Longitudinal changes in subcortical morphology in Huntington Disease and the relationship with clinical, motor and neurocognitive outcomes
Creators: name: Wilkes, Fiona
Publisher: name: The Australian National University
Year: 2021

description: Huntington disease (HD) is a devastating inherited neurodegenerative disease which causes progressive motor, psychiatric and cognitive disturbances as well as neurodegeneration. Mapping the spatiotemporal progression of neuroanatomical change in HD is fundamental to developing biomeasures suitable for prognostication and to aid in development and testing of potential treatments. The neostriatum is central to HD and is known to start to degenerate more than a decade before observable motor onset. It is central to a number of frontostriatal re-entrant circuits which regulate motor control and other forms of behaviour. Changes in striatal morphology can consequently be correlated with observable clinical, motor and cognitive outcomes. However, the neostriatum is merely one part of the "hubs and spokes" of neural circuitry and neurodegeneration in HD also occurs in other areas of the brain. The hippocampus has been less fully studied in HD and has implications for neural plasticity, particularly given neurogenesis continues into adulthood in this region. Furthermore, thickness of the corpus callosum may be used as a proxy for cortical changes that are known to occur later in HD. This thesis uses data from the IMAGE-HD study to characterise neuroanatomical changes in HD, with the aim to improve knowledge of HD-associated neurodegenerative pathways and to provide further insight to relate quantitative measures of morphology to function. A number of analytical techniques are used to investigate changes in size and shape of neuroanatomical structures and to correlate these with clinical, motor and neurocognitive outcomes. This thesis demonstrates that shape changes in the neostriatum in HD and pre-symptomatic HD correlate with functional measures subserved by corticostriatal circuits, and identifies significant longitudinal differences in putaminal and caudate shape. Only the putamen has a significant group by time interaction, suggesting that it is a better marker for longitudinal change in pre-symptomatic HD and HD. While HD has its most marked effects on the neostriatum, it also has more subtle effects on other subcortical areas. This thesis shows surface contraction occurring in HD in the hippocampus compared to controls, although without correlations to functional measures or significant longitudinal change. Unlike these "hubs", this thesis finds that the large "spoke" of the corpus callosum is not impacted early in the HD process but becomes affected after symptom onset, highlighting the spread of neurodegeneration in other structures. This is the first time that such robust statistical analysis of longitudinal shape change in HD has been able to be performed and shows the neostriatum, particularly the putamen, as a potentially useful structural basis for the characterisation of an endophenotype of HD. This thesis provides a more comprehensive picture of neuroanatomical change in HD by using a "hubs and spokes" approach to analyse key areas, increasing knowledge about neurodegenerative pathways and functional outcomes.