Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

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 Duchenne muscular dystrophy (DMD). 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 for patients with muscular dystrophy, therapeutic
interventions have been lacking, and outcome measures for clinical trials have been limited
to measures of muscle function, serum biomarkers of muscle breakdown and invasive muscle
biopsies. 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. As such, this
proposal 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 examine the intramuscular lipid content, muscle damage/inflammation and
contractile area in the lower extremity and/or upper extremity muscles of 200 ambulatory or
non-ambulatory boys with DMD and 100 healthy age matched boys using a combination of MRI and
MRS technologies. In order to assess the sensitivity of each MR measure to disease
progression, all boys with DMD will be reevaluated in yearly or 6 month intervals. In
addition, the investigators will correlate changes in MR measures with standard measures of
disease progression, such as loss in muscle strength and functional ability. Using MRI/MRS
the investigators will also examine the effect of initiating corticosteroid treatment on
skeletal muscle characteristics and composition. Finally, the investigators will deposit
immortalized fibroblasts from carefully characterized DMD boys participating in this study in
established tissue repositories.

The investigators anticipate that the MR techniques developed and validated in this proposal
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 5-18) 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
(<2%) and/or DNA confirmation of a dystrophin mutation.

2. Subjects will not be excluded based on corticosteroid treatment

Inclusion Criteria for age matched controls:

1. Ambulatory males (ages 5-18) without disease or injury to the lower extremities

Exclusion Criteria:

1. Males with a contraindication to an MR examination

2. Males with unstable medical problems

3. Males who are not able to cooperate during testing

4. Males with a secondary condition that may impact muscle metabolism, muscle function or
functional ability (i.e. cerebral palsy, endocrine disorders, mitochondrial disease)

5. Healthy boys who participate in competitive sports specific training in excess of 8
hours per week. Participation in multiple recreational sports activities is not an
exclusion.