Clinical importance of changes in magnetic resonance biomarkers for Duchenne muscular dystrophy

Abstract

Objective: Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset.

Methods: Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day-to-day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed.

Results: MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI-T₂ ), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI-T₂ .

Interpretation: MR measures of FF and MRI T₂ are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.

Figure 1

Magnetic resonance images (gradient echo) from the mid‐thigh and fullest part of the calf of three boys with Duchenne muscular dystrophy, a 7‐year‐old who can rise from the floor (Group I), a 10‐year‐old who can walk but cannot rise from the floor (Group II), and a 14‐year‐old who is nonambulatory (Group III). White boxes illustrate the voxel used for MRS acquisition, and the measured fat fraction value from the vastus lateralis in the thigh and soleus in the calf are given for each subject.

Figure 2

Day‐to‐day reproducibility of MRI and MRS biomarkers in ambulatory individuals with Duchenne muscular dystrophy, with Pearson correlation coefficient for the group as a whole as well as for each site separately.

Figure 3

Responsiveness of magnetic resonance biomarkers at different disease stages. The size of each bubble corresponds to the number of data points available to calculate the standardized response mean (SRM) value; SRM is increasingly robust with larger sample sizes. Error bars show the 95% confidence intervals of the bootstrap. Vertical lines at 0.5 and 0.8 indicate traditional thresholds for medium and large effect sizes.

Figure 4

Annualized change in fat fraction (FF) is dependent on baseline FF value, with small changes at low FFs and higher values at mid‐range FF values. Composite FF has relatively large changes across a wider range of values than either vastus lateralis or soleus FF.