Cited by 771Multiple Sclerosis Research StudiesCerebrospinal fluid and hydrocephalusHereditary Neurological Disorders

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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis

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Bridel, Claire, van Wieringen, Wessel N., Zetterberg, Henrik, Tijms, Betty M., Teunissen, Charlotte E., and the NFL Group, Alvarez-Cermeño, José C., Andreasson, Ulf, Axelsson, Markus, Bäckström, David C., Bartos, Ales, Bjerke, Maria, Blennow, Kaj, Boxer, Adam, Brundin, Lou, Burman, Joachim, Christensen, Tove, Fialová, Lenká, Forsgren, Lars, Frederiksen, Jette L., Gisslén, Magnus, Gray, Elizabeth, Gunnarsson, Martin, Hall, Sara, Hansson, Oskar, Herbert, Megan K., Jakobsson, Joel, Jessen-Krut, Jan, Janelidze, Shorena, Johannsson, Gudmundur, Jonsson, Michael, Kappos, Ludwig, Khademi, Mohsen, Khalil, Michael, Kuhle, Jens, Landén, Mikael, Leinonen, Ville, Logroscino, Giancarlo, Lu, Ching-Hua, Lycke, Jan, Magdalinou, Nadia K., Malaspina, Andrea, Mattsson, Niklas, Meeter, Lieke H., Mehta, Sanjay R., Modvig, Signe, Olsson, Tomas, Paterson, Ross W., Pérez-Santiago, Josué, Piehl, Fredrik, Pijnenburg, Yolande A. L., Pyykkö, Okko T., Ragnarsson, Oskar, Rojas, Julio C., Romme Christensen, Jeppe, Sandberg, Linda, Scherling, Carole S., Schott, Jonathan M., Sellebjerg, Finn T., Simone, Isabella L., Skillbäck, Tobias, Stilund, Morten, Sundström, Peter, Svenningsson, Anders, Tortelli, Rosanna, Tortorella, Carla, Trentini, Alessandro, Troiano, Maria, Turner, Martin R., van Swieten, John C., Vågberg, Mattias, Verbeek, Marcel M., Villar, Luisa M., Visser, Pieter Jelle, Wallin, Anders, Weiss, Andreas, Wikkelsø, Carsten, Wild, Edward J.·2019·JAMA Neurology

DOI 10.1001/jamaneurol.2019.1534PMC PMC6580449

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Abstract

IMPORTANCE: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. OBJECTIVES: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. DATA SOURCES: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. STUDY SELECTION: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. DATA EXTRACTION AND SYNTHESIS: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. MAIN OUTCOME AND MEASURE: The cNfL levels adjusted for age and sex across diagnoses. RESULTS: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. CONCLUSIONS AND RELEVANCE: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

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Authors: Bridel, C., van Wieringen, W. N., Zetterberg, H., Tijms, B. M., Teunissen, C. E., and the NFL Group, Alvarez-Cermeño, J. C., Andreasson, U., Axelsson, M., Bäckström, D. C., Bartos, A., Bjerke, M., Blennow, K., Boxer, A., Brundin, L., Burman, J., Christensen, T., Fialová, L., Forsgren, L., Frederiksen, J. L., Gisslén, M., Gray, E., Gunnarsson, M., Hall, S., Hansson, O., Herbert, M. K., Jakobsson, J., Jessen-Krut, J., Janelidze, S., Johannsson, G., Jonsson, M., Kappos, L., Khademi, M., Khalil, M., Kuhle, J., Landén, M., Leinonen, V., Logroscino, G., Lu, C.-H., Lycke, J., Magdalinou, N. K., Malaspina, A., Mattsson, N., Meeter, L. H., Mehta, S. R., Modvig, S., Olsson, T., Paterson, R. W., Pérez-Santiago, J., Piehl, F., Pijnenburg, Y. A. L., Pyykkö, O. T., Ragnarsson, O., Rojas, J. C., Romme Christensen, J., Sandberg, L., Scherling, C. S., Schott, J. M., Sellebjerg, F. T., Simone, I. L., Skillbäck, T., Stilund, M., Sundström, P., Svenningsson, A., Tortelli, R., Tortorella, C., Trentini, A., Troiano, M., Turner, M. R., van Swieten, J. C., Vågberg, M., Verbeek, M. M., Villar, L. M., Visser, P. J., Wallin, A., Weiss, A., Wikkelsø, C., & Wild, E. J.
Affiliations: Amsterdam Neuroscience (NL)
Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, the Netherlands
Sahlgrenska University Hospital (SE)
Hospital Universitario Ramón y Cajal (ES)
Multiple Sclerosis Unit, Ramon y Cajal University Hospital, Madrid, Spain
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
University of Gothenburg (SE)
Charles University (CZ)
Third Faculty of Medicine, Department of Neurology, Charles University and General University Hospital, Prague, Czech Republic
University of Antwerp (BE)
University of California, San Francisco (US)
Karolinska University Hospital (SE)
Uppsala University (SE)
Aarhus University (DK)
Copenhagen University Hospital (DK)
University of Oxford (GB)
Lund University (SE)
University of Basel (CH)
Department of Medicine, University Hospital and University of Basel, Basel, Switzerland
University of Eastern Finland (FI)
China Medical University Hospital (TW)
National Hospital for Neurology and Neurosurgery (GB)
Queen Mary University of London (GB)
Erasmus MC (NL)
University of Puerto Rico, Medical Sciences Campus (PR)
Puerto Rico OMICS Centre, University of Puerto Rico Comprehensive Cancer Centre, San Juan
Department of Neurology, Faculty of Medicine and Health, Orebro University Hospital, Orebro, Sweden
Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Belmont University (US)
Azienda Ospedaliera San Camillo-Forlanini (IT)
Danderyds sjukhus (SE)
Pia Fondazione di Culto e Religione Azienda Ospedaliera "Card. G. Panico" (IT)
University of Ferrara (IT)
Alzheimer Centre and Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands
Radboud University Nijmegen (NL)
Maastricht University (NL)
Evotec (Germany) (DE)
Corresponding author: Bridel, Claire
ORCID: Bridel, Claire
Zetterberg, Henrik
Tijms, Betty M.
Teunissen, Charlotte E.
Axelsson, Markus
Bäckström, David C.
Bjerke, Maria
Blennow, Kaj
Boxer, Adam
Brundin, Lou
Burman, Joachim
Christensen, Tove
Fialová, Lenká
Forsgren, Lars
Frederiksen, Jette L.
Gisslén, Magnus
Gray, Elizabeth
Hall, Sara
Hansson, Oskar
Herbert, Megan K.
Jakobsson, Joel
Janelidze, Shorena
Johannsson, Gudmundur
Jonsson, Michael
Kappos, Ludwig
Khademi, Mohsen
Khalil, Michael
Landén, Mikael
Leinonen, Ville
Logroscino, Giancarlo
Lu, Ching-Hua
Lycke, Jan
Malaspina, Andrea
Mattsson, Niklas
Meeter, Lieke H.
Mehta, Sanjay R.
Modvig, Signe
Olsson, Tomas
Paterson, Ross W.
Piehl, Fredrik
Pijnenburg, Yolande A. L.
Rojas, Julio C.
Schott, Jonathan M.
Sellebjerg, Finn T.
Simone, Isabella L.
Skillbäck, Tobias
Stilund, Morten
Sundström, Peter
Svenningsson, Anders
Tortelli, Rosanna
Tortorella, Carla
Trentini, Alessandro
Turner, Martin R.
Vågberg, Mattias
Verbeek, Marcel M.
Villar, Luisa M.
Visser, Pieter Jelle
Wallin, Anders
Weiss, Andreas
Wikkelsø, Carsten
Wild, Edward J.
Venue: JAMA Neurology
Publisher: American Medical Association (AMA)
Published: 2019-09-01
Volume: 76
Issue: 9
Pages: 1035
ISSN: 2168-6149 (ISSN-L)
DOI: 10.1001/jamaneurol.2019.1534
PMC: PMC6580449
OpenAlex: W2950228559
Cited by: 764
References: 107
Citations by year: 2026: 76 · 2025: 116 · 2024: 115 · 2023: 105 · 2022: 119 · 2021: 108 · 2020: 102 · 2019: 21
FWCI: 65.69
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA Neurology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Research Publications (Maastricht University) (publishedVersion, other-oa)
Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Archive ouverte UNIGE (University of Geneva) (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
UCL Discovery (University College London) (submittedVersion)
Pure Amsterdam UMC (submittedVersion, other-oa)
Radboud Repository (Radboud University) (submittedVersion)
CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, other-oa)
Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Research Publications (Maastricht University) (submittedVersion, other-oa)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: Eli Lilly and Company
AstraZeneca
Bayer
Sanofi
Biogen
CHDI Foundation
Teva Pharmaceutical Industries
Itä-Suomen Yliopisto
Universität Basel
European Committee for Treatment and Research in Multiple Sclerosis
EU Joint Programme – Neurodegenerative Disease Research
European Federation of Pharmaceutical Industries and Associations (115372)
European Huntington's Disease Network
National Institute for Health and Care Research (CL-2016-18-004)
Motor Neurone Disease Association (TURNER/OCT18/989-797, MALASPINA/APR13/817-791, MR/ K01014X/1, TURNER/OCT15/972-797)
European Commission (HORIZON2020, 733050202, 115372, 633666)
Bayer HealthCare
National Research Foundation
ZonMw (733050202, 733050822, 733050824)
Radboud Universiteit
Vrije Universiteit Amsterdam
Universiteit Maastricht
Gentofte Hospital
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (733050822)
Karolinska Institutet
Kuopion Yliopistollinen Sairaala
China Medical University Hospital
Sahlgrenska Universitetssjukhuset
Università degli Studi di Ferrara
China Medical University
Red Española de Esclerosis Múltiple
Karl-Franzens-Universität Graz
Novo Nordisk Fonden (NNF17OC0026978)
Medizinische Universität Graz
Stichting Dioraphte
Alzheimer Nederland
H. Lundbeck A/S
Barts Health NHS Trust
Janssen Prevention Center
Allergan
University of California, San Diego
Avid Radiopharmaceuticals
Medical Research Council (MR/K01014X/1, MR/M008592/1)
Economic and Social Research Council (ES/K000365/1)
Instituto de Salud Carlos III
National Institute on Aging (K23AG059888, P01AG019724, T32AG023481)
Topics: Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords: neurofilament light chain, cerebrospinal fluid biomarkers, neuroaxonal damage, age and sex effects, differential diagnosis, frontotemporal dementia, HIV-associated neurocognitive disorders, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, dementia, neuroinflammation, diagnostic accuracy, neurodegeneration

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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis

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