Author Identifiers

Danielle Megan Bartlett

ORCID: 0000-0002-6096-3760

Date of Award

2018

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health SciencesS

First Advisor

Professor Mel Ziman

Second Advisor

Dr Travis Cruickshank

Field of Research Code

1109

Abstract

Background: Huntington’s disease (HD) is a rare, neurodegenerative disease caused by an expanded cytosine-adenine-guanine (CAG) sequence in the Huntingtin gene, resulting in the production of an aberrant protein, mutant huntingtin (mHTT). The mHTT protein exhibits a toxic loss and gain in function, leading to degeneration of neurons in the brain. Consequently, the classic triad of motor, cognitive and mood features of the disease develop. Among the earliest features of HD are circadian rhythm and sleep disturbances. These anomalies present many years prior to formal clinical diagnosis of HD and, while it has been postulated that these disturbances arise as a result of hypothalamic pathology, the neurobiological mechanisms underpinning these sleep disturbances have not yet been robustly investigated. The hypothalamus of the brain contains several key nuclei that are essential in maintaining circadian rhythm and sleep/wake cycles. Hypothalamic pathology and dysregulation of neuroendocrine factors that mediate the sleep/wake cycle have been reported in HD, as early as the premanifest stage. It is not known however if hypothalamic pathology precedes neuroendocrine dysregulation. Identification of mechanisms underpinning sleep and circadian rhythm disturbances will enable the development of therapeutic strategies aimed at mitigating sleep and circadian rhythm anomalies. To date, no therapies exist to combat pathological changes in sleep architecture and circadian rhythm.

Evidence from mouse models of HD shows that the circadian rhythm and sleep-wake cycle are amenable to environmental interventions, including exercise, bright light therapy and temporally scheduled feeding. Furthermore, previous studies in HD of multidisciplinary rehabilitation- a construct of exercise and cognitive training, along with social interaction have been shown to increase grey matter volume in the caudate tail and dorsolateral prefrontal cortex in manifest HD, with accompanying improvements in verbal learning and memory. It is postulated that this intervention paradigm could also improve sleep outcomes in HD. Studies in Parkinson’s disease have shown that multidisciplinary rehabilitation improves sleep quality, however, the effects of multidisciplinary rehabilitation on circadian rhythm and sleep outcomes have not yet been investigated in HD and particularly not in premanifest HD when the effects of intervention would be most beneficial.

Aims: The initial aim of this thesis was to determine, through a review of the literature, the potential neurobiological mechanisms associated with circadian rhythm and sleep disturbances in individuals with premanifest HD. This was used to inform the next study, which was to determine whether hypothalamic pathology was associated with circadian rhythm and habitual sleep disturbances in individuals with premanifest HD. The next aim was to then determine if nine-months of multidisciplinary rehabilitation could impact on circadian rhythm and habitual sleep outcomes and associated hypothalamic volume in individuals with premanifest HD. The aim of the final study was to explore the effects of a nine-month multidisciplinary rehabilitation program on sleep architecture in individuals with premanifest HD.

Methods: For the study presented in Chapter 3 (aim 2), 32 individuals with premanifest HD and 29 healthy age- and gender-matched controls underwent magnetic resonance imaging scans to evaluate hypothalamic volume. Circadian rhythm and habitual sleep were assessed via measurement of morning and evening cortisol and melatonin levels, wrist-worn actigraphy, the Consensus Sleep Diary and sleep questionnaires. Information on mood, physical activity levels and body composition were also collected.

In the study presented in Chapter 4 (aim 3) 18 individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group) and were compared to a community sample of 11 individuals with premanifest HD receiving standard care (control group). Hypothalamic volume, blood-based BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns and stress, anxiety and depression symptomatology were all evaluated prior to and following the intervention. Sixteen of these individuals also underwent polysomnography and sleep-dependent memory consolidation prior to and following the ninemonth intervention to assess sleep architecture and sleep-dependent memory consolidation (Chapters 4 and 5).

Results: Here in Chapter 2, a review of the literature revealed the hypothalamus as a potential modulator of circadian rhythm and sleep disturbances in HD. Chapter 3 shows that hypothalamic grey matter volume in premanifest HD individuals is reduced compared to ageand gender-matched healthy controls. We also observed reduced sleep quality and an increased number of awakenings in premanifest HD individuals compared to healthy controls. Contrary to expectation, there were no strong associations between sleep outcomes and hypothalamic volume. There were, however, differences in the associations between hypothalamic volume and neuroendocrine factors in premanifest HD individuals compared to healthy controls.

Following nine months of multidisciplinary rehabilitation, a reduced rate of loss of grey matter volume in the hypothalamus was observed in the premanifest HD intervention group compared to the premanifest HD standard care group (Chapter 4). This was accompanied by a maintenance of brain-derived neurotrophic factor (BDNF) levels in the intervention compared to the control group. No robust changes were observed in the release of circadian-regulated hormones or in habitual sleep outcomes; however, exploratory data revealed changes in sleep architecture, particularly in REM percentage and latency, following the nine-month intervention (Chapter 5).

Conclusion: Data presented in this thesis suggests that, although hypothalamic volume is reduced in individuals with premanifest HD, circadian rhythm is maintained, perhaps via neural compensation. Moreover, we provide, for the first time, preliminary data suggesting that multidisciplinary rehabilitation is useful in reducing the loss of volume of the hypothalamus and, while no robust effects on circadian rhythm were observed, improvements in sleep architecture were observed in individuals with premanifest HD. Further randomised controlled studies in a larger cohort of individuals with premanifest and manifest HD are required to confirm and extend on these preliminary findings

Available for download on Thursday, December 16, 2021

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