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Multicenter Study
. 2020 Jun 9;94(23):e2457-e2467.
doi: 10.1212/WNL.0000000000009571. Epub 2020 May 20.

Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis

Ali Manouchehrinia  1 , Pernilla Stridh  2 , Mohsen Khademi  2 , David Leppert  2 , Christian Barro  2 , Zuzanna Michalak  2 , Pascal Benkert  2 , Jan Lycke  2 , Lars Alfredsson  2 , Ludwig Kappos  2 , Fredrik Piehl  2 , Tomas Olsson  2 , Jens Kuhle  2 , Ingrid Kockum  2
Affiliations
Multicenter Study

Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis

Ali Manouchehrinia et al. Neurology. .

Abstract

Objective: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.

Methods: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).

Results: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.

Conclusions: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.

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Figures

Figure 1
Figure 1. Association between pNfL level and age in population-based controls
pNfL percentiles at different ages in 1,026 controls obtained from Generalized Additive Models for Location, Scale, and Shape (GAMLSS) with Box-Cox t distribution. pNfL = plasma neurofilament light chain
Figure 2
Figure 2. Association between pNfL level and age at the time of sampling in MS cases
pNfL levels increased by 0.18 pg/mL (95% CI: 0.17–0.20, p < 0.001) per each year of age in controls, by −0.05 pg/mL (95% CI: −0.07 to −0.04, p = 0.001) in relapsing remitting patients, by 0.12 pg/mL (95% CI: 0.09–0.16, p < 0.001) in SP patients, and by 0.14 pg/mL (95% CI: 0.08–0.19, p < 0.001) in primary progressive patients. CI = confidence interval; pNfL = plasma neurofilament light chain; SP = secondary progressive.
Figure 3
Figure 3. Plasma NfL level comparisons between MS subtypes and population-based controls
Comparison of pNfL levels between 1,026 healthy controls, 3,664 patients with relapsing-remitting MS, 511 patients with secondary progressive multiple sclerosis, and 129 patients with primary progressive MS. Significance code: ****<0.0001. MS = multiple sclerosis; pNfL = plasma neurofilament light chain.
Figure 4
Figure 4. Risk of reaching major disability milestones stratified by baseline pNfL levels
Adjusted hazard ratios (95% confidence intervals) and p value for risks of conversion to secondary progressive multiple sclerosis (SPMS) type, reaching sustained EDSS scores 3.0, 4.0, and 6.0 in patients at different pNfL levels. >C80, >C95, and >C99: pNfL levels higher than the 80th, 95th, and 99th percentiles of pNfL levels in controls. Numbers in the box denote the number of patients included in each analysis (number of events). EDSS = Expanded Disability Status Scale; pNfL = plasma neurofilament light chain.
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