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Investigation of Parkinson's disease related pattern and altered dopamine release pattern in treatment-induced complications and non-motor symptoms of Parkinson's disease

University of British Columbia

Parkinson's Disease is the second most common neurodegenerative disorder. Apart from motor symptoms, cognitive deficits are also common. Treatments, mainly in the form of dopamine (DA) replacement therapy, although reduce motor symptoms at first, can lead to treatment-induced complications. Abnormal spatial covariance metabolic pattern linked to the motor and cognitive symptoms of Parkinson's Disease (PD) have previously been defined using Fludeoxyglucose (FDG) Positron Emission Tomography (PET). In contrast, little is known about the functional networks in the serotonergic system, which is known to be closely related to cognitive dysfunctions of the disease. In this thesis work, we want to investigate the interactions between the dopaminergic and serotonergic pathways in presymptomatic and early stages of the disease, and their contributions to treatment-induced complications and non-motor symptoms in PD subjects. In the first part of this project, we investigated the PD and LRRK2 mutation related patterns in the serotonergic system by studying 12 asymptomatic LRRK2 mutation carriers (LRRK2-AMC), 9 healthy controls (HC), and 18 PD subjects using [¹¹C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET and a principal component analysis (PCA) based regional covariance model with bootstrap resampling. The serotonergic PD-related pattern (SPDRP) significantly separated PD subjects from HC subjects (p<0.0001). A distinct asymptomatic LRRK2 mutation-related pattern (LRRK2-AMRP) significantly separated LRRK2-AMC with HC subjects (p<0.0001). In the second part of the project, we analyzed the medication-induced DA release pattern for 10 early PD subjects using double [¹¹C]-Raclopride scans. We found a significant negative correlation between DA release and age of onset in the striatum. These findings, although obtained with a small number of subjects, suggest that the serotonergic system may be affected by PD in a specific pattern and regions relatively preserved binding may contribute to cognitive dysfunctions related to PD. LRRK2-AMC subjects showed a distinct pattern, which indicates that either such increase is of compensatory nature or is a characteristic of this specific mutation. The combination of abnormal medication-induced DA release pattern and upregulation of the serotonergic system may be able to explain the occurrence of treatment-induced complications and non-motor symptoms in PD patients, and act as a potential early marker for the disease.

Text

2016-08-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58816

Physics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/