Magnetic Resonance Biomarkers Can Measure DMD Disease Progression

April 3, 2020

Prospective, observational study data suggest that MRS fat fractions and MRI quantitative T2 values can provide disease progression measures in a sensitive and noninvasive manner.

Bill D. Rooney, PhD

New data from a study which sought to quantify disease progression in patients with Duchenne muscular dystrophy (DMD) using magnetic resonance spectroscopy (MRS) and imaging (MRI) biomarkers of leg muscles suggest that fat fractions (FFs) and MRI quantitative T2 (qT2) values can provide just such measures in a sensitive and noninvasive manner.

The effort, which was published in Neurology and included Bill D. Rooney, PhD, director, Advanced Imaging Research Center, and associate professor, Behavioral Neuroscience, School of Medicine, Oregon Health & Science University, and colleagues, ultimately showed that both MRS FF and MRI qT2­ increased with DMD disease duration, with marked differences in progression time constants between individuals and across muscles

“This study presents a modeling approach to characterize MR biomarkers longitudinally and provides a comprehensive view of the natural history of skeletal muscle involvement in DMD,” Rooney and colleagues wrote. “The [cumulative distribution function] model that we used is simple and reliable and represents the data well across a wide range of progression characteristics. The modeling described here provides an efficient summary of complex temporal datasets with output parameters that are easy to understand, have biological significance, are relevant to clinical disease characteristics, are sensitive to treatment effects, and are available at individual and population levels.”

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All told, the prospective, observational study included MRI and MRS biomarkers from 104 individuals with DMD and 51 healthy controls, followed up yearly for up to 6 years. The FFs in vastus lateralis (VL) and soleus (SOL) muscles were determined with 1H MRS, while MRI qT2 values were measured for 3 muscles of the upper leg—VL, biceps femoris long head (BFLH), and gracilis (GRA)—and 5 muscles of the lower leg—SOL, medial gastrocnemius (MG), peroneus (PER), tibialis anterior (TA), and tibialis posterior (TP).

At study entry, 81 of those with DMD were being treated with corticosteroids—deflazacort (69%), followed by prednisone (26%), and prednisolone (5%)—and 23 participants with DMD were untreated. Of the 81 participants, 1 went off steroids within a year after enrollment and remained off for the remaining 5 years of the study duration, and thus was categorized as corticosteroid negative.

The comparison between the images collected at annual follow-ups showed a marked increase in signal hyperintensities for almost every muscle group explored, but greater increases were observed in muscles proximal to the trunk. The TP, GRA, and TA muscles had modest or no increases.

“Visual inspection of the extent of hyperintensity on T1-weighted MRI data is frequently used to evaluate muscle involvement in DMD using a qualitative scale,” Rooney et al. wrote, noting that MRS FFs in the SOL and VL muscles in DMD showed marked increases with time.

Additionally, at baseline, the mean FFs were significantly elevated (P <10—6) in those with DMD for VL (mean, 0.187 [standard deviation (SD), 0.172]) compared to the healthy control group (mean, 0.024 [SD, 0.015]), as well as for SOL (DMD: mean, 0.097 [SD, 0.072]; control: mean, 0.024 [SD, 0.014]) muscles, with large effect sizes (Cohen d >1).

Similar baseline qT2 values were observed. Those with DMD had elevated values (range, 37.1—50.7 milliseconds) compared to controls (range, 32.6–34.6 milliseconds) for all muscles investigated (P <10−6; Cohen d >1). GRA, TA, and TP muscles all showed smaller differences than other muscles.

The average age at half-maximal muscle involvement (μ) occurred 4.8 years earlier in VL than SOL, and these measures were strongly associated with loss-of-ambulation (LOA) age (P <.0001). Results from the Cox proportional hazard model resulted in significant associations of μ with LOA age for both VL (LOA hazard ratio [HR] for 1-year decrement, 2.43; 95% CI, 1.77—3.35; R2 = 0.544; P <10−6) and SOL (HR, 2.25; 95% CI, 1.65—3.05; R2 = 0.429; P <10−7). There were also significant links between µ and LOA age for the composite measure of VL and SOL (HR, 2.71; 95% CI, 1.92—3.81; R2 = 0.474; P <10−7).

“To put this in context, for a 1-year decline in VL μ, the hazard of LOA increased by a factor of 2.43,” Rooney et al. wrote. “It is clear that the LOA age increases for larger μ values.”

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.

"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,” Rooney and colleagues concluded. “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.”

REFERENCE

Rooney WD, Berlow YA, Triplett WT, et al. Modeling disease trajectory in Duchenne muscular dystrophy. Neurology. 2020;94:1-12. doi:10.1212/WNL.0000000000009244