The relationship of genetics with cognitive and behavioral impairments in idiopathic Parkinson’s disease patients
Date
2021-06-10
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Abstract
Parkinson’s disease (PD) is currently characterized by cardinal motor symptoms of rigidity, tremor and bradykinesia. However, this disease is far from a mere movement disorder, and non-motor symptoms have a substantial adverse effect on the quality of life for PD patients. PD patients suffer from a broad range of non-motor symptoms but two of them are the focus of this thesis, neuropsychiatric and cognitive impairments. The true cause of these symptoms’ manifestation is still unknown, but it is speculated that they might originate from the extensive neuronal damage due to PD. The investigation of genetic variants associated with these non-motor symptoms can provide valuable information on the possible causes of non-motor symptoms, their prevention, and even their treatment. In this thesis, the association of some specified genetic variants were investigated with neuropsychiatric symptoms and cognitive impairments in idiopathic PD patients (iPD). In the 1st part, mild behavioral impairment (MBI) in iPD patients was investigated using the mild behavioral impairment checklist (MBI-C). In chapter 3, the association of MBI and rs6265 in the Brain-Derived-Neurotrophic-Factor (BDNF) was studied and it was shown that the Met allele for this variant was linked to higher risk of MBI. It was observed that the Met allele was associated with specific neuropsychiatric symptoms related to emotional dysregulation and distorted thoughts. In chapter 4, the relationship between rs4680 in Catechol-O-methyltransferase (COMT) and rs28363170 in Solute carrier family 3 member 6 (SLC6A3) with MBI was explored in iPD patients. These two variants are both pertinent in the regulation of dopamine availability in the frontal lobe. No association was found for either of these variants with MBI in iPD patients. In the second part, the association of a specific variant rs894280 in Synuclein-alpha (SNCA) and mild cognitive impairment (MCI) in iPD patients was explored. In chapter 5, a machine learning analysis was used to predict cognition in iPD patients. rs894280 was ranked as the second most important feature for prediction of cognition in PD patients. The post-hoc analysis demonstrated a connection between this variant and overall cognition, attention and visual-spatial abilities in iPD patients. This variant was further investigated in chapter 6 using longitudinal data from the Parkinson’s Progression Marker Initiative (PPMI) dataset. It was shown that rs894280 was linked to the cognitive status of drug-naïve iPD patients at baseline. This variant was associated with the rate of MCI conversion in iPD patients longitudinally, but no association was found between the variant and neuropsychiatric symptoms. In conclusion, this thesis presents genetic association with two prominent non-motor symptoms in iPD patients. These findings can be used to assist identification of PD patients at risk of cognitive decline or neuropsychiatric impairments. Nonetheless, further studies should be conducted to elucidate and validate the results of this thesis further. Limitations of the present projects and a framework for future studies are discussed in the last chapter.
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parkinson's disease, mild cognitive impairment (MCI), mild behavioural impairment (MBI), idiopathic Parkinson's disease, genetics, synuclein alpha (SNCA), Brain-derived-neurotrophic-factor-derived-neurotrophic-factor (BDNF), catechol-O-methyltransferase (COMT), Solute Carrier Family 6 member 3 (SLC6A3), non-motor symptoms, candidate gene approach
Citation
Ramezani, M. (2021). The relationship of genetics with cognitive and behavioral impairments in idiopathic Parkinson’s disease patients (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.