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Thesis Format

Integrated Article

Degree

Master of Science

Program

Medical Biophysics

Collaborative Specialization

Molecular Imaging

Supervisor

Hoffman, Lisa M.

Abstract

Duchenne muscular dystrophy (DMD) is one of the most commonly inherited musculoskeletal disorders affecting 1 in 3500 boys worldwide. The disorder is due to a lack of functional dystrophin protein, which, in turn, results in a loss of cell membrane integrity in skeletal, cardiac muscle and the brain leading to changes in perfusion. As such, within DMD tissue, necrosis is commonly observed, and it has been previously hypothesized that this may be due to a reduction in regional blood supply. Here, we aim to measure hemodynamic changes during disease progression in DMD (Mdx/Utrn+/+) mice, using dynamic contrast enhanced computed tomography imaging and histology across two time points; 4-5 weeks and 8-10 weeks.

Preliminary DCE-CT data collected at the 4–5-week time point (n=3-5) showed a 17.00% increase in blood flow (p=0.14) and 16.06% (p=0.13) increase in blood volume in the brain between Mdx/Utrn+/+ and C57bl/10 mice. Similarly, the heart showed an increase in blood flow by 8.76% (p=0.29) and increased blood volume by 9.47% (p=0.22) between the two groups at the same time point. Furthermore, pathologic differences in (Mdx/Utrn+/+) mice have been shown within the cardiac, brain, and skeletal muscle tissue compared to the wild-type mice (C57bl/10). Currently, there is insufficient knowledge of functional tissue perfusion parameters in DMD. Therefore, this research will provide insight as to whether or not non-invasive diagnostic measures can assess perfusion differences before the onset of serious complications leading to death.

Keywords: Duchenne muscular dystrophy, Ischemia, CT perfusion, Oxidative Stress, Mdx

Summary for Lay Audience

Duchenne muscular dystrophy (DMD) is one of the most commonly inherited musculoskeletal disorders affecting 1 in 3500 boys. The disorder is due to a lack of functional dystrophin protein, which, in turn, results in a loss of cell membrane integrity in skeletal, cardiac muscle and the brain leading to changes in perfusion. As such, within DMD tissue, necrosis is commonly observed, and it has been previously hypothesized that this may be due to a reduction in regional blood supply. Here, we aim to measure hemodynamic changes during disease progression in the Mdx/Utrn+/+ murine model of DMD and C57bl/10 mice using dynamic contrast enhanced computed tomography (DCE-CT) imaging across two time points; 4-5 weeks and 8-10 weeks. These time points have been associated with the pre-fibrotic condition and onset of fibrosis respectively within literature.

Furthermore, pathologic differences in (Mdx/Utrn+/+) mice have been shown within the cardiac, brain, and skeletal muscle tissue compared to the wild-type mice (C57bl/10) and were used to validate DCE-CT data. Currently, there is insufficient knowledge of functional tissue perfusion parameters in DMD. Therefore, this research may provide guidance as to whether or not it is feasible that non-invasive diagnostic measures can assess perfusion differences before the onset of complications.

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