PT - JOURNAL ARTICLE AU - Michelle L. Mellion AU - Per Widholm AU - Markus Karlsson AU - André Ahlgren AU - Rabi Tawil AU - Kathryn R. Wagner AU - Jeffrey M. Statland AU - Leo Wang AU - Perry B. Shieh AU - Baziel G.M. van Engelen AU - Joost Kools AU - Lucienne Ronco AU - Adefowope Odueyungbo AU - John Jiang AU - Jay J. Han AU - Maya Hatch AU - Jeanette Towles AU - Olof Dahlqvist Leinhard AU - Diego Cadavid TI - Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI AID - 10.1212/WNL.0000000000200757 DP - 2022 Aug 30 TA - Neurology PG - e877--e889 VI - 99 IP - 9 4099 - http://n.neurology.org/content/99/9/e877.short 4100 - http://n.neurology.org/content/99/9/e877.full SO - Neurology2022 Aug 30; 99 AB - Background and Objectives Facioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials.Methods Participants aged 18–65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0–5), and ≥1 short tau inversion recovery–positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4–12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed.Results Seventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36–85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (ρ = 0.71, ρ = 0.83), FSHD-TUG (ρ = 0.73, ρ = 0.73), and RWS (left arm: ρ = −0.71, ρ = −0.53; right arm: ρ = −0.61, ρ = −0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (Sw) 0.5% and 1.5%; and MFItot (Sw), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and Sw were higher in intermediate (MFI ≥0.10; MFF <0.50) than in normal (MFI <0.10, MFF <0.50) muscles.Discussion We developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials.Classification of Evidence This study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.COA=clinical outcome assessment; CV=coefficient of variation; FSHD=facioscapulohumeral muscular dystrophy; LMV=lean muscle volume; MFF=muscle fat fraction; MFI=muscle fat infiltration; NMD=neuromuscular disorder; RSA=relative surface area; RWS=reachable workspace; SQI=signal quality issue; STIR=short tau inversion recovery; Sw=within-subject SD; TMV=total muscle volume; TUG=timed up and go; WB-MSK-MRI=whole-body musculoskeletal MRI