include outcomes tailored to the affected brain networks.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":""},"PeriodicalIF":31.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002219","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":"Somatic mosaicism in the brain: linking development, ageing and neurodegeneration.","authors":"Zinan Zhou, Christopher A Walsh","doi":"10.1038/s41582-026-01268-x","DOIUrl":"https://doi.org/10.1038/s41582-026-01268-x","url":null,"abstract":"<p><p>Somatic mosaicism is increasingly recognized as a pervasive feature of the human brain and a potential contributor to neurological disease across the lifespan. Unlike germline variants, somatic variants arise post-zygotically and are unevenly distributed across regions, cell types and even individual neurons, enabling focal biological effects that can scale to network-level dysfunction. In this Review, we synthesize current evidence that developmental timing, clonal architecture and cell-type-specific selective pressures shape how somatic variants influence brain structure and function. Early embryonic variants can produce broad regional clones and severe phenotypes, whereas later events are usually more restricted; with ageing, ongoing DNA damage and imperfect repair generate private variants that might cumulatively reduce cellular resilience. We also summarize advances in detection approaches, including bulk, error-corrected and single-cell sequencing, and discuss their strengths and current limitations for clinical translation. Emerging data link brain somatic variants to neurodevelopmental and neurodegenerative phenotypes, supporting a unified framework in which mosaic genetics bridges focal lesions and distributed neurological syndromes. Integrating genomic, cellular and physiological analyses in longitudinal human studies will be essential to define causality, identify biomarkers and guide future targeted interventions.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":" ","pages":""},"PeriodicalIF":31.2,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970389","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 \u0000 (,&nbsp;)","doi":"10.1038/s41582-026-01269-w","DOIUrl":"10.1038/s41582-026-01269-w","url":null,"abstract":"A phase III trial of obinutuzumab β shows striking efficacy in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder. The findings reinforce B cell depletion as a therapeutic principle while raising a more fundamental question: which B cell populations must be depleted, and how completely?","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 11","pages":"665-666"},"PeriodicalIF":31.2,"publicationDate":"2026-09-09","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":"Cortical lesions in multiple sclerosis: 25 years of progress, remaining challenges and future directions","authors":"Massimiliano Calabrese,&nbsp;Roberta Magliozzi,&nbsp;Agnese Tamanti,&nbsp;Stefano Ziccardi,&nbsp;Chiara Eccher,&nbsp;Pietro Biasi,&nbsp;Francesca Benedetta Pizzini,&nbsp;Damiano Marastoni","doi":"10.1038/s41582-026-01263-2","DOIUrl":"10.1038/s41582-026-01263-2","url":null,"abstract":"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. Cortical lesions are now recognized as a central component of multiple sclerosis pathophysiology. This Review summarizes the neuropathological and radiological evidence linking cortical pathology to disease mechanisms and assesses their diagnostic, prognostic and therapeutic relevance.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 11","pages":"667-681"},"PeriodicalIF":31.2,"publicationDate":"2026-09-07","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":"Role of complement and complement-targeted therapeutics in neurological diseases","authors":"Marinos C. Dalakas,&nbsp;Jan D. Lünemann","doi":"10.1038/s41582-026-01261-4","DOIUrl":"10.1038/s41582-026-01261-4","url":null,"abstract":"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. This Review outlines the main components of the complement cascade associated with initiating or propagating the progression of key autoimmune neurological diseases. The authors also highlight how current and emerging complement-targeted therapeutics are destined to redefine treatment paradigms.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 11","pages":"695-711"},"PeriodicalIF":31.2,"publicationDate":"2026-09-03","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":"Effects of obesity on brain health and cognition","authors":"Cali M. McEntee,&nbsp;Masha G. Savelieff,&nbsp;Mohamed H. Noureldein,&nbsp;Stephanie A. Eid,&nbsp;Wolfgang Grisold,&nbsp;Jason J. Hassenstab,&nbsp;Eva L. Feldman","doi":"10.1038/s41582-026-01251-6","DOIUrl":"10.1038/s41582-026-01251-6","url":null,"abstract":"Obesity is a global health issue, and cognitive impairment and elevated risk of dementia are emerging as important consequences. Clinical studies have documented that obesity over the life course is associated with cognitive decline, with midlife obesity carrying a particularly high risk. Evidence from both preclinical and clinical studies suggests that obesity has multiple pathophysiological effects on the brain, including hypothalamic dysregulation and disruptions in biological processes that affect the hippocampus and prefrontal cortex, such as metabolic, inflammatory and vascular dysfunction. In this Review, we summarize the global epidemiology of obesity and examine its clinical relevance as a risk factor for cognitive impairment and dementia. We also discuss the peripheral and central mechanisms through which obesity affects brain function and review obesity-related interventions that have been shown to improve cognition. We conclude by identifying crucial gaps in the existing clinical, translational and intervention-focused literature that warrant future investigation. Obesity is emerging as a key risk factor for cognitive impairment and dementia. This article reviews the global epidemiology of obesity and highlights its pathophysiological effects on the brain. In addition, the authors consider obesity-related interventions that might improve cognitive function, including bariatric surgery and GLP-1 receptor agonists.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 10","pages":"606-624"},"PeriodicalIF":31.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875503","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,&nbsp;Pat Doherty,&nbsp;Zahinoor Ismail,&nbsp;Anne Corbett,&nbsp;Jeffrey L. Cummings","doi":"10.1038/s41582-026-01260-5","DOIUrl":"10.1038/s41582-026-01260-5","url":null,"abstract":"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&nbsp;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. Symptomatic treatment remains central to the clinical management of Alzheimer disease, 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 Alzheimer disease.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 11","pages":"682-694"},"PeriodicalIF":31.2,"publicationDate":"2026-09-01","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":"Reverse electron transport connects tauopathy to mitochondrial dysfunction","authors":"Heather Wood","doi":"10.1038/s41582-026-01265-0","DOIUrl":"10.1038/s41582-026-01265-0","url":null,"abstract":"A new study shows that tau promotes mitochondrial reverse electron transport in a phosphorylation-dependent manner, thereby providing a mechanistic link between tau pathology and mitochondrial dysfunction.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 10","pages":"603-603"},"PeriodicalIF":31.2,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840438","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}