Magnetic Resonance Spectroscopy Imaging as a Biomarker for FSHD

Principal Investigator: Kathryn Wagner

Sponsored by the American Academy of Neurology -- 2011 AAN Clinical Research Training Fellowship.

Recent advances in the study of heritable neuromuscular disorders have led to multiple promising therapeutic approaches to formerly untreatable, and sometimes fatal, disorders. As clinical trials proceed, the need for reliable biomarkers of muscle disease becomes increasingly important. Current outcome measures include muscle strength, timed function tests and patient-reported quality of life. These outcomes have several practical limitations: there can be wide variability between patients, some can take months to become measurable, and they can be confounded by multiple factors not related to the disease or intervention. Biomarkers are defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic process, or pharmacologic response to a therapeutic intervention." While a biomarker for muscle degeneration -- creatine kinase -- exists, there are no biomarkers for muscle regeneration. As multiple therapies enter the clinical trial stage, such a biomarker is urgently needed for both biological confirmation and as a surrogate outcome measure.

Musculoskeletal imaging has likewise advanced beyond the rendering of static images to the exploration of metabolic, physiologic and functional activities of skeletal muscle. Prior studies have demonstrated the potential utility of magnetic resonance spectroscopy imaging (MRSI) in the evaluation of muscle disorders. MRSI studies of both Duchenne and limb-girdle muscular dystrophies have demonstrated that the metabolic characteristics of affected muscles differ from those of controls [6-8]. Marked increases in magnetic field strength and computation technology open up even greater possibilities to provide a non-invasive biomarker of muscle disease.

The overall goal of the proposed study is to develop an MRSI biomarker as a surrogate outcome measure for clinical trials in muscular dystrophy. We will do this by evaluating skeletal muscle in patients with facioscapulohumeral muscular dystrophy (FSHD) using advanced techniques in magnetic resonance imaging, particularly proton spectroscopy, and correlating our findings to muscle strength and histology. By profiling the metabolic derangements in affected muscle compared to controls, we can establish a noninvasive biomarker of disease severity that can be applied to future therapeutic trials of FSHD and other muscular dystrophies.