In Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting approximately 1 of 3,500 newborn human males, skeletal and cardiac muscles progressively degenerate and are replaced by fibrous tissue and fat. Consequent muscle weakness typically presents by age 5 in afflicted boys who are usually unable to walk by age 10 and die by their late teens or early twenties.12-15 No treatment currently halts or reverses DMD progression, but a host of important molecular discoveries have lead to a wide range of treatment prospects.16-22 However, translating these prospects to clinical trials has been delayed by inadequate outcome measures that lack sensitivity to individual muscles, fail to correlate to life altering events (e.g. loss of ambulation), and/or do not provide meaningful measures until late stages of disease development.2 The failure of conventional tests to serve as early and specific indicators of clinically meaningful outcomes represents a major gap in realizing new treatments for DMD and the other 30+ types of muscular dystrophies in children and adults. There is an unmet need for a validated, noninvasive measure of the impact of dystrophin deficiency on the composition and function of individual muscles. To address this need, our laboratory is developing a novel double-push (DP) acoustic radiation force (ARF) ultrasound imaging method that noninvasively and focally discriminates the mechanical properties of muscle to delineate compositional and structural changes associated with DMD.30 Our preliminary data in Golden Retriever Muscular Dystrophy (GRMD) dogs, a relevant model of human DMD,31-36 supports that DP ARF discriminates fibrous deposition in the rectus femoris (RF) and true hypertrophy in the cranial sartorius (CS) muscles of affected dogs,37 which is consistent with prior pathologic studies of these muscles.31,33,34 Comparable DP ARF results were obtained in a crossbred GRMD dog with myostatin inhibition,38-40 indicating that this trend towards fibrous deposition (RF) and true hypertrophy (CS) is preserved in the context of promoted muscle growth, as expected. Further developing DP ARF ultrasound as a validated tool for noninvasively monitoring degenerative mechanical and compositional changes in dystrophic muscles is the long-term goal of this research program. As a critical first step toward achieving our long-term goal, the objectives of the proposed research are to demonstrate DP ARF for describing dystrophic muscle mechanical property and composition. Our investigation will follow two parallel thrusts: 1) in vivo imaging in GRMD dogs in the NIH National Center for Canine Models of DMD at UNC-CH with pathological validation and comparison to MRI, and 2) in vivo imaging in DMD boys in the Muscular Dystrophy Association (MDA) clinic and the Wellstone Muscular Dystrophy Cooperative Research Center at UNC-CH with correlation to standard quantitative muscle testing (QMT) and timed function tests (TFTs). We anticipate that this approach, while challenging in its scope, will allow the individual parts of the project to be synergistic without being interdependent on one another for completion, should problems arise in one area. We hypothesize that DP ARF ultrasound delineates changes in muscle composition and function in individual dystrophic muscles, from early through late stages of disease development, that correlate to time to loss of ambulation in patient volunteers.

Public Health Relevance

Duchenne muscular dystrophy (DMD) leads to muscle weakness in afflicted boys who are generally unable to walk by age 10 and die by their late teens or early twenties. A wide range of treatment prospects exist, but their translation to clinical use has been delayed by insufficient testing methods. The objectives of this research proposal are to demonstrate a new noninvasive imaging method - Double Push (DP) Acoustic Radiation Force (ARF) ultrasound - as a better test of DMD progression and response to treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Porter, John D
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University of North Carolina Chapel Hill
Biomedical Engineering
Schools of Medicine
Chapel Hill
United States
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Czernuszewicz, Tomasz J; Gallippi, Caterina M (2016) On the Feasibility of Quantifying Fibrous Cap Thickness With Acoustic Radiation Force Impulse (ARFI) Ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control 63:1262-75
Selzo, Mallory R; Moore, Christopher J; Hossain, Md Murad et al. (2016) On the Quantitative Potential of Viscoelastic Response (VisR) Ultrasound Using the One-Dimensional Mass-Spring-Damper Model. IEEE Trans Ultrason Ferroelectr Freq Control 63:1276-87
Czernuszewicz, Tomasz J; Streeter, Jason E; Dayton, Paul A et al. (2013) Experimental validation of displacement underestimation in ARFI ultrasound. Ultrason Imaging 35:196-213
Behler, Russell H; Czernuszewicz, Tomasz J; Wu, Chih-Da et al. (2013) Acoustic radiation force beam sequence performance for detection and material characterization of atherosclerotic plaques: preclinical, ex vivo results. IEEE Trans Ultrason Ferroelectr Freq Control 60:2471-87
Selzo, Mallory R; Gallippi, Caterina M (2013) Viscoelastic response (VisR) imaging for assessment of viscoelasticity in Voigt materials. IEEE Trans Ultrason Ferroelectr Freq Control 60:2488-500
Scola, Mallory R; Baggesen, Leslie M; Gallippi, Caterina M (2012) Multi-push (MP) acoustic radiation force (ARF) ultrasound for assessing tissue viscoelasticity, in vivo. Conf Proc IEEE Eng Med Biol Soc 2012:2323-6