Importance: Quantitative, sensitive and operator-independent biomarkers of disease progression are needed to minimize the size, duration, and cost of clinical trials in amyotrophic lateral sclerosis (ALS) to allow a more effective investigation of promising therapeutic agents. Objective: We assess the potential of skeletal muscle magnetic resonance imaging (MRI) as a sensitive and reliable outcome measure for future ALS clinical trials. Design: In this longitudinal cohort study, muscle MRI of head-neck, upper, and lower limb regions, along with clinical and functional assessments, were acquired at three timepoints over the individual maximum observation period (iMOP) of 1 year. Participants: Twenty consecutive ALS patients were recruited from a motor neuron disease clinic between 2015 and 2017, along with 16 healthy controls. Main outcomes and measures: Quantitative MRI parameters CSA (cross-sectional area), VOL (muscle volume), FF (fat fraction), functional rest muscle area (fRMA) and water T2 (T2m) were used to assess progressive muscle degeneration and were correlated with changes in clinical parameters of disease severity (functional rating scales and myometry). Standardized response mean (SRM) was calculated for MRI outcome measures. Results: Out of 20 ALS patients, 17 were available for follow-up. A significant decline in VOL of the dominant hand (rs=0.66, p<0.001) and head and neck muscles (partial eta squared=0.47, p=0.002) as well as CSA of the lower limbs (thighs: partial eta squared=0.56, p<0.001, calves: partial eta squared=0.54, p<0.001) was observed over iMOP, with highest responsiveness for progressive atrophy in hand (SRM -1.17) and leg muscles (thigh: SRM -1.09; calf: SRM -1.08). Furthermore, lower limb FF and T2m increased over time, with distal leg muscles being most affected (FF: partial eta squared =0.54, p=0.002, SRM 0.81; T2m: partial eta squared =0.37, p=0.01, SRM 0.74). Finally, longitudinal MRI changes showed correlation with strength in leg muscles (knee extension: r=0.77, p=0.001, 95% CI 0.46-0.91; plantar flexion: r=0.78, p<0.001, 95% CI 0.47-0.92), and fRMA decrease at thigh and calf level correlated with global clinical disease progression measured with ALSFRS (r=0.52, p=0.03, and r=0.68, p=0.004 respectively). Conclusions and Relevance: Our findings demonstrate the effectiveness of muscle MRI as a sensitive neuroimaging biomarker of disease progression in ALS, highlighting its potential application in clinical trials.

The authors have declared no competing interest.

This study was supported by the UCLH NIHR Biomedical Research Centre. UK is funded by KD-UK. PF is funded by an MRC and MNDA LEW Fellowship. LG is the Graham Watts Senior Research Fellow funded by the Brain Research Trust.

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The UCL Research Ethics Committee gave ethical approval for this work (11/LO/1425) and written informed consent was obtained from all participants.

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