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. 2019 Sep 1;76(9):1035-1048.
doi: 10.1001/jamaneurol.2019.1534.

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

Claire Bridel  1 Wessel N van Wieringen  2   3 Henrik Zetterberg  4   5   6   7 Betty M Tijms  8 Charlotte E Teunissen  1 and the NFL GroupJosé C Alvarez-Cermeño  9 Ulf Andreasson  4 Markus Axelsson  5 David C Bäckström  10 Ales Bartos  11   12 Maria Bjerke  13 Kaj Blennow  4   5 Adam Boxer  14 Lou Brundin  15   16 Joachim Burman  17 Tove Christensen  18 Lenká Fialová  19   20 Lars Forsgren  10 Jette L Frederiksen  21 Magnus Gisslén  22 Elizabeth Gray  23 Martin Gunnarsson  24 Sara Hall  25   26 Oskar Hansson  25   26 Megan K Herbert  27   28 Joel Jakobsson  5 Jan Jessen-Krut  22 Shorena Janelidze  25   26 Gudmundur Johannsson  27   28 Michael Jonsson  5 Ludwig Kappos  29 Mohsen Khademi  15   16 Michael Khalil  30 Jens Kuhle  29 Mikael Landén  5 Ville Leinonen  31   32 Giancarlo Logroscino  33 Ching-Hua Lu  34   35 Jan Lycke  5 Nadia K Magdalinou  36 Andrea Malaspina  34   37   38   39 Niklas Mattsson  25   26 Lieke H Meeter  40   41 Sanjay R Mehta  42 Signe Modvig  43 Tomas Olsson  15   16 Ross W Paterson  44 Josué Pérez-Santiago  45 Fredrik Piehl  15   16 Yolande A L Pijnenburg  8 Okko T Pyykkö  31   32 Oskar Ragnarsson  24 Julio C Rojas  14 Jeppe Romme Christensen  21 Linda Sandberg  10 Carole S Scherling  46 Jonathan M Schott  44 Finn T Sellebjerg  21 Isabella L Simone  47   48 Tobias Skillbäck  5 Morten Stilund  18 Peter Sundström  10 Anders Svenningsson  49 Rosanna Tortelli  33   50 Carla Tortorella  47 Alessandro Trentini  51 Maria Troiano  47 Martin R Turner  23 John C van Swieten  40 Mattias Vågberg  10 Marcel M Verbeek  52   53 Luisa M Villar  54 Pieter Jelle Visser  8   55 Anders Wallin  5 Andreas Weiss  56 Carsten Wikkelsø  5 Edward J Wild  57
Affiliations

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

Claire Bridel et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: (In alphabetical order): Dr Alvarez-Cermeño reported receiving payment for lecturing, travel expenses, or research grants from Merck Serono, Biogen, Sanofi Genzyme, Roche, Bayer, and Novartis. Dr Axelsson reported receiving compensation for lectures and/or advisory board participation from Biogen, Genzyme, and Novartis. Dr Blennow reported serving as a consultant to or on advisory boards for Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International, Merck, Novartis, Pfizer, and Roche Diagnostics and reported being a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture–based platform company at the University of Gothenburg. Dr Boxer reported receiving research support from National Institutes of Health grants U54NS092089, R01AG031278, R01AG038791, R01AG032306, and R01AG022983 and from the Tau Research Consortium, the Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, and the Alzheimer’s Association; reported serving as a consultant for AbbVie, Celgene, Ionis, Janssen, Merck, Novartis, UCB, and Toyama; reported receiving research support from Avid, Biogen, BMS, C2N, Cortice, Forum, Genentech, Janssen, Pfizer, Eli Lilly, Roche, and TauRx; reported holding stock/options in Aeton, Alector, and Delos; and reported receiving an honorarium from Denali Therapeutics. Dr Brundin reported receiving travel grants from Sanofi/Genzyme and Biogen and reported participating in advisory boards for Genzyme, Sanofi, Biogen, and Merck. Dr Burman reported receiving travel support and/or lecture honoraria from Almirall, Biogen, Genzyme (a Sanofi Company), Hospira, and Merck Serono and reported receiving unconditional research grants from Biogen and Merck Serono. Dr Frederiksen reported serving on scientific advisory boards for and receiving funding for travel related to these activities; reported receiving honoraria from Biogen Idec, Merck Serono, Sanofi Aventis, Teva, Novartis, and Almirall; reported receiving speaker honoraria from Biogen Idec, Teva, and Novartis; and reported serving as an advisor on preclinical development for Takeda. Dr Gisslén reported receiving research grants from Abbott/AbbVie, Baxter, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche, and Tibotec and reported receiving honoraria as speaker and/or scientific advisor from Abbott/AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, and Merck. Dr Gunnarsson reported serving on an advisory board for Teva and reported receiving travel funding and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma. Dr Hansson reported receiving research support (for the institution) from Roche, GE Healthcare, Biogen, Avid Radiopharmaceuticals, Fujirebio, and EUROIMMUN and in the past 2 years reported receiving consultancy/speaker fees (paid to the institution) from Lilly, Roche, and Fujirebio. Dr Jakobsson reported being an employee of AstraZeneca. Dr Johannsson reported periodic consulting for AstraZeneca, Shire, Novo Nordisk, Pfizer, and Merck Serono and reported receiving lecture fees from Eli Lilly, Merck Serono, Novartis, Novo Nordisk, Pfizer, Otsuka, and Shire. Dr Jonsson reported serving on the scientific advisory board for Eli Lilly. Dr Kappos reported receiving in the last 3 years and used exclusively for research support steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and Xenoport; reported receiving speaker fees from Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, and Teva; reported receiving support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; reported receiving license fees for Neurostatus products; and reported receiving grants from Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and the Swiss National Research Foundation. Dr Khalil reported receiving funding for travel and speaker honoraria from Bayer HealthCare, Novartis Genzyme, Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd and reported receiving a research grant from Teva Pharmaceutical Industries Ltd. Dr Kuhle reported receiving and using exclusively for research support consulting fees from Biogen, Novartis, Protagen AG, Roche, and Teva; reported receiving speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, and Genzyme; reported receiving travel expenses from Merck Serono, Novartis, and Roche; reported receiving grants from the ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation (320030_160221), Bayer AG, Biogen, Genzyme, Merck, Novartis, and Roche. Dr Landén reported over the past 36 months receiving lecture honoraria from Lundbeck and AstraZeneca Sweden and reported serving as scientific consultant for EPID Research Oy. Dr Leinonen reported receiving research grants from Janssen R&D. Dr Lycke reported receiving travel support and/or lecture honoraria from Biogen, Novartis, Teva, and Genzyme/Sanofi Aventis; reported serving on scientific advisory boards for Almirall, Teva, Biogen, Novartis, Merck, and Genzyme/Sanofi Aventis; reported serving on the editorial board of Acta Neurologica Scandinavica; and reported receiving unconditional research grants from Biogen, Novartis, and Teva. Dr Modvig reported receiving travel support from Biogen, Genzyme, and Allergan. Dr Olsson reported receiving unrestricted research grants from Biogen, Novartis, and Genzyme and reported receiving advisory board honoraria from the same companies. Dr Piehl reported receiving unrestricted academic research grants from Biogen, Genzyme, and Novartis and on behalf of his department reported receiving travel support and/or compensation for lectures from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva, which have been exclusively used for the support of research activities. Dr Schott reported receiving research funding and positron emission tomographic tracer from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); reported consulting for Roche, Eli Lilly, Biogen, and MSD; reported giving educational lectures sponsored by Eli Lilly; and reported serving on a data safety monitoring committee for Axon Neuroscience SE. Dr Simone reported receiving honoraria from Genzyme, Teva, and Merck Serono for educational lectures. Dr Teunissen reported serving on advisory boards for Fujirebio and Roche; reported receiving nonfinancial support in the form of research consumables from ADxNeurosciences and EUROIMMUN; and reported performing contract research or receiving grants from Probiodrug, Janssen Prevention Center, Boehringer, Brains On-Line, Axon Neurosciences, EIP Pharma, and Roche. Dr Tortorella reported receiving honoraria for consultancy and speaking from Biogen, Sanofi Aventis, Serono, Bayer-Schering, Teva, Genzyme, Novartis, and Almirall. Dr Troiano reported serving on scientific advisory boards for Biogen, Novartis, Roche, and Genzyme; reported receiving speaker honoraria from Biogen, Sanofi Aventis, Merck Serono, Teva, Genzyme, Novartis, and Roche; and reported receiving research grants for her institution from Biogen, Merck Serono, and Novartis. Dr Turner reported serving as scientific innovation committee member for Ontario Brain Institute (2013-2017) (annual honorarium); reported being data and safety monitoring board member for Cytokinetics Inc·VITALITY-ALS study (2015-2017) (unpaid); reported serving paid consultancies for Genentech Inc·on the topic of amyotrophic lateral sclerosis (ALS) biomarkers in 2017 and for various anonymous clients through GLG Consulting on the topic of ALS diagnosis and management; reported serving as a scientific advisory board member of Orphazyme (2018-2020); reported being paid in kind for undertaking independent neurofilament study in ALS (kits provided by EUROIMMUN UK) (2017-2018); and reported commissioning and serving as associate editor of Journal of Neurology, Neurosurgery and Psychiatry (2015-2020). Dr Vågberg reported receiving unconditional research grants and lecture honoraria from Biogen Idec AB and Neuro Sweden; reported receiving travel grants from Biogen Idec AB, Novartis, and Baxter Medical AB; and reported receiving writing honoraria from Pharma Industry and Best Practice Multiple Sclerosis. Dr Verbeek reported receiving grants from Alzheimer Nederland, ZonMW–Memorabel Program, Weston Brain Institute, Stofwisselkracht, and EU-ITN-Marie Skłodowska-Curie and reported serving on a scientific advisory board for Fujirebio. Dr Villar reported receiving research grants and speaker honoraria from Biogen, Merck, Roche, and Sanofi Genzyme. Dr Visser reported receiving nonfinancial support from GE Healthcare; reported receiving other support from Eli Lilly and Janssen Pharmaceutica; and reported receiving grants from Biogen. Dr Weiss reported being an employee of Evotec AG. Dr Wild reported serving on scientific advisory boards for Hoffmann-La Roche Ltd, Ionis, Shire, GSK, and Wave Life Sciences (all honoraria for these advisory boards were paid through UCL Consultants Ltd, a wholly owned subsidiary of University College London) and reported that his host clinical institution, University College London Hospitals NHS Foundation Trust, receives funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer, and Teva Pharmaceuticals. Dr Zetterberg reported serving on advisory boards for Eli Lilly, Roche Diagnostics, and Wave and reported receiving travel support from Teva.

Figures

Figure 1.
Figure 1.. Neurofilament Light in Cerebrospinal Fluid (cNfL) Levels Across Diagnostic Categories
A, Levels of cNfL are shown corrected for age and sex. B, Estimated fold changes are compared with healthy controls (HC). AD indicates Alzheimer disease; ALS, amyotrophic lateral sclerosis; BD, bipolar disorder; CBS, corticobasal syndrome; CIDP/GBS, chronic inflammatory demyelinating polyradiculopathy and Guillain-Barré syndrome; CIS, clinically isolated syndrome; DLB, dementia with Lewy bodies; DNS, dementia not specified; FTD, frontotemporal dementia; FTD/ALS, combined frontotemporal dementia and amyotrophic lateral sclerosis; HD, Huntington disease; iHIV, HIV positive with cognitive impairment; IND, inflammatory neurological disorders other than multiple sclerosis; iNPH, idiopathic normal-pressure hydrocephalus; MCI, mild cognitive impairment; MD, mixed dementia; MSA, multiple system atrophy; NID, noninflammatory neurological disorders; ON, optic neuritis; PD, Parkinson disease; PDD, Parkinson disease dementia; pgFTD, presymptomatic genetic frontotemporal dementia; pHD, premanifest Huntington disease; PPMS, primary progressive multiple sclerosis; PSP, progressive supranuclear palsy; SCD, subjective cognitive decline; SNC, subjective neurological complaint; SPMS, secondary progressive multiple sclerosis; tRRMS, treated relapsing-remitting multiple sclerosis; uRRMS, untreated relapsing-remitting multiple sclerosis; and VaD, vascular dementia.
Figure 2.
Figure 2.. Neurofilament Light in Cerebrospinal Fluid (cNfL) in Neurological Conditions According to Age
A-C, Log cNfL values are shown according to age across diagnoses. Shading around regression lines represents standard errors. AD indicates Alzheimer disease; CBS, corticobasal syndrome; CIS, clinically isolated syndrome; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; HC, healthy controls; iHIV, HIV positive with cognitive impairment; MSA, multiple system atrophy; PD, Parkinson disease; PDD, Parkinson disease dementia; PPMS, primary progressive multiple sclerosis; PSP, progressive supranuclear palsy; SPMS, secondary progressive multiple sclerosis; tRRMS, treated relapsing-remitting multiple sclerosis; uRRMS, untreated relapsing-remitting multiple sclerosis; and VaD, vascular dementia.

References

    1. Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem. 1996;67(5):2013-2018. doi:10.1046/j.1471-4159.1996.67052013.x - DOI - PubMed
    1. Khademi M, Dring AM, Gilthorpe JD, et al. . Intense inflammation and nerve damage in early multiple sclerosis subsides at older age: a reflection by cerebrospinal fluid biomarkers. PLoS One. 2013;8(5):e63172. doi:10.1371/journal.pone.0063172 - DOI - PMC - PubMed
    1. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group . Preferred Reporting Items for Systematic Reviews and Meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269, W64. doi:10.7326/0003-4819-151-4-200908180-00135 - DOI - PubMed
    1. Vandenbroucke JP, von Elm E, Altman DG, et al. ; STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiology 2007;18(6):805-835. Medline:18049195 doi:10.1097/EDE.0b013e3181577511 - DOI - PubMed
    1. Whiting PF, Rutjes AW, Westwood ME, et al. ; QUADAS-2 Group . QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):529-536. doi:10.7326/0003-4819-155-8-201110180-00009 - DOI - PubMed