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

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 clinico-electrophysiological and radiological cohort study was performed. Twenty-nine MND patients and 22 age 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 clinic presentation and four months later. Between-group differences and associations were assessed using age 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 MND patients had 30% higher relative T2 muscle signal than controls at baseline (all-regions mean, 95%CI 15%, 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95%CI -0.017, -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 four months in MND patients (right: 10.2%, 95%CI 2.0%, 18.4%, p=0.017; left: 14.1%, 95%CI 3.4%, 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

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

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 diffusion-weighted 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

Analysis of brain and spinal MRI measures in a common domain to investigate directional neurodegeneration in motor neuron disease

Background Magnetic resonance imaging (MRI) of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology. This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus or retrograde, dying-back. Methods In this cross-sectional study, MRI was performed on 75 MND patients and 13 healthy controls. Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy (FA) from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox. To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to z-scores, referenced to healthy control norms. Mixed-effects linear regression models were then fitted to these z-scores, with gradients hypothesised to represent directionality of neurodegeneration. Results At group-level, z-scores did not differ significantly between precentral gyral and intracranial corticospinal tract tissue damage estimates (regression coefficient − 0.24, [95% CI − 0.62, 0.14], p = 0.222), but step-changes were evident between intracranial corticospinal tract and C1 (1.14, [95% CI 0.74, 1.53], p < 0.001), and between C5 and C6 cord levels (0.98, [95% CI 0.58, 1.38], p < 0.001). Discussion Analysis of brain and cervical spinal MRI data in a common domain enabled investigation of pathophysiological hypotheses in vivo. A cranio-caudal step-change in MND patients was observed, and requires further investigation in larger cohorts

Imaging denervation in motor neuron disease for future clinical trials: a longitudinal cohort study

A key area-of-need in motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) translational research is a tool to objectively track disease progression over short timescales, to reduce duration and cost of clinical trials. Previous studies have focused on the central nervous system

Jobi Basteri med. doct., Acad. Caes. ... Opuscula subseciva : observationes miscellaneas de animalculis et plantis, quibusdam marinis, eorumque ovariis et seminibus continentia

t.1-2 (1760-1765

Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in people living with amyotrophic lateral sclerosis using phosphorus-31 magnetic resonance spectroscopy, the modality of choice to assess energy metabolism in vivo. We recruited twenty patients and 10 healthy age and gender-matched controls in this cross-sectional clinico-radiological study. Phosphorus-31 magnetic resonance spectroscopy was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: adenosine triphosphate, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of adenosine triphosphate hydrolysis, phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in brainstem where Gibbs free energy of adenosine triphosphate hydrolysis and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting Gibbs free energy of adenosine triphosphate hydrolysis, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in amyotrophic lateral sclerosis in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. Phosphorus-31 magnetic resonance spectroscopy represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in amyotrophic lateral sclerosis and a potential tool for future clinical trials targeting bioenergetic dysfunction