Thesis Format

Integrated Article

An approach for the in-vivo characterization of brain and heart inflammation in Duchenne Muscular Dystrophy

Author

Joanne Tang, The University of Western OntarioFollow

Degree

Master of Science

Program

Medical Biophysics

Collaborative Specialization

Molecular Imaging

Supervisor

Anazodo, Udunna C.

2nd Supervisor

Hoffman, Lisa M.

Joint Supervisor

Abstract

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely unknown in DMD despite being prevalent in other neurodegenerative diseases. Considering the well-known consequences of unchecked chronic inflammation, inflammation’s contribution towards multi-organ degeneration must be explored. Thus, this study explored inflammatory marker translocator protein positron emission tomography (TSPO-PET) to evaluate immune cell infiltration within the hearts and brains of DMD murine models. Four DMD and six healthy mice underwent whole-body PET imaging using the TSPO radiotracer [¹⁸F]FEPPA. Confirmatory TSPO-immunofluorescence staining of cardiac and neural tissues were also conducted. Our results indicated that DMD mice showed significant elevations in heart and brain [¹⁸F]FEPPA activity, which correlated with increased ex-vivo fluorescence intensity. In summary, this study suggests cardiac and neuroinflammation presence in DMD and highlights TSPO-PET’s utility as a tool for in-vivo assessment of inflammation in several organs simultaneously within DMD.

Summary for Lay Audience

Duchenne muscular dystrophy is characterized by progressive skeletal and heart weakness, and cognitive impairment. Current therapies have increased patient longevity, revealing the emergence of heart and brain degenerative symptoms at the later stages of the disease. Thus, there is a need to better assess, understand, and track the potential sources of multi-organ dysfunction in DMD. Inflammation is thought to be a prime contributor to these dysfunctions because it is widespread in both the DMD patient’s muscle and blood. However, not much is known about inflammation in the brain of DMD subjects. This work addresses this gap in knowledge through the assessment of inflammation in the brains and hearts of DMD mice using live animal imaging and tissue measurements of [¹⁸F]FEPPA, a radiotracer that accumulates in inflammatory cells. We found higher [¹⁸F]FEPPA in the hearts and brains of DMD mice compared to healthy mice. This research demonstrates that imaging using [¹⁸F]FEPPA can be a useful tool to assess inflammation in multiple organs in live mice models of DMD.

Recommended Citation

Tang, Joanne, "An approach for the in-vivo characterization of brain and heart inflammation in Duchenne Muscular Dystrophy" (2020). Electronic Thesis and Dissertation Repository. 7394.
https://ir.lib.uwo.ca/etd/7394