Twelve-month change in quantitative MRI calf muscle fat fraction in CMT1A predicts clinical change over 4 years

We measured clinical and quantitative MRI outcome measures in CMT1A to assess long-term responsiveness, establish longitudinal validity and assess MRI as a bridging biomarker.

Twenty patients with CMT1A and 20 matched controls underwent MRI, myometry and clinical assessments up to four times over mean 4-year follow-up. Bilateral calf muscle MRI included T1-weighted sequences with Mercuri grading and three-point Dixon quantitative fat fraction assessment. Patients were grouped on baseline calf muscle fat fraction: normal <5%, intermediate 5%-70% and end stage >70%.

Controls showed no significant change on MRI. CMT1A patients' calf muscle fat percentage progressed across all follow-up visits: mean absolute change was +1.3 ± 1.2% (mean ± SD) at 12 months, +2.3 ± 2.2% at 27 months and 2.8 ± 2.9% at 49 months. Mercuri grades increased by 0.07 ± 0.11 per year. Responsiveness of individual muscle fat was less than for both calves combined. Patients with intermediate baseline calf muscle fat showed greater progression of 3.7 ± 2.3% at 27 months. There was strong correlation between rate of progression of calf muscle fat and CMT Examination Score (ρ = 0.71, P = 0.005). Calf muscle fat progression at 12 months correlated significantly with annualised CMT Examination Score progression at final visit (ρ = 0.65, P = 0.01).

We demonstrated a consistent progression of calf muscle MRI fat over 4 years, significant longitudinal correlation between CMT Examination Score and calf muscle fat, and potential as a bridging biomarker by 1 year change in fat correlating with long-term clinical progression. Increasing study duration minimally increased responsiveness; however, selecting patients with intermediate fat fraction significantly increased responsiveness.