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.

Serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy

“…Additionally, 30 age‐matched healthy controls were included, and age‐adjusted reference values of a large cohort investigated earlier by our laboratory were used …”

Vitamin D supplementation and neurofilament light chain in multiple sclerosis

“…16 The concentration of NFL is elevated in the cerebrospinal fluid (CSF) of MS patients, 17 and it is reduced by effective immunomodulatory treatments such as fingolimod and natalizumab. 22,23 Only one observational study has so far addressed the relationship between vitamin D and NFL in MS, showing that high serum levels of 25-hydroxyvitamin D were associated with low CSF levels of NFL. 22,23 Only one observational study has so far addressed the relationship between vitamin D and NFL in MS, showing that high serum levels of 25-hydroxyvitamin D were associated with low CSF levels of NFL.…”

Are neurofilaments valuable biomarkers for long-term disease prognostication in MS?

“…Most notably, higher serum NfL levels were further related to future brain and cervical spinal volume loss in this study. 7 These are very promising results that support the potential clinical value of Nf measurements in MS. In particular, serum NfL chain levels can be regarded as an easy-to-measure marker of neuro-axonal damage in MS.…”

“…6 Several studies have proven that NfL in CSF and serum are very well correlated to each other, supporting the notion that serum NfL may be used as a bloodderived marker for neuro-axonal damage. [7][8][9] There is evidence showing that both CSF and serum Nfs levels are associated with disease activity, physical disability, and magnetic resonance imaging (MRI) changes in MS; however, clinical follow-up time was relatively short in most of these studies. 1,2,7 In a recent study in 51 MS patients, it has been shown that higher CSF NfH values could prognosticate an unfavourable disease evolution during a follow-up time of 15 years.…”

“…[7][8][9] There is evidence showing that both CSF and serum Nfs levels are associated with disease activity, physical disability, and magnetic resonance imaging (MRI) changes in MS; however, clinical follow-up time was relatively short in most of these studies. 1,2,7 In a recent study in 51 MS patients, it has been shown that higher CSF NfH values could prognosticate an unfavourable disease evolution during a follow-up time of 15 years. 3 Another study in 95 MS cases with a median follow-up time of 14 years could demonstrate that elevated CSF NfL levels were predictive of future physical disability.…”