Gordon, Elizabeth; (2020) Longitudinal neuroimaging measures of volumetric change across the frontotemporal dementia spectrum. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Frontotemporal dementia (FTD) is a common cause of young onset dementia, encompassing several clinical, genetic and pathological subgroups. Currently there are no treatments, but there are promising candidates in development. However, proven biomarkers of disease progression in FTD are lacking and urgently needed to facilitate these trials. Investigating large sporadic and genetic FTD cohorts, this thesis provides a comprehensive comparison of longitudinal neuroimaging measures of structural change within the clinical, genetic and pathological FTD subgroups. Effect size and sample size estimates are computed to explore the feasibility of these brain measures as surrogate markers of disease progression in order to detect disease-modifying treatment effects. The first project compares 17 automated techniques for extracting whole-brain atrophy measures. Many of the techniques showed great promise, producing sample sizes of substantially less than 100 patients required to detect a disease-modifying effect. Significant differences in performance were found between both techniques and patient subgroups, highlighting the importance of informed biomarker choice in matching the optimal marker to the patient group to be enrolled in a trial. In the following chapters, I explored lobar and subcortical change across the disease spectrum. The different patient subgroups presented with unique profiles of change but, interestingly, automated measures of temporal lobe, caudate and thalamic atrophy proved to be particularly sensitive markers of change, producing low sample size estimates across the FTD subgroups. Importantly, I found significantly increased rates of amygdala, hippocampus, caudate and thalamic atrophy in differing patterns across presymptomatic mutation carriers, providing the first comprehensive assessment of the utility of such markers for early therapeutic intervention at this ideal stage before symptoms develop. In summary, this work expands current knowledge and builds on the limited longitudinal investigations currently available in FTD, as well as providing valuable information about the potential of non-invasive biomarkers for sporadic and genetic FTD trials.

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