Modeling disease trajectory in Duchenne muscular dystrophy

Abstract

ObjectiveTo quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles.MethodsMRI 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.ResultsMRS 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.ConclusionsMRS 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.ClinicalTrials.gov identifier:NCT01484678.

Musculoskeletal magnetic resonance imaging in the DE50-MD dog model of Duchenne muscular dystrophy

“…Similarities to the GRMD dog model seen in affected DE50-MD dog pelvic limb skeletal muscle volumes were expected as both models follow the same disease progression and see the same pathological changes. DE50-MD dogs had higher global muscle T2 values in all pelvic limb muscles apart from CS muscle, when compared to WT dogs: global muscle T2 increase has previously been reported in boys with DMD and in the GRMD dog model [20,[29][30][31][32][33], although more recently, global muscle T2 maps have been replaced by Dixon or water T2 maps [20,[34][35][36][37][38][39][40]. Water or fat T2 map SI continues to be the most sensitive marker for observing changes in dystrophic muscle as patients age and when compared to controls [29-32, 34, 36-40, 52].…”

Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy

“…In our cohort, the highest percentage of measurable change peaked in those muscles having intermediate fat fraction of ~ 0.40–0.50 at baseline; with large changes in fat fraction (≥ 0.20) only seen in less affected muscles. This has been described in other muscular dystrophies such as Duchenne muscular dystrophy [ 15 , 16 ].…”

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

“…This study had two primary outcome measures: (1) safety and tolerability and (2) change from baseline in lower leg muscle health as determined by the MRI transverse relaxation time constant (T 2 ) from a composite of five muscles (soleus, gastrocnemius, anterior and posterior tibialis, peroneus). These muscles have been identified previously to encompass muscles at various stages of disease progression [26][27][28][29] . MRI assessments were made at four imaging centers (Children's Hospital of Philadelphia, University of Florida, Oregon Health & Science University, Cedars) using 3T MR systems at baseline and then every 12 weeks as previously described [29 , 30] .…”