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The Role of Serotonergic and Dopaminergic Mechanisms and Their IMPERIAL COLLEGE LONDON DEPARTMENT of MEDICINE DIVISION of BRAIN SCIENCES The role of serotonergic and dopaminergic mechanisms and their interaction in levodopa–induced dyskinesias A thesis submitted for the degree of Doctor of Philosophy Andreas–Antonios Roussakis 1 Table of contents Page Abstract……………………………………………………………………..………….. 6 Declaration of originality and Preface……………….……………………………… 8 Copyright declaration……………………………………………..………………….. 9 Acknowledgements……………………………………………………….................... 10 Statement of contribution…………………………………………………………….. 11 Peer–reviewed publications contributing to this thesis ……………………........... 13 Overview of Chapters………………………………………………………………… 16 List of tables……………………………………………………………………………. 18 List of figures and graphs…………………………………………………………….. 19 List of boxes……………………………………….………………………………….... 20 Glossary of abbreviated terms………………………………….………………......... 21 Chapter 1 – Introduction……………………………………………………………... 24 1.1 Parkinson’s disease – A brief overview…………………….…………………… 25 1.2 Neuropathological features of Parkinson’s disease……………………………. 26 1.3 Diagnosis of Parkinson’s disease………………………………………………… 27 1.4 Motor and non–motor symptoms …………………………………………......... 28 1.5 Pharmacotherapy in Parkinson’s disease……………………………………….. 31 1.6 Common side effects related to dopaminergic agents………………………… 32 1.7 Levodopa–induced dyskinesias: phenomenology …………….………………. 33 1.8 An overview of available ant–dyskinetic treatments…………………….......... 35 1.8.1 Continuous intestinal levodopa infusion…………………………………. 36 1.8.2 Surgical treatment of dyskinesia…………………………………………... 37 1.8.3 Amantadine………………………………………………………………….. 38 1.9 Understanding dyskinesia pathophysiology…………………………………... 39 1.9.1 An overview of neurotransmission and neurotransmitter transporters………….………………………………………………………. 39 1.9.2 Dopamine and levodopa………………………………………………….... 42 1.9.3 Dopamine transporter (DAT)….…………………………………………... 46 1.9.4 Serotonin transporter (SERT)………………………………………………. 47 1.9.5 Preclinical and clinical studies…………………………………………….. 48 1.10 Rationale ………………………………………………………………………….. 54 1.11 Aims of the studies conducted for this thesis ………………..……………….. 55 Chapter 2 – Methodology……………………………………………………………. 56 2.1 Ethical approval………………………………………………………………........ 58 2.2 Screening of potential participants and subject recruitment…….……………. 58 2.3 Clinical data………………………………………………………………………... 60 2.3.1 Evaluation of motor symptoms………………………………..…………... 60 2.3.2 Calculation of disease duration…………………………………………… 60 2.3.3 Calculation of levodopa equivalent doses..……………………….……… 60 2.3.4 Evaluation of LIDs………………….………………….…..………………... 61 2 2.3.5 Evaluation of depression………………………..…………….……………. 61 2.3.6 Evaluation of cognitive impairment…………….…………..…………….. 61 2.4 Principles of brain PET and SPECT technology and kinetic modelling …….. 62 2.4.1 Principles from in vitro binding studies…………………………………… 67 2.4.2 Binding Potential…………………………………………………………….. 69 2.4.3 Compartmental modelling for in vivo binding studies………………….. 70 2.4.4 Principles of radioligand kinetic properties for in vivo binding………... 71 2.4.5 Principles from clinical pharmacology……………………………………. 74 2.4.6 Modified Binding Potential………………………………………………… 74 2.4.7 Reference tissue compartmental model…………………………………… 75 2.4.7.1 Three compartment model (two tissue compartment) – kinetics... 76 2.4.7.2 Two compartment model (single tissue compartment) – kinetics.. 77 2.4.7.3 The reference tissue model – kinetics………………………………. 78 2.4.8 Simplified reference tissue model…………………………………………. 80 2.4.9 Determination of specific binding using the Simplified Reference Tissue Model………………………………………………………………... 81 2.4.10 Determination of specific binding using the Peak Equilibrium Model. 84 2.5 Molecular PET and SPECT targets in Parkinson’s disease………….………… 86 2.5.1 123I–Ioflupane………………………………………………………………... 88 2.5.2 11C–DASB………………….…………………………………………………. 91 2.5.3 11C–PE2I………………………………………………………………………. 93 2.6 Tomography scanners…………………………………………………………….. 94 2.7 Supply of radioligands……..……………………………………………………... 95 2.8 Scanning procedures…………………………………………………………........ 96 2.8.1 PET scanning procedures…………………………………………………... 96 2.8.2 SPECT scanning procedures……………………………………………….. 97 2.8.3 MRI scanning procedures…………………….…………………………….. 97 2.9 Analysis of imaging data…………………………………………………………. 98 2.9.1 Image registration (or image fusion, matching or warping)……………. 98 2.9.2 Definitions of ROIs………………………………………………………….. 99 2.9.3 Analysis of 11C–DASB PET data acquired on Siemens ECAT Exact HR PET tomography scanner………………………………………………. 102 2.9.4 Analysis of 123I–Ioflupane SPECT imaging data……………………......... 104 2.9.5 Analysis of 11C–DASB and 11C–PE2I PET imaging data acquired on Siemens Biograph TruePoint HI-REZ 6 PET/CT tomography scanner……………………………………………………………………........ 108 2.9.6 Calculation of SERT–to–DAT binding ratios …………..…………............ 110 2.10 Statistical analyses……….…………………………………………………......... 111 Chapter 3 – Retrospective analysis of DAT terminals’ availability in the 113 striatum of de novo Parkinson’s disease patients: relevance to dyskinesias…. 3.1 Introduction………………………………………………………………………... 114 3.2 Aim and hypothesis……………………………………………………………….. 114 3.3 Methods…………………………………………………………………………….. 114 3.3.1 Participants…………………………………………………………………... 114 3.3.2 Clinical assessments……………………………………………………........ 115 3 3.3.3 Imaging procedures…………………………………………………………. 115 3.3.4 123I–Ioflupane SPECT imaging data analysis……………………………... 116 3.3.5 Statistical analyses…………………………………………………………... 116 3.4 Results…………………………………………………………………………….... 116 3.4.1 Clinical data………………………………………………………………….. 116 3.4.2 Imaging data……………………………………………………………........ 118 3.5 Summary of findings…………………………………………………………........ 120 Chapter 4 – Changes over time in striatal DAT availability in relation to the development of dyskinesias………………………………………………………… 122 4.1 Introduction………………………………………………………………………... 123 4.2 Aim and hypothesis………………………………………………………………. 123 4.3 Methods………………………………………………………………………........ 124 4.3.1 Participants………………………………………………………………….. 124 4.3.2 Clinical assessments……………………………………………………........ 124 4.3.3 Imaging procedures…………………………………………………………. 125 4.3.4 123I–Ioflupane SPECT imaging data analysis…………………………….. 125 4.3.5 Statistical analyses………………………………………………………….. 125 4.4 Results……………………………………………………………………………... 126 4.4.1 Clinical data…………………………………………………………………. 126 4.4.2 Imaging data………………………………………………………………… 128 4.5 Summary of findings……………………………………………………………… 132 Chapter 5 – Striatal SERT–to–DAT binding ratios in Parkinson’s disease: relevance to LIDs………………………………………………. 134 5.1 Introduction………………………………………………………………………. 135 5.2 Aim and hypothesis…………………………………………………………….. 136 5.3 Methods………………………………………………………………………........ 136 5.3.1 Participants………………………………………………………………….. 136 5.3.2 Clinical assessments……………………………………………………....... 137 5.3.3 Imaging procedures…………………………………………………………. 138 5.3.4 11C–DASB PET imaging data analysis…………………………………….. 138 5.3.5 123I–Ioflupane SPECT imaging data analysis…………………………….. 138 5.3.6 SERT–to–DAT binding ratios……………………………………………… 138 5.3.7 Statistical analyses…………………………………………………………... 138 5.4 Results……………………………………………………………………………… 139 5.4.1 Clinical data…………………………………………………………………. 139 5.4.2 Imaging data………………………………………………………………… 141 5.4.3 Correlations………………………………………………………………….. 146 5.5 Summary of findings……………………………………………………………… 148 Chapter 6 – Striatal SERT–to–DAT binding ratios in Parkinson’s disease in relation to LIDs: a longitudinal study……………………………………………. 150 6.1 Introduction………………………………………………………………………. 151 6.2 Aims and hypotheses………………………………………………………......... 151 4 6.3 Methods……………………………………………………………………………. 152 6.3.1 Participants………………………………………………………………….. 152 6.3.2 Clinical assessments………………………………………………………… 152 6.3.3 Imaging procedures………………………………………………………… 153 6.3.4 PET imaging data analysis………………………………………………… 153 6.3.5 Calculation of SERT–to–DAT binding ratios...………………………….. 153 6.3.6 Statistical analyses………………………………………………………….. 153 6.4 Results……………………………………………………………………………… 154 Cross–sectional study 6.4.1 Clinical and Imaging data…………………………………………………. 154 6.4.2 Correlations………………………………………………………………….. 159 Longitudinal study 6.4.3 Clinical and Imaging data………………………………………………….. 161 6.5 Summary of findings……………………………………………………………… 164 Chapter 7 – Discussion on findings, limitations, clinical relevance and future 166 plans……..……………………………………………………………………... 7.1 Discussion on findings…………………..……………………………………….. 167 7.2 Limitations…………………………………………………………………………. 180 7.3 Clinical relevance and future plans……………………………………………… 187 Funding………………………………………………………………………………… 191 Bibliography…………………………………………………………………………... 192 Appendices……………………………………………………………………………. 219 Appendix I……………………………………………………………………………... 219 Appendix II………………………………………………………………………......... 220 Appendix III……………………………………………………………………………. 228 Appendix IV…………………………………………………………………………… 229 Appendix V…………………………………………………………………………….. 230 Appendix VI…………………………………………………………………………… 231 Appendix VII………………………………………………………………………….. 232 Appendix VIII…………………………………………………………………………. 235 Appendix IX.………………………………….……………………………………….. 238 5 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
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