Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis

Abstract

IMPORTANCE Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease.OBJECTIVE To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. DESIGN, SETTING, AND PARTICIPANTSNested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding.EXPOSURES Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). MAIN OUTCOMES AND MEASUREMENTSLog-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models.RESULTS Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for Ն5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009). CONCLUSIONS AND RELEVANCEThe levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.

Blood neurofilament light: a critical review of its application to neurologic disease

“…11 The high sensitivity of the SIMOA â technology provided the reliable quantification of blood NfL in MS. 11 On the group level, blood NfL in MS was higher than in healthy controls 32,44,62,66 with progressive MS having higher levels of blood NfL than relapsing MS. 16,32 The increased levels of blood NfL in progressive versus relapsing MS was unexpected and contrasted with lower levels of NfL in the CSF in progressive versus relapsing MS. 67 This remains unexplained but could be related to a breakdown of the BBB in progressive MS linked to aging and/or a contribution from the peripheral nervous system. Ascherio's group reported that in a military cohort, blood NfL was able to identify neuronal damage 6 years prior to the clinical disease onset, 68 thus neurodegeneration was already present at the prodromal stage of MS. A number of studies have found that disease activity as measured by clinical or MRI assessment is associated with an increase in blood NfL levels in both adult 16,32,66,[69][70][71][72][73] and pediatric patients. 74,75 Of note, the association of blood NfL with disability was less in progressive MS, which may be related to the older age of this population that also have comorbidities.…”

Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode

“…10 In MS, elevated levels of serum neurofilament light have been shown to correlate with disease activity 11 and worse long-term clinical and paraclinical outcomes. 7,[11][12][13][14][15][16][17][18][19][20][21] Although these studies demonstrate utility for serum neurofilament light level as a potential biomarker associated with disease activity and shorter-term prognosis, information is scarce on the association of serum neurofilament light level at first MS presentation with long-term disease outcomes.…”

Neurofilament light chain in demyelinating conditions of the central nervous system: a promising biomarker

“…Furthermore, higher NfL levels at baseline were associated with a more rapid decrease in brain volume and predicted higher number of enhancing lesions, confirming the role of NfL as a potential marker of neuronal and axonal damage in CIS and early MS. Finally, in a case-control study performed among US military that analyzed serum samples of 60 subjects asymptomatic at time of sampling who then developed MS (6 years later as a median), the authors observed increased serum NfL levels in cases that would develop MS in comparison to healthy controls, demonstrating a potentially useful value of serum NfL in predicting future development of/ evolution to MS [31] .…”