Muscle MRI Scans Can Serve as Biomarker for DMD Progression
MRI scans of muscle can be used as a biomarker to assess disease progression in Duchenne muscular dystrophy (DMD) and to support the evaluation of different therapies in clinical trials, an analysis showed.
“The results of this study provide further support for the use of imaging as an objective, noninvasive biomarker for use in DMD clinical trials,” the investigators wrote, noting that such studies in the past “have proven to be challenging, due in part to the lack of robust biomarkers that are sensitive to detecting disease progression.”
According to the researchers, this is the first study that used MRI scans to analyze the participants’ “entire thigh, rather than small regions in individual muscle groups.”
Their analysis, “Quantitative muscle MRI biomarkers in Duchenne muscular dystrophy: cross-sectional correlations with age and functional tests,” was published in the journal Biomarkers in Medicine.
Mutations in the DMD gene result in a deficiency or lack of the protein dystrophin, which is essential for muscle fiber stability. People who carry these mutations — usually boys, with the disease occurring in roughly one of every 3,500 male births — face progressive muscle degradation, inflammation, impaired muscle regeneration, and the replacement of muscle with fat tissue, all leading to weakness and difficulties with mobility.
Although DMD currently has no cure, treatments can slow muscle degradation. However, determining the benefit of investigational treatments in clinical trials involving Duchenne patients have been hampered due to the lack of objective outcomes. Biomarkers that can detect DMD progression and the efficacy of therapies over a short period of time also are lacking.
The researchers noted that physical function tests, such as those assessing a patient’s ability to climb stairs or walk, are important to demonstrate the long-term efficacy of a potential treatment. However, these function outcomes can pose several problems, including variability of disease progression, outcomes measure inconsistency, and subjectivity in the voluntary performance and measurement of motor tasks.
More objective measures thus are needed in DMD to detect underlying biological processes and disease progression, while being sensitive to the impact of treatments.
Studies show that MRI can be a valuable non-invasive tool for monitoring DMD disease progression, one shown to correlate with functional tests; as such, MRI can be an important biomarker for future clinical trials.
This underscores the need to detail the relationship between various MRI measures and functional outcomes. Furthermore, for MRI to be used widely in clinical trials, scanning protocols must be widely accessible at imaging centers, and methods must be scalable to analyze large numbers of MRI results.
In this study, funded and conducted by Pfizer, pre-treatment (baseline) MRI and functional data were analyzed from a Phase 2 clinical study (NCT02310763) that evaluated the company’s investigational medicine domagrozumab in boys with DMD. Of note, this study failed to meet its primary goal, and further development of domagrozumab was terminated.
“The relationships between functional tests and scalable MRI assessments, together with an understanding of age-related changes, will help inform future clinical trial design,” the scientists wrote.
The study enrolled 121 DMD boys ages 6-15 who were able to walk. One participant was omitted from the analysis due to the lack of baseline MRI scans. All images focused on the thigh muscles and were collected without the use of sedatives, the researchers noted.
Key MRI measures included thigh muscle volume, thigh fat fraction, and a muscle volume index — a measure of the fraction of the total thigh muscle that is lean. T2 mapping, a measure of muscle inflammation and fat infiltration, also was investigated.
Functional measurements examined in this study included timed tests, such as the four-stair climb, rise from the floor, 10-meter run, and six-minute walking distance. The North Star Ambulatory Assessment (NSAA) of motor abilities was added as well as knee extension strength evaluation.
The analysis showed that muscle volume had the weakest correlations to timed functional tests and NSAA, and had no correlation to patient age.
Muscle volume or “MV did not show a clear trend of increasing with age in boys with DMD, as may be anticipated in a growing child,” the team wrote. “This finding is particularly interesting when keeping in mind that the MV captured the entire thighs of boys.”
In contrast, knee extension strength assessments strongly correlated with muscle volume.
“The finding that MV is correlated with strength is aligned with a previous report looking at muscle cross-sectional area in patients with DMD and age-matched controls,” the investigators added.
Muscle volume index had a moderate correlation with timed assessments, NSAA, and age, but was weakly associated with knee extension strength. Also, this index declined with age, which was “consistent with previously published results showing MVI [muscle volume index] of the lower limbs was significantly lower in boys with DMD compared with healthy boys, and that decreases in thigh MVI were significantly correlated with age.”
The results also showed that fat fraction had a moderate correlation with timed functional tests, NSAA, and age, but a weak correlation with knee extension strength. On average, fat fraction demonstrated the highest correlation with timed functional assessments compared with all other imaging measures.
T2-mapping measures were moderately associated with timed functional tests, NSAA, and patient age, and weakly with strength tests.
An examination of age alone found either a weak or weak-to-moderate correlation with the timed tests, NSAA, and strength assessment.
“This lack of functional decline in this age range would need to be a consideration when planning a study with functional end points [measures],” researchers wrote.
Overall, the analysis provided important information for researchers in setting up clinical trials, the scientists said.
“Taken together, our findings further support the use of [muscle volume index], fat fraction analysis and T2-mapping to measure disease progress in patients with DMD,” they added. “MV may be an additional biomarker of interest to help quantify changes in strength or evaluate the pharmacologic effect based on the mechanism of action of a potential therapy.”
“The overall moderate correlation between an array of functional tests and several MRI measures provides further evidence of the utility of MRI as an objective biomarker for future clinical trials,” the team concluded.