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.

Inclusion Criteria:

- Diagnosis of HD, confirmed by genetic testing

- Above the age of 18

- A participant (current or newly enrolled) in the Enroll-HD study

- Up to and including stage 2 disease status (TFC 7-13)

Exclusion Criteria:

- Diagnosis of juvenile onset HD

- History of co-morbid neurological conditions such as multiple sclerosis or stroke

- Acute orthopaedic conditions (within a month) e.g. ankle sprain or fracture

- Inability or unwillingness of participant or legal guardian to give written informed
consent