PHysical Activity and Exercise Outcomes in Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disease causing dysfunction and death of medium spiny striatal projection neurons and thus disruption of corticostriatal pathways with resultant impairment of cognition, motor function, and behaviour. These impairments result in decreasing independence in activities of daily living and quality of life even from relatively early in the disease. The potential to develop interventions to facilitate independent living and strategies to manage symptoms is crucial to managing both the personal and economic effects of this devastating disease. Although to date there are no successful pharmacological interventions that are able to slow disease progression, there is now clear emerging evidence of disease specific motor function and general health benefits of shorter exercise in HD. Although it has been possible to successfully deliver exercise and behaviour change interventions in HD over the shorter term, there is now a need to conduct studies that actively facilitate exercise adherence over a longer term (e.g. one year) to realistically begin to assess the impact of physical activity and structured exercise on disease progression. Therapeutic exercise interventions present an exciting, transformative area of research in neurodegenerative diseases. Addressing motor impairments in neurodegeneration may provide a long-term beneficial effect in delaying disease progression and maximizing functional abilities over a longer period. Loss of independent mobility and care dependency have been shown to be important predictors of nursing home admissions. The potential to develop interventions that facilitate independent living and strategies to manage symptoms is crucial to managing both the personal and economic effects of this devastating disease. Although to date there are no successful pharmacological or other interventions that are able to slow disease progression, there is some suggestion that lifestyle factors, such as activity level and education alongside specific motor training may help to drive compensatory neural networks, that may in turn compensate for the failing brain, and change the course of the disease. Studies to date in HD have relied on retrospective data, and robust evaluation of lifestyle factors contributing to disease progression is needed. If shown to be effective, exercise programs have the potential to be used in combination with disease-modifying drugs, cell replacement therapy or genetic manipulations, when available, to maximize the functional benefits of these interventions by facilitating adaptive neuroplasticity. The investigators have set out to systematically evaluate the feasibility of exercise and physical activity interventions in people with HD using a two-pronged approach. The first approach evaluated the feasibility of short-term aerobic and strengthening exercise programs in HD. This led to the recently completed study funded by the Gossweiler Foundation, Exert-HD, a 3-month randomized controlled trial of aerobic (performed between 60-85% age predicted heart rate max) and strengthening exercise. Participants in the exercise group demonstrated significantly improved predicted VO2 max and Unified Huntington Disease Rating Scale (UHDRS) modified Motor Scores (mMS), but no effect was seen on cognition or other measures of motor function.This study had high retention and adherence, and was well tolerated by participants. Alongside this, there was the development and evaluation of the feasibility of a behavioural change intervention to increase levels of physical activity (Engage-HD; ISRCTN65378754). The intervention aimed to evaluate the efficacy of a physical activity intervention (6 sessions over 14 weeks) utilizing a workbook-based behavioural change program compared to a social contact control. This study demonstrated improvements in self-reported physical activity, self-efficacy for exercise, and cognition, however no changes were noted for HD-specific motor function. In PACE-HD the investigators seek to address three issues that naturally arise from the preliminary studies completed to date. First, there has been no evaluation of long-term (e.g. 12 month) aerobic and strengthening exercise interventions in HD. While studies to date have demonstrated improvements in motor and cognitive function in the short term, it is unclear whether exercise behaviour can be maintained over a longer term, and to what degree any improvements in cognition or motor function can be maintained or enhanced with a longer term intervention. Second, there is a lack of understanding of the role of physical activity in disease progression in HD. Preliminary work has utilized 7 day activity monitors that have improved functionality to obtain more detailed data on physical activity behavior, including light and moderate- vigorous physical activity, sedentary behavior and sleep patterns over the intervention period. In this trial, the investigators will utilize 7 day activity monitors to evaluate activity patterns longitudinally over a year period in a cohort of 120 people with HD. This longitudinal evaluation alongside standardized evaluations of motor, cognitive and functional abilities will aid in validation of wearable activity devices and evaluate how physical fitness and physical activity may be related to disease progression. Third, there is lack of understanding of the mechanisms by which exercise may achieve its effect in HD. Trials of longer term exercise interventions are difficult to deliver, not least in terms of the complexity of the intervention but also due to the challenges in accurately characterising the different dimensions of real-life physical activity and understanding individual response to exercise. Our preliminary research has shown that exercise has the potential to improve aerobic fitness using measurements of estimated (predicted) VO2max. This trial will incorporate longitudinal assessment of VO2max, a surrogate measure of fitness and a direct measure of oxygen uptake that is related to central nervous system (CNS) function and structure.

Time frame: Baseline, 6 months (RCT only), 12 months