Evans, Matthew Rahim Broumand; (2020) Refinement of quantitative MRI as an outcome measure in inherited neuropathies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Recent acceleration in discovery of potential drug treatments for inherited neuromuscular diseases (NMD) heralds the urgent need for scientifically sound clinical trials. Given the rarity and slow progression of most of these conditions, simply increasing sample size, or extending trial duration to increase study power, are not viable options. Trials in NMD are in desperate need of highly responsive outcome measures. Lower limb muscle quantitative MRI (qMRI) allows non-invasive assessment of sequelae of nerve and muscle disease. It has recently been shown to be reliable, valid and responsive in a number of NMD, but further refinement is vital in order to ensure the ability to undertake rigorous and meaningful clinical trials in small cohorts of patients with rare and slowly progressive diseases, over short durations. This thesis aims to examine and improve qMRI responsiveness for application in trials for NMD. Two separate inherited neuropathies have been studied. In Charcot-Marie-Tooth disease type 1A (CMT1A), extended follow up has revealed that qMRI has large internal responsiveness over five years, measuring significant fat fraction (FF) change of 0.7 ± 0.6%/year with standardised response mean (SRM) of 1.07 over 5 years. Excellent validity of qMRI-determined FF is confirmed by strong correlation with clinical measures at baseline, and longitudinal validity is demonstrated for the first time in CMT1A with strong correlation with changes in CMT examination score and remaining muscle area. In Hereditary Sensory Neuropathy type 1, qMRI measures significant FF change at all anatomical levels examined, with large responsiveness at calf levels (distal calf FF change 2.2 ± 2.7%, SRM=0.83; proximal calf FF change 2.6 ± 3.0%, SRM=0.84 over 12 months). In both diseases, significant muscle fat gradients are shown to exist with the potential to devastate or enhance longitudinal analysis. FF change is predicted by baseline FF and other MRI measures in both diseases. Improvement in qMRI responsiveness is demonstrated through a host of evidence-based manipulations aimed at maximising and homogenising mean FF change. Quantitative MRI determined FF is shown to be highly responsive as an outcome measure in two different inherited neuropathies, and is ready to be used as a primary outcome measure in drug trials for rare neuromuscular diseases.

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