| Summary: | Huntington’s Disease (HD) is a devastating hereditary neurodegenerative disease for which there are currently only symptomatic treatments. Several potentially curative pharmaceutical and genetic therapies are however in varying stages of development and therefore an increasing number of large-scale clinical trials of disease-modifying therapies are imminent. There is consequently a need for biomarkers which are sensitive to beneficial attenuation of disease-related changes. Functional, neuroimaging and biochemical biomarkers have been developed in HD (Andre et al. 2014;Weir et al. 2011). Neuroimaging biomarkers are strong candidates based on their clear relevance to the neuropathology of disease, proven precision and superior sensitivity compared with some standard functional measures (Tabrizi et al. 2011;Tabrizi et al. 2012). Their use in early-stage clinical trials, as surrogate end-points providing initial evidence of biological effect, is becoming increasingly common. Comparison of biomarkers in HD will help to clarify which measures, over varying time intervals, are most sensitive to disease progression. Additionally, the identification of robust fully-automated methods, comparable to manual and semi-automated gold-standards, would facilitate large-scale volumetric analysis. These methods however require validation in observational studies of neurodegenerative disease before they can be applied to sensitive clinical trial data. This thesis will develop and evaluate biomarkers for use in HD; both furthering our understanding of the disease and in preparation for use as end-points in clinical trials. A direct comparison of the sensitivity of diffusion and volumetric imaging biomarkers to HD-related change will be reported for the first time. Several exploratory imaging investigations are also described which enhance current knowledge of the relationship between neuroimaging metrics, brain functioning and behaviour, additionally strengthening the argument for the clinical relevance of neuroimaging measures as surrogate end-points in HD. The thesis will conclude with a comprehensive biomarker evaluation in early-stage HD, along with suggested strategies for selection of primary and secondary trial end-points based on effect sizes and corresponding sample size requirements.
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