Imaging muscle as a potential biomarker of denervation in motor neuron disease

Abstract

Objective: To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo.

Methods: A prospective, longitudinal, observational, clinicoelectrophysiological and radiological cohort study was performed. Twenty-nine patients with MND and 22 age-matched and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinical presentation and 4 months later. Between-group differences and associations were assessed using age-adjusted and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset.

Results: Patients with MND had 30% higher relative T2 muscle signal than controls at baseline (all regions mean, 95% CI 15% to 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95% CI -0.017 to -0.001, p=0.023) and with clinical weakness and lower MUNIX in multiple individual muscles. Relative T2 signal in bilateral tibialis anterior increased over 4 months in patients with MND (right: 10.2%, 95% CI 2.0% to 18.4%, p=0.017; left: 14.1%, 95% CI 3.4% to 24.9%, p=0.013). Anatomically, contiguous disease spread on MRI was not apparent in this model.

Conclusions: Whole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology.

Figure 1

Flow chart of patients’ assessment and dropout. MND, motor neuron disease; MUNIX, motor unit number index.

Figure 2

Baseline data in patients and controls. The central panel shows illustrative central coronal slices from whole-body T2-weighted datasets obtained in a healthy control (left) and a patient with MND (right). Extracted regions of interest are demonstrated in controls on the left and a patient with MND on the right in the tongue (yellow arrows), right biceps (red arrows), right thoracic paraspinal (green arrows) and right anterolateral leg compartment encompassing tibialis anterior (blue arrows).

Figure 3

Box plots illustrating means and SD of relative T2 signal in patients with MND (red) and controls (blue) in the (A) tongue, (B) right biceps, (C) left biceps, (D) thoracic paraspinals, (E) right TA, (F) left TA and (G) mean all regions. Ctrls, controls; L, left; Pts, patients; R, right; TA, tibialis anterior.

Figure 4

Graphs depict longitudinal changes in TA parameters: (A) percentage relative T2 signal on right, (B) coronal T2-weighted slices from a patient with motor neuron disease at baseline and 4 months illustrating an increase in relative T2 signal on the right (yellow arrow), (C) percentage relative T2 signal change on left, (D) dynamometry on right, (E) MUNIX tested, (F) dynamometry on left, (G) MRC score on right and (H) MRC score on left. The bold blue line represents mean change. Asterisks indicate statistically significant change on paired t-tests (p<0.05 corrected for multiple comparisons). MRC, Medical Research Council; MUNIX, motor unit number index; TA, tibialis anterior.