Pub Date : 2025-05-02DOI: 10.1038/s41582-025-01089-4
Claude Steriade, Jan Bauer, Christian G. Bien
Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity. In this Perspective, the authors provide a detailed description of rare autoimmune encephalitic conditions that present with recurrent seizures that are resistant to immunotherapy, grouped under the term autoimmune encephalitis-associated epilepsy. The article considers the clinical characteristics and pathophysiological mechanisms of these conditions, alongside current knowledge of treatment and outcomes.
{"title":"Autoimmune encephalitis-associated epilepsy","authors":"Claude Steriade, Jan Bauer, Christian G. Bien","doi":"10.1038/s41582-025-01089-4","DOIUrl":"10.1038/s41582-025-01089-4","url":null,"abstract":"Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity. In this Perspective, the authors provide a detailed description of rare autoimmune encephalitic conditions that present with recurrent seizures that are resistant to immunotherapy, grouped under the term autoimmune encephalitis-associated epilepsy. The article considers the clinical characteristics and pathophysiological mechanisms of these conditions, alongside current knowledge of treatment and outcomes.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 6","pages":"312-326"},"PeriodicalIF":33.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901402","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}
Pub Date : 2025-05-01DOI: 10.1038/s41582-025-01091-w
Charlotte E. Teunissen, Lisa Vermunt
Plasma biomarker tests for Alzheimer disease are becoming increasingly reliable, which enables implementation in clinical settings in which cerebrospinal fluid analysis and PET scans are unavailable. However, a new study shows that some patients have discordant plasma and PET biomarker results. Clinicians need clear guidance to identify and manage patients who do not fit into standard clinical or biological categories.
{"title":"Implications of AD plasma and PET biomarker discordance","authors":"Charlotte E. Teunissen, Lisa Vermunt","doi":"10.1038/s41582-025-01091-w","DOIUrl":"10.1038/s41582-025-01091-w","url":null,"abstract":"Plasma biomarker tests for Alzheimer disease are becoming increasingly reliable, which enables implementation in clinical settings in which cerebrospinal fluid analysis and PET scans are unavailable. However, a new study shows that some patients have discordant plasma and PET biomarker results. Clinicians need clear guidance to identify and manage patients who do not fit into standard clinical or biological categories.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 6","pages":"295-296"},"PeriodicalIF":33.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893131","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}
Pub Date : 2025-04-14DOI: 10.1038/s41582-025-01071-0
Laura Castro-Aldrete, Melanie Einsiedler, Julie Novakova Martinkova, Herman Depypere, Ting Fang Alvin Ang, Michelle M. Mielke, Shireen Sindi, Harris A. Eyre, Rhoda Au, Anne Marie Schumacher Dimech, Anna Dé, Cassandra Szoeke, Maria Carmela Tartaglia, Antonella Santuccione Chadha
Alzheimer disease (AD) is a life-limiting neurodegenerative disorder that disproportionately affects women. Indeed, sex and gender are emerging as crucial modifiers of diagnostic and therapeutic pathways in AD. This Review provides an overview of the interactions of sex and gender with important developments in AD and offers insights into priorities for future research to facilitate the development and implementation of personalized approaches in the shifting paradigm of AD care. In particular, this Review focuses on the influence of sex and gender on important advances in the treatment and diagnosis of AD, including disease-modifying therapies, fluid-based biomarkers, cognitive assessment tools and multidomain lifestyle interventional studies. Sex and gender influence the entire healthcare ecosystem of Alzheimer disease (AD). In this Review, Castro-Aldrete et al. present a holistic view of sex and gender in AD, and discuss how these factors affect research and policy efforts to improve AD prevention, diagnosis and treatment.
{"title":"Alzheimer disease seen through the lens of sex and gender","authors":"Laura Castro-Aldrete, Melanie Einsiedler, Julie Novakova Martinkova, Herman Depypere, Ting Fang Alvin Ang, Michelle M. Mielke, Shireen Sindi, Harris A. Eyre, Rhoda Au, Anne Marie Schumacher Dimech, Anna Dé, Cassandra Szoeke, Maria Carmela Tartaglia, Antonella Santuccione Chadha","doi":"10.1038/s41582-025-01071-0","DOIUrl":"10.1038/s41582-025-01071-0","url":null,"abstract":"Alzheimer disease (AD) is a life-limiting neurodegenerative disorder that disproportionately affects women. Indeed, sex and gender are emerging as crucial modifiers of diagnostic and therapeutic pathways in AD. This Review provides an overview of the interactions of sex and gender with important developments in AD and offers insights into priorities for future research to facilitate the development and implementation of personalized approaches in the shifting paradigm of AD care. In particular, this Review focuses on the influence of sex and gender on important advances in the treatment and diagnosis of AD, including disease-modifying therapies, fluid-based biomarkers, cognitive assessment tools and multidomain lifestyle interventional studies. Sex and gender influence the entire healthcare ecosystem of Alzheimer disease (AD). In this Review, Castro-Aldrete et al. present a holistic view of sex and gender in AD, and discuss how these factors affect research and policy efforts to improve AD prevention, diagnosis and treatment.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 5","pages":"235-249"},"PeriodicalIF":33.1,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827314","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}
Pub Date : 2025-04-14DOI: 10.1038/s41582-025-01088-5
Lisa Kiani
Nature Reviews Neurology is interviewing individuals who are driving efforts to address disparities in neurology through a broad spectrum of diversity, equity and inclusion initiatives. We spoke with neurologist Esther Bui from Canada about her work to improve neurological health for women. We spoke with neurologist Esther Bui from Canada about her work to improve neurological health for women.
{"title":"Women’s neurology: a growing subspeciality to tackle sex and gender disparities","authors":"Lisa Kiani","doi":"10.1038/s41582-025-01088-5","DOIUrl":"10.1038/s41582-025-01088-5","url":null,"abstract":"Nature Reviews Neurology is interviewing individuals who are driving efforts to address disparities in neurology through a broad spectrum of diversity, equity and inclusion initiatives. We spoke with neurologist Esther Bui from Canada about her work to improve neurological health for women. We spoke with neurologist Esther Bui from Canada about her work to improve neurological health for women.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 5","pages":"229-230"},"PeriodicalIF":33.1,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831801","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}
Pub Date : 2025-04-10DOI: 10.1038/s41582-025-01084-9
Lisa Kiani
{"title":"Microglia underlie amyloid-β clearance in immunized people with Alzheimer disease","authors":"Lisa Kiani","doi":"10.1038/s41582-025-01084-9","DOIUrl":"10.1038/s41582-025-01084-9","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 5","pages":"233-233"},"PeriodicalIF":33.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813471","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}
Pub Date : 2025-04-10DOI: 10.1038/s41582-025-01082-x
Ian Fyfe
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.
{"title":"Walking the Talk for Dementia — an experience to break down barriers","authors":"Ian Fyfe","doi":"10.1038/s41582-025-01082-x","DOIUrl":"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":"21 5","pages":"231-232"},"PeriodicalIF":33.1,"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}
Pub Date : 2025-04-04DOI: 10.1038/s41582-025-01081-y
Marjo S. van der Knaap, Rogier Min
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. Autoimmunity in multiple sclerosis (MS) is generally considered to be directed against components of myelin or oligodendrocytes. However, this Perspective argues that an immune attack on the ion and water homeostasis machinery in astrocytic endfeet is the primary event in MS and that myelin damage results from astrocyte dysfunction.
{"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":"10.1038/s41582-025-01081-y","url":null,"abstract":"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. Autoimmunity in multiple sclerosis (MS) is generally considered to be directed against components of myelin or oligodendrocytes. However, this Perspective argues that an immune attack on the ion and water homeostasis machinery in astrocytic endfeet is the primary event in MS and that myelin damage results from astrocyte dysfunction.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"21 5","pages":"283-289"},"PeriodicalIF":33.1,"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}
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