MR biomarkers predict clinical function in Duchenne muscular dystrophy

Abstract

Objective: To investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function.

Methods: One hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T2 biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed. Participants returned for follow-up data collection at 12, 24, 36, and 48 months.

Results: Longitudinal analysis of the MR biomarkers revealed that vastus lateralis FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 biomarkers were the fastest progressing biomarkers over time in this primarily ambulatory cohort. Biomarker values tended to demonstrate a nonlinear, sigmoidal trajectory over time. The lower extremity biomarkers predicted functional performance 12 and 24 months later, and the magnitude of change in an MR biomarker over time was related to the magnitude of change in function. Vastus lateralis FF, soleus FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 were the strongest predictors of future loss of function, including loss of ambulation.

Conclusions: This study supports the strong relationship between lower extremity MR biomarkers and measures of clinical function, as well as the ability of MR biomarkers, particularly those from proximal muscles, to predict future ambulatory function and important clinical milestones.

Clinicaltrialsgov identifier: NCT01484678.

© 2020 American Academy of Neurology.

Figures

Figure 1. MRIs, MR biomarker values, and functional status for a participant across 48 months

This figure represents the natural history of a single individual's disease progression from 8.8 years (baseline) to 12.9 years (48 months) of age. The lower leg and thigh images are axial T1-weighted images that demonstrate the progressive fatty infiltration of the musculature. Magnetic resonance (MR) spectroscopy fat fraction (FF) and MRI T2 values with the corresponding functional test results are listed for each year. 6MWT =6-minute walk test; STS = supine-to-stand; VL = vastus lateralis.

Figure 2. Binned and individual participant MR biomarker trajectories

(A and B) With binning of all available data points for each age, the progression of MRI T2 and magnetic resonance (MR) spectroscopy (MRS) fat fraction (FF) with increasing age reveals that vastus lateralis (VL) FF, VL MRI T2, and biceps femoris long head (BFLH) MRI T2 are most elevated within each age group. (C–F) The trajectories of MR biomarkers from each individual participant demonstrate heterogeneity in disease progression among participants, even participants of similar ages. GRA = gracilis; MG = medial gastrocnemius; PER = peroneal group; SOL = soleus; TA = tibialis anterior; TP = tibialis posterior.

Figure 3. Longitudinal relationship between VL MR biomarkers and ambulatory function

(A and B) For the 6-minute walk test (6MWT), distances declined in a linear manner as vastus lateralis (VL) MRI T2 and VL fat fraction (FF) increased. Once participants were walking only ≈200 m, VL MRI T2 was >65 millisecond, or VL FF was >0.4, loss of the ability to perform the 6MWT became likely. (C–H) Functional test times were expressed as velocities to allow visualization of loss of ability. As the velocity of functional task performance decreased, there was an associated increase in magnetic resonance (MR) biomarker values. Supine-to-stand velocity tended to decrease more rapidly and at lower VL MR biomarker values than stair climb or 10-m walk/run velocities.

Figure 4. Baseline VL FF and the probability of functional test change

(A–D) The probability of functional test improvement, stability, decline, or loss over 12 months was estimated with ordinal logistic regression. At baseline fat fractions (FFs)

Figure 5. Loss of functional ability vs magnetic resonance biomarkers

(A) A Kaplan-Meier plot for loss of 3 functional skills (supine-to-stand [STS], stair climb, and ambulation) in relation to vastus lateralis (VL) fat fraction (FF). (B–D) There is a strong relationship between baseline VL FF and the loss of functional skills over 24 months (white = ambulatory, can climb stairs, and can perform STS; light gray = ambulatory and can climb stairs but cannot perform STS; dark gray = ambulatory, unable to climb stairs or perform STS; black = nonambulatory). Very few individuals with VL FFs ≤0.20 lost functional skills over 12 months, and only a small proportion lost abilities over 24 months. Individuals who were ambulatory at baseline with VL FFs >0.30 were the most likely to lose ambulation within 24 months. (Note that all participants included in this analysis were ambulatory at baseline.)