Natural History of Muscle Volume and Muscle Fat Content Biomarkers in FSHD Based on Whole-Body Fat-Referenced MRI

Topic:

Translational Research

Poster Number: P302

Author(s):

Markus Karlsson, PhD, AMRA Medical, Per Widholm, MD, AMRA Medical, Jonathan Pini, PhD, Peripheral Nervous System and Muscle Department, University Côte d’Azur, Angela Puma, MD, Peripheral Nervous System and Muscle Department, University Côte d’Azur, Luisa Villa, MD, Peripheral Nervous System and Muscle Department, University Côte d’Azur, Michele Cavali, MD, Peripheral Nervous System and Muscle Department, University Côte d’Azur, Andra Ezaru, MD, Peripheral Nervous System and Muscle Department, University Côte d’Azur, Guillaume Bassez, MD, Unité de Morphologie Neuromusculaire, Institut de Myologie Sorbonne University, Benjamin Marty, PhD, Unité de Morphologie Neuromusculaire, Institut de Myologie Sorbonne University, Teresinha Evangelista, MD, Institute of Myology, Romain Thomas, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, CHU Lille, Loïc Danjoux, MD, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, CHU Lille, Céline Tard, MD, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, CHU Lille, Sabrina Sacconi, MD, Peripheral Nervous System and Muscle Department, University Côte d’Azur

Background
Heterogeneity in disease onset pattern and slow progression makes it challenging to show a treatment effect in FSHD clinical trials. Fat-referenced, quantitative whole-body MRI biomarkers have demonstrated the ability to identify intermediately affected muscles with high likelihood of near-term progression in clinical trials but reports from natural history studies are scarce.

Aim
Describe one-year progression of fat-referenced MRI biomarkers in an FSHD natural history cohort and investigate if selecting intermediately affected muscles increases the progression rate of the biomarkers.

Methods
Whole-body Dixon MRI from the CTRN FSHD France (NCT04038138) Natural history study was analyzed using AMRA Researcher. 18 muscle groups were volumetrically analyzed bilaterally, and lean muscle volume (LMV), muscle fat fraction (MFF), and muscle fat infiltration (MFI) were quantified. Muscles were classified at baseline as Normal Appearing (MFI<10% & MFF<50%), Intermediate (MFI>10% & MFF<50%), or End-Stage (MFF>50%). Measurements from individual muscles were combined into composites. Responsiveness was assessed using standardized response mean (SRM).

Results
56 patients were included with age, mean(SD), 50.1(12.2) years, Clinical Severity Score, median[min,max], 6[2,9]. One year progression in whole-body composite LMV/MFF/MFI (mean±SE, (SRM)) was -2.33±0.47%, (-0.66) / 0.93±0.16pp, (0.77) / 0.21±0.06 pp, (0.46). Progression in intermediate muscles was -4.10±0.67%, (-0.86) / 1.89±0.33pp, (0.8) / 0.37±0.11pp, (0.47), and -1.59±0.49%, (-0.43) / 0.58±0.12pp, (0.64) / 0.19±0.06pp, (0.43), in normal appearing muscles. Progression in intermediate muscle composites (for LMV and MFF) was significantly higher compared to composites of either normal appearing muscles or all muscles (p<0.01). Conclusion This study showed that whole-body composites of intermediate muscles (1) demonstrated the highest progression rate, validating the methods performance in identifying fast-progressing muscles, (2) reduces the impact of disease heterogeneity as a confounding factor in describing progression. This makes it a highly responsive biomarker for monitoring of disease progression (SRM=0.86) in a slowly progressing, heterogenous diseases such as FSHD.