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  • Review Article
  • Published:

Neurofilaments as biomarkers in neurological disorders — towards clinical application

Abstract

Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.

Key points

  • Neurofilament proteins have emerged as one of the most important body fluid biomarkers of neuro-axonal injury in a wide range of neurological diseases.

  • High-sensitivity analytical platforms enable reliable quantification of neurofilament light chain (NfL) levels in blood samples, paving the way for their use in clinical practice.

  • Establishment of large reference databases of physiological blood levels of NfL adjusted for age and BMI was a major milestone towards the clinical use of NfL.

  • Neurofilament levels can often not be used to diagnose disease entities but are useful as a diagnostic type biomarker in the preclinical phases of neurodegenerative diseases and as markers of disease progression, prognosis, and treatment response.

  • Neurofilament levels are increasingly used as an outcome measure in clinical trials; FDA approval of tofersen was based on changes in blood NfL levels, marking a paradigm shift in the importance of biomarkers in regulatory approvals.

  • Standardization and cross-compatibility of neurofilament measures taken with current emerging analytic platforms are key to completing the translation of neurofilaments into clinical practice.

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Fig. 1: Neurofilament release after axonal damage and detection of cleavage products in the blood.
Fig. 2: Physiological levels of NfL in different age groups.
Fig. 3: Age-related percentiles for serum NfL.

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Acknowledgements

C.E.T.’s research is supported by the European Commission (Marie Curie International Training Network, grant agreement No. 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant No. 831434), European Platform for Neurodegenerative Diseases (IMI 2 Joint Undertaking (JU), grant No. 101034344) and European Union Joint Programme – Neurodegenerative Disease Research (JPND; bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, Health Holland, the Dutch Research Council (ZonMw), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, and Alzheimer Netherlands. C.T.E. is a recipient of ABOARD, which is a public–private partnership receiving funding from ZonMw (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). C.E.T. is recipient of TAP-dementia, a ZonMw-funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. S.L. is supported by the Fondation pour la Recherche Médicale (FRM), the Claude Pompidou Foundation, H2020 Marie Skłodowska-Curie Actions MIRIADE project, and the European Metrology Programme for Innovation and Research Neuromet2 project. M.O. was supported by the JPND networks Genfi-Prox (01ED2008A) and bPRIDE (01ED2001), the German Federal Ministry of Education and Research (FTLDc 01GI1007A, Moodmarker 01EW200), the EU (MIRIADE 860197, FAIR-PARK II 633190), the German Research Foundation/DFG (SFB1279), the Foundation of the State Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009) and the Thierry Latran Foundation. F.P. is funded by the Swedish MRC (grant no. 2020-02700), the Knut and Alice Wallenberg Foundation, and the Swedish Brain Foundation. S.B. is supported by the Deutsche Forschungsgemeinschaft (DFG, SFB CRC-TR-128 and CRC-TR-355) and the Hermann and Lilly Schilling Foundation. T.G. acknowledges research support from the Austrian Science Fund and the Austrian Neurological Society. S.A.-R. received support from the Medical Faculty of Martin-Luther-University Halle-Wittenberg (Clinician Scientist-Programm No. CS22/06). S.T. is supported by the MS Canada for Postdoctoral Fellowship. H.T. acknowledges research support by DMSG (German Multiple Sclerosis Society), MWK-BW (Ministry of Science, Research and Arts of the State Baden-Württemberg), University of Ulm, and Chemische Fabrik Karl Bucher. A.P. acknowledges support from the National Institute of Health and Care Research Biomedical Research Centre at Moorfields Eye Hospital and the UK Department of Health. K.B. is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hjärnfonden Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (#ALFGBG-715986 and #ALFGBG-965240), the JPND (JPND2019-466-236), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer’s Association 2022-2025 Grant (SG-23-1038904 QC). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No. 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860197 (MIRIADE), the JPND (JPND2021-00694), the National Institute for Health and Care Research UCL Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). D.L. is supported by the International Progressive MS Alliance (grant PA-2002-36227). J.K. is supported by the Swiss MS Society, the Swiss National Research Foundation (320030_189140/1 and 212534/1), the University of Basel and the International Progressive MS Alliance. Parts of the manuscript have been generated by members of the BioMS-eu consortium.

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M.K. has received funding for travel and speaker honoraria from Bayer, Biogen Idec, Merck, Novartis, and Teva Pharmaceutical Industries and serves on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, and Roche outside the submitted work. C.E.T. has collaboration contracts with ADx Neurosciences, Eli Lilly, and Quanterix and has performed contract research or received grants from AC Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, and Vivoryon. She is editor of Alzheimer Research and Therapy, and serves on the editorial boards of Medidact Neurologie/Springer and Neurology: Neuroimmunology & Neuroinflammation. S.L. has served as a consultant or on advisory boards for Biogen, Fujirebio-Europe, Lilly, Roche Diagnostics and Shimadzu. M.O. has given scientific advice to AXON, AviadoBio, Biogen, Fujirebio and Roche. F.P. has received research grants from Janssen, Merck KGaA and UCB, has received fees for serving on Data Monitoring Committees (DMC) in clinical trials with Chugai, Lundbeck and Roche, and has prepared an expert witness statement for Novartis. T.Z. has contributed to scientific advisory boards and/or has consulted for Biogen, Celgene, Novartis, Merck and Roche, has received compensation for serving on speakers bureaus for Biogen, Celgene, Merck, Novartis, Roche and Sanofi, and has received research support from Biogen, Merck, Novartis, and Sanofi. S.B. has received honoraria from Biogen Idec, Bristol Meyer Squibbs, Hexal, Merck Healthcare, Novartis, Roche, Sanofi-Genzyme and Teva. M.P.S. has received consulting fees from Alexion, Biogen, Immunic, Merck, Novartis, Roche and Sanofi. T.G. has received travel grants and speakers’ honoraria from Amgen, Bayer, Boehringer Ingelheim, Novartis and Pfizer outside the submitted work. A.A. has received research grants from Denali Therapeutics and Roche, outside the submitted work. A.G. has received research grants from Denali Therapeutics and F. Hoffmann-La Roche. A.G. has received personal fees from JAMA Neurology, Neurona and Pipeline Pharmaceuticals outside the submitted work. A.G. also has a patent pending for a small-molecule drug for remyelination. The institutes of L.K. (University Hospital Basel and the Research Center for Neuroimmunology and Neuroscience Basel) have received the following exclusively for research support: steering committee, advisory board and consultancy fees from Bayer, Biogen, BMS, Janssen (J&J), Merck, Novartis, Roche, Sanofi, Santhera and TG Therapeutics; speaker fees from Bayer, Biogen, Merck, Novartis, Roche and Sanofi; support of educational activities from Merck, Novartis, Roche and Sanofi; license fees for Neurostatus products; and grants from Bayer, Biogen, the European Union, Innosuisse, Merck, Novartis, Roche, the Swiss MS Society and the Swiss National Research Foundation. M.C. has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Biogen Idec, Bristol Myers Squibb, Genzyme, Merk Serono, Novartis, Teva Pharmaceuticals and Sanofi-Aventis. H.T. has participated in meetings sponsored by or received honoraria for acting as an advisor or speaker for Alexion, Bayer, Biogen, Bristol Myers Squibb, Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen-Cilag, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens and Teva. M.S.F. has received research or educational grants from Sanofi-Genzyme Canada, has received honoraria or consultation fees from Alexion/Astra Zeneca, BiogenIdec, EMD Inc./EMD Serono/Merck Serono, Find Therapeutics, Hoffman-La Roche, Novartis, Quanterix, Sanofi-Genzyme, and Teva Canada Innovation, is a member of company advisory boards, boards of directors or similar for Alexion/Astra Zeneca, Atara Biotherapeutics, Bayer Healthcare, Celestra Health, EMD Inc./Merck Serono, Find Therapeutics, Hoffman-La Roche, Actelion/Janssen (J&J), Novartis, Sanofi-Genzyme, and Setpoint Medical, and has participated in a company-sponsored speaker’s bureau for EMD Serono and Sanofi-Genzyme. A.P. has received grant support for remyelination trials in multiple sclerosis to the Amsterdam University Medical Centre. K.B. has served as a consultant and on advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac, Novartis, Ono Pharma, Prothena, Roche Diagnostics and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programmes for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work in this paper. H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work in this paper. D.L. is Chief Medical Officer of GeNeuro. J.K. has received speaker fees, research support, travel support, and/or served on advisory boards from Alnylam, Bayer, Biogen, Bristol Myers Squibb, Celgene, Immunic, Merck, Neurogenesis, Novartis, Octave Bioscience, Quanterix, Roche, Sanofi and Stata DX. S.A.-R., S.T. and P.B. declare no competing interests.

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Khalil, M., Teunissen, C.E., Lehmann, S. et al. Neurofilaments as biomarkers in neurological disorders — towards clinical application. Nat Rev Neurol 20, 269–287 (2024). https://doi.org/10.1038/s41582-024-00955-x

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