Modeling disease trajectory in Duchenne muscular dystrophy

Abstract

Objective: To quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles.

Methods: MRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach.

Results: MRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (μ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay μ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay.

Conclusions: MRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels.

Clinicaltrialsgov identifier: NCT01484678.

© 2020 American Academy of Neurology.

Figures

Figure 1. Qualitative fat fraction changes in the leg muscles of a control and participant with DMD over 2 years

Axial T1-weighted MRI of the (A–D) lower leg and (E–H) upper leg with the corresponding magnetic resonance (MR) spectroscopy (MRS) from the soleus and vastus lateralis muscles. MRI/MRS from a 9-year-old unaffected participant is shown in panels A and E. (B and F) Baseline MRI/MRS of a participant with DMD (age 5 years), (C and G) 1-year follow-up, and (D and H) 2-year follow-up. Fat deposits appear bright in these images, with greater contributions subcutaneously and intramuscularly in the participant with Duchenne muscular dystrophy (DMD) compared to an unaffected participant. The proton MR spectra are labeled to indicate water (1H2O) and principal fat peaks. As seen in the images, most muscle groups of the upper leg and lower leg show increased hyperintensity with age. In contrast, the tibialis anterior and posterior are relatively preserved across time.

Figure 2. Longitudinal magnetic resonance spectroscopy FF for VL and SOL muscles in DMD

(A and B) Changes in soleus (SOL) and vastus lateralis (VL) fat fraction (FF) for individual participants. Each measurement is indicated by a filled circle, and tie lines connect individual participants. Substantial heterogeneity in FF progression can be observed between individuals. Solid blue curves in panels A and B represent population-average progression determined from nonlinear mixed effects modeling using equation 1 for SOL and VL, respectively, with A = 0.89 and C = 0.01. Dashed lines indicate 1 SD in average age at half-maximal muscle involvement (μ), calculated from values estimated for individuals (i.e., μi). (C and D) Breakout of the first 81 individual participants for each thumbnail plot. Filled circles represent FF values obtained at each visit, and the solid line shows the best model fit. Inspection of the individual fits demonstrates excellent fitting of individual disease progression for a wide range of progression rates. Data for the participant presented in figure 1 are indicated by the blue square.

Figure 3. Population-average trajectories for MRI qT2 and annual ΔMRI qT2 measures

Population-average trajectories for (A) MRI quantitative T2 (qT2) and (B) annual ΔMRI qT2 in muscles of the upper and lower leg. Biceps femoris long head (BFLH) and vastus lateralis (VL) muscles show the most rapid MRI qT2 increase. The group average behavior of soleus (SOL), peroneus (PER), medial gastrocnemius (MG), and gracilis (GRA) muscles shows an intermediate increase in MRI qT2 with time, and the tibialis anterior (TA) and tibialis posterior (TP) muscles have the slowest average MRI qT2 progression. In panel B, the shaded area represents the 95% confidence interval of ΔqT2 indicating no change for an individual participant. These muscles provide sensitivity to detect an annual qT2 change in the individual from 5 to 25 years on the basis of 95% ΔqT2 confidence interval of ≈2 milliseconds.

Figure 4. Population estimates for FF trajectories for Steroid+ and Steroid− groups

Population estimates for vastus lateralis (VL) and soleus (SOL) fat fraction (FF) trajectories with and without corticosteroid treatment. (A) VL and (B) SOL MRS FF age trajectories for participants with Duchenne muscular dystrophy who were treated with corticosteroid (solid lines, n = 86 for VL, n = 88 for SOL) and untreated (lighter lines, n = 14 for both VL and SOL). The population estimated age at half-maximum FF (μ) occurs 1.0 years earlier in VL and 4.8 years earlier in SOL in the corticosteroid-untreated compared to the corticosteroid-treated group. The disease progression time constant (σ) is 3.5 and 3.0 years for the VL corticosteroid-treated and untreated groups, respectively; σ is 6.0 and 3.9 years for the SOL untreated and corticosteroid-treated groups, respectively.

Figure 5. Relationship between age at LOA and μ for leg muscles

(A) Plot presenting the age at loss of ambulation (LOA) against the average age at half-maximal involvement (μ) for vastus lateralis (VL) and soleus (SOL) (μ = [μ(VL) + μ(SOL)]/2; VLSOL). Filled symbols represent individuals with Duchenne muscular dystrophy (n = 28), and the solid line represents the linear regression (LOA 1.0 μ), all with significant associations (r = 0.84; p < 0.0001) between LOA and μ. (B) Ambulation survival curves for VLSOL μ at 25 (gray), 50 (orange), and 75 (blue) percentile values demonstrating a substantially larger probability of retaining ambulation at older age with increased μ.