1. The Epidemiology of Parkinson’s disease Samuel M. Goldman, MD, MPH Parkinson’s Institute Sunnyvale, California, USA The Epidemiology of Parkinson’s disease Samuel M. Goldman, MD, MPH Parkinson’s Institute Sunnyvale, California, USA

2. Parkinson’s disease: overview  Progressive neurodegenerative disease of aging  Depicted in ancient texts: Maimonides, others  Described fully by James Parkinson in 1817  1-2% > age 60 affected  Unknown cause  Clinical syndrome with well-defined pathology  Progressive neurodegenerative disease of aging  Depicted in ancient texts: Maimonides, others  Described fully by James Parkinson in 1817  1-2% > age 60 affected  Unknown cause  Clinical syndrome with well-defined pathology

3. Parkinsonism: A Clinical Syndrome Cogwheel rigidity Cogwheel rigidity Postural reflex impairment Postural reflex impairment Cogwheel rigidity Cogwheel rigidity Postural reflex impairment Postural reflex impairment Akinesia/Bradykinesia Resting tremor

4. Parkinson’s disease pathology: loss of pigmented neurons

5. Parkinson’s disease pathology: Lewy Body

6. What Causes PD? Is the disease inherited? OR Is it due to something in the environment? Is it due to something in the environment?

7. The Great Genetics vs. Environment Debate “...paralysis agitans is not a family disease” Charcot, 1877 “Many patients with the disease have a strong family history ….” Gowers, 1888 “Many patients with the disease have a strong family history ….” Gowers, 1888 “...paralysis agitans is not a family disease” Charcot, 1877 “Many patients with the disease have a strong family history ….” Gowers, 1888 “Many patients with the disease have a strong family history ….” Gowers, 1888

8. This debate was brought into sharp focus in the closing decades of the 20 th Century by two discoveries

10. MPTP – Induced Parkinsonism Cardinal signs of PD L-dopa benefit Progressive in some BUT BBB Complex I Mitochondrion DopamineTransporter Substantia Nigra DA Neuron Similar to Parkinson’s Disease Acute onset No Lewy bodies

11. Alpha synuclein mutation (chromosome 4q) PARK 1 (Polymeropoulos et al, 1996)  Autosomal dominant  Rare:  < 70 cases in 6 families  none in "sporadic" PD  Some atypical features   -synuclein identified as major component of Lewy Body  Autosomal dominant  Rare:  < 70 cases in 6 families  none in "sporadic" PD  Some atypical features   -synuclein identified as major component of Lewy Body

12. Environment vs. Genetics  1980s: Discovery of MPTP focused tremendous attention on environmental causes  1990s: Renaissance of interest in genetics of Parkinson’s disease with the discovery of mono- genetic forms of parkinsonism  In the 2000s:  More environmental associations; better animal models  Several genetic forms of parkinsonism identified  1980s: Discovery of MPTP focused tremendous attention on environmental causes  1990s: Renaissance of interest in genetics of Parkinson’s disease with the discovery of mono- genetic forms of parkinsonism  In the 2000s:  More environmental associations; better animal models  Several genetic forms of parkinsonism identified

13. EpidemiologyEpidemiology The study of the distribution and determinants of diseases in populations

14. Epidemiologic Methods  Descriptive epidemiology: “Who has disease?”  Prevalence and Incidence studies  Generate hypotheses  Disease patterns may provide clues to causes  Analytic epidemiology: “Why do they have disease?  Case-control: “retrospective” design  Cohort studies: prospective design  Test hypotheses, attempt to find causal associations  Descriptive epidemiology: “Who has disease?”  Prevalence and Incidence studies  Generate hypotheses  Disease patterns may provide clues to causes  Analytic epidemiology: “Why do they have disease?  Case-control: “retrospective” design  Cohort studies: prospective design  Test hypotheses, attempt to find causal associations

15. Challenges in studying Parkinson’s disease  No diagnostic test  Late life disorder  Long pre-clinical period  Exposure may occur years before symptoms  Affected may die before symptomatic  No diagnostic test  Late life disorder  Long pre-clinical period  Exposure may occur years before symptoms  Affected may die before symptomatic

16. Part 1: Descriptive Epidemiology Distribution of disease

17. Incidence of Parkinson’s Disease (unadjusted for age) Location Incidence/ 100,000/yr Publication Yonago, Japan 10 (Harada et al, 1983) Ferrara, Italy 10 (Granieri et al, 1991) Rochester, Minn., USA 10.8 (Bower et al, 1999) Hawaii, USA (Japanese men) 11.1 (Morens et al, 1996) N.California, USA (HMO) 13.4 (Van Den Eeden, 2003) New York City (multi-ethnic) 13.0 (Mayeux et al, 1995) Finland17.2 (Kuopio et al, 1999)

18. Age

19. Ethnicity-specific PD Incidence Kaiser Study, 2003 Age- and Gender-Adjusted Incidence, per 100,000

20. Descriptive Epidemiology: What We Know  PD occurs everywhere in the world  95% of cases begin over age 50  Incidence increases with age at least through the 9 th decade  Men more frequently affected than women  Risk may be related to ethnicity or geography  Unclear if incidence is increasing over time  PD occurs everywhere in the world  95% of cases begin over age 50  Incidence increases with age at least through the 9 th decade  Men more frequently affected than women  Risk may be related to ethnicity or geography  Unclear if incidence is increasing over time

21. Part 2: Analytic Epidemiology Searching for the Cause in the ENVIRONMENT

22. Association  Causation Are you sure about this? It seems odd that a pointy head and long beak is what makes birds fly.

23. Smoking is Protective  > 50 studies find inverse association of smoking and PD; only 5 report no association  Risk ratios ~ 0.5 in prospective, retrospective, and twin study designs  Dose-response: ~ 20% risk reduction/10 pack-years smoked  > 50 studies find inverse association of smoking and PD; only 5 report no association  Risk ratios ~ 0.5 in prospective, retrospective, and twin study designs  Dose-response: ~ 20% risk reduction/10 pack-years smoked

24. 1 1 1023 Relative risks from case control and cohort studies of smoking and PD * Relative risks * Hernan et al, Ann Neurol 2002; 52:276-284

25. Smoking and PD: Hypotheses  Nicotine neuroprotective in several animal models  Upregulation of hepatic detoxifying enzymes  MAO inhibition  Other compounds in smoke?  Nicotine neuroprotective in several animal models  Upregulation of hepatic detoxifying enzymes  MAO inhibition  Other compounds in smoke?

26. Occupations associated with increased risk of PD in case-control studies  Agriculture work  Pesticides?  Rural residence?  Well water?  Other?  Teaching and Healthcare  Infection?  Pre-morbid personality?  Agriculture work  Pesticides?  Rural residence?  Well water?  Other?  Teaching and Healthcare  Infection?  Pre-morbid personality?

27. Pesticides and PD Risk  Pesticide use at work or home associated with PD in >20 case-control studies in US, Europe, Asia  However, specific compounds are rarely associated  Pesticide use at work or home associated with PD in >20 case-control studies in US, Europe, Asia  However, specific compounds are rarely associated

28. Pesticides &PD  Paraquat: Prevalent case-control study, Taiwan  Dieldrin: In brains of PD cases, not AD or controls  Organochlorine pesticides:  Prevalent case-control study, Germany  Higher levels in PD substantia nigra than AD, LBD, control  DDE (DDT metabolite) in Inuit, Greenland  Dithiocarbamates: Prevalent case-control study, Alberta, Canada  Paraquat: Prevalent case-control study, Taiwan  Dieldrin: In brains of PD cases, not AD or controls  Organochlorine pesticides:  Prevalent case-control study, Germany  Higher levels in PD substantia nigra than AD, LBD, control  DDE (DDT metabolite) in Inuit, Greenland  Dithiocarbamates: Prevalent case-control study, Alberta, Canada

29. Pesticides & PD: Hypotheses  Mitochondrial Complex 1 inhibition  Rotenone animal model  Oxidative Stress/Redox cycling  Paraquat animal model  Potentiation of  -synuclein fibrillization  Proteosomal inhibition  Mitochondrial Complex 1 inhibition  Rotenone animal model  Oxidative Stress/Redox cycling  Paraquat animal model  Potentiation of  -synuclein fibrillization  Proteosomal inhibition

30. Is the increased risk of Parkinson’s disease associated with farming or rural residence due to pesticide exposure?

31. An Alternative Hypothesis  Nocardia asteroides (LeWitt, Beaman et al)  Animal model with nigral neural loss: rodents, primates  L-dopa responsive movement disorder  ? L-forms  Streptomycetes species (McNaught et al)  Animal model: rodents (still being characterized)  Proteasome inhibitors  Others?  BMAA (  -N-methylamino-L-alanine) from cyanobacteria  Nocardia asteroides (LeWitt, Beaman et al)  Animal model with nigral neural loss: rodents, primates  L-dopa responsive movement disorder  ? L-forms  Streptomycetes species (McNaught et al)  Animal model: rodents (still being characterized)  Proteasome inhibitors  Others?  BMAA (  -N-methylamino-L-alanine) from cyanobacteria Could the increased risk be due to a common soil pathogen?

32. Environmental Pollutants & PD risk  Persistent organic pollutants  PD risk increased in Greenland Inuits with traditional diets (Wermuth 2004)  PCB congeners elevated in PD brain (Corrigan 1998)  Solvents  Trichloroethylene case reports, rodent model (Guehl, 1999)  Acute/subacute parkinsonism case reports  Long term exposure case-control study (McDonnell, 2003)  Persistent organic pollutants  PD risk increased in Greenland Inuits with traditional diets (Wermuth 2004)  PCB congeners elevated in PD brain (Corrigan 1998)  Solvents  Trichloroethylene case reports, rodent model (Guehl, 1999)  Acute/subacute parkinsonism case reports  Long term exposure case-control study (McDonnell, 2003)

33. Metals & PD  Hypotheses  oxidative stress, Fenton reaction  promote  -synuclein aggregation (Yamin, 2003)  Epidemiologic Support  dysregulated iron metabolism in PD (Dexter, 1992)  dietary iron in case-control study (Powers, 2003)  occupational exposure to copper, lead (Gorell, 2004; Kuhn 1998)  ? PD more prevalent near iron & copper industries (Rybicki, 1993)  Hypotheses  oxidative stress, Fenton reaction  promote  -synuclein aggregation (Yamin, 2003)  Epidemiologic Support  dysregulated iron metabolism in PD (Dexter, 1992)  dietary iron in case-control study (Powers, 2003)  occupational exposure to copper, lead (Gorell, 2004; Kuhn 1998)  ? PD more prevalent near iron & copper industries (Rybicki, 1993)

34. Diet and PD Risk Increased risk associated with higher intake of:  Dairy products: Environmental pollutants?  Animal fat: Oxidative stress; environmental pollutants?  Tetraisoquinolines (TIQs) Decreased risk associated with higher intake of: Decreased risk associated with higher intake of:  Coffee or Caffeine  Dose-response gradient  Effect magnitude similar to that of smoking  Nuts & legumes  Niacin Increased risk associated with higher intake of:  Dairy products: Environmental pollutants?  Animal fat: Oxidative stress; environmental pollutants?  Tetraisoquinolines (TIQs) Decreased risk associated with higher intake of: Decreased risk associated with higher intake of:  Coffee or Caffeine  Dose-response gradient  Effect magnitude similar to that of smoking  Nuts & legumes  Niacin

35. Part 3 Genetic Epidemiology of Parkinson’s disease

36. Genes linked to familial PD LocusProteinInheritLB Frequency & Possible Mechanism PARK1  -Synuclein AD+ Rare. Missense or genomic duplication. Protein aggregation. PARK2ParkinAR- 25 - 50% of young onset cases (< 40). Ubiquitin-protein ligase loss of function. PARK5UCH-L1AD? Rare. Ubiquitin-proteosome loss of fxn. Some polymorphisms may be protective. PARK6PINK1AR? Rare. Mitochondrial kinase loss of fxn. May  proteosomal vulnerability. PARK7DJ-1AR? Mutant protein misfolds, may sensitize mitochondria to oxidative stressors. PARK8LRRK2AD+/- Common? Penetrance? Typical onset age. Quite variable clincally; synuclein/ tau pathology. Toxic gain of fxn.

37. Family Studies of PD Risk

38. Twin Studies  Compare concordance for PD in mono- zygotic (MZ) vs. dizygotic (DZ) twin pairs  Higher concordance among MZ pairs supports a genetic cause  Similar rates of concordance argues against a major genetic etiologic role  Compare concordance for PD in mono- zygotic (MZ) vs. dizygotic (DZ) twin pairs  Higher concordance among MZ pairs supports a genetic cause  Similar rates of concordance argues against a major genetic etiologic role

39. NAS WW II Twins Cohort: Tanner et al, 1999  16,000 white male twin pairs born 1917-1927  Two-stage screening with in-home exams  Concordance in MZ and DZ pairs was similar when PD onset > 50  However, when PD onset < 50, MZ concordance was 6-fold higher  Suggests genetic basis for young-onset disease, environmental basis for typical-onset  16,000 white male twin pairs born 1917-1927  Two-stage screening with in-home exams  Concordance in MZ and DZ pairs was similar when PD onset > 50  However, when PD onset < 50, MZ concordance was 6-fold higher  Suggests genetic basis for young-onset disease, environmental basis for typical-onset

40. Part 4 Genes AND Environment?

41. Exposure of the brain to environmental toxins is controlled by enzymes and transporters in lung, intestine, liver, kidney and blood brain barrier. Circulation MDR1 Toxicant CYP2D6 OCT2 MDR1 MRP1,2 GST NAT MDR1 OCT1 MRP2

42. ConclusionsConclusions  Parkinson’s disease and monogenic or toxicant- induced parkinsonism likely have common pathogenic mechanisms  Typical disease is likely due to the interaction of multiple environmental and genetic risk factors  Specific causes may be different in different individuals  Collaboration of epidemiologists, clinicians and laboratory scientists is critical  Parkinson’s disease and monogenic or toxicant- induced parkinsonism likely have common pathogenic mechanisms  Typical disease is likely due to the interaction of multiple environmental and genetic risk factors  Specific causes may be different in different individuals  Collaboration of epidemiologists, clinicians and laboratory scientists is critical

43. AcknowledgementsAcknowledgements Parkinson’s Institute Caroline Tanner Bill Langston Dino Di Monte Kathleen Comyns Monica Korell Cheryl Meng Anjali Gupta Grace Bhudikanok Sauda Yerabati NIEHS Jane Hoppin Freya Kamel Parkinson’s Institute Caroline Tanner Bill Langston Dino Di Monte Kathleen Comyns Monica Korell Cheryl Meng Anjali Gupta Grace Bhudikanok Sauda Yerabati NIEHS Jane Hoppin Freya Kamel Stanford University Lorene M. Nelson Neil Risch Pacific Health Research Institute Web Ross Kaiser Permanente Stephen Van Den Eeden UCSF Patricia Quinlan Sarah Jewell