New Investigation Analyzes Magnetic Resonance Measures of DMD for Disease Progression

Magnetic resonance measures of fat fraction (FF) and MRI transverse relaxation time (MRI-T2) have been shown in a new study to be reliable measures of disease progression among individuals who have Duchenne muscular dystrophy (DMD). According to the findings published in Annals of Clinical and Translational Neurology,¹ they are also highly responsive to disease progression as biomarkers, which endorses their ability for use in DMD and other muscular dystrophies.

Investigators in this study evaluated the potential of biomarkers of disease progression in Duchenne muscular dystrophy.

“Robust demonstration of therapeutic efficacy has been a challenge in DMD,” the study authors wrote. “Many factors contribute to the difficulty of running successful trials in DMD, but it is widely agreed that sensitive biomarkers of disease progression are needed to improve trial design.”

Female and male individuals can get DMD, because the abnormal dystrophin gene is located on the X chromosome²; however, DMD is typically seen in young boys because with them only having 1 X chromosome, they lack a functioning gene that can compensate.³

Data for this analysis was originally collected through the ImagingDMD study (NCT01484678) conducted at University of Florida, Oregon Health & Science University, and Children’s Hospital of Philadelphia. The 180-patient cohort was recruited between 2010 and 2018, and all attended annual follow-up visits; the medium follow-up was 4 (range, 0-8) years, and there were 925 visits overall. At each follow-up visit, standardized MR measurements were taken, and among the 111 ambulatory participants, measurements were repeated within a week. This group also completed the 6-minute walk test, 10-m walk/run test, 4-stair climb test, and supine-to-standing test at each follow-up visit. Ultimately, participants were divided into 3 groups:

• Group 1 could stand up from the floor in under 45 seconds; these patients had a mean (SD) age of 9.3 (2.4) years
• Group 2 lacked the ability to stand up from the floor; their mean age was 12.2 (2.3) years
• Group 3 could not complete the 10-m walk/run test unassisted in under 45 seconds; their mean age was 13.7 (2.6) years

Group 1 (n = 147 and 494 observations) had the lowest total mean (of all annual visits) FF measures for the vastus lateralis muscles (VL) and the soleus (SOL), and the lowest composite score vs Groups 2 and 3, respectively:

• VL: 0.18 (95% CI, 0.15-0.20) vs 0.48 (95% CI,, 0.45-0.50) and 0.64 (95% CI, 0.61-0.67)
• SOL: 0.10 (95% CI, 0.09-0.11) vs 0.23 (95% CI, 0.20-0.26) and 0.42 (95% CI, 0.38-0.46)
• Composite score: 0.14 (95% CI, 0.12-0.15) vs 0.35 (95% CI, 0.33-.38) and 0.52 (95% CI, 0.49-0.55)

Group 1 also had the lowest values for VL, long head of the biceps femoris (BFLH), medial gastrocnemis (MG), and tibialis posterior peroneus longus and brevis (PER) when MRI-T2 was evaluated. Again, composite scores were lowest: 45.2 (44.2-46.2) vs 56.8 (55.2-58.4) and 63.9 (62.6-65.2) in Groups 2 and 3, respectively.

As for annualized change, Group 2 most often had the highest values and Groups 1 and 3 varied, when looking at FF and MRI-T2:

1. FF:
   1. VL: 0.08 (95% CI, 0.07-0.09) vs 0.06 (95% CI, 0.06-0.07) and 0.07 (95% CI, 0.05-0.09), respectively
   2. SOL: 0.06 (95% CI, 0.05-0.08) vs 0.02 (95% CI, 0.02-0.03) and 0.07 (95% CI, 0.06-0.09)
   3. Composite: 0.07 (95% CI, 0.06-0.08) vs 0.04 (95% CI, 0.04-0.05) and 0.07 (95% CI, 0.06-0.08)
2. MRI-T2:
   1. VL: 4.2 (95% CI, 3.3-5.0) vs 3.7 (95% CI, 3.2-4.2) and 2.2 (95% CI,1.2-3.2)
   2. BFLH: 4.1 (95% CI, 3.3-5.0) vs 4.4 (95% CI, 3.8-5.0) and 0.8 (95% CI, –0.3 to 1.8)
   3. MG: 2.7 (95% CI, 1.8-3.8) vs 1.3 (95% CI, 1.0-1.7) and 2.0 (95% CI, 1.1-2.9)
   4. PER: 3.3 (95% CI, 2.5-4.2) vs 1.7 (95% CI, 1.4-2.1) and 1.6 (95% CI, 0.6-2.5)
   5. SOL: 3.1 (95% CI, 2.3-4.1) vs 1.4 (95% CI, 1.2-1.8) and 2.3 (95% CI, 1.6-3.1)
   6. Composite: 3.7 (95% CI, 3.1-4.4) vs 2.5 (95% CI, 2.2-2.9) and 1.8 (95% CI, 0.8-2.7)

The study authors noted that they classified their population into 3 groups because similar patient populations are targeted in clinical trials and optimal imaging biomarkers can differ according to disease stage. They also noted that this study population represented an expansion from an earlier analysis of 30 young boys.⁴

“The most important outcome from this analysis is that composite biomarkers incorporating both upper and lower leg muscles are highly responsive throughout the range of disease stages investigated here,” they concluded. “Ongoing work in our group aims to identify a statistically optimal approach to generating a composite MR measurement.”

References

1. Willcocks RJ, Barnard AM, Daniels MJ, et al. Clinical importance of changes in magnetic resonance biomarkers for Duchenne muscular dystrophy. Ann Clin Transl Neurol. Published online November 6, 2023. doi:10.1002/acn3.51933
2. Duchenne muscular dystrophy. Muscular Dystrophy Association. Accessed November 30, 2023. https://tinyurl.com/3vpcvy6w
3. Does Duchenne muscular dystrophy only affect men? Muscular Dystrophy UK. September 6, 2022. Accessed November 30, 2023. https://tinyurl.com/yc4n6t6e
4. Forbes SC, Walter GA, Rooney WD, et al. Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MRimaging and MR spectroscopy. Radiology. 2013;269:198-207. doi:10.1148/radiol.13121948