Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Finger, Elizabeth C

2nd Supervisor

Mitchell, Derek GV

Joint Supervisor

Abstract

Frontotemporal Dementia (FTD) is a neurodegenerative disorder that results in atrophy within the frontal and/or temporal lobes. Clinically, patients with FTD present with progressive deterioration in behaviour and/or language abilities. FTD has a strong genetic component with approximately 40% of patients reporting a family history. Specifically, mutations in microtubule-associated protein tau (MAPT), progranulin (GRN) and expanded repeats in the chromosome 9 open reading frame 72 (C9orf72) are the main genetic causes of FTD. Currently, no disease-modifying treatments exist, and off-label medications have been used for symptomatic management of behaviours. Substantial progress has been made to understand the underlying pathology of the disease and clinical trials targeting FTD are in progress. As clinical trials begin, the identification of disease markers will be critical to measure treatment effects, indicate when treatments should be initiated and serve as potential targets for treatments. Therefore, there is a critical need to identify disease markers in FTD.

The present work aimed to elucidate behavioural, structural, and functional changes in FTD from the preclinical to the symptomatic disease stage. Study I delineated the initial symptoms in patients with genetic FTD and in at-risk gene mutation carriers (preclinical mutation carriers and non-mutation carriers). This study revealed gene-specific patterns of initial symptoms during the preclinical and symptomatic disease period. Study II examined the brain’s ventricular volumes in genetically at-risk mutation carriers. Preclinical mutation carriers exhibited larger ventricular volume (i.e. greater neuronal atrophy), relative to biologically related mutation non-carriers. Study III delineated the functional neural correlates underlying disinhibition and behavioural flexibility in patients with FTD. Relative to healthy controls, patents with FTD exhibited decreased activity within the ventral and dorsal lateral regions of the prefrontal cortex. This study reveals that patients with FTD exhibit aberrant neural functioning relative to healthy controls in a task indexing behavioural flexibility.

Overall, this work suggests that behavioural and neuroanatomical disease-alteration occur during the preclinical disease stage and functional neural deficits underlying behavioural difficulties can be detected in symptomatic patients. These results may be applied to future clinical trial designs to assess the efficacy of treatments and determine potential treatment targets.

Summary for Lay Audience

Frontotemporal Dementia (FTD) is a specific type of dementia that leads to brain tissue loss. Patients with FTD demonstrate behaviour and/or language problems including disinhibition, loss of empathy, difficulty attributing the correct meaning to words and word production. Although no disease-modifying treatments exist, substantial progress has been made to understand the pathology of the disease. As clinical trials begin, the identification of biomarkers will be essential to: (1) indicate disease presence and progression, (2) measure treatment effectiveness, (3) indicate when treatments should be administered, and (4) lead to the selection of treatment targets. Thus, there is a critical need to identify disease markers of FTD.

The present thesis examined the behavioural, structural, and functional changes in FTD from the preclinical (prior to disease occurrence) to the disease stage. Study I examined the initial symptoms in patients with FTD and in preclinical mutation carriers (individuals with the disease-causing mutation but who do not yet meet the criteria for the disease), and non-mutation carriers (individuals who are not carrying the disease-causing mutation). This study found that patients’ initial symptoms differ based on the underlying genetic mutation, and preclinical mutation carriers show unique symptoms relative to mutation non-carriers. Study II examined the volumes of the brain’s ventricles (cavities filled with cerebrospinal fluid) in genetically at-risk mutation carriers. Preclinical mutation carriers exhibited greater brain tissue loss relative to biologically related mutation non-carriers. Study III assessed the functional neural correlates underlying poor behavioural flexibility in patients with FTD. Relative to healthy controls, patients with FTD showed decreased activity within the regions of the frontal lobe known to be important for appropriate decision-making.

Overall, this work suggests that disease-alterations in behaviour and brain structure occur and can be detected during the preclinical disease stage prior to the onset of the disease. Furthermore, this work also demonstrates that problems in brain function related to behaviour flexibility can be detected in patients with FTD. These results may inform the selection of disease markers for clinical trial designs.

Available for download on Sunday, November 01, 2020

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