Muscle MRI quantifies disease progression in Amyotrophic Lateral Sclerosis
Authors: Klickovic Uros , Zampedri Luca , Zafeiropoulos Nick , Ziff Oliver J , Sinclair Christopher DJ , Wastling Stephen J , Dudziec Magda , Allen Jodie , Trimmel Karin , Howard Robin S , Malaspina Andrea , Sharma Nikhil , Sidle Katie CL , Shah Sachit , Nasel Christian , Yousry Tarek A , Greensmith Linda , Morrow Jasper M , Thornton John S , Fratta Pietro 
Published: April 2024

ABSTRACTImportanceQuantitative, 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.ObjectiveWe assess the potential of skeletal muscle magnetic resonance imaging (MRI) as a sensitive and reliable outcome measure for future ALS clinical trials.DesignIn 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.ParticipantsTwenty consecutive ALS patients were recruited from a motor neuron disease clinic between 2015 and 2017, along with 16 healthy controls.Main outcomes and measuresQuantitative 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.ResultsOut 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 η²=0.47, p=0.002) as well as CSA of the lower limbs (thighs: partial η²=0.56, p<0.001, calves: partial η²=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 T2mincreased over time, with distal leg muscles being most affected (FF: partial η²=0.54, p=0.002, SRM 0.81; T2m:partial η²=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 RelevanceOur findings demonstrate the effectiveness of muscle MRI as a sensitive neuroimaging biomarker of disease progression in ALS, highlighting its potential application in clinical trials.Key PointsQuestion:Can quantitative muscle MRI track disease progression over time in patients with amyotrophic lateral sclerosis (ALS)?Findings:Longitudinal quantitative MRI reliably detects progressive intramuscular fat infiltration, oedema and atrophy, which correlate with progressive loss of muscle strength.Meaning:Muscle MRI has the potential to be utilised as a biomarker for ALS disease progression and could contribute to reduce the size and duration of clinical trials facilitating future drug developments.