Tracking and Understanding Parkinson’s Disease Progression Through the Lens of Quantitative Magnetic Resonance Imaging
Open Access
- Author:
- Sterling, Nicholas William
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 21, 2016
- Committee Members:
- Xuemei Huang, Dissertation Advisor/Co-Advisor
Xuemei Huang, Committee Chair/Co-Chair
Thomas Allen Lloyd, Committee Member
Diane M Thiboutot, Committee Member
Ming Wang, Committee Member
Martin Styner, Special Member - Keywords:
- Parkinson's disease
cholesterol
imaging
neuroprotection - Abstract:
- Parkinson's disease (PD) is an age-related neurodegenerative disorder that typically begins with prodromal non-motor symptoms (such as loss of olfaction and sleep dysfunction) and relatively subtle motor changes (such as reduced arm swing). The current clinical diagnosis is based on the presence of classic motor symptoms such as bradykinesia, rigidity, and tremor at rest. As PD progresses, many patients develop severe motor (including gait and postural changes) and cognitive disability which ultimately lead to the loss of independence. The current treatment of PD is mainly based on management of symptoms, and there is no known therapy that can halt or reverse the progression of neuropathology. As life expectancies increase globally, PD is expected to double in prevalence over the next 25 years. Neuroprotective strategies that can modify the course of the disease, therefore, are critically needed. Past efforts to identify, understand and evaluate potentially neuroprotective treatments for PD, however, have been hindered by the lack of cellular or animal model that exactly mimic human disease, and the lack of objective and reliable in vivo markers of PD-related pathology in humans. The goals of this research were to identify structural magnetic resonance imaging (MRI) markers of PD progression and utilize these markers to understand the factors that may influence the progression of PD. After providing an introduction that underscores the importance of my research goals (Section I) and the strengths and limitations of the approaches that I used (versus the current art of the field), I discuss in Section II the use of structural magnetic resonance imaging to explore gray matter changes in various stages of PD. Striatal atrophy was found to be related to early changes in PD, and cortical atrophy (particularly loss of cortical folding) was found to be associated with worsening clinical symptoms and longer disease duration. These findings were consistent with the known pathologic trajectory of PD, where PD-related pathology affects brainstem and nigrostriatal structures well before the time of diagnosis, and Lewy pathology subsequently progresses in an ascending fashion to later involve higher-level cortex structures. In Section III, I examine the relationships between cortical gray matter atrophy and changes in subcortical white matter. Poorer subcortical white matter diffusion characteristics were found to be associated with cortical atrophy in PD, and opposite associations were found in control subjects. These data provided the foundation for Section IV, where I utilized these newly described cortical imaging markers, along with changes in cognitive function, to explore the role of plasma cholesterol in PD. The link between plasma low density lipoprotein (LDL) cholesterol and PD had been pioneered by my research mentor’s laboratory, and the studies described in this dissertation are the first attempts to associate LDL-cholesterol with specific in vivo cortical changes in PD. This relationship, if proven, may be a topic of high public health relevance, given the widespread use of cholesterol-lowering therapies. Higher plasma cholesterol, indeed, was found to be associated with preserved cognitive function and delayed loss of cortical gyrification in PD. Finally, I summarize in Section V the clinical and scientific implications of my work and offer future clinical and research directions. Of note, I propose that structural imaging measurements of the cortex are useful as markers of PD progression, and that subcortical white matter changes associated with cortical atrophy are an aspect of PD that may reflect altered neuroplasticity during PD progression. Finally, I show that higher plasma cholesterol is associated with delayed loss of cortical gyrification and slower motor and cognitive decline in PD, supporting the hypothesis drawn from case-control and epidemiological data. Thus, my research has shown how structural MRI can offer powerful biomarkers to gauge PD progression and also provide clues about how specific factors might influence the course of PD.