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