Neurocognitive Mechanisms & Genetic Variants Underlying Apathy in Neurodegenerative Dementias
Abstract
Apathy refers to a reduction in self-initiated, goal-directed behaviour and is present in many neurodegenerative dementias, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy Body dementia (LBD), and Parkinson’s disease (PD). There are no robustly effective treatments for symptoms of apathy present in these dementias; this is, in part, because apathy is phenotypically diverse, yet is often understood and clinically treated as a single, homogenous syndrome. The current thesis aimed to use a combination of behavioural, genetic, and imaging data to better characterize the neurocognitive and genetic underpinnings of apathy across neurodegenerative dementias. Study One leveraged data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to examine associations between single nucleotide polymorphisms and 3T MRI structural imaging data in a cohort of patients with apathy and mild cognitive impairment (MCI) or AD. A partial least squares correspondence analysis (PLS-CA) revealed a novel genotype of minor homozygosity for the DAT1 gene and the possession of one APOE ε4 allele associated with significant brain atrophy in frontal, temporal, parietal, insular, and subcortical brain regions in patients with apathy. Study Two used computer-based tasks to index core cognitive and behavioural components of apathy, including option generation, amotivation, and avolition deficits. These computer tasks were employed in patients with neurodegenerative dementias, including AD, FTD, LBD/PD, and healthy controls. Results showed significant deficits in an option generation task related to a subtype of apathy characterized by impairments in initiation, option generation, and effort. Study Three involved 3T structural imaging data, collected at the Centre for Functional and Metabolic Mapping (CFMM), from participants who completed the computer tasks in Study Two. Based on findings from Study Two, deficits in the option generation task and an apathy latent factor (comprised of initiation, option generation, and effort indices) were expected to predict atrophy in the dorsal anterior cingulate cortex (dACC), anterior prefrontal cortex (PFC), medial PFC, and dorsolateral PFC. Results revealed a significant association between the apathy predictors and atrophy in the ACC. Overall, this thesis demonstrates novel genetic and cognitive underpinning of apathy in neurodegenerative dementias that can be used to inform future clinical trials for apathy.