{"title":"Walking the Talk for Dementia — an experience to break down barriers","authors":"Ian Fyfe","doi":"10.1038/s41582-025-01082-x","DOIUrl":"https://doi.org/10.1038/s41582-025-01082-x","url":null,"abstract":"Walking the Talk for Dementia is no ordinary conference, but an experience that is designed to bring together people with diverse perspectives on dementia, including people with lived experience, and to foster new ways of thinking and collaborating. We asked founder Fernando Aguzzoli-Peres to tell us more about his unique initiative.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"25 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813467","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":"Multi-ancestry GWAS identifies 16 novel Alzheimer disease risk loci","authors":"Lisa Kiani","doi":"10.1038/s41582-025-01086-7","DOIUrl":"https://doi.org/10.1038/s41582-025-01086-7","url":null,"abstract":"<p>A genome-wide association study (GWAS) of people with Alzheimer disease (AD) from diverse ancestral backgrounds has identified 16 genetic loci previously unknown to be associated with the disease. The study included individuals from the All of Us cohort, 78% of whom are from non-white groups that are underrepresented in biomedical research, alongside the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), National Institute of Mental Health and the UK Biobank. The GWAS revealed 5 common and 11 rare AD-associated loci, and the study highlights the benefit of using data from diverse cohorts.</p><blockquote><p>“The GWAS revealed 5 common and 11 rare AD-associated loci”</p></blockquote>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"217 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813466","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":"Multiple sclerosis: an immune attack on astrocyte-mediated ion and water homeostasis","authors":"Marjo S. van der Knaap, Rogier Min","doi":"10.1038/s41582-025-01081-y","DOIUrl":"https://doi.org/10.1038/s41582-025-01081-y","url":null,"abstract":"<p>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. The chain of events that results in demyelinating lesions is not understood, although most theories assume a primary immune attack on myelin. However, the glial cell adhesion molecule GlialCAM, which forms part of a protein complex in astrocytic endfeet that is crucial for brain ion and water homeostasis, was recently identified as a target for autoimmunity in patients with MS. This complex also includes the astrocytic transmembrane protein MLC1, the water channel aquaporin 4 (AQP4) and the potassium channel KIR4.1. Autoimmunity against AQP4 underlies another demyelinating disorder, neuromyelitis optica, and autoimmunity against KIR4.1 has been implicated in a subtype of MS. Genetic defects in any of these proteins cause leukodystrophies with disruption of brain ion and water homeostasis, which is regulated by astrocytes and secondarily affects myelin. In this Perspective, we argue that an immune attack on the ion and water homeostasis machinery in astrocytic endfeet, rather than directly on myelin, is the primary event in MS and that myelin damage is a consequence of astrocyte dysfunction. This hypothesis is supported by pathological studies on tissue from people with MS and has important implications for disease models and therapy targets.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"37 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782398","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":"Epigenetic reprogramming of glioblastoma to overcome chemotherapy resistance","authors":"Heather Wood","doi":"10.1038/s41582-025-01083-w","DOIUrl":"https://doi.org/10.1038/s41582-025-01083-w","url":null,"abstract":"Researchers have developed a CRISPR–Cas9-based epigenetic editing approach that sensitizes glioblastoma cells to standard chemotherapy drugs and could improve the treatment of tumours that have developed resistance to these drugs.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"183 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775593","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}
Apostolos Manolopoulos, Pamela J. Yao, Dimitrios Kapogiannis
{"title":"Extracellular vesicles: translational research and applications in neurology","authors":"Apostolos Manolopoulos, Pamela J. Yao, Dimitrios Kapogiannis","doi":"10.1038/s41582-025-01080-z","DOIUrl":"https://doi.org/10.1038/s41582-025-01080-z","url":null,"abstract":"<p>Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us closer to understanding the complex pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis and multiple sclerosis. We describe how translational research on EVs might unfold bidirectionally, proceeding from basic to clinical studies but also in the opposite direction, with biomarker findings in the clinic leading to novel hypotheses that can be tested in the laboratory. We demonstrate the potential value of EVs across all stages of the therapeutic development pipeline, from identifying therapeutic targets to the use of EVs as reporters in model systems and biomarkers in clinical research. Finally, we discuss how the cargo and physicochemical properties of naturally occurring and custom-engineered EVs can be leveraged as novel treatments and vehicles for drug delivery, potentially revolutionizing neurotherapeutics.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"69 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766380","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}
Anouk Tosserams, Alfonso Fasano, Moran Gilat, Stewart A. Factor, Nir Giladi, Simon J. G. Lewis, Caroline Moreau, Bastiaan R. Bloem, Alice Nieuwboer, Jorik Nonnekes
{"title":"Management of freezing of gait — mechanism-based practical recommendations","authors":"Anouk Tosserams, Alfonso Fasano, Moran Gilat, Stewart A. Factor, Nir Giladi, Simon J. G. Lewis, Caroline Moreau, Bastiaan R. Bloem, Alice Nieuwboer, Jorik Nonnekes","doi":"10.1038/s41582-025-01079-6","DOIUrl":"https://doi.org/10.1038/s41582-025-01079-6","url":null,"abstract":"<p>Freezing of gait (FOG) is a debilitating motor symptom that commonly occurs in Parkinson disease, atypical parkinsonism and other neurodegenerative conditions. Management of FOG is complex and requires a multifaceted approach that includes pharmacological, surgical and non-pharmacological interventions. In this Expert Recommendation, we provide state-of-the-art practical recommendations for the management of FOG, based on the latest insights into the pathophysiology of the condition. We propose two complementary treatment flows, both of which are linked to the pathophysiology and tailored to specific FOG phenotypes. The first workflow focuses on the reduction of excessive inhibitory outflow from the basal ganglia through use of dopaminergic medication or advanced therapies such as deep brain stimulation and infusion therapy. The second workflow focuses on facilitation of processing across cerebral compensatory networks by use of non-pharmacological interventions. We also highlight interventions that have potential for FOG but are not supported by sufficient evidence to recommend for clinical application. Our updated recommendations are intended to enable effective symptomatic relief once FOG has developed, but we also consider potential targets for preventive approaches. The recommendations are based on scientific evidence where available, supplemented with practice-based evidence informed by our clinical experience.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"22 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758089","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}
Charlotte Martial, Pauline Fritz, Olivia Gosseries, Vincent Bonhomme, Daniel Kondziella, Kevin Nelson, Nicolas Lejeune
{"title":"A neuroscientific model of near-death experiences","authors":"Charlotte Martial, Pauline Fritz, Olivia Gosseries, Vincent Bonhomme, Daniel Kondziella, Kevin Nelson, Nicolas Lejeune","doi":"10.1038/s41582-025-01072-z","DOIUrl":"https://doi.org/10.1038/s41582-025-01072-z","url":null,"abstract":"<p>Near-death experiences (NDEs) are episodes of disconnected consciousness that typically occur in situations that involve an actual or potential physical threat or are perceived as such, and the experiences are characterized by a rich content with prototypical mystical features. Several explanatory theories for NDEs have been proposed, ranging from psychological or neurophysiological to evolutionary models. However, these concepts were often formulated independently, and, owing to the fragmented nature of research in this domain, integration of these ideas has been limited. Lines of empirical evidence from different areas of neuroscience, including non-human studies, studies investigating psychedelic-induced mystical experiences in humans, and research on the dying brain, are now converging to provide a comprehensive explanation for NDEs. In this Review, we discuss processes that might underlie the rich conscious experience in NDEs, mostly focusing on prototypical examples and addressing both the potential psychological mechanisms and neurophysiological changes, including cellular and electrophysiological brain network modifications and alterations in neurotransmitter release. On the basis of this discussion, we propose a model for NDEs that encompasses a cascade of concomitant psychological and neurophysiological processes within an evolutionary framework. We also consider how NDE research can inform the debate on the emergence of consciousness in near-death conditions that arise before brain death.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"28 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736561","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":"Knowing the enemy: strategic targeting of complement to treat Alzheimer disease","authors":"Andrea J. Tenner, Tiffany J. Petrisko","doi":"10.1038/s41582-025-01073-y","DOIUrl":"https://doi.org/10.1038/s41582-025-01073-y","url":null,"abstract":"<p>The complement system protects against infection, positively responds to tissue damage, clears cell debris, directs and modulates the adaptive immune system, and functions in neuronal development, normal synapse elimination and intracellular metabolism. However, complement also has a role in aberrant synaptic pruning and neuroinflammation — processes that lead to a feedforward loop of inflammation, injury and neuronal death that can contribute to neurodegenerative and neurological disorders, including Alzheimer disease. This Review provides justification, largely from preclinical mouse models but also from correlates with human tissue and biomarkers, for targeting specific complement components for therapeutic intervention in Alzheimer disease. We discuss promising strategies to slow the progression of cognitive loss with minimal undesired effects. The diverse interactions and functions of complement system components can influence biological processes in the healthy and diseased brain; here, these functions are described as a prerequisite to selecting appropriate, safe and effective therapeutic targets for translation to the clinic.</p>","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"57 1","pages":""},"PeriodicalIF":38.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695753","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":"Bioengineering to address progression in multiple sclerosis","authors":"Ian Fyfe","doi":"10.1038/s41582-025-01078-7","DOIUrl":"10.1038/s41582-025-01078-7","url":null,"abstract":"The use of bioengineered implants has provided insight into the immunological processes that underlie progression in multiple sclerosis.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 4","pages":"175-175"},"PeriodicalIF":28.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635126","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":"Exploring factors that confer cognitive resilience","authors":"Heather Wood","doi":"10.1038/s41582-025-01077-8","DOIUrl":"10.1038/s41582-025-01077-8","url":null,"abstract":"A new paper presents insights from an individual who survived to an advanced age without developing dementia, despite the presence of genetic risk factors for Alzheimer disease and substantial amyloid pathology in the brain.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 4","pages":"174-174"},"PeriodicalIF":28.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582747","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}