Title: Bridging the gap between memory decline and medication in Parkinson’s disease.
Funder: Department of Health (England)

Abstract: PD is a degenerative brain disease, marked by motor symptoms such as tremor, slowed movement, difficulty initiating voluntary movements7,8,61. These abnormalities are linked to dopamine depletion in the mesofrontal-striatal system8. Different classes of drug target the dopamine system with the aim of boosting dopamine production and activity in this circuit, thereby remediating the motor problems Slow-release second-generation dopamine agonists are associated with a significantly reduced risk for motor complications (dyskinesias), their symptomatic effects do not depend on the presence of dopamine producing cells9-11,61. For these reasons, switching from one agonist to another, and combining agonists together has become common practice in the treatment of mild and moderate PD12,61. A lesser-known symptom of PD is memory decline13-21, the origins of which maybe linked to dopamine depletion in frontal-memory systems of the brain17,22. It's assumed, therefore, that the same drugs that control motor symptoms will also remediate PD-dependent memory decline18. In the first pilot to explore this assumption18, we examined episodic memory in the same (24) patients on 2 separate occasions, when medicated (90mins after taking medication) and unmedicated (following a 12hour over-night period of medication withdrawl and before they had taken their next day’s medication). We predicted improved performance when patients were medicated compared to unmedicated. However, we found the opposite effect. Furthermore, our data suggested the drug-dependent memory decline was caused by slow-release dopamine agonists, with the effect most pronounced for patients on pramipexole compared to ropinirole. This finding is consistent with feedback from patients and carers who report poorer memory on agonists compared to other antiparkinsonian drugs. The pilot was a simple observational study of 24 patients where memory was examined ON and OFF prescribed medication. There was no randomisation to a set of treatment groups; it was open-label with researchers knowing which drug each patients was taking at the time of data collection. And so, whilst the pilot is important in implicating a relationship between agonists and memory decline, the possibility remains that individual differences, including clinical heterogenity between patients may have contributed to our findings. This feasibility study is needed prior to going straight into a randomised clinical trial for the following reasons: we need to: (i) replicate pilot data suggesting that agonists impair memory in PD using a more rigorous design, that employs randomisation and larger patients numbers; (ii) use the data from the feasibility study to determine within-group effects and variance of the drug-treatments, response rates, drop-out rates to inform a power-calculation; (iii) additional to testing, explore barriers to participation with patient-participants and carers/spouses using a semi-structured interview. These findings are important, because they suggest that a better understanding of drug-effects on memory in PD will provide clinicians with an evidence-base to make decisions about which agonists to prescribe to particular patient subgroups (maybe at different disease stages, and/or incombination with other drugs) providing maximal control over motor symptoms but minimise memory side-effects. The next step towards achieving this goal is to conduct a feasibility study. Assuming we meet the aim and objectives, a fully powered RCT will follow bringing tangible benefits to patient management within 5years. There is also the potential for individual patients to benefit from their participation in this feasibility study by providing them with the opportunity to try out different a different agonist, which may suit them better in relation to offering good control of motor symptoms whilst having a lesser impact on memory. The decision about which agonist patients are maintained on after completing the study will take place during the end-of-study clinical assessment.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH;NEUROLOGICAL