Genetic determinants of cognitive heterogeneity in Parkinson’s disease
Date of Award
Doctor of Philosophy
School of Medical and Health Sciences
Dr Megan Thomas
Associate Professor Romola Bucks
Dr Robert White
Professor Wei Wang
People with Parkinson’s disease (PD) display an increased rate of cognitive decline heterogeneous in its presentation and detrimental to a person’s quality of life. The causes of cognitive diversity are unclear, however exploration of the genetic contribution to cognitive profiles is unearthing promising developments. This thesis comprises three studies that use statistical analysis of individual differences to unravel the genetic contribution of genes central to alpha-synuclein (-syn), tau, and noradrenergic pathologies to cognitive outcomes in a Western Australian community-based PD cohort.
First, the cognitive and mood heterogeneity (assessed while the participant was in the “on” state throughout this thesis) within glucocerebrosidase-associated PD (GBA-PD) was explored. Whilst rare (five out of 127 participants with PD), glucocerebrosidase gene (GBA) mutations contribute to widespread Lewy body (LB) pathology and are associated with a younger age of onset, severe disease progression, and a higher risk of dementia. In order to investigate cognitive disturbances within GBA-PD, two statistical methods specifically developed for small number studies were employed, and are novel in their application to the genetics field. Whilst a certain cognitive profile is associated with young-onset GBA-PD as a whole, the results in this thesis demonstrate that there is a high level of cognitive heterogeneity amongst GBA-PD individuals irrespective of age at onset. Longitudinal analysis of these participants’ cognitive decline offers promise in identifying which cognitive profiles reported here are at a higher risk of developing dementia. Moreover, I have shown that the individual differences approach used here is a robust way to investigate the impact of low frequency genotypes on cognition, and therefore can be applied to the exploration of other rare genotype-phenotype associations.
Second, I investigated the impact of genes central to Lewy body and tau pathology on the longitudinal cognitive profile (N = 121). The genes I chose to investigate were alphasynuclein (SNCA), microtubule-associated protein tau (MAPT) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Specifically, I was interested in the genetic contribution to early cognitive decline characteristic of PD (executive function, semantic memory, and episodic verbal learning and memory), as it would enable identification of individuals at risk of cognitive deterioration. Our findings indicate that the MAPT H1/H1 genotype is associated with accelerated cognitive decline in episodic verbal learning and memory. In addition, the DYRK1A rs8126696 TT genotype has been associated with semantic memory performance at baseline and over a 4-year period. These results highlight the role of tau pathology in PD cognition even in its early stages, possibly via different pathways (directly via the MAPT genetic variation, and indirectly via deregulation of tau via DYRK1A).
Finally, I examined the noradrenergic genetic impact on global cognitive decline in PD by investigating the contribution of two functional single nucleotide polymorphisms within beta-2-adrenegic receptor (ADRB2), Arg16Gly and Gln27Glu, to Mini-Mental State Examination performance over a 4-year period (N = 115). For the first time, I report an association between ADRB2 Glu27Glu genotype and cognitive impairment in PD, with affected individuals developing global cognitive decline at a disproportionally higher rate. Moreover, I propose a mediation model where the effect of ADRB2 Glu27Glu is partially mediated by anxiety (as measured by a self-report anxiety questionnaire). These results suggest that the often overlooked adrenergic system and stress response play a significant role in cognitive and mood symptoms in PD.
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Drozdova, A. (2016). Genetic determinants of cognitive heterogeneity in Parkinson’s disease. https://ro.ecu.edu.au/theses/1942