Decision-making in Huntington's Disease

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion mutation in the huntingtin gene. Gene carriers are currently diagnosed with manifest HD when a movement disorder becomes apparent although such problems are often preceded by cognitive and psychiatric features which can impair decision-making (DM). Given the nature of living with a progressive, genetic disease, the consequences of decisions made by HD gene carriers can be particularly impactful at all stages of the condition.

A decision requires individuals to perceive and process information, estimate likelihoods, to evaluate options, reflect on past choices and select actions. Decision science spans many disciplines, from psychology to neuroscience and economics, which has generated a contemporary theory to explain DM as a rational-intuitive dual-process. People have an extraordinary ability to use logic and rationality to make complex choices as well as an efficient intuitive strategy to make decisions when cognitive costs are high and time is limited. To date, the rational-intuitive metaphor has not been applied to understand decision making problems in HD, neither in theory nor in practice.

This thesis presents a number of clinical studies in which some aspects of the rational-intuitive theory of DM is investigated in HD, followed by two studies where interventions based on this theory are tested.

I first explored the wider literature to learn about the neuroscience of DM, its neurobiological overlap with HD, how it has been studied previously and what conclusions have been made in HD. This highlighted gaps in our knowledge, particularly on the low-level perceptual and high-level reflective processes that are involved in DM in HD patients. I have shown that perceptual DM is impaired in premanifest individuals, and this gets worse in manifest patients (compared to controls) but there are no differences in metacognition.

I next sought to dissect DM from a rational-intuitive perspective. There was no suitable task to do this across patient and control populations so I built and tested a new cognitive task that could be carefully controlled in an experimental setup. I went on to test this in a larger cohort to characterise choice deliberation and consistency across the adult lifespan. I show that the use of choice attributes declines gradually with age, choice consistency is maintained and possibly enhanced with age, and intuitive processing, while unpredictable and inconsistent, is also maintained across the lifespan.

I show in a subsequent study that patients with HD and Parkinson’s disease do not display differences to controls in DM in my task, and instead it is again increasing age, not disease status, that confers a gradual decline in the use of choice attributes, while intuitive processing is unaffected by both age and disease.

Finally, I investigated two mechanisms to support rational DM in HD patients and older adults. First, a pharmacological study of acute dopaminergic and noradrenergic medication effects on rational processing. Second, I designed and co-built a smartphone application called Triage to help users recognise important emails and letters, and to highlight key terms requiring decisions in the text.

In summary, these investigations suggest that there are perceptual DM impairments in HD but not in metacognition or aspects of rational processing. Instead, increasing age alone is associated with reduced rational DM. Using these findings as a platform, it is possible to build interventions to support continued cognitive function and autonomy in patients with HD and healthy older adults with applications to other chronic neurodegenerative disorders.