Development of radiological and neurophysiological biomarkers in neuromuscular disorders. (2021-2027)

Disease area:

MND, Muscular Dystrophy

Research Project Description

Aims:

• Determine the diagnostic utility of neuromuscular ultrasound and Dual Energy Xray Absorptiometry (DEXA) in Amyotrophic Lateral Sclerosis (ALS) and Facioscapular Humeral Dystrophy (FSHD)
• Assess the association between neuromuscular US, Motor Unit Index (MUNIX), DEXA, wearable activity tracking (HPA) and other measures of disease severity in ALS and FSHD
• Evaluate the reliability, validity and responsiveness of neuromuscular ultrasound, DEXA and wearable activity tracking (HPA) as outcome measures in ALS and FSHD

Hypothesis:

That quantitative neuromuscular ultrasound, DEXA lean muscle mass and wearable activity tracking can: (i) differentiate ALS and FSHD from healthy controls, (ii) correlate with disease severity in ALS and FSHD, and (iii) provide a responsive outcome measure in ALS and FSHD, with immediate clinical utility to therapeutic drug trials

Background:

Current outcome measures in neuromuscular disorders (NMD) lack sensitivity, and this is a barrier to clinical trials for disease modifying therapy. Quantitative neuromuscular ultrasound is a growing area of interest in neuromuscular research, due to its potential as a non-invasive diagnostic biomarker and an outcome measure. Dual energy xray absorptiometry (DEXA) utilizes low dose x-ray to measure the relative proportions of bone, fat and skeletal muscle mass, and has potential as an outcome in NMD as a surrogate for muscle atrophy. Habitual Physical Activity (HPA) refers to someone's physical performance in their free living environment, and has been associated with fatigue, functional limitation and disease severity in NMD.

Wearable sensors and activity monitors can provide the clinician with a measure of HPA through data on activity levels, step count, heart rate and gait metrics. This project will compare healthy controls with two distinct neuromuscular cohorts, specifically Amyotrophic Lateral Sclerosis (ALS) and Facioscapular humeral dystrophy (FSHD) using neuromuscular ultrasound, Motor unit number index (MUNIX), DEXA and wearable activity trackers. Participants will be studied longitudinally over 12 months. This research will explore the reliability, validity and responsiveness of these three techniques as potential outcome measures in Amyotrophic Lateral Sclerosis (ALS) and Facioscapular humeral dystrophy (FSHD), two conditions representative of the broader neuromuscular spectrum.

Phase 1 - Healthy Controls:

Initially studies will be undertaken in healthy controls at a single time point in order to establish normative data for each parameter (muscle/nerve ultrasound, MUNIX and wearable activity tracking) and determine reliability. In total, 50 healthy controls will be recruited across a range of ages and genders. Subjects with a history of limb surgery (minor surgery excluded if no nerve or muscle involvement), neuromuscular disease, symptoms suggesting neuromuscular disease, or diabetes mellitus will be excluded.

Phase 2 - ALS and FSHD Cross Sectional studies

After establishing normative values and reproducibility, the techniques will be applied to ALS and FSHD subjects. In total, 30 patients will be studied for each group. Patients will be recruited through the Westmead and Concord Hospital Neuromuscular clinics.

Phase 3 - ALS and FSHD Longitudinal studies

ALS and FSHD patients will undergo longitudinal assessment at baseline, 6 and 12 months. Visit window in which data can be collected will be +/- 7 days from due visit date. Qualitative and Quantitative muscle strength along with functional assessment, muscle and nerve ultrasound, DEXA and MUNIX will be performed at each visit. Linear mixed effect model and multivariable analysis will be used to determine the prognostic utility of each measure in ALS.