Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease

Abstract

Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2-and diffusionweighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7-29%, p < 0.01), maximal in leg muscles (left tibialis anterior 71% (95% CI 33-122%, p < 0.01). Clinical and electrophysiological associations were evident. By 12 months, 16 patients had died or could not continue. In the remainder, relative T2-signal increased over 12 months by 14-29% in right tibialis anterior, right quadriceps, bilateral hamstrings and gastrocnemius/soleus (p < 0.01), independent of onset-site, and paralleled progressive weakness and electrophysiological loss of motor units. Highest clinical, electrophysiological and radiological SRMs were found for revised ALS-functional rating scale scores (1.22), tibialis anterior MUNIX (1.59), and relative T2-weighted leg muscle MR (right hamstrings: 0.98), respectively. Diffusion MR detected minimal changes. Conclusion MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site.

Muscle MRI in motor neuron diseases: a systematic review

“…Among these 28 articles, there were 14 MND/ ALS (18-31), 13 SMA (32-44) and three SBMA (20,29,45) patient groups. There were eight multiple-region (21,(24)(25)(26)28,29,37,45), 13 lower-limb (19,20,(32)(33)(34)(35)(36)38,(40)(41)(42)(43)(44), one paraspinal (30), three bulbar (18,22,23) and three whole-body (27,31,39) studies. These papers are summarized in Tables 1 and 2.…”

“…Studies in motor neuron diseases have applied quantitative (18,19,(22)(23)(24)29,(31)(32)(33)35,39,(42)(43)(44)(45), qualitative (18,20,21,25,26,(28)(29)(30)(32)(33)(34)(36)(37)(38)(39)(40)(41)45), and semi-quantitative (27,31) techniques, often in combination, and imaging protocols vary between studies. Most qualitative studies used the fivepoint Mercuri scale, which grades change from an early moth-eaten appearance to muscle replacement by connective tissue and fat (46).…”

“…Frequent issues identified were omission of a control group (32,33,36,37,(39)(40)(41)43), lack of blinding (18)(19)(20)23,31,(34)(35)(36)(39)(40)(41)(42)(43)45) and inadequate ascertainment of disease status (23,25,40). Only four studies justified the sample size (22,27,31,38). More than 20% cohort attrition was reported in 5/9 longitudinal studies, typical in MND research.…”

“…The first whole-body muscle MRI application in MND was reported in 2018, with further longitudinal follow-up in 2020 (27,31). Whole-body semi-quantitative T2-weighted scans were acquired in 29 MND patients (26 ALS, three progressive muscular atrophy (PMA)), and 22 age/gendermatched healthy controls.…”

Evaluation of Motor Neuron Injury in ALS by Different Parameters of Diffusion Tensor Imaging

“…ADC is used to reflect the diffusion speed and range of water molecules. When the axons or (and) myelin sheath of the white matter tract are involved in various lesions, the FA value of the involved area will be reduced to some extent, while the ADC value will be increased to some extent [47], [48].…”