Doctor of Philosophy
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.
Summary for Lay Audience
Apathy is a debilitating symptom that occurs widely in neurodegenerative dementias. The presence of apathy in dementia is associated with accelerated cognitive decline and increased morbidity in patients. There are currently no widely available treatment options for apathy in neurodegenerative dementias. This is largely due to a lack of understanding of the mechanisms in the brain and the genetic factors that give rise to apathy symptoms. As such, this thesis aims to elucidate the processes in the brain and genetic variants that underlie apathy in a population of patients with neurodegenerative dementias, including frontotemporal dementia (FTD), Lewy Body Dementia (LBD), Parkinson’s Disease (PD), and Alzheimer’s Disease (AD). The first study uses neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to assess the relationship between genetic polymorphisms and brain atrophy patterns as they relate to apathy in a cohort of patients with AD and mild cognitive impairment (MCI). The second study used computer-based tasks to examine deficits in option generation, motivation, and volition related to apathy in patients with FTD, AD, LBD/PD, and healthy controls. The third study used structural MRI scans to assess patterns of brain atrophy associated with the apathy deficits found in study two. Together, our results point to a novel genotype involving a dopamine transporter gene and deficits in option generation related to atrophy in the anterior cingulate cortex (ACC) that may give rise to apathy in neurodegenerative dementias.
Malik, Rubina, "Neurocognitive Mechanisms & Genetic Variants Underlying Apathy in Neurodegenerative Dementias" (2023). Electronic Thesis and Dissertation Repository. 9888.
Available for download on Monday, July 01, 2024