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Parkinson’s Disease is a chronic progressive neurodegenerative disease that affects approximately 2000 out of 100 000 people over the age of 80. This disease is typically characterized by impaired motor function, as well as cognitive and autonomic dysfunction as the pathology worsens. The two main hallmarks typically associated with PD are the dopaminergic loss in the nigrostriatal pathway and the presence of Lewy bodies. However, a cellular dysfunction has been commonly found in neurodegenerative diseases, known as the hyperactivation of the Cdk5/p25 complex. This complex is an essential target to focus on the protection of neurons and prevent the pathology of PD to worsen as treatments are currently only temporary in symptom relief. Truncated Peptide 5 (TP5) is a Cdk5/p25 inhibitor that has demonstrated potential therapeutic effects in neurodegenerative disease models such as Alzheimer’s Disease. Paraquat is an herbicide that has implicated Parkinson’s Disease symptoms in those who have been exposed to this toxin. The purpose of this study was to explore TP5’s therapeutic effects to determine if TP5 has the potential drug to treat towards PD. TP5 was tested in vitro and in vivo models that are exposed to paraquat to induce Parkinson’s Disease like phenotypes and biochemical features. A truncated fragment of TP5, known as Peptide A, was also further explored to determine potential therapeutic effects like TP5. TP5 has shown its ability to protect differentiated SH-SY5Y cells and the dopaminergic morphology and behaviour of C. elegans when exposed to paraquat. These results further support that TP5 has neuroprotective effects against models of Parkinson’s Disease. TP5 was also able to regulate the physiological mechanism of Cdk5, such as neurite outgrowth, to further understand its relationship with Cdk5 activity. Lastly, TP5 restored dopaminergic morphology against worms exposed to paraquat. These results suggest TP5 influences the pathology of PD, in both neuroprotective and neurorestorative manner, to confirm that TP5’s potential as a therapeutic drug for Parkinson’s Disease. / Thesis / Master of Science (MSc)

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Background Visual hallucinations (VH) are an important non-motor complication of Parkinson’s disease (PD) which carries a negative prognosis, but their biological basis is unclear. Multi-modal magnetic resonance imaging (MRI) can be used to evaluate structural and functional brain mechanisms underpinning VH in PD. Methods To assess cerebral microstructure and resting functional activities in patients with idiopathic PD and VH, I compared PD patients with VH (PDVH) and PD patients without VH (PDnonVH), while healthy controls (HC) were also recruited for comparison. Diffusion tensor imaging was used to calculate mean diffusivity (MD) and fractional anisotropy (FA). Structural MRI was used to calculate voxel-based intensity of grey matter (GM) and white matter (WM) across the entire brain and compared among groups. Furthermore, functional magnetic resonance imaging of the brain, acquired during rest, was processed to calculate the amplitude of low-frequency fluctuations (ALFF) and functional connectivity (FC) to inform a model of VH. In addition, hippocampal volume, shape, mean diffusivity and FC across the whole brain was further examined. Hippocampal dependent visual spatial memory performance was compared between groups, and predicted correlations with hippocampal microstructural indices and VH severity were tested. Results In the first study, PDVH had lower FA than both PDnonVH and HC in the right occipital lobe and left parietal lobe, but increased FA in the right infero-medial fronto-occipital fasciculus and posterior inferior longitudinal fasciculus. Moreover, PDVH patients showed less GM volume compared to PDnonVH in the right lingual gyrus of the occipital lobe. In the second study, PDVH patients compared to non-hallucinators showed lower ALFF in occipital lobes, with greater ALFF in temporo-parietal region, limbic lobe and right cerebellum. The PDVH group also showed alteration in functional connectivity between occipital region and corticostriatal regions. Finally in the third study, although there were no gross hippocampal volume and shape differences across groups, individuals with PDVH had higher diffusivity in hippocampus than PDnonVH and HC. Both PD groups had significantly poorer visuospatial memory compared to HC. Poorer visuospatial memory was correlated with higher hippocampal diffusivity in HC and more severe VH in the PDVH group.FC between hippocampus and primary visual cortex, dorsal/ventral visual pathways was also lower in PDVH than other groups, whereas FC between hippocampus and default mode network regions was greater in PDVH group compared to others. Conclusion Compared to PDnonVH groups, the PDVH group had multiple structural deficits in primary and associative visual cortices. In term of hemodynamic activity, the PDVH group had lower ALFF in occipital lobe, but greater ALFF in regions that comprise the dorsal visual pathway. Moreover, this lower ALFF in the primary visual cortex was accompanied by lower functional connectivity across components of the ventral/dorsal visual pathway in the PDVH group compared to the PDnonVH group. Moreover, evidence supporting a specific role for the hippocampus in PDVH was obtained. In the absence of gross macrostructural anomalies, hippocampal microstructure and functional connectivity was compromised in PDVH. I observed an association between visuospatial memory and hippocampal integrity and suggest that hippocampal pathology and consequent disruption in visuospatial memory plays a key contribution to VH in PD. Thus, in the PDVH group, "bottom-up" primary visual cortex and “top-down” visual association pathways and attentional networks appear to be disrupted. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--University of Canterbury, 2007. / Typescript (photocopy). "November 2007." Includes bibliographical references (p. 241-278). Also available via the World Wide Web.

Thesis (Ph. D.)--University of Sydney, 2006. / Title from title screen (viewed 12 February 2009). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Medicine, Faculty of Medicine. Includes bibliographical references. Also available in print form.

Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references (p. 98-123).

Thesis (M.A.)--Miami University, Dept. of Speech Pathology and Audiology, 2004. / Title from first page of PDF document. Includes bibliographical references (p. 52-57).

Thesis (Ph. D. in Molecular Physiology and Biophysics)--Vanderbilt University, Aug. 2007. / Title from title screen. Includes bibliographical references.