Monitoring disease activity in multiple sclerosis using serum neurofilament light protein

Abstract

Objective: To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).

Methods: NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.

Results: In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).

Conclusions: Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.

Figure 1. Serum NFL concentrations in patients with MS at baseline and follow-up and in HCs

Serum NFL concentrations at baseline and follow-up in patients with MS who remained untreated, in patients with MS who initiated treatment with DMTs, in patients with MS who escalated DMT to more effective therapy, in patients with MS who changed treatment between DMTs of similar efficacy, and in HCs. The figure shows median and 95% confidence interval of serum NFL concentrations. DMT = disease-modifying therapy; HC = healthy control; MS = multiple sclerosis; NFL = neurofilament light.

Figure 2. Serum NFL concentrations in patients with MS with different numbers of Gd-enhancing lesions

Serum NFL concentration in patients with no Gd-enhancing lesions (n = 236) was 16.8 (IQR 10.5–24.6) ng/L, with 1 Gd-enhancing lesion (n = 30) was 21.3 (IQR 12.8–36.5) ng/L, with 2 Gd-enhancing lesions (n = 24) was 31.9 (IQR 14.5–39.9) ng/L in serum, and with ≥3 Gd-enhancing lesions (n = 34) was 31.9 (IQR 17.4–55.6) ng/L. Box indicates IQR; bar indicates median, and whiskers indicate 95% confidence interval. Extreme values are marked with open dots (±1.5 × IQR) or with asterisks (±3 × IQR). IQR = interquartile range; MS = multiple sclerosis; NFL = neurofilament light.

Figure 3. Correlation between serum and CSF NFL in patients with MS, HCs, and patients with ONDs

Correlation between NFL concentrations in serum and CSF (A) in patients with MS was ρ = 0.620 (95% CI 0.558–0.675, p < 0.001), (B) in HCs was ρ = 0.385 (95% CI 0.092–0.616, p < 0.001), and (C) in patients with OND was ρ = 0.740 (95% CI 0.571–0.849, p < 0.001). CI = confidence interval; HC = healthy control; MS = multiple sclerosis; NFL = neurofilament light; OND = other neurological disorder or symptom.

Figure 4. ROC curve showing specificity and sensitivity of NFL in serum and CSF for disease activity

ROC curve with AUC for NFL in serum and CSF indicating specificity and sensitivity to discriminate patients with MS with disease activity from patients with MS without disease activity. AUC for serum NFL was 0.663 (95% CI 0.591–0.735, 80% specificity and 45% sensitivity) and for CSF NFL was 0.774 (95% CI 0.714–0.835, 75% specificity and 67% sensitivity). AUC = area under the curve; CI = confidence interval; MS = multiple sclerosis; NFL = neurofilament light; ROC = receiver operating characteristic.