Early Markers of Dysfunction in Frontotemporal Dementia
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.