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      A multicentre validation study of the diagnostic value of plasma neurofilament light

      research-article
      1 , 2 , 3 , 4 , , 5 , 6 , 5 , 7 , 1 , 8 , 9 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 16 , 18 , 19 , 18 , 19 , 18 , 19 , 3 , 20 , 21 , 22 , 21 , 23 , 23 , 24 , 25 , 1 , 2 , 26 , 27 , 28 , 27 , 29 , 27 , 28 , 29 , 30 , 6 , 31 , 8 , 9 , 32 , 33 , 34 , 3 , 35 , 5 , 36 , 5 , 3 , 4 , 37 , 7 , 5 , 38 , 1 , 26 , 39 , 40 , 1 , 39 , 3 , 4 , 37 , 5 , 36 ,
      Nature Communications
      Nature Publishing Group UK
      Neurodegeneration, Diagnostic markers, Predictive markers

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          Abstract

          Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London ( n = 805) and the Swedish BioFINDER study ( n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

          Abstract

          Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.

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          Most cited references67

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          NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

          In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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            Neurofilaments as biomarkers in neurological disorders

            Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.
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              Amyotrophic Lateral Sclerosis

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                Author and article information

                Contributors
                nicholas.ashton@gu.se
                oskar.hansson@med.lu.se
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                7 June 2021
                7 June 2021
                2021
                : 12
                : 3400
                Affiliations
                [1 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, , The Sahlgrenska Academy at the University of Gothenburg, ; Mölndal, Sweden
                [2 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Wallenberg Centre for Molecular and Translational Medicine, , University of Gothenburg, ; Gothenburg, Sweden
                [3 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, , King’s College London, ; London, UK
                [4 ]GRID grid.454378.9, NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, ; London, UK
                [5 ]GRID grid.4514.4, ISNI 0000 0001 0930 2361, Clinical Memory Research Unit, Department of Clinical Sciences Malmö, , Lund University, ; Lund, Sweden
                [6 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Basic and Clinical Neuroscience, , Maurice Wohl Clinical Neuroscience Institute, King’s College London, ; London, UK
                [7 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Neurology and Alzheimer Center, , Erasmus University Medical Center, ; Rotterdam, Netherlands
                [8 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Translational Neuroimaging Laboratory, , The McGill University Research Centre for Studies in Aging, ; Montreal, QC Canada
                [9 ]GRID grid.416102.0, ISNI 0000 0004 0646 3639, Montreal Neurological Institute, ; Montreal, QC Canada
                [10 ]GRID grid.413396.a, ISNI 0000 0004 1768 8905, Memory Unit, Department of Neurology, , Hospital de la Santa Creu i Sant Pau, ; Barcelona, Spain
                [11 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, , Instituto de Salud Carlos III, ; Madrid, Spain
                [12 ]GRID grid.9027.c, ISNI 0000 0004 1757 3630, Laboratory of Clinical Neurochemistry, Neurology Clinic, , University of Perugia, ; Perugia, Italy
                [13 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, Fondazione IRCCS Ca’ Granda, , Ospedale Policlinico, ; Milan, Italy
                [14 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Dino Ferrari Center, , University of Milan, ; Milan, Italy
                [15 ]GRID grid.412451.7, ISNI 0000 0001 2181 4941, Department of Neuroscience, Imaging and Clinical Sciences, , University G.d’Annunzio of Chieti-Pescara, ; Chieti, Italy
                [16 ]GRID grid.7637.5, ISNI 0000000417571846, Neurology Unit, Department of Clinical and Experimental Sciences, , University of Brescia, ; Brescia, Italy
                [17 ]Parkinson’s Disease Rehabilitation Centre, FERB ONLUS, Trescore Balneario, BG Italy
                [18 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, Sahlgrenska Academy, , University of Gothenburg, ; Gothenburg, Sweden
                [19 ]GRID grid.1649.a, ISNI 000000009445082X, Department of Neurology, , Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [20 ]GRID grid.9918.9, ISNI 0000 0004 1936 8411, Department of Health Sciences, , University of Leicester, ; Leicester, UK
                [21 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Neurology, , University of California San Francisco, Memory and Aging Center, ; San Francisco, CA USA
                [22 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Radiology & Biomedical Imaging, , University of California, ; San Francisco, CA USA
                [23 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Stress, Psychiatry and Immunology Lab & Perinatal Psychiatry, Maurice Wohl Clinical Neuroscience Institute, , King’s College London, ; London, UK
                [24 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, , National Institutes of Health, ; Baltimore, MD USA
                [25 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, , National Institutes of Health, ; Baltimore, MD USA
                [26 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, , University College London, ; London, UK
                [27 ]GRID grid.432380.e, Neurosciences Area, , Biodonostia Health Research Institute, ; San Sebastián, Spain
                [28 ]GRID grid.414651.3, Department of Neurology, , Donostia University Hospital, Osakidetza, ; San Sebastián, Spain
                [29 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, CIBERNED, , Carlos III Health Institute, ; Madrid, Spain
                [30 ]GRID grid.11480.3c, ISNI 0000000121671098, Department of Neurosciences, , Basque Country University, ; San Sebastián, Spain
                [31 ]GRID grid.46699.34, ISNI 0000 0004 0391 9020, Department of Neurology, , King’s College Hospital, ; London, UK
                [32 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; London, UK
                [33 ]GRID grid.37640.36, ISNI 0000 0000 9439 0839, South London and Maudsley NHS Foundation Trust, ; London, UK
                [34 ]London Down Syndrome Consortium (LonDowns), London, UK
                [35 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Clinical Neuroscience, , Karolinska Institutet, ; Stockholm, Sweden
                [36 ]GRID grid.411843.b, ISNI 0000 0004 0623 9987, Memory Clinic, , Skåne University Hospital, ; Malmö, Sweden
                [37 ]GRID grid.412835.9, ISNI 0000 0004 0627 2891, Centre for Age-Related Medicine, , Stavanger University Hospital, ; Stavanger, Norway
                [38 ]GRID grid.411843.b, ISNI 0000 0004 0623 9987, Department of Neurology, , Skåne University Hospital, Lund University, ; Lund, Sweden
                [39 ]GRID grid.1649.a, ISNI 000000009445082X, Clinical Neurochemistry Laboratory, , Sahlgrenska University Hospital, ; Mölndal, Sweden
                [40 ]GRID grid.83440.3b, ISNI 0000000121901201, UK Dementia Research Institute, , University College London, ; London, UK
                Author information
                http://orcid.org/0000-0002-3579-8804
                http://orcid.org/0000-0002-7406-9831
                http://orcid.org/0000-0003-1422-4358
                http://orcid.org/0000-0002-2568-5478
                http://orcid.org/0000-0002-9284-5953
                http://orcid.org/0000-0002-7891-8466
                http://orcid.org/0000-0002-7712-930X
                http://orcid.org/0000-0002-9132-5091
                http://orcid.org/0000-0001-7800-1781
                http://orcid.org/0000-0003-1112-7464
                http://orcid.org/0000-0002-4924-7712
                http://orcid.org/0000-0002-9267-1930
                http://orcid.org/0000-0003-3930-4354
                http://orcid.org/0000-0002-1890-4193
                http://orcid.org/0000-0001-8467-7286
                Article
                23620
                10.1038/s41467-021-23620-z
                8185001
                34099648
                91bd26ad-298a-4c0f-b148-b595b0a79c1b
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 August 2020
                : 4 May 2021
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                © The Author(s) 2021

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                neurodegeneration,diagnostic markers,predictive markers
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                neurodegeneration, diagnostic markers, predictive markers

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