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Access Type

WSU Access

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Psychiatry and Behavioral Neurosciences

First Advisor

jeffrey stanley

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized histologically by the loss of dopaminergic neurons in the substantia nigra (SN), and clinically by motor symptoms. PD pathology extends beyond the SN, and involves the presence of intraneuronal inclusions in neuronal bodies (Lewy bodies) and dendrites (Lewy dendrites). A staging system for Lewy pathology has been proposed, where it is hypothesized that the disease initiates in the peripheral nerves system and spreads along a caudal-rostral pathway to the brain stem and the cerebral cortex. Histological and imaging studies highlight a role for cortical Lewy pathology and atrophy, respectively, in mediating the cognitive decline with disease progression. In this regard, little is known about the cortical microstructural effects preceding cortical atrophy. Neurite orientation dispersion and density imaging (NODDI) is a diffusion model that characterizes tissue microstructures through three main indices, intracellular volume fraction (ICVF), orientation dispersion index (ODI) and isotropic volume fraction. Our study utilized two diffusion MRI models, diffusion tensor imaging and NODDI, in combination with cortical thickness assessment to study the microstructural changes in the cerebral cortex of a PD cohort (n=18) compared to healthy controls (n=8). We demonstrated that PD pathology is associated with reduced cortical tissue organization as reflected by significant reductions in ICVF and fractional anisotropy in the cingulate, fusiform and temporal regions, indicating reduced dendritic complexity in these regions. Moreover, decreased ODI in the caudate was associated with PD-pathology, possible reflecting dendritic regression as a result of dopaminergic denervation. White matter (WM) microstructural abnormalities were also characterized in the corpus callosum, and significant FA and ICVF reductions, in parallel with increased ODI were consistently found in the genu subregion. These results might indicate that PD pathology is associated with WM axonal loss and morphological changes. In summary, we believe that the detected pattern of abnormalities in diffusion metrics in gray and white matter regions highly relevant for PD Lewy pathology and might be a future biomarker for tracking disease progression.

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