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The role of serotonergic and dopaminergic mechanisms and their interaction in Levodopa-induced dyskinesias

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Title: The role of serotonergic and dopaminergic mechanisms and their interaction in Levodopa-induced dyskinesias
Authors: Roussakis, Andreas Antonios
Item Type: Thesis or dissertation
Abstract: Long–term levodopa treatment in Parkinson’s disease (PD) is commonly associated with troublesome levodopa–induced dyskinesias (LIDs). Striatal serotonergic terminals amid the degenerating dopaminergic ones are proposed to play an important role in LIDs by taking up exogenous levodopa and releasing dopamine in an unregulated fashion. However, to date, the underlying mechanisms of LIDs are not fully understood. By using single photon emission computed tomography (SPECT) with 123I–Ioflupane and positron emission tomography (PET) with 11C–DASB and 11C–PE2I, the clinical studies conducted for this thesis aimed (a) to estimate the role of striatal dopamine transporter (DAT) availability in early PD as a prognostic marker for LIDs, (b) to explore whether striatal DAT availability changes over time are related to the appearance of LIDs, (c) to estimate the role of striatal serotonin-to-dopamine transporter (SERT–to–DAT) binding ratios to LIDs, and (d) to look for a relation between the changes in striatal SERT, DAT and SERT–to–DAT binding ratios over time and the appearance of LIDs. The main findings are as follows: (a) in early PD, striatal DAT availability alone does not predict the appearance of future LIDs, (b) at later stages, the occurrence of LIDs may be dependent on the magnitude of DAT decline in the putamen, (c) the SERT–to–DAT binding ratio in the putamen is increased in PD patients as compared to controls, and within PD, it is higher in patients with LIDs as compared to nondyskinetic patients, (d) as PD continues to progress, putaminal serotonergic terminals remain relatively unchanged in comparison to the dopaminergic ones and the aforementioned imbalance (as reflected by the binding ratio) increases over time. These findings provide fundamental insight in the pathophysiology of LIDs and have direct implications for further research towards novel therapeutics in PD dyskinesia.
Content Version: Open Access
Issue Date: Jan-2018
Date Awarded: Jun-2018
URI: http://hdl.handle.net/10044/1/75512
DOI: https://doi.org/10.25560/75512
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence.
Supervisor: Piccini, Paola
Funder's Grant Number: WMCN_P36587
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses