Magnetic resonance imaging and biomarkers for muscular dystrophy

The purpose of this research study is to determine the potential of magnetic resonance imaging, spectroscopy, and whole body imaging to monitor disease progression and to serve as an objective outcome measure for clinical trials in Muscular Dystrophy (MD).

The investigators will compare the muscles of ambulatory or non-ambulatory boys/men with DMD with muscles of healthy individuals of the same age and monitor disease progression in those with DMD over a 5-10 year period. The amount of muscle damage and fat that the investigators measure will also be related to performance in daily activities, such as walking and the loss of muscle strength. In a small group of subjects the investigators will also assess the effect of corticosteroid drugs on the muscle measurements.

Additionally, the investigators will map the progression of Becker MD following adults with this rare disease. The primary objective is to conduct a multi-centered study to validate the potential of non-invasive magnetic resonance imaging and magnetic resonance spectroscopy to monitor disease progression and to serve as a noninvasive surrogate outcome measure for clinical trials in DMD and BMD. The secondary objective is to characterize the progressive involvement of the lower extremity, upper extremity, trunk/respiratory muscles in boys/men with DMD and BMD guiding clinical trials.

The overall objective of this proposal is to validate the potential of noninvasive magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and to serve as an outcome measure for clinical trials in muscular dystrophies. Duchenne muscular dystrophy (DMD) is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function, quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Closely related to DMD, Becker muscular dystrophy (BMD) has also been largely neglected in therapeutic development, due to its heterogeneity, small patient population, lack of outcome measures and uncertainty surrounding the patterns of disease progression, which may be mutation-dependent. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials in both forms of muscular dystrophy. As such, this project targets the development and validation of magnetic resonance as a noninvasive biomarker of disease progression in muscular dystrophy. Using a multi-site research design this study will characterize the intramuscular lipid content, cellular muscle damage and contractile area in the lower and/or upper extremity muscles of 200 ambulatory or non-ambulatory boys/men with DMD, 105 ambulatory or non-ambulatory men with BMD, and 110 healthy age matched boys/men using a combination of sophisticated MRI and MRS technologies. The trunk and respiratory muscles will be characterized in a subgroup of subjects (80 DMD, 20 BMD and 10 controls). In order to assess the sensitivity of each MR measure individually as well as composite MR measures (combination of muscles) to disease progression, all boys/men with DMD or BMD will be re-evaluated in yearly or 6 month intervals. The predictive outcome value of MRI/MRS will be further evaluated by determining the relationship between changes in MR measures and loss in muscle strength and/or functional ability. Using MRI/MRS we will also examine the effect of initiating corticosteroid treatment on skeletal muscle characteristics and composition. Examination of muscles in BMD patients will allow us to increase our understanding of how much dystrophin is needed to protect the muscle. To this end we will specifically examine the relationship between the MR phenotype (e.g. fast or slow increases in fat fraction) and dystrophin mutations, dystrophin expression and other histological markers. Finally, to ensure the rigor of this study we will examine the day-day reproducibility, inter MR system reproducibility and inter-validate the MR measures using localized MRS (golden standard). We anticipate that the MR techniques developed and validated in this study will be suitable for clinical trials in a wide range of muscular dystrophies and other neuromuscular diseases. In addition, MR characterization may serve as a powerful tool to further advance our understanding of the pathogenesis of muscular dystrophy and help guide the design of future trials.

Inclusion Criteria for boys with Dmd:

1. Ambulatory and non-ambulatory males (ages 5-30 at baseline testing) previously diagnosed

With Dmd based on:

• clinical features with onset of symptoms before age five

• elevated serum creatine kinase level or

• absence of dystrophin expression, as determined by immunostain or western blot (