McColgan, Peter; (2018) Structural Brain Network Degeneration and Functional Up-regulation In Huntington’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene on chromosome 4. In recent years there have been significant advances in understanding both the cellular pathology and the macrostructural changes that occur in the striatum and cortical structures as the disease proceeds. However, it remains unclear how abnormalities at the cellular level lead to characteristic patterns of macrostructural change in the brains of HD patients. In this thesis I aim to link structural and functional brain network abnormalities with regional changes at the cellular level. Using diffusion tractography and resting state functional MRI in well characterised HD cohorts I examine the relationship between structural and functional brain network organisation. I link these changes in structure and function to the neuropsychiatric symptoms prevalent in HD, occurring years before the manifestation of motor symptoms. By characterising changes in white matter brain networks I reveal how the brain network breaks down as HD progresses and show how this network deterioration leads to the emergence of clinical deficits. Using characteristics of the healthy white matter brain network I demonstrate how it is possible to predict the atrophy of specific brain connections in HD over time. In doing so I highlight a hierarchy of white matter connection vulnerability showing cortico-striatal connections are the first to be affected. In order to link these macrostructural white matter changes to cellular level abnormalities I utilise data from the Allen Institute transcription atlas and show how differences in regional gene expression in the healthy brain can account for the selective vulnerability of specific white matter connections in HD. The work presented in this thesis demonstrates how linking systems and cellular pathobiology in HD can inform us about disease mechanisms that drive brain atrophy and ultimately lead to clinical deficits.

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