Shepherd, Thomas Andrew (2016) Exploring the effect of dopaminergic medication on recognition memory in idiopathic Parkinson’s disease: Trials and Challenges. Doctoral thesis, Keele University.

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Abstract

Parkinson’s disease (PD) is caused by the degeneration of dopaminergic cells in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain. Until recently, PD research predominantly focused on motor symptoms which are synonymous with the condition. Along with the acknowledgment that PD is no longer considered a ‘motor disorder’, there has been a significant increase in research designed to increase the understating of the nature, origins and management of a range of nonmotor symptoms, which can accompany a PD diagnosis.

Investigations into a frequently reported memory decline in PD, have largely neglected to account for the influence of dopamine replacement therapies on such decline and specifically, the impact of second generation, non-ergot derived, D2 agonists, ropinirole and pramipexole have yet to be explored.

In a between groups comparison, 2 clinically matched subgroups of PD patients, 1 medicated with ropinirole and the other with pramipexole were administered a test of recognition memory, familiarly and recollection on two separate occasions, once in a medicated state and once after a period of withdrawal. Results revealed that when in a medicated state, the PD subgroup medicated with pramipexole exhibited a significantly poorer recollection performance than the subgroup medicated with ropinirole. Furthermore, recollection significantly improved in the subgroup medicated with pramipexole when tested after a period of withdrawal, whilst ropinirole had no effect on memory performance. These findings suggested for the first time that pramipexole may induce a recollection impairment in PD. However, with the between groups methodology employed in this study, 3 possible scenarios remain as potential explanations of these findings; a PD phenotype, characterized by a memory decline, for which pramipexole is a only a
maker based on its effectiveness in alleviating tremor and depressive symptoms; an drug effect, the high binding affinity that pramipexole has for d3 subreceptors, prevalent in the hippocampus, disrupts hippocampally dependent episodic memory processes, whereas ropinirole does not by virtue of a broad spectrum binding affinity for d2/d3/d4 subreceptors; a phenotype*drug interaction, a synthesis of the other 2 scenarios, where a PPX phenotype has a memory deficit which is particularly vulnerable to further impairment induced by pramipexole.

To investigate these findings further, a fully powered, randomised controlled, crossover trial is required, whereby a PD cohort usually medicated with either ropinirole or pramipexole are combined and subsequently tested on each drug. A pilot trial was conducted to show how analysis could investigate the 3 scenarios described above, to obtain recollection estimates for a power calculation and to validate a battery of neuropsychological assessments to inform the design of a fully powered trial. Furthermore, recall measures were used and their relationship with recollection assessed to identify a clinically accessible test that could be administered in a clinical environment that is simpler and quicker to complete than a recollection assessment based on the remember/know paradigm.

Throughout the duration of the pilot trial, recruitment was a major challenge. To explore this, eligible PD patients who declined to participate - and their caregivers - were interviewed to explore their perceived barriers to participation in clinical trials. A thematic analysis revealed four themes (switching medication, trial accessibility, fear of the unknown and caregiver workload) and several sub themes which represent decliner’s primary concerns.

The findings presented in this thesis, contribute to current understanding of how memory is affected in PD, not just by the disease pathology but by dopamine replacement therapies. Findings have implications for dopaminergic modulation of hippocampal processes literature. Potential mechanisms for the dopaminergic disruption of glutamatergic and cholinergic modulation of hippocampal processes and the adequacy of the dopamine overdose model in accounting for acute dopamine therapies and the clinical management of PD are discussed. Furthermore, a number of recommendations are made to reduce perceived barriers to recruitment when designing and managing drug trials, not just with PD patients, but other clinical populations.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Natural Sciences > School of Psychology
Depositing User: Lisa Bailey
Date Deposited: 01 Dec 2016 09:28
Last Modified: 01 Dec 2016 09:28
URI: http://eprints.keele.ac.uk/id/eprint/2558

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