Pub Date : 2024-06-11DOI: 10.1038/s41582-024-00989-1
Michelle M. Mielke, Nicole R. Fowler
In the past 5 years, we have witnessed the first approved Alzheimer disease (AD) disease-modifying therapy and the development of blood-based biomarkers (BBMs) to aid the diagnosis of AD. For many reasons, including accessibility, invasiveness and cost, BBMs are more acceptable and feasible for patients than a lumbar puncture (for cerebrospinal fluid collection) or neuroimaging. However, many questions remain regarding how best to utilize BBMs at the population level. In this Review, we outline the factors that warrant consideration for the widespread implementation and interpretation of AD BBMs. To set the scene, we review the current use of biomarkers, including BBMs, in AD. We go on to describe the characteristics of typical patients with cognitive impairment in primary care, who often differ from the patient populations used in AD BBM research studies. We also consider factors that might affect the interpretation of BBM tests, such as comorbidities, sex and race or ethnicity. We conclude by discussing broader issues such as ethics, patient and provider preference, incidental findings and dealing with indeterminate results and imperfect accuracy in implementing BBMs at the population level. Blood-based biomarkers have the potential to transform the Alzheimer disease diagnostic pathway, but many questions remain regarding their implementation and utilization. This Review considers factors that might affect the interpretation of blood-based biomarker tests, including comorbidities, sex and race or ethnicity, and discusses broader issues surrounding their use at the population level.
在过去的 5 年中，我们见证了首例获批的阿尔茨海默病（AD）疾病改变疗法，也见证了血液生物标志物（BBM）的发展，以帮助诊断阿尔茨海默病。与腰椎穿刺（采集脑脊液）或神经影像学检查相比，基于血液的生物标记物因其可及性、侵入性和成本等诸多原因，更容易被患者接受，也更可行。然而，在人群中如何更好地使用 BBM 仍存在许多问题。在本综述中，我们将概述在广泛实施和解释 AD BBM 时需要考虑的因素。首先，我们回顾了目前在 AD 中使用生物标记物（包括 BBMs）的情况。我们接着描述了典型的初级医疗认知障碍患者的特征，他们通常不同于 AD BBM 研究中使用的患者群体。我们还考虑了可能影响 BBM 检验解释的因素，如合并症、性别、种族或民族。最后，我们讨论了更广泛的问题，如伦理、患者和医疗服务提供者的偏好、偶然发现、处理不确定的结果以及在人群层面实施 BBM 时的不完全准确性。
{"title":"Alzheimer disease blood biomarkers: considerations for population-level use","authors":"Michelle M. Mielke, Nicole R. Fowler","doi":"10.1038/s41582-024-00989-1","DOIUrl":"10.1038/s41582-024-00989-1","url":null,"abstract":"In the past 5 years, we have witnessed the first approved Alzheimer disease (AD) disease-modifying therapy and the development of blood-based biomarkers (BBMs) to aid the diagnosis of AD. For many reasons, including accessibility, invasiveness and cost, BBMs are more acceptable and feasible for patients than a lumbar puncture (for cerebrospinal fluid collection) or neuroimaging. However, many questions remain regarding how best to utilize BBMs at the population level. In this Review, we outline the factors that warrant consideration for the widespread implementation and interpretation of AD BBMs. To set the scene, we review the current use of biomarkers, including BBMs, in AD. We go on to describe the characteristics of typical patients with cognitive impairment in primary care, who often differ from the patient populations used in AD BBM research studies. We also consider factors that might affect the interpretation of BBM tests, such as comorbidities, sex and race or ethnicity. We conclude by discussing broader issues such as ethics, patient and provider preference, incidental findings and dealing with indeterminate results and imperfect accuracy in implementing BBMs at the population level. Blood-based biomarkers have the potential to transform the Alzheimer disease diagnostic pathway, but many questions remain regarding their implementation and utilization. This Review considers factors that might affect the interpretation of blood-based biomarker tests, including comorbidities, sex and race or ethnicity, and discusses broader issues surrounding their use at the population level.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 8","pages":"495-504"},"PeriodicalIF":28.2,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304479","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 : 2024-06-04DOI: 10.1038/s41582-024-00984-6
Ian Fyfe
{"title":"Potassium regulation could be key to healthy brain ageing","authors":"Ian Fyfe","doi":"10.1038/s41582-024-00984-6","DOIUrl":"10.1038/s41582-024-00984-6","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 7","pages":"379-379"},"PeriodicalIF":28.2,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237879","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 : 2024-06-04DOI: 10.1038/s41582-024-00985-5
Ian Fyfe
{"title":"APOE α4 homozygosity — a genetic form of Alzheimer disease?","authors":"Ian Fyfe","doi":"10.1038/s41582-024-00985-5","DOIUrl":"10.1038/s41582-024-00985-5","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 7","pages":"379-379"},"PeriodicalIF":28.2,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237906","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 : 2024-06-04DOI: 10.1038/s41582-024-00979-3
Heather Wood
A new study has identified prematurely senescent microglia in the vicinity of amyloid-β plaques in the brains of individuals with Alzheimer disease.
一项新的研究发现，在阿尔茨海默病患者大脑中的淀粉样β斑块附近存在早衰的小胶质细胞。
{"title":"Microglial senescence is a potential therapeutic target for Alzheimer disease","authors":"Heather Wood","doi":"10.1038/s41582-024-00979-3","DOIUrl":"10.1038/s41582-024-00979-3","url":null,"abstract":"A new study has identified prematurely senescent microglia in the vicinity of amyloid-β plaques in the brains of individuals with Alzheimer disease.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 7","pages":"379-379"},"PeriodicalIF":28.2,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237849","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 : 2024-05-29DOI: 10.1038/s41582-024-00978-4
Michael Benatar, Joanne Wuu, Edward D. Huey, Corey T. McMillan, Ronald C. Petersen, Ronald Postuma, Caroline McHutchison, Laynie Dratch, Jalayne J. Arias, Anita Crawley, Henry Houlden, Michael P. McDermott, Xueya Cai, Neil Thakur, Adam Boxer, Howard Rosen, Bradley F. Boeve, Penny Dacks, Stephanie Cosentino, Sharon Abrahams, Neil Shneider, Paul Lingor, Jeremy Shefner, Peter M. Andersen, Ammar Al-Chalabi, Martin R. Turner, Attendees of the Second International Pre-Symptomatic ALS Workshop
{"title":"Publisher Correction: The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology","authors":"Michael Benatar, Joanne Wuu, Edward D. Huey, Corey T. McMillan, Ronald C. Petersen, Ronald Postuma, Caroline McHutchison, Laynie Dratch, Jalayne J. Arias, Anita Crawley, Henry Houlden, Michael P. McDermott, Xueya Cai, Neil Thakur, Adam Boxer, Howard Rosen, Bradley F. Boeve, Penny Dacks, Stephanie Cosentino, Sharon Abrahams, Neil Shneider, Paul Lingor, Jeremy Shefner, Peter M. Andersen, Ammar Al-Chalabi, Martin R. Turner, Attendees of the Second International Pre-Symptomatic ALS Workshop","doi":"10.1038/s41582-024-00978-4","DOIUrl":"10.1038/s41582-024-00978-4","url":null,"abstract":"","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 6","pages":"377-377"},"PeriodicalIF":38.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41582-024-00978-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174324","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}
Pub Date : 2024-05-23DOI: 10.1038/s41582-024-00974-8
Sebastian Ocklenburg, Annakarina Mundorf, Robin Gerrits, Emma M. Karlsson, Marietta Papadatou-Pastou, Guy Vingerhoets
No two human brains are alike, and with the rise of precision medicine in neurology, we are seeing an increased emphasis on understanding the individual variability in brain structure and function that renders every brain unique. Functional and structural brain asymmetries are a fundamental principle of brain organization, and recent research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. In this Review, we provide an overview of brain asymmetries, variations in such asymmetries and their relevance in the clinical context. We review recent findings on brain asymmetries in neuropsychiatric and neurodevelopmental disorders, as well as in specific learning disabilities, with an emphasis on large-scale database studies and meta-analyses. We also highlight the relevance of asymmetries for disease symptom onset in neurodegenerative diseases and their implications for lateralized treatments, including brain stimulation. We conclude that alterations in brain asymmetry are not sufficiently specific to act as diagnostic biomarkers but can serve as meaningful symptom or treatment response biomarkers in certain contexts. On the basis of these insights, we provide several recommendations for neurological clinical practice. Functional and structural brain asymmetries are a fundamental principle of brain organization, and research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. This Review provides an overview of brain asymmetries, variations in such asymmetries and their relevance in the context of clinical neurology.
{"title":"Clinical implications of brain asymmetries","authors":"Sebastian Ocklenburg, Annakarina Mundorf, Robin Gerrits, Emma M. Karlsson, Marietta Papadatou-Pastou, Guy Vingerhoets","doi":"10.1038/s41582-024-00974-8","DOIUrl":"10.1038/s41582-024-00974-8","url":null,"abstract":"No two human brains are alike, and with the rise of precision medicine in neurology, we are seeing an increased emphasis on understanding the individual variability in brain structure and function that renders every brain unique. Functional and structural brain asymmetries are a fundamental principle of brain organization, and recent research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. In this Review, we provide an overview of brain asymmetries, variations in such asymmetries and their relevance in the clinical context. We review recent findings on brain asymmetries in neuropsychiatric and neurodevelopmental disorders, as well as in specific learning disabilities, with an emphasis on large-scale database studies and meta-analyses. We also highlight the relevance of asymmetries for disease symptom onset in neurodegenerative diseases and their implications for lateralized treatments, including brain stimulation. We conclude that alterations in brain asymmetry are not sufficiently specific to act as diagnostic biomarkers but can serve as meaningful symptom or treatment response biomarkers in certain contexts. On the basis of these insights, we provide several recommendations for neurological clinical practice. Functional and structural brain asymmetries are a fundamental principle of brain organization, and research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. This Review provides an overview of brain asymmetries, variations in such asymmetries and their relevance in the context of clinical neurology.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 7","pages":"383-394"},"PeriodicalIF":28.2,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085187","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 : 2024-05-20DOI: 10.1038/s41582-024-00961-z
Michael Benatar, Joanne Wuu, Edward D. Huey, Corey T. McMillan, Ronald C. Petersen, Ronald Postuma, Caroline McHutchison, Laynie Dratch, Jalayne J. Arias, Anita Crawley, Henry Houlden, Michael P. McDermott, Xueya Cai, Neil Thakur, Adam Boxer, Howard Rosen, Bradley F. Boeve, Penny Dacks, Stephanie Cosentino, Sharon Abrahams, Neil Shneider, Paul Lingor, Jeremy Shefner, Peter M. Andersen, Ammar Al-Chalabi, Martin R. Turner, Attendees of the Second International Pre-Symptomatic ALS Workshop
Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum — from clinically silent, to prodromal, to clinically manifest — and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes — motor neuron, frontotemporal and extrapyramidal — rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers. In this Perspective, the authors propose a new classification system for amyotrophic lateral sclerosis and related neurodegenerative disorders that recognizes, in parallel, the clinical syndromes and the underlying biology of disease. The framework emerged from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023).
{"title":"The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology","authors":"Michael Benatar, Joanne Wuu, Edward D. Huey, Corey T. McMillan, Ronald C. Petersen, Ronald Postuma, Caroline McHutchison, Laynie Dratch, Jalayne J. Arias, Anita Crawley, Henry Houlden, Michael P. McDermott, Xueya Cai, Neil Thakur, Adam Boxer, Howard Rosen, Bradley F. Boeve, Penny Dacks, Stephanie Cosentino, Sharon Abrahams, Neil Shneider, Paul Lingor, Jeremy Shefner, Peter M. Andersen, Ammar Al-Chalabi, Martin R. Turner, Attendees of the Second International Pre-Symptomatic ALS Workshop","doi":"10.1038/s41582-024-00961-z","DOIUrl":"10.1038/s41582-024-00961-z","url":null,"abstract":"Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum — from clinically silent, to prodromal, to clinically manifest — and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes — motor neuron, frontotemporal and extrapyramidal — rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers. In this Perspective, the authors propose a new classification system for amyotrophic lateral sclerosis and related neurodegenerative disorders that recognizes, in parallel, the clinical syndromes and the underlying biology of disease. The framework emerged from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023).","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 6","pages":"364-376"},"PeriodicalIF":38.1,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069436","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 : 2024-05-17DOI: 10.1038/s41582-024-00967-7
Roberta Rudà, Craig Horbinski, Martin van den Bent, Matthias Preusser, Riccardo Soffietti
Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, d-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas. Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. Small-molecule inhibitors of mutant IDH are emerging as a new therapeutic strategy for IDH-mutant cancers, and this Review charts their pathway of development for IDH-mutant gliomas.
{"title":"IDH inhibition in gliomas: from preclinical models to clinical trials","authors":"Roberta Rudà, Craig Horbinski, Martin van den Bent, Matthias Preusser, Riccardo Soffietti","doi":"10.1038/s41582-024-00967-7","DOIUrl":"10.1038/s41582-024-00967-7","url":null,"abstract":"Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, d-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas. Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. Small-molecule inhibitors of mutant IDH are emerging as a new therapeutic strategy for IDH-mutant cancers, and this Review charts their pathway of development for IDH-mutant gliomas.","PeriodicalId":19085,"journal":{"name":"Nature Reviews Neurology","volume":"20 7","pages":"395-407"},"PeriodicalIF":28.2,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954151","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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