^.,-wtM IC REGlSTRAh )0M 261 ^ER3!TY OF LONDON :«VATE HOUSE ‘LET STREET ' ’“IN WC1E7KU THE ROLE OF WELL WATER AND OTHER FACTORS IN THE AETIOLOGY OF PARKINSON’S DISEASE YOAV BEN-SHLOMO A thesis submitted for the degree of Doctor of Philosophy University College London, 2003 1 UMI Number: U602452 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U602452 Published by ProQuest LLC 2014. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Objectives: To determine the risk of early onset Parkinson’s disease (PD) associated with well water consumption and other risk factors. Design: A case control study with strata matching by age group, gender and current urban or rural residence. Setting: Republic of Ireland, between 1993 to 1995. Participants: Cases with Parkinson’s disease, fulfilling at least two of the four cardinal features, with date of birth from 1st January 1926 and disease onset before 56 years. Controls were selected using stratified random sampling from the electoral register. Outcome measures: Odds ratio and 95% confidence interval for well water consumption and other risk factors. Results: Increased risk was associated with well water consumption (odds ratio per 20 years exposure 1.33, 95% Cl 1.00 to 1.77), family history of PD (odds ratio 2.15, 95% Cl 1.09 to 4.27), and serious head injury (odds ratio 3.08, 95% Cl 1.66 to 5.71). Decreased risk was associated with childhood contact with a dog (odds ratio 0.44, 0.25 to 0.78), recall of chicken pox (odds ratio 0.51, 95% Cl 0.32 to 0.83), smoking status (odds ratio for 30 or more pack years for smokers 0.19, 95% Cl 0.07 to 0.57), exposure to insecticides (odds ratio 0.44, 95% Cl 0.25 to 0.77), glue (odds ratio 0.52, 95% Cl 0.29 to 0.93), paints (odds ratio 0.37, 95% Cl 0.22 to 0.60) and cumulative socioeconomic position (odds ratio for a point reduction in socioeconomic position 0.74,95% Cl 0.61 to 0.90). Conclusions: These results have identified a wide range of exposures from childhood to adulthood that may influence the risk of PD across the life course. Because of potential biases, it is important that these results are replicated in other designs such as occupational or population based cohort studies. 2 Acknowledgements This study was funded by a grant from the Wellcome Trust. Yoav Ben-Shlomo was funded by a Wellcome Fellowship in Clinical Epidemiology. Part of the literature review has already appeared as a published paper (Ben-Shlomo Y. "How far are we in understanding the cause of Parkinson's disease?" Journal of Neurology, Neurosurgery and Psychiatry 1996; 61: 4-16). I would mainly like to thank my wife for putting up with the prolonged separation whilst carrying out the fieldwork in Ireland and all the usual aggravations of doing a PhD. I would also like to thank the following for their help; Prof. Michael Marmot as my supervisor and Wellcome sponsor, Prof. George Davey Smith for his support, enthusiasm and drinking sessions, Prof. Stephen Frankel for encouragement and a free meal, Dr. Paul McKeigue for his clear thoughts and ideas, Shane Allwright for both professional and personal support and making it possible for me to be based at Trinity College, Prof. Tom O'Dowd for his help and encouragement and Prof. Brendan Whelan from the Economic and Social Research Institute for help with ascertaining control subjects. My thanks also go out to Finola Finnan, Fiona O'Reilly and Patricia McCrink for their hard work in helping to interview subjects and data processing. Deirdre Handy provided superlative clerical support and always made sure we got to where we should have been at the right time. In addition, I would like to thank staff members in the Department of Community Health for their friendship and encouragement, and in particular the late Prof. Petr Skrabanek who challenged my views on epidemiology with limited success. Finally I would like to thank all the consultant neurologists, the Parkinson's Disease Society of Ireland and subjects who agreed to take part in the study. Whilst I was driving my way around 15,000 miles of Irish roads I came across the following comment in the Irish Times. Whilst providing no empirical data I can provide qualitative support for its validity. "... the Mercedes-Benz company has been driving a fleet o f 22 cars on the roads o f the West ofIreland and Connemara to “test their mettle Groups o f experts and motoring journalists were flown from all over the world. The car's drivers say that the roads were chosen because they were “interesting or unusual or simply bad ” the newspaper stated. ” 3 Statement of authorship I declare that the work in this thesis was carried out in accordance with the regulations for University College London. The work is original and has not been submitted for any other higher degree. I was involved with the conception, design, management of the study as well as data collection, analysis and writing up. Any views expressed in the thesis are those of the author and do not represent those of the University. Signed Date 4 TABLE OF CONTENTS 1. INTRODUCTION............................................................................................ 13 2. BACKGROUND TO THE EPIDEMIOLOGY OF PARKINSON’S DISEASE..................................................................................................................15 2.1 Clinical diagnosis of Parkinson’s disease ........................................................15 2.2 Validity of diagnostic criteria ......................... .............................................. 17 2.3 The preclinical phase of PD: what does it tell us aboutenvironmental factors?.......................................................................................................................22 2.4 The role of genes interacting with environmental factors ...............................27 2.4.1 Twin, family and migrant studies ....................................................................27 2.4.2 Genetic polymorphisms ..................................................................................31 2.4.3 Gene environment interactions ........................................................................32 3. DESCRIPTIVE EPIDEMIOLOGY OF PARKINSON’S DISEASE...........34 3.1 Geographical patterns..................................................................................... 34 3.2 Temporal patterns ...........................................................................................40 3.2.1 Mortality rates ............................................................................................... 40 3.2.2 Prevalence rates .............................................................................................46 3.2.3 Incidence rates .............................................................................................. 49 3.3 Sociodemographic factors............................................................................... 51 3.3.1 Age...............................................................................................................51 3.3.2 Sex...............................................................................................................52 3.3.3 Socioeconomic position and occupation ...........................................................53 3.3.4 Ethnicity ........................................................................................................59 4. ANALYTICAL EPIDEMIOLOGY OF PARKINSON’S DISEASE ............61 4.1 Type of neighbourhood ...................................................................................61 4.1.1 Rural versus urban residence .......................................................................... 61 4.1.2 Well water.....................................................................................................66 4.2 Neurotoxins .....................................................................................................70 4.2.1 Herbicides & Pesticides ..................................................................................71 4.2.1.1 Case control studies ....................................................................................71 4.2.1.2 Cohort studies ............................................................................................76 4.2.2 Metals and solvents ........................................................................................77 4.2.3 Residence near industrial areas ....................................................................... 79 5 4.2.4 General Anaesthesia ...................................................................................... 79 4.3 Infectious exposures ....................................................................................... 80 4.3.1 Seroepidemiology..........................................................................................81 4.3.2 Self-reported history of infection .....................................................................81 4.3.3 Contact with animals ....................................................................................