Parkinson s Disease: Deep Brain Stimulation and FDOPA-PET

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1 Parkinson s Disease: Deep Brain Stimulation and FDOPA-PET

2 The work described in this thesis was performed at the Department of Neurology, University Medical Center, Groningen (the Netherlands). A.T. Portman ISBN: Print: Stichting Drukkerij C. Regenboog, Groningen. Cover: Lauwersoog (2004). Lyrics: Senses working overtime by Andy Partridge (1982). The studies of this thesis were financially supported by the Stichting Internationaal Parkinson Fonds (Hoofddorp, the Netherlands). Publication of this thesis was financially supported by: Ziekenhuis Refaja (Stadskanaal), Boehringer Ingelheim bv, Medtronic, Roche Nederland B.V., Biogen Idec International, Novartis Pharma B.V., TEVA Pharma B.V., UCB Pharma, GlaxoSmithKline B.V., Sanofi-Aventis and Ipsen Farmaceutica.

3 Rijksuniversiteit Groningen Parkinson s Disease: Deep Brain Stimulation and FDOPA-PET Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 2 november 2005 om uur door Axel Tiddo Portman geboren op 30 januari 1965 te Groningen

4 Promotores: Copromotor: Prof. dr. K. L. Leenders Prof. dr. M. J. Staal Dr. T. van Laar Beoordelingscommissie: Prof. dr. R. A. C. Roos Prof. dr. J. H. A. de Keyser Prof. dr. J. J. A. Mooij

5 And all the world is football-shaped it s just for me to kick in space And I can see, hear, smell, touch, taste and I ve got one, two, three, four, five Senses working overtime trying to take this all in

6

7 Contents Preface and outline of the thesis 1 Chapter 1 General introduction and aims of the thesis 3 Chapter 2 Study design and patient population 33 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chronic stimulation of the subthalamic nucleus increases daily on-time without dyskinesia in advanced Parkinson s Disease 37 Striatal FDOPA uptake and cognition in advanced non-demented Parkinson s Disease: a clinical and FDOPA-PET study 51 Disease progression continues in patients with advanced Parkinson s Disease and effective subthalamic nucleus stimulation 65 Presurgical FDOPA-PET and motor outcome of subthalamic nucleus stimulation in Parkinson s Disease 81 Chapter 7 Summary and conclusions 93 Chapter 8 Samenvatting en conclusies 97 Appendices 101 Dankwoord 109 Curriculum Vitae 113

8

9 Preface and outline of the thesis Parkinson s Disease (PD) is a common neurodegenerative disorder of unknown etiology, characterised by a progressive loss of dopaminergic and other neurons in the mesencephalon. In addition to the classical treatment strategies in PD, which are mainly focussed on motor symptom control, a major therapeutic aim nowadays is halting the disease process itself. In recent years advances in the understanding of the cause and pathogenesis of PD have permitted the rational selection of putative neuroprotective drugs for study in PD. However, thus far study results have been disappointing. The introduction of Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) in the late 1990s offered long-term motor benefit for PD patients with advanced disease. Clinical, experimental and pathophysiological considerations gave rise to expectations that DBS of the STN might even offer a novel neuroprotective approach in PD. The clinical introduction of bilateral STN-DBS in our hospital in 1999 brought the possibility to start a study on disease progression in STN stimulated PD patients, and to investigate the relationship between striatal dopaminergic activity and clinical responses of PD patients to DBS. In this study nigrostriatal dopaminergic integrity was monitored by Positron Emission Tomography (PET) using the ligand FDOPA. All clinical and PET study data in this thesis were collected between 1999 and In Chapter 1 the reader is provided with the current knowledge on etiology, pathophysiology, and treatment options in PD. The pivotal role of the STN and the potential of STN-DBS to attenuate dopaminergic cell decline in PD are emphasised. In Chapter 2 we present the employed study design and recruitment of study population in the University Medical Center Groningen. Chapter 3 shows the results of STN-DBS on motor function in advanced PD, while Chapter 4 presents data on the nature of the relationship between striatal dopamine depletion and cognitive function in PD. Chapter 5 shows the results of a prospective two-center study on disease progression after successful STN-DBS in PD, and in Chapter 6 the predictive value of the nigrostriatal dopaminergic status on the efficacy of STN-DBS in advanced PD is discussed. Finally, in Chapters 7 and 8 all study results are reviewed and summarised, and the conclusions of this thesis are stated. 1

10 Preface and outline of the thesis In 1817 James Parkinson wrote his, by now, famous Essay on the Shaking Palsy, but he already debuted scientifically in the field of medicine 30 years earlier. On February 4 th 1787 he read a paper at the meeting of the Medical Society in London, concerning the effects of lightning on the physical health of men. Nowadays it may seem that Parkinson reached full circle realising that he himself was also interested in the striking effect of electric stimulation of the brain. 2

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