Motor unit number index (MUNIX) in the D50 disease progression model reflects disease accumulation independently of disease aggressiveness in ALS

Abstract

The neurophysiological technique motor unit number index (MUNIX) is increasingly used in clinical trials to measure loss of motor units. However, the heterogeneous disease course in amyotrophic lateral sclerosis (ALS) obfuscates robust correlations between clinical status and electrophysiological assessments. To address this heterogeneity, MUNIX was applied in the D50 disease progression model by analyzing disease aggressiveness (D50) and accumulation (rD50 phase) in ALS separately. 237 ALS patients, 45 controls and 22 ALS-Mimics received MUNIX of abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. MUNIX significantly differed between controls and ALS patients and between ALS-Mimics and controls. Within the ALS cohort, significant differences between Phase I and II revealed in MUNIX, compound muscle action potential (CMAP) and motor unit size index (MUSIX) of APB as well as in MUNIX and CMAP of TA. For the ADM, significant differences occurred later in CMAP and MUNIX between Phase II and III/IV. In contrast, there was no significant association between disease aggressiveness and MUNIX. In application of the D50 disease progression model, MUNIX can demonstrate disease accumulation already in early Phase I and evaluate effects of therapeutic interventions in future therapeutic trials independent of individual disease aggressiveness.

Figure 1

Principles and parameters of the D50 disease progression model: (A) calculated sigmoidal curves based on obtained ALSFRS-R scores (dots). D50 represents the individual time cape in months from symptom onset to halved functionality. Three example patients with high (red curve, D50 = 8.92 months), intermediate (yellow curve, D50 = 26.43 months) and low (green curve, D50 = 60.13 months) disease aggressiveness. (B) The individual disease duration in reference to D50 yields the parameter relative D50 (rD50). Patients with different D50 values go through similar phases (I–IV) of disease accumulation. rD50 allows to compare patients with vastly different disease aggressiveness. (C) Histograms of D50 model parameters of the ALS MUNIX cohort (n = 237, red bars) and of the whole ALS cohort (n = 565, green bars) available at our center.

Figure 2

Scatterplots of the ALS cohort of MUNIX (A,B), MUSIX (C,D) and CMAP (E,F) divided for each muscle into three groups based on: (A,C,E) rD50 phases: the early semistable Phase I (0 ≤ rD50 < 0.25, in green), the early progressive Phase II (0.25 ≤ rD50 < 0.5, in blue), and the late progressive and stable Phase III/IV (rD50 ≥ 0.5, in gray). (B,D,F) High (0 ≤ D50 < 20 months, in red), intermediate (20 ≤ D50 < 40, in yellow) and low (D50 ≥ 40, in green) disease aggressiveness. *p < 0.05, **p < 0.01, ***p < 0.001. Comparisons with Kruskal–Wallis test, pairwise comparisons with Bonferroni correction. Bars indicate median and interquartile range. ADM abductor digiti minimi, APB abductor pollicis brevis, CMAP compound muscle action potential (in mV), MUNIX motor unit number index, MUSIX motor unit size index, TA tibialis anterior.

Figure 3

Scatterplots of CMAP (A), MUNIX (B) and MUSIX (C) of APB, TA and ADM of the three different groups. Bars indicate median and interquartile range. *p < 0.05, **p < 0.01, ***p < 0.001. Comparisons with Kruskal–Wallis test, pairwise comparisons with Bonferroni correction. ADM abductor digiti minimi, ALS amyotrophic lateral sclerosis, APB abductor pollicis brevis, TA tibialis anterior.