Morrow, JM; (2017) Development of quantitative MRI as an outcome measure in Charcot-Marie-Tooth disease and inclusion body myositis. Doctoral thesis , UCL (University College London).

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Abstract

Lack of sensitive outcome measures is a major obstacle to clinical trials in many neuromuscular diseases (NMD). Lower limb muscle MRI allows non-invasive visualisation of acute and chronic pathology in NMD. This thesis aims to assess the reliability, validity and responsiveness of quantitative MRI in chronic neuromuscular diseases. A comprehensive quantitative MRI protocol of lower limb muscles was developed including T1, T2, fat fraction and magnetisation transfer ratio (MTR) measurements. The protocol was assessed for reliability and sensitivity to physiological variation in 47 healthy volunteers with 15 rescanned at a two week interval. This protocol was then performed together with detailed clinical assessments and isokinetic/isometric dynamometry in 20 patients with inclusion body myositis (IBM), 20 patients with Charcot-Marie-Tooth disease (CMT) and matched health volunteers twice at a 12 month interval. In the healthy volunteers, the inter-scan and inter-observer reliability was high (ICC 0.62-0.99) despite small observed physiological variation between subjects. Fat fraction, T2 and MTR showed significant correlations with subject age in thigh and calf muscles and with subject weight in thigh muscles whereas gender did not influence quantitative parameters. Cross-sectional analysis showed strong correlations with both muscle strength and clinical severity measures demonstrating validity of MRI measurements as outcome measures. Longitudinal assessment demonstrated excellent sensitivity to change of MRI measures; in particular muscle fat fraction quantification exceeded that of myometry and clinical measurements with standardised response mean (SRM) over 12 months of 1.1 in IBM and 0.8 in CMT indicating a high level of responsiveness. Annual change in fat fraction could be predicted based on baseline MRI measurements, providing the opportunity to improve SRM further. This thesis demonstrates the reliability, validity and responsiveness of quantitative MRI as an outcome measure providing a comprehensive practical protocol for clinical trials in NMD.

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