TY - JOUR
T1 - Serum Neurofilament Light Chain Levels in Patients with Presymptomatic Multiple Sclerosis
AU - Bjornevik, Kjetil
AU - Munger, Kassandra L.
AU - Cortese, Marianna
AU - Barro, Christian
AU - Healy, Brian C.
AU - Niebuhr, David W.
AU - Scher, Ann I.
AU - Kuhle, Jens
AU - Ascherio, Alberto
N1 - Funding Information:
Funding/Support: The study was funded by grants from the Swiss National Research Foundation (320030 160221) awarded to Dr Kuhle and the National Institute of Neurologic Disorders and Stroke (R01 NS103891) awarded to Dr Ascherio.
Funding Information:
reported personal fees from Novartis outside the submitted work. Dr Barro reported other support from Novartis outside the submitted work. Dr Healy reported grants from Merck Serono, Novartis, Verily Life Sciences, and Genzyme outside the submitted work. Dr Kuhle reported receiving speaker fees, research support, travel support, and/or served on advisory boards by ECTRIMS, Swiss MS Society, Swiss National Research Foundation (320030_160221), University of Basel, Bayer, Biogen, Genzyme, Merck, Novartis, Protagen AG, Roche, and Teva. Dr Ascherio reported grants from National Institutes of Health during the conduct of the study. No other disclosures were reported.
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072204892&partnerID=8YFLogxK
U2 - 10.1001/jamaneurol.2019.3238
DO - 10.1001/jamaneurol.2019.3238
M3 - Article
C2 - 31515562
AN - SCOPUS:85072204892
SN - 2168-6149
VL - 77
SP - 58
EP - 64
JO - JAMA Neurology
JF - JAMA Neurology
IS - 1
ER -