Serum neurofilament light chain correlates with myelin and axonal magnetic resonance imaging markers in multiple sclerosis

Jackie T Yik; Pierre Becquart; Jasmine Gill; John Petkau; Anthony Traboulsee; Robert Carruthers; Shannon H Kolind; Virginia Devonshire; Ana-Luiza Sayao; Alice Schabas; Roger Tam; G R Wayne Moore; David K B Li; Sophie Stukas; Cheryl Wellington; Jacqueline A Quandt; Irene M Vavasour; Cornelia Laule

doi:10.1016/j.msard.2021.103366

Serum neurofilament light chain correlates with myelin and axonal magnetic resonance imaging markers in multiple sclerosis

Mult Scler Relat Disord. 2022 Jan:57:103366. doi: 10.1016/j.msard.2021.103366. Epub 2021 Nov 3.

Authors

Jackie T Yik¹, Pierre Becquart², Jasmine Gill², John Petkau³, Anthony Traboulsee⁴, Robert Carruthers⁴, Shannon H Kolind⁵, Virginia Devonshire⁴, Ana-Luiza Sayao⁴, Alice Schabas⁴, Roger Tam⁶, G R Wayne Moore⁷, David K B Li⁸, Sophie Stukas², Cheryl Wellington⁷, Jacqueline A Quandt², Irene M Vavasour⁹, Cornelia Laule¹⁰

Affiliations

¹ Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada.
² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Department of Statistics, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵ Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
⁶ Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
⁷ International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁸ Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
⁹ International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
¹⁰ Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Radiology, University of British Columbia, Vancouver, BC, Canada. Electronic address: claule@physics.ubc.ca.

PMID: 35158472
DOI: 10.1016/j.msard.2021.103366

Abstract

Background: Neurofilaments are cytoskeletal proteins that are detectable in the blood after neuroaxonal injury. Multiple sclerosis (MS) disease progression, greater lesion volume, and brain atrophy are associated with higher levels of serum neurofilament light chain (NfL), but few studies have examined the relationship between NfL and advanced magnetic resonance imaging (MRI) measures related to myelin and axons. We assessed the relationship between serum NfL and brain MRI measures in a diverse group of MS participants.

Methods and materials: 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting, 30 secondary progressive, 20 primary progressive) underwent 3T MRI to obtain myelin water fraction (MWF), geometric mean T₂ (GMT₂), water content, T₁_; high angular resolution diffusion imaging (HARDI)-derived axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA); diffusion basis spectrum imaging (DBSI)-derived AD, RD, FA; restricted, hindered, water and fiber fractions; and volume measurements of normalized brain, lesion, thalamic, deep gray matter (GM), and cortical thickness. Multiple linear regressions assessed the strength of association between serum NfL (dependent variable) and each MRI measure in whole brain (WB), normal appearing white matter (NAWM) and T₂ lesions (independent variables), while controlling for age, expanded disability status scale, and disease duration.

Results: Serum NfL levels were significantly associated with metrics of axonal damage (FA: R²_WB-HARDI = 0.29, R²_NAWM-HARDI = 0.31, R²_NAWM-DBSI = 0.30, R²_Lesion-DBSI = 0.31; AD: R²_WB-HARDI=0.31), myelin damage (MWF: R²_WB = 0.29, R²_NAWM = 0.30, RD: R²_WB-HARDI = 0.32, R²_NAWM-HARDI = 0.34, R²_Lesion-DBSI = 0.30), edema and inflammation (T₁: R²_Lesion = 0.32; GMT₂: R²_WB = 0.31, R²_Lesion = 0.31), and cellularity (restricted fraction R²_WB = 0.30, R²_NAWM = 0.32) across the entire MS cohort. Higher serum NfL levels were associated with significantly higher T₂ lesion volume (R² = 0.35), lower brain structure volumes (thalamus R² = 0.31; deep GM R² = 0.33; normalized brain R² = 0.31), and smaller cortical thickness R² = 0.31).

Conclusion: The association between NfL and myelin MRI markers suggest that elevated serum NfL is a useful biomarker that reflects not only acute axonal damage, but also damage to myelin and inflammation, likely due to the known synergistic myelin-axon coupling relationship.

Keywords: Diffusion; MRI; Multiple sclerosis; Myelin water; Neurofilament light chain.

MeSH terms

Axons
Biomarkers
Brain / diagnostic imaging
Diffusion Magnetic Resonance Imaging
Humans
Intermediate Filaments
Magnetic Resonance Imaging
Multiple Sclerosis* / diagnostic imaging
Myelin Sheath
White Matter* / diagnostic imaging

Substances

Biomarkers