Quantitative magnetic resonance imaging in muscular dystrophies

Abstract

Muscular dystrophies are rare diseases characterised by progressive muscle wasting and weakness. Putative therapies are being evaluated; the slowly progressive nature makes outcome measures difficult to design. Four pathological hallmarks of muscular dystrophies include: muscle necrosis, inflammation, fibrosis, and adipose transformation. This thesis evaluates novel methods of quantifying pathological hallmarks of muscular dystrophy in both skeletal and cardiac muscle using magnetic resonance imaging (MRI). To quantify fibrosis in a mouse model of Duchenne muscular dystrophy, EP3533, a collagen-specific contrast agent, was assessed in quantification of fibrosis in muscle. EP3533-measures correlated with functional tests and histological quantification of fibrosis. Extracellular volume (ECV) was calculated in a limb muscular dystrophy type R9 cohort (LGMDR9), a Becker muscular dystrophy cohort and healthy controls. ECV was found comparable to traditional measures of cardiac dysfunction and demonstrated regional dysfunction. A multicentre study followed up 24 participants with LGMDR9 over 6 years. The three-point Dixon method of fat fraction calculation was evaluated in this cohort and compared to functional assessments. All muscles showed significantly increased fat fractions over 6 years, which was more responsive than functional assessments. As patients with muscular dystrophies can have difficulties remaining supine during scanning, a method of reducing acquisition time in measurement of left ventricular (LV) indices was evaluated. Accelerated images were compared to conventional imaging with accelerated imaging producing images with a high fidelity. No significant changes were seen in LV functional indices or cardiac tagging measures over five years was assessed in an LGMDR9 cohort, this may be due to confounding variables. The MRI methods described can be successfully used to quantify progression of disease pathology in muscular dystrophies. These findings can be used to support further trials of EP3533 and ECV as an outcome measure in muscular dystrophies and to inform study design of future trials into LGMDR9