Date of Award

2015

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical Sciences

Faculty

Health, Engineering and Science

First Advisor

Professor Melanie Ziman

Second Advisor

Professor Roger Barker

Abstract

Background

Huntington’s disease (HD) is a chronic neurodegenerative disorder characterised by a progressive loss of cognitive function, motor control and psychiatric features. Individuals also display a variety of systemic features. Progressive neuronal dysfunction and neuronal cell death are thought to underlie the onset and progression of many clinical features of HD.

Despite scientific progress, there is still no cure or disease modifying therapy for HD, and available pharmaceutical agents only provide partial relief of motor and psychiatric features. An emerging body of evidence indicates that lifestyle enrichment may delay the onset and progression of clinical features, and exert favourable effects on neuropathological aspects of HD. Few studies have evaluated the effects of lifestyle enrichment strategies like multidisciplinary rehabilitation on the clinical features of HD. Moreover, no study has evaluated the effects of multidisciplinary rehabilitation on neuropathological aspects of HD.

Aims

The initial aim of this thesis was to determine factors that contribute to features of the disease that negatively impact on activities of daily living such as mobility and balance (Chapter 2), and to identify, using a literature review, a rehabilitation strategy that could positively impact on these features of HD (Chapter 3). These studies informed our ultimate aim which was to investigate the clinical utility of multidisciplinary rehabilitation on clinical and neuropathological features of HD (Chapters 4, 5 and 6)

Methods

In study 1 (Chapter 2), 22 participants were assessed using a battery of balance, mobility, cognitive tests, assessments of muscle strength and body composition measures. Data was

. then statistically examined using stepwise linear regression to identify factors that contribute to balance and mobility impairments in individuals with manifest HD. In study 2 (Chapter 3), a systematic search of journal databases was made from inception to July 2014 for studies reporting on resistance exercise in patients with neurodegenerative disorders. Selected studies were abstracted and critically appraised using a quality control checklist.

For the intervention studies, (3 and 4 Chapters 4 and 5), 20 participants with manifest HD were randomly assigned to either a control or training group. Individuals randomised to the intervention group were provided with a nine month multidisciplinary intervention comprising once weekly supervised clinical exercise, thrice weekly home based exercise and fortnightly occupational therapy, while those randomised to the control group were asked to continue with their standard care and daily activities. Participants were assessed using motor, cognitive, psychological, body composition and quality of life measures at baseline and at the completion of the intervention. In study 5 (Chapter 6), 15 participants with manifest HD were assessed using magnetic resonance imaging and a battery of cognitive assessments after nine months of multidisciplinary rehabilitation to see whether such a therapy is capable of inducing favourable changes in brain structure and cognitive function.

Results

The main factors that contribute to mobility and balance impairments in patients with manifest HD were found to be lower limb muscle weakness and a loss of cognitive function (Study 1). Systematic evaluation of the effects of resistance exercise for neurodegenerative disorders showed that it is beneficial for multiple sclerosis and Parkinson’s disease. In particular, improvements in muscle strength, mobility, balance, clinical disease progression, fatigue, functional capacity, quality of life, disease biology, electromyography activity, mood, skeletal muscle volume and architecture were reported in individuals with multiple sclerosis or Parkinson’s disease (PD) after resistance exercise. The most robust effects of resistance exercise were found for muscle strength outcomes, and were more pronounced in individuals with PD (Study 2).

The multidisciplinary rehabilitation intervention studies conducted as part of this thesis significantly improved isometric and isokinetic muscle strength, self-perceived balance, body mass, lean tissue mass and fat mass in patients with HD (Studies 3 and 4). Moreover, multidisciplinary rehabilitation also increased grey matter (GM) volume in the caudate nucleus and dorsolateral prefrontal cortex of patients. The significant increases in GM volume were accompanied by, and correlated to, a significant improvement in performance in verbal learning and memory.

Conclusions

The work presented here shows that lower extremity muscle weakness and a loss of cognitive function significantly contribute to impairments in mobility and balance. This work also shows that strength training has favourable effects on motor function, including strength, mobility and balance, as well as other clinical features in similar neurodegenerative disorders, and thus should be integrated into multidisciplinary rehabilitation interventions for HD. In addition, this study provides evidence that multidisciplinary rehabilitation can significantly improve aspects of motor control, cognitive function and body composition. Finally we show, for the first time, that multidisciplinary rehabilitation can increase GM volume in structures known to degenerate in HD, and that such increases are functionally related to changes in verbal learning and memory. Future work is urgently required to confirm and expand on these exciting findings, particularly with respect to the neurorestorative properties of multidisciplinary rehabilitation.

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