Date of Award
2008
Degree Type
Thesis
Degree Name
Master of Science
Program
Medical Biophysics
Supervisor
Dr. Ting-Yim Lee
Second Advisor
Dr. Savita Dhavantari
Third Advisor
Dr. Ian Welch
Abstract
Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease which arises from the mutation of the cytoskeletal structural protein, dystrophin. Currently, no established non-invasive method exists to assess disease progression. In the present study we have used dynamic contrast-enhanced computed tomography (DCE-CT), positron emission tomography (PET) and high frequency ultrasound (HFU) imaging to non-invasively measure changes in muscle perfusion, metabolism and architecture starting at 6 weeks of age for 16 weeks in two dystrophie murine models, mdx (mutated dystrophin) and udx (mdx:utrophin-null). Methods: Mice were divided into 4 groups by genotype and exercise treatment to induce muscle damage: (1) wild-type (wt)-run, (2) mutated dystrophin (mdx)-run, (3) mdx-walk, and (4) mdx/utrophin-null (udx)-walk. All mice in the ‘run’ groups were exercised on a motorized treadmill at a speed of 15 meters per minute (mpm) and a 7- degree incline for 30 minutes, 3 times weekly from 6 to 22 weeks of age. All ‘walk’ mice followed the same exercise regime but walked for 10 minutes at 5-7 mpm with no incline. Mice were imaged at baseline, imaging was then bi-weekly after exercise sessions with DCE-CT, FDG-PET and HFU to measure gastrocnemius muscle blood flow (BF) and volume (BV), F-FDG uptake (metabolism) as standardized uptake value (SUV) and to grade skeletal musculature changes using HFU. Results: Mean gastrocnemius blood flow in udx and mdx mice peaked at 8 weeks of age and was 40% and 35% higher (p<0.05), respectively, than baseline or those for wt mice. Udx and mdx mice at early post exercise had 55% and 20% higher SUV iii (p<0.05), respectively, than wt mice. Initial increases in BF, BV and SUV were followed by a slow decline with increased duration post exercise. HFU discriminated the severity of muscle damage between wt and dystrophie models, as well as between the mdx and udx dystrophie models. Udx mice displayed continual increase in muscle damage throughout the study. Mdx mice (Ex, N.E) displayed an initial increase in muscle damage followed by reduced degeneration till 22 weeks of age. Conclusion: The patterns of changes in imaging parameters are consistent with initial muscle de/regeneration, inflammation and subsequent muscle necrosis seen in histology. Imaging was capable of differentiating between wild type and affected animals as an non-invasive assessment of disease progression.
Recommended Citation
Ahmad, Nabeel, "Non-Invasive Assessment of Disease Progression in Transgenic Murine Models of Duchenne Muscular Dystrophy" (2008). Digitized Theses. 4321.
https://ir.lib.uwo.ca/digitizedtheses/4321