Article Figures & Data
Figures
- Figure 1 Association of sNfL With Severe Focal Neuronal Damage Reflected by Persistent T1 Hypointense Lesions in Patients With MS
(A) Correlation matrix showing the correlation coefficients of the associations between log-transformed y0 serum neurofilament light chain (sNfL) and clinical and MRI parameters at baseline and 6-year follow-up. Ellipses are used as glyphs for correlations. With increasing absolute value of r, the minor axis of the ellipse decreases, whereas a correlation with r close to 0 approximates more and more to a circle. The glyphs of the negative correlation coefficients are plotted as a reflection of their positive counterparts. Because it is difficult to distinguish small correlation coefficients from the ellipse shape, Pearson r is additionally translated into a color pallet ranging from deep red (r = −1) to dark blue (r = +1). Correlations with p < 0.05 were considered statistically significant, and the corresponding ellipse is marked with *. (B) The Venn diagram shows the corrected R2 values of different linear regression models, all with y0 sNfL as the dependent variable, to determine which combination of NEDA criteria best explains the variance of y0 sNfL. For example, the model in the middle considered the combination of all possible criteria, namely, absence of clinical relapse, absence of new T2 hyperintense lesion/GD+ lesions, absence of EDSS progression, and the absence of new persistent T1 hypointense lesions on follow-up MRI. This is visually indicated by the area being proportionally included in all 4 ellipses. The corrected R2 value of this specific model was 0.193. The black arrow illustrates the drop in R2 from 0.193 to 0.084 only due to the exclusion of absence of new persistent T1 hypointense lesions from this model. Accordingly, the second model can only explain less of the y0 sNfL variance. EDSS = Expanded Disability Status Scale; NfL = neurofilament light chain; NEDA = no evidence of disease activity; EDSS change = difference between y0 EDSS and y6 EDSS; Gd+ no. = number of GD+ MRI lesions; sNfL = serum neurofilament light chain; T2 no. = number of hyperintense lesions in T2-weighted MRI sequences; new T1 no. = number of new persistent hypointense lesions in T1-weighted MRI sequences at y6 compared with y0; y0 = year 0/baseline; y6 = year 6/follow-up.
- Figure 2 Y0 sNfL Levels Identify Patients With Future Focal Neuronal Damage and Predict NEDA-3T1 Status
(A) Trial profile: 153 patients with RRMS and clinically isolated syndrome (CIS) were prospectively followed within the NaloMS cohort. Of these, 54 fulfilled the NEDA-3T1 criteria, whereas 99 patients showed clinical relapse, new T2 hyperintense/Gd+ lesions on MRI, EDSS progression, or new persistent T1 hypointense lesions on y6 MRI, defined as EDAT1. (B) y6 sNfL showed a trend toward a drop from initially high y0 sNfL values to lower values in patients with evidence of disease activity (EDAT1) according to the NEDA-3T1 criteria (y0 sNfL 10.2 pg/mL (5.8–14.8) to y6 sNfL 8.2 (6.3–12.3); Wilcoxon test, p = 0.095). Stable patients reaching NEDA-3T1 criteria, showed unchanged y6 sNfL values (y0 sNfL 4.9 pg/mL (3.3–8.1) y6 sNfL 5.4 pg/mL (4.1–6.8); Wilcoxon test, p = 0.955). EDAT1 patients had higher sNfL levels at both y0 and y6 compared with NEDA-3T1 patients (y0, p < 0.001; y6, p = 0.001). (C) Binary logistic regression model with no evidence of disease activity (NEDA-3T1) as the dependent variable revealed reduced y0 sNfL (OR 0.883, 95% CI 0.819–0.952, p < 0.001) and reduced disease duration (OR 0.851, 95% CI 0.755, 0.974) as predictors for NEDA-3T1 status at y6. In contrast, age (OR 0.956, 95% CI 0.914–1.000, p = 0.050), y0 EDSS (OR 0.810, 95% CI 0.519–1.264 p = 0.353), number of Gd+ lesions at y0 (OR 1.148, 95% CI 0.851–1.549, p = 0.366), number of T2 hyperintense lesions at y0 (OR 1.024, 95% CI 0.982–1.068, p = 0.270), relapses within the last 5 years (OR 0.670, 95% CI 0.441–1.017, p = 0.670), basic disease-modifying therapy (DMT) (OR 1.935, 95% CI 0.491–7.627, p = 0.345), moderate DMT (OR 1.591, 95% CI 0.382–6.633, p = 0.524), and high DMT (OR 1.763, 95% CI 0.582–5.341, p = 0.316) were not predictors of NEDA-3T1 status at y6. (D) By adding sNfL to a risk score (incorporating age, Gd enhancement at baseline, T2 hyperintense lesions at baseline, y0 EDSS, relapses within the last 5 years, and disease duration), the AUC for prediction of NEDA-3T1 status could be significantly improved from 0.704 (95% CI 0.627–0.776, p < 0.009) for the risk score alone (green line) to 0.820 (95% CI 0.749–0.879, p < 0.001) after additional incorporation of y0 sNfL (blue line, p for difference between the AUC of the risk score ± y0 sNfL, p < 0.001). (E) Survival analysis with regard to time fulfilling NEDA-3T1 status in patients with sNfL >8.6 pg/mL (blue line) compared with patients with sNfL ≤8.6 pg/mL (green line). Patients with sNfL ≤8.6 pg/mL were more likely to stay on NEDA-3T1 at y6 (HR 0.244, 95% CI 0.142–0.419 vs HR 4.101, 95% CI 2.387–7.048, log-rank test p < 0.001). The median time until EDA was 78 months (95% CI 68–86) for patients with sNfL >8.6 pg/mL compared with 93 months (95% CI 81–103) for patients with lower sNfL values. *p < 0.05, ***p ≤ 0.001. EDSS = Expanded Disability Status Scale; EDSS change = difference between y0 EDSS and y6 EDSS; Gd+ no. = number of gadolinium-enhancing MRI lesions; NfL = neurofilament light chain; sNfL = serum neurofilament light chain; T2 no. = number of hyperintense lesions in T2-weighted MRI sequences; new T1 no. = number of new persistent hypointense lesions in T1-weighted MRI sequences at y0 compared with y6; y0 = year 0/baseline; y6 = year 6/follow-up.
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