Neurofilaments as biomarkers in neurological disorders - towards clinical application

Michael Khalil; Charlotte E Teunissen; Sylvain Lehmann; Markus Otto; Fredrik Piehl; Tjalf Ziemssen; Stefan Bittner; Maria Pia Sormani; Thomas Gattringer; Samir Abu-Rumeileh; Simon Thebault; Ahmed Abdelhak; Ari Green; Pascal Benkert; Ludwig Kappos; Manuel Comabella; Hayrettin Tumani; Mark S Freedman; Axel Petzold; Kaj Blennow; Henrik Zetterberg; David Leppert; Jens Kuhle

doi:10.1038/s41582-024-00955-x

Neurofilaments as biomarkers in neurological disorders - towards clinical application

Nat Rev Neurol. 2024 Apr 12. doi: 10.1038/s41582-024-00955-x. Online ahead of print.

Authors

Michael Khalil¹, Charlotte E Teunissen², Sylvain Lehmann³, Markus Otto⁴, Fredrik Piehl⁵, Tjalf Ziemssen⁶, Stefan Bittner⁷, Maria Pia Sormani^{8

9}, Thomas Gattringer^{10

11}, Samir Abu-Rumeileh⁴, Simon Thebault¹², Ahmed Abdelhak¹³, Ari Green¹³, Pascal Benkert^{14

15}, Ludwig Kappos^{14

15}, Manuel Comabella¹⁶, Hayrettin Tumani¹⁷, Mark S Freedman¹⁸, Axel Petzold^{19

20}, Kaj Blennow^{21

22

23

24}, Henrik Zetterberg^{21

22

25

26

27

28}, David Leppert^{14

15}, Jens Kuhle^{29

30}

Affiliations

¹ Department of Neurology, Medical University of Graz, Graz, Austria. michael.khalil@medunigraz.at.
² Neurochemistry Laboratory Department of Laboratory Medicine, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, Netherlands.
³ LBPC-PPC, Université de Montpellier, INM INSERM, IRMB CHU de Montpellier, Montpellier, France.
⁴ Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
⁵ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁶ Center of Clinical Neuroscience, Department of Neurology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁷ Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁸ Department of Health Sciences, University of Genova, Genova, Italy.
⁹ IRCCS Ospedale Policlinico San Martino, Genova, Italy.
¹⁰ Department of Neurology, Medical University of Graz, Graz, Austria.
¹¹ Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.
¹² Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
¹⁴ Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
¹⁵ Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
¹⁶ Neurology Department, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹⁷ Department of Neurology, CSF Laboratory, Ulm University Hospital, Ulm, Germany.
¹⁸ Department of Medicine, University of Ottawa, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁹ Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology, MS Centre and Neuro-ophthalmology Expertise Centre Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
²⁰ Moorfields Eye Hospital, The National Hospital for Neurology and Neurosurgery and the Queen Square Institute of Neurology, UCL, London, UK.
²¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²³ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁴ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P. R. China.
²⁵ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²⁶ UK Dementia Research Institute at UCL, London, UK.
²⁷ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
²⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
²⁹ Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland. Jens.Kuhle@usb.ch.
³⁰ Department of Neurology, University Hospital and University of Basel, Basel, Switzerland. Jens.Kuhle@usb.ch.

PMID: 38609644
DOI: 10.1038/s41582-024-00955-x

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.

Publication types

Review