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Original Investigation
September 13, 2019

Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis

Author Affiliations
  • 1Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 2Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
  • 3Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston, Massachusetts
  • 4Department of Neurology, Harvard Medical School, Boston, Massachusetts
  • 5Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts
  • 6Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland
  • 7Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 8Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA Neurol. Published online September 13, 2019. doi:10.1001/jamaneurol.2019.3238
Key Points

Question  How long is the prodromal phase of multiple sclerosis?

Findings  In this nested case-control study, we found that serum levels of neurofilament light chain were elevated in case patients with multiple sclerosis compared with matched control individuals 6 years before the clinical onset. This difference between cases and controls increased with decreasing time to the case clinical onset, and clinical onset was associated with a marked increase in neurofilament light chain levels.

Meaning  Multiple sclerosis may have a prodromal phase lasting several years, and neuroaxonal damage may occur already during this phase.

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 Participants  Nested 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 Measurements  Log-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 ≥5 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 Relevance  The 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.

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