Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis
Abstract
Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.
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Higher absolute blood NfL after symptoms appear matches findings in progressive supranuclear palsy, Huntington's disease, and multiple sclerosis.
“Increased absolute NfL levels in the blood in the symptomatic disease phase is consistent with similar observations in progressive supranuclear palsy28, Huntington’s disease30, and multiple sclerosis14.”
From Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019) · cites this paper as [14]
In mice and in several neurological conditions, including proteopathic neurodegenerative diseases, fluid NfL changes have been associated with brain damage and atrophy.
“Changes of NfL in bodily fluids have been linked to brain damage and brain atrophy in mouse models and multiple neurological disorders including proteopathic neurodegenerative diseases11,13–16.”
From Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019) · cites this paper as [14]
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- Authors
- Barro, C., Benkert, P., Disanto, G., Tsagkas, C., Amann, M., Naegelin, Y., Leppert, D., Gobbi, C., Granziera, C., Yaldizli, Ö., Michalak, Z., Wuerfel, J., Kappos, L., Parmar, K., & Kuhle, J.
- Affiliations
- University of Basel (CH)
- Neurocentre of Southern Switzerland, Ospedale Civico, Lugano, Switzerland
- Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-05-30
- Volume
- 141
- Issue
- 8
- Pages
- 2382-2391
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2806791998
- Cited by
- 517
- References
- 28
- Citations by year
- 2026: 36 · 2025: 53 · 2024: 84 · 2023: 66 · 2022: 75 · 2021: 70 · 2020: 68 · 2019: 55 · 2018: 9
- FWCI
- 38.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Funders
- Swiss National Research Foundation (320030_160221)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Health Sciences › Medicine › Oncology › Polyomavirus and related diseases
- Keywords
- multiple sclerosis, serum neurofilament light chain, brain atrophy, spinal cord atrophy, Expanded Disability Status Scale, clinically isolated syndrome, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, MRI lesion activity, neuroinflammation, neurodegeneration, disease activity markers
- MeSH terms
- Single Molecule Imaging, Adult, Atrophy, Brain, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Nervous System Malformations, Spinal Cord, Cohort Studies, Biomarkers, Neurofilament Proteins, Disease Progression, Cervical Cord
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