Dopamine and cognition in Huntington's disease
Research type
Research Study
Full title
Investigation of the neural and cognitive effects of dopamine manipulation in Huntington’s disease patients and healthy controls
IRAS ID
224309
Contact name
Roger Barker
Contact email
Sponsor organisation
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Huntington’s disease (HD) is a neurodegenerative disorder which affects levels of the neurotransmitter dopamine (DA). In the early stages of HD, DA levels are increased and this leads to involuntary movements.
HD patients also display a decline in cognitive function beginning in the premanifest period and progressing throughout the course of the disease. Patients exhibit deficits in processes such as attention, memory and planning, mediated by the frontal lobe and the striatum (Arnaldi et al 2012). As dopamine regulates normal cognition in these brain areas, it is possible that the cognitive deficits seen in HD are related to the aberrant levels of DA.
HD is normally treated with medication which reduces the levels of DA in the brain, in order to alleviate the motor symptoms. However, it is likely that this medication also has an impact on cognition but this has never been formally assessed. To investigate this possibility, we have recently administered a one- off dose of sulpiride, a drug which decreases dopamine and which is used in the treatment of HD, to HD patients and healthy controls. Ninety minutes later, participants performed a battery of fronto- striatal based cognitive tasks. When compared to placebo, sulpiride significantly improved the performance of HD patients in the cognitive tasks (Schwab et al unpublished data).
Background: HD patients exhibit an early profile of cognitive dysfunction that is consistent with disruption of their corticostriatal circuitry. This area of the brain is under the control of the mesocorticolimbic dopamine system that acts to modulate cognitive processes in the healthy brain via an “inverted U” shaped function - too much or too little dopamine impairs function. Dopaminergic abnormalities in the CNS have been described in HD and linked to the motor features of the condition but its role in HD related cognitive decline is unknown. This question forms the basis of our proposal.
Design: 40 patients (20 pre-HD & 20 early HD) and 40 matched controls will undergo four fMRI scans. At each scan an acute dose of either placebo, sulpiride (D2 receptor antagonist), bromocriptine (D1/D2 receptor agonist) or the combined administration of sulpiride and bromocriptine will be randomly administered. The co-administration design will elucidate the specific role of the D1 and D2 receptors in any imaging changes. Specifically, if the effects are mediated by the D2 receptors any individual effect of either bromocriptine or sulpiride relative to placebo should be abolished by co-administration of both drugs.
Functional connectivity in the brain will be measured at rest (rs-fMRI) and during cognitive tasks (Tower of London, set-shifting) and anatomical connectivity will be measured using diffusion tensor imaging (DTI).
Aim: To investigate whether: (1) neural response to dopaminergic drugs differs in HD gene carriers compared to controls; (2) this relates to cognitive performance; (3) this is mediated by disease stage and/or individual differences in anatomical structure and connectivity and finally; (4) these effects are receptor specific.
Impact: This study will provide the necessary data to design and power a formal clinical trial to look at the long-term efficacy of using dopaminergic therapies to improve cognitive performance in early HD.
REC name
South Central - Oxford B Research Ethics Committee
REC reference
18/SC/0259
Date of REC Opinion
31 May 2018
REC opinion
Further Information Favourable Opinion