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Correlations of serum neurofilament light chain and quantitative magnetic resonance imaging metrics in multiple sclerosis Yik, Jackie T.


Neurofilaments are neuronal-specific proteins involved in neuroaxonal functions like determining axonal diameter and transporting organelles and other proteins. After neuronal tissue damage, neurofilaments are detectable in the cerebrospinal fluid and blood in many neurological diseases including multiple sclerosis (MS). Metrics derived from quantitative magnetic resonance imaging (MRI) techniques specific to myelin content and axonal integrity have been proposed as potential biomarkers of MS disease processes. While there have been studies associating higher neurofilament levels, particularly the light chain (NfL), in blood with disease progression, greater lesion volume, and atrophy, few studies have examined the relationship between NfL and advanced imaging measures in MS. In this thesis, linear regressions were used to assess the relationship between serum NfL and MRI measures in the whole brain, normal appearing white matter, and lesions. 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting MS, 30 secondary progressive MS, 20 primary progressive MS) underwent 3T MRI to obtain the measures myelin water fraction (MWF), water content, high angular resolution diffusion imaging (HARDI) derived axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA), diffusion basis spectrum imaging (DBSI) derived AD, RD, FA, water, fiber, restricted, and hindered ratios, T1, geometric mean T2 (GMT2), normalized brain, lesion, thalamic, and deep grey matter (GM) volumes, and cortical thickness. Blood was collected on the same day as MR experiments and quantified using single molecule array (SIMOA) technology (Quanterix). Some measures were transformed for normality and multiple comparison correction was applied. Higher serum NfL levels were associated with lower brain structure volumes (thalamus, deep GM, normalized brain volume) and cortical thickness as well as higher lesion volume. Furthermore, increasing serum NfL levels were seen with increasing metrics of myelin damage (MWF decrease, RD increase), axonal damage (FA decrease, AD increase), edema and inflammation (T1, GMT2 increase), and decreasing metrics for cellularity (restricted ratio). The results show that myelin and axonal health are strongly coupled where there is a cascade of damage occurring in the MS brain causing NfL release. Serum NfL may be a useful biomarker that reflects not only axonal loss, but also myelin damage and brain volume changes.

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