The Epidemiology of The Epidemiology of Parkinson’s diseaseParkinson’s disease

Samuel M. Goldman, MD, MPHSamuel M. Goldman, MD, MPH

Parkinson’s InstituteParkinson’s Institute

Sunnyvale, California, USASunnyvale, California, USA

The Epidemiology of The Epidemiology of Parkinson’s diseaseParkinson’s disease

Samuel M. Goldman, MD, MPHSamuel M. Goldman, MD, MPH

Parkinson’s InstituteParkinson’s Institute

Sunnyvale, California, USASunnyvale, California, USA

Parkinson’s disease: overviewParkinson’s disease: overviewParkinson’s disease: overviewParkinson’s disease: overview

Progressive neurodegenerative disease of agingProgressive neurodegenerative disease of aging

Depicted in ancient texts: Maimonides, othersDepicted in ancient texts: Maimonides, others

Described fully by James Parkinson in 1817Described fully by James Parkinson in 1817

1-2% > age 60 affected1-2% > age 60 affected

Unknown causeUnknown cause

Clinical syndrome with well-defined pathology Clinical syndrome with well-defined pathology

Progressive neurodegenerative disease of agingProgressive neurodegenerative disease of aging

Depicted in ancient texts: Maimonides, othersDepicted in ancient texts: Maimonides, others

Described fully by James Parkinson in 1817Described fully by James Parkinson in 1817

1-2% > age 60 affected1-2% > age 60 affected

Unknown causeUnknown cause

Clinical syndrome with well-defined pathology Clinical syndrome with well-defined pathology

Parkinsonism:Parkinsonism:

A Clinical SyndromeA Clinical Syndrome Parkinsonism:Parkinsonism:

A Clinical SyndromeA Clinical Syndrome • Cogwheel rigidityCogwheel rigidity

• Postural reflex impairmentPostural reflex impairment

• Cogwheel rigidityCogwheel rigidity

• Postural reflex impairmentPostural reflex impairment

• Akinesia/Bradykinesia• Akinesia/Bradykinesia

• Resting tremor• Resting tremor

Parkinson’s disease pathology: Parkinson’s disease pathology: loss of pigmented neuronsloss of pigmented neurons

Parkinson’s disease pathology: Parkinson’s disease pathology: loss of pigmented neuronsloss of pigmented neurons

Parkinson’s disease pathology: Parkinson’s disease pathology: Lewy BodyLewy Body

Parkinson’s disease pathology: Parkinson’s disease pathology: Lewy BodyLewy Body

What Causes PD?What Causes PD?What Causes PD?What Causes PD?

Is the disease inherited?Is the disease inherited?Is the disease inherited?Is the disease inherited?

OROR

Is it due to something in the

environment?

Is it due to something in the

environment?

The Great Genetics vs. The Great Genetics vs. Environment DebateEnvironment Debate

The Great Genetics vs. The Great Genetics vs. Environment DebateEnvironment Debate

““...paralysis agitans is not a family disease” ...paralysis agitans is not a family disease” Charcot, 1877Charcot, 1877

“ “Many patients with the disease have a strong Many patients with the disease have a strong family history ….”family history ….”

Gowers, 1888Gowers, 1888

““...paralysis agitans is not a family disease” ...paralysis agitans is not a family disease” Charcot, 1877Charcot, 1877

“ “Many patients with the disease have a strong Many patients with the disease have a strong family history ….”family history ….”

Gowers, 1888Gowers, 1888

This debate was brought This debate was brought into sharp focus in the into sharp focus in the

closing decades of the 20closing decades of the 20thth Century by two discoveriesCentury by two discoveries

This debate was brought This debate was brought into sharp focus in the into sharp focus in the

closing decades of the 20closing decades of the 20thth Century by two discoveriesCentury by two discoveries

MPTP – Induced Parkinsonism

•Cardinal signs of PD•L-dopa benefit•Progressive in some

BUT

BBB

Complex IComplex I

Mitochondrion

DopamineDopamineTransporterTransporter

Substantia Nigra DA Neuron

Similar to Parkinson’s Disease

•Acute onset•No Lewy bodies

Alpha synuclein mutation (chromosome 4q)Alpha synuclein mutation (chromosome 4q)PARK 1 PARK 1 (Polymeropoulos et al, 1996) (Polymeropoulos et al, 1996)

Autosomal dominantAutosomal dominant

Rare: Rare: < 70 cases in 6 families < 70 cases in 6 families

none in "sporadic" PD none in "sporadic" PD

Some atypical featuresSome atypical features

-synuclein identified as major component -synuclein identified as major component of Lewy Bodyof Lewy Body

Autosomal dominantAutosomal dominant

Rare: Rare: < 70 cases in 6 families < 70 cases in 6 families

none in "sporadic" PD none in "sporadic" PD

Some atypical featuresSome atypical features

-synuclein identified as major component -synuclein identified as major component of Lewy Bodyof Lewy Body

Environment vs. GeneticsEnvironment vs. GeneticsEnvironment vs. GeneticsEnvironment vs. Genetics

1980s1980s: Discovery of MPTP focused tremendous : Discovery of MPTP focused tremendous attention on attention on environmental causesenvironmental causes

1990s1990s: Renaissance of interest in genetics of : Renaissance of interest in genetics of Parkinson’s disease with the discovery of Parkinson’s disease with the discovery of mono-mono-genetic formsgenetic forms of parkinsonism of parkinsonism

In the 2000sIn the 2000s: : More More environmentalenvironmental associations; better associations; better animal modelsanimal models

Several Several genetic formsgenetic forms of parkinsonism identified of parkinsonism identified

1980s1980s: Discovery of MPTP focused tremendous : Discovery of MPTP focused tremendous attention on attention on environmental causesenvironmental causes

1990s1990s: Renaissance of interest in genetics of : Renaissance of interest in genetics of Parkinson’s disease with the discovery of Parkinson’s disease with the discovery of mono-mono-genetic formsgenetic forms of parkinsonism of parkinsonism

In the 2000sIn the 2000s: : More More environmentalenvironmental associations; better associations; better animal modelsanimal models

Several Several genetic formsgenetic forms of parkinsonism identified of parkinsonism identified

EpidemiologyEpidemiologyEpidemiologyEpidemiology

The study of the distribution The study of the distribution and determinants of and determinants of

diseases in populationsdiseases in populations

The study of the distribution The study of the distribution and determinants of and determinants of

diseases in populationsdiseases in populations

Epidemiologic MethodsEpidemiologic MethodsEpidemiologic MethodsEpidemiologic MethodsDescriptive epidemiology: Descriptive epidemiology: “Who has disease?”“Who has disease?”

Prevalence and Incidence studiesPrevalence and Incidence studies

GenerateGenerate hypotheses hypotheses

Disease patterns may provide clues to causesDisease patterns may provide clues to causes

Analytic epidemiology: Analytic epidemiology: “Why do they have “Why do they have disease?disease?Case-control: “retrospective” designCase-control: “retrospective” design

Cohort studies: prospective designCohort studies: prospective design

TestTest hypotheses, attempt to find causal associations hypotheses, attempt to find causal associations

Descriptive epidemiology: Descriptive epidemiology: “Who has disease?”“Who has disease?”Prevalence and Incidence studiesPrevalence and Incidence studies

GenerateGenerate hypotheses hypotheses

Disease patterns may provide clues to causesDisease patterns may provide clues to causes

Analytic epidemiology: Analytic epidemiology: “Why do they have “Why do they have disease?disease?Case-control: “retrospective” designCase-control: “retrospective” design

Cohort studies: prospective designCohort studies: prospective design

TestTest hypotheses, attempt to find causal associations hypotheses, attempt to find causal associations

Challenges in studying Challenges in studying Parkinson’s diseaseParkinson’s disease

Challenges in studying Challenges in studying Parkinson’s diseaseParkinson’s disease

No diagnostic testNo diagnostic test

Late life disorderLate life disorder

Long pre-clinical periodLong pre-clinical periodExposure may occur years before symptomsExposure may occur years before symptoms

Affected may die before symptomaticAffected may die before symptomatic

No diagnostic testNo diagnostic test

Late life disorderLate life disorder

Long pre-clinical periodLong pre-clinical periodExposure may occur years before symptomsExposure may occur years before symptoms

Affected may die before symptomaticAffected may die before symptomatic

Part 1:Part 1:Descriptive EpidemiologyDescriptive Epidemiology

Part 1:Part 1:Descriptive EpidemiologyDescriptive Epidemiology

Distribution of diseaseDistribution of diseaseDistribution of diseaseDistribution of disease

Incidence of Parkinson’s Disease Incidence of Parkinson’s Disease (unadjusted for age)(unadjusted for age)

Incidence of Parkinson’s Disease Incidence of Parkinson’s Disease (unadjusted for age)(unadjusted for age)

LocationLocation

Incidence/ Incidence/ 100,000/yr100,000/yr Publication Publication

Yonago, JapanYonago, Japan 1010 (Harada et al, 1983)(Harada et al, 1983)

Ferrara, ItalyFerrara, Italy 1010 (Granieri et al, 1991)(Granieri et al, 1991)

Rochester, Minn., USARochester, Minn., USA 10.810.8 (Bower et al, 1999(Bower et al, 1999))

Hawaii, USA (Japanese men)Hawaii, USA (Japanese men) 11.111.1 (Morens et al, 1996)(Morens et al, 1996)

N.California, USA (HMO)N.California, USA (HMO) 13.413.4 (Van Den Eeden, 2003)(Van Den Eeden, 2003)

New York City (multi-ethnic)New York City (multi-ethnic) 13.013.0 (Mayeux et al, 1995)(Mayeux et al, 1995)

FinlandFinland 17.217.2 (Kuopio et al, 1999)(Kuopio et al, 1999)

Age-Specific PD Incidence Kaiser STUDY, 2003 (n = 442)

0

20

40

60

80

100

120

140

160

180

200

30-39 40-49 50-59 60-69 70-79 80+

PD

Inci

den

ce p

er 1

00,0

00

Male Female

Age

Ethnicity-specific PD IncidenceEthnicity-specific PD IncidenceKaiser Study, 2003Kaiser Study, 2003

Ethnicity-specific PD IncidenceEthnicity-specific PD IncidenceKaiser Study, 2003Kaiser Study, 2003

0

24

6

810

12

1416

18

Hispanic non-HispanicWhite

Asian Black

0

24

6

810

12

1416

18

Hispanic non-HispanicWhite

Asian Black

Age- and Gender-Adjusted Incidence, per 100,000

Descriptive Epidemiology:Descriptive Epidemiology:What We Know What We Know

Descriptive Epidemiology:Descriptive Epidemiology:What We Know What We Know

PD occurs everywhere in the worldPD occurs everywhere in the world

95% of cases begin over age 5095% of cases begin over age 50

Incidence increases with age at least through Incidence increases with age at least through the 9the 9thth decade decade

Men more frequently affected than womenMen more frequently affected than women

Risk may be related to ethnicity or geographyRisk may be related to ethnicity or geography

Unclear if incidence is increasing over timeUnclear if incidence is increasing over time

PD occurs everywhere in the worldPD occurs everywhere in the world

95% of cases begin over age 5095% of cases begin over age 50

Incidence increases with age at least through Incidence increases with age at least through the 9the 9thth decade decade

Men more frequently affected than womenMen more frequently affected than women

Risk may be related to ethnicity or geographyRisk may be related to ethnicity or geography

Unclear if incidence is increasing over timeUnclear if incidence is increasing over time

Part 2:Part 2:Analytic EpidemiologyAnalytic Epidemiology

Part 2:Part 2:Analytic EpidemiologyAnalytic Epidemiology

Searching for the Cause Searching for the Cause in the in the ENVIRONMENTENVIRONMENT

Searching for the Cause Searching for the Cause in the in the ENVIRONMENTENVIRONMENT

Association Causation

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

Smoking is ProtectiveSmoking is ProtectiveSmoking is ProtectiveSmoking is Protective

> 50 studies find inverse association of > 50 studies find inverse association of smoking and PD; only 5 report no smoking and PD; only 5 report no associationassociation

Risk ratios ~ 0.5 in prospective, Risk ratios ~ 0.5 in prospective, retrospective, and twin study designsretrospective, and twin study designs

Dose-response: ~ 20% risk reduction/10 Dose-response: ~ 20% risk reduction/10 pack-years smokedpack-years smoked

> 50 studies find inverse association of > 50 studies find inverse association of smoking and PD; only 5 report no smoking and PD; only 5 report no associationassociation

Risk ratios ~ 0.5 in prospective, Risk ratios ~ 0.5 in prospective, retrospective, and twin study designsretrospective, and twin study designs

Dose-response: ~ 20% risk reduction/10 Dose-response: ~ 20% risk reduction/10 pack-years smokedpack-years smoked

•1

•1

10 2 3

Relative risks from case control and cohort studies of smoking and PD *

Relative risks

* Hernan et al, Ann Neurol 2002; 52:276-284

Smoking and PD: HypothesesSmoking and PD: HypothesesSmoking and PD: HypothesesSmoking and PD: Hypotheses

Nicotine neuroprotective in several Nicotine neuroprotective in several animal modelsanimal models

Upregulation of hepatic detoxifying Upregulation of hepatic detoxifying enzymesenzymes

MAO inhibitionMAO inhibition

Other compounds in smoke?Other compounds in smoke?

Nicotine neuroprotective in several Nicotine neuroprotective in several animal modelsanimal models

Upregulation of hepatic detoxifying Upregulation of hepatic detoxifying enzymesenzymes

MAO inhibitionMAO inhibition

Other compounds in smoke?Other compounds in smoke?

Occupations associated with increased Occupations associated with increased risk of PD in case-control studiesrisk of PD in case-control studies

Occupations associated with increased Occupations associated with increased risk of PD in case-control studiesrisk of PD in case-control studies

Agriculture workAgriculture workPesticides?Pesticides?Rural residence?Rural residence?Well water?Well water?Other?Other?

Teaching and HealthcareTeaching and HealthcareInfection?Infection?Pre-morbid personality?Pre-morbid personality?

Agriculture workAgriculture workPesticides?Pesticides?Rural residence?Rural residence?Well water?Well water?Other?Other?

Teaching and HealthcareTeaching and HealthcareInfection?Infection?Pre-morbid personality?Pre-morbid personality?

Pesticides and PD RiskPesticides and PD Risk

Pesticide use at work or Pesticide use at work or home associated with home associated with PD in >20 case-control PD in >20 case-control studies in US, Europe, studies in US, Europe, AsiaAsia

However, specific However, specific compounds are rarely compounds are rarely associatedassociated

Pesticide use at work or Pesticide use at work or home associated with home associated with PD in >20 case-control PD in >20 case-control studies in US, Europe, studies in US, Europe, AsiaAsia

However, specific However, specific compounds are rarely compounds are rarely associatedassociated

Pesticides &PDPesticides &PDPesticides &PDPesticides &PD

Paraquat: Prevalent case-control study, TaiwanParaquat: Prevalent case-control study, Taiwan

Dieldrin: In brains of PD cases, not AD or controlsDieldrin: In brains of PD cases, not AD or controls

Organochlorine pesticides:Organochlorine pesticides:

Prevalent case-control study, GermanyPrevalent case-control study, Germany

Higher levels in PD substantia nigra than AD, LBD, Higher levels in PD substantia nigra than AD, LBD, controlcontrol

DDE (DDT metabolite) in Inuit, GreenlandDDE (DDT metabolite) in Inuit, Greenland

Dithiocarbamates: Prevalent case-control study, Dithiocarbamates: Prevalent case-control study, Alberta, CanadaAlberta, Canada

Paraquat: Prevalent case-control study, TaiwanParaquat: Prevalent case-control study, Taiwan

Dieldrin: In brains of PD cases, not AD or controlsDieldrin: In brains of PD cases, not AD or controls

Organochlorine pesticides:Organochlorine pesticides:

Prevalent case-control study, GermanyPrevalent case-control study, Germany

Higher levels in PD substantia nigra than AD, LBD, Higher levels in PD substantia nigra than AD, LBD, controlcontrol

DDE (DDT metabolite) in Inuit, GreenlandDDE (DDT metabolite) in Inuit, Greenland

Dithiocarbamates: Prevalent case-control study, Dithiocarbamates: Prevalent case-control study, Alberta, CanadaAlberta, Canada

Pesticides & PD: HypothesesPesticides & PD: HypothesesPesticides & PD: HypothesesPesticides & PD: Hypotheses

Mitochondrial Complex 1 inhibitionMitochondrial Complex 1 inhibitionRotenone animal modelRotenone animal model

Oxidative Stress/Redox cyclingOxidative Stress/Redox cyclingParaquat animal modelParaquat animal model

Potentiation of Potentiation of -synuclein fibrillization-synuclein fibrillization

Proteosomal inhibitionProteosomal inhibition

Mitochondrial Complex 1 inhibitionMitochondrial Complex 1 inhibitionRotenone animal modelRotenone animal model

Oxidative Stress/Redox cyclingOxidative Stress/Redox cyclingParaquat animal modelParaquat animal model

Potentiation of Potentiation of -synuclein fibrillization-synuclein fibrillization

Proteosomal inhibitionProteosomal inhibition

Is the increased risk of Parkinson’s disease associated with farming or rural

residence due to pesticide exposure?

An Alternative HypothesisAn Alternative HypothesisAn Alternative HypothesisAn Alternative Hypothesis

Nocardia asteroides (LeWitt, Beaman et al)Nocardia asteroides (LeWitt, Beaman et al)Animal model with nigral neural loss: rodents, primates Animal model with nigral neural loss: rodents, primates

L-dopa responsive movement disorderL-dopa responsive movement disorder

? L-forms? L-forms

Streptomycetes species (McNaught et al)Streptomycetes species (McNaught et al)Animal model: rodents (still being characterized)Animal model: rodents (still being characterized)

Proteasome inhibitorsProteasome inhibitors

Others?Others?BMAA (BMAA (--NN-methylamino-L-alanine) from cyanobacteria-methylamino-L-alanine) from cyanobacteria

Nocardia asteroides (LeWitt, Beaman et al)Nocardia asteroides (LeWitt, Beaman et al)Animal model with nigral neural loss: rodents, primates Animal model with nigral neural loss: rodents, primates

L-dopa responsive movement disorderL-dopa responsive movement disorder

? L-forms? L-forms

Streptomycetes species (McNaught et al)Streptomycetes species (McNaught et al)Animal model: rodents (still being characterized)Animal model: rodents (still being characterized)

Proteasome inhibitorsProteasome inhibitors

Others?Others?BMAA (BMAA (--NN-methylamino-L-alanine) from cyanobacteria-methylamino-L-alanine) from cyanobacteria

Could the increased risk be due to a common soil pathogen?Could the increased risk be due to a common soil pathogen?

Environmental Pollutants & PD riskEnvironmental Pollutants & PD riskEnvironmental Pollutants & PD riskEnvironmental Pollutants & PD risk

Persistent organic pollutantsPersistent organic pollutants PD risk increased in Greenland Inuits with traditional diets PD risk increased in Greenland Inuits with traditional diets

(Wermuth 2004)(Wermuth 2004)

PCB congeners elevated in PD brain (Corrigan 1998)PCB congeners elevated in PD brain (Corrigan 1998)

SolventsSolvents Trichloroethylene case reports, rodent model (Guehl, 1999)Trichloroethylene case reports, rodent model (Guehl, 1999)

Acute/subacute parkinsonism case reportsAcute/subacute parkinsonism case reports

Long term exposure case-control study (McDonnell, 2003)Long term exposure case-control study (McDonnell, 2003)

Persistent organic pollutantsPersistent organic pollutants PD risk increased in Greenland Inuits with traditional diets PD risk increased in Greenland Inuits with traditional diets

(Wermuth 2004)(Wermuth 2004)

PCB congeners elevated in PD brain (Corrigan 1998)PCB congeners elevated in PD brain (Corrigan 1998)

SolventsSolvents Trichloroethylene case reports, rodent model (Guehl, 1999)Trichloroethylene case reports, rodent model (Guehl, 1999)

Acute/subacute parkinsonism case reportsAcute/subacute parkinsonism case reports

Long term exposure case-control study (McDonnell, 2003)Long term exposure case-control study (McDonnell, 2003)

Metals & PDMetals & PDMetals & PDMetals & PDHypothesesHypotheses

oxidative stress, Fenton reactionoxidative stress, Fenton reaction

promote promote -synuclein aggregation (Yamin, 2003)-synuclein aggregation (Yamin, 2003)

Epidemiologic SupportEpidemiologic Supportdysregulated iron metabolism in PD (Dexter, 1992)dysregulated iron metabolism in PD (Dexter, 1992)

dietary iron in case-control study (Powers, 2003)dietary iron in case-control study (Powers, 2003)

occupational exposure to copper, lead (Gorell, 2004; occupational exposure to copper, lead (Gorell, 2004; Kuhn 1998)Kuhn 1998)

? PD more prevalent near iron & copper industries ? PD more prevalent near iron & copper industries (Rybicki, 1993)(Rybicki, 1993)

HypothesesHypothesesoxidative stress, Fenton reactionoxidative stress, Fenton reaction

promote promote -synuclein aggregation (Yamin, 2003)-synuclein aggregation (Yamin, 2003)

Epidemiologic SupportEpidemiologic Supportdysregulated iron metabolism in PD (Dexter, 1992)dysregulated iron metabolism in PD (Dexter, 1992)

dietary iron in case-control study (Powers, 2003)dietary iron in case-control study (Powers, 2003)

occupational exposure to copper, lead (Gorell, 2004; occupational exposure to copper, lead (Gorell, 2004; Kuhn 1998)Kuhn 1998)

? PD more prevalent near iron & copper industries ? PD more prevalent near iron & copper industries (Rybicki, 1993)(Rybicki, 1993)

Diet and PD RiskDiet and PD RiskDiet and PD RiskDiet and PD Risk

Increased risk associated with higher intake of:Increased risk associated with higher intake of: Dairy products: Environmental pollutants?Dairy products: Environmental pollutants?

Animal fat: Oxidative stress; environmental pollutants?Animal fat: Oxidative stress; environmental pollutants?

Tetraisoquinolines (TIQs)Tetraisoquinolines (TIQs)

Decreased risk associated with higher intake of:Decreased risk associated with higher intake of: Coffee or CaffeineCoffee or Caffeine

Dose-response gradientDose-response gradient Effect magnitude similar to that of smokingEffect magnitude similar to that of smoking

Nuts & legumesNuts & legumes

NiacinNiacin

Increased risk associated with higher intake of:Increased risk associated with higher intake of: Dairy products: Environmental pollutants?Dairy products: Environmental pollutants?

Animal fat: Oxidative stress; environmental pollutants?Animal fat: Oxidative stress; environmental pollutants?

Tetraisoquinolines (TIQs)Tetraisoquinolines (TIQs)

Decreased risk associated with higher intake of:Decreased risk associated with higher intake of: Coffee or CaffeineCoffee or Caffeine

Dose-response gradientDose-response gradient Effect magnitude similar to that of smokingEffect magnitude similar to that of smoking

Nuts & legumesNuts & legumes

NiacinNiacin

Part 3Part 3Part 3Part 3

Genetic Epidemiology of Genetic Epidemiology of Parkinson’s diseaseParkinson’s disease

Genetic Epidemiology of Genetic Epidemiology of Parkinson’s diseaseParkinson’s disease

Genes linked to familial PDGenes linked to familial PDGenes linked to familial PDGenes linked to familial PD

LocusLocus ProteinProtein InheritInherit LBLB Frequency & Possible MechanismFrequency & Possible Mechanism

PARK1PARK1 -Synuclein-Synuclein ADAD ++ Rare. Missense or genomic duplication. Rare. Missense or genomic duplication. Protein aggregation.Protein aggregation.

PARK2PARK2 ParkinParkin ARAR -- 25 - 50% of young onset cases (< 40). 25 - 50% of young onset cases (< 40). Ubiquitin-protein ligase loss of function.Ubiquitin-protein ligase loss of function.

PARK5PARK5 UCH-L1UCH-L1 ADAD ?? Rare. Ubiquitin-proteosome loss of fxn. Rare. Ubiquitin-proteosome loss of fxn. Some polymorphisms may be protective.Some polymorphisms may be protective.

PARK6PARK6 PINK1PINK1 ARAR ?? Rare. Mitochondrial kinase loss of fxn. Rare. Mitochondrial kinase loss of fxn. May May proteosomal vulnerability. proteosomal vulnerability.

PARK7PARK7 DJ-1DJ-1 ARAR ?? Mutant protein misfolds, may sensitize Mutant protein misfolds, may sensitize mitochondria to oxidative stressors.mitochondria to oxidative stressors.

PARK8PARK8 LRRK2LRRK2 ADAD +/-+/- Common? Penetrance? Typical onset Common? Penetrance? Typical onset age. Quite variable clincally; synuclein/ age. Quite variable clincally; synuclein/ tau pathology. Toxic gain of fxn.tau pathology. Toxic gain of fxn.

Family Studies of PD RiskFamily Studies of PD RiskFamily Studies of PD RiskFamily Studies of PD Risk

Study Cases/ Controls

Odds Ratio

Population

Semchuk et al, 1993 130/260 2.4 National Health

Morano et al, 1994 74/148 3.9 Specialty clinic

Payami et al, 1994 114/114 3.5 Specialty cinic

Bonifati et al, 1995 100/100 4.9 Specialty clinic

Marder et al, 1996 233/1172 2.3 Population based

Twin StudiesTwin StudiesTwin StudiesTwin Studies

Compare concordance for PD in mono-Compare concordance for PD in mono-zygotic (MZ) vs. dizygotic (DZ) twin pairszygotic (MZ) vs. dizygotic (DZ) twin pairs

Higher concordance among MZ pairs Higher concordance among MZ pairs supports a genetic causesupports a genetic cause

Similar rates of concordance argues Similar rates of concordance argues against a major genetic etiologic roleagainst a major genetic etiologic role

Compare concordance for PD in mono-Compare concordance for PD in mono-zygotic (MZ) vs. dizygotic (DZ) twin pairszygotic (MZ) vs. dizygotic (DZ) twin pairs

Higher concordance among MZ pairs Higher concordance among MZ pairs supports a genetic causesupports a genetic cause

Similar rates of concordance argues Similar rates of concordance argues against a major genetic etiologic roleagainst a major genetic etiologic role

NAS WW II Twins Cohort: NAS WW II Twins Cohort: Tanner et al, 1999Tanner et al, 1999NAS WW II Twins Cohort: NAS WW II Twins Cohort: Tanner et al, 1999Tanner et al, 1999

16,000 white male twin pairs born 1917-192716,000 white male twin pairs born 1917-1927

Two-stage screening with in-home examsTwo-stage screening with in-home exams

Concordance in MZ and DZ pairs was similar Concordance in MZ and DZ pairs was similar when PD onset > 50when PD onset > 50

HoweverHowever, when PD onset , when PD onset << 50, MZ 50, MZ concordance was 6-fold higherconcordance was 6-fold higher

Suggests genetic basis for young-onset Suggests genetic basis for young-onset disease, environmental basis for typical-onset disease, environmental basis for typical-onset

16,000 white male twin pairs born 1917-192716,000 white male twin pairs born 1917-1927

Two-stage screening with in-home examsTwo-stage screening with in-home exams

Concordance in MZ and DZ pairs was similar Concordance in MZ and DZ pairs was similar when PD onset > 50when PD onset > 50

HoweverHowever, when PD onset , when PD onset << 50, MZ 50, MZ concordance was 6-fold higherconcordance was 6-fold higher

Suggests genetic basis for young-onset Suggests genetic basis for young-onset disease, environmental basis for typical-onset disease, environmental basis for typical-onset

Part 4Part 4Part 4Part 4

Genes Genes ANDAND Environment? Environment?Genes Genes ANDAND Environment? Environment?

Exposure of the brain to environmental toxins is controlled by enzymes and transporters in lung, intestine, liver, kidney and blood brain barrier.

Circulation

MDR1

ToxicantCYP2D6

OCT2

MDR1

MRP1,2

GSTNATMDR1

OCT1

OCT1MRP2

MRP2

ConclusionsConclusionsConclusionsConclusions

Parkinson’s disease and monogenic or toxicant-Parkinson’s disease and monogenic or toxicant-induced parkinsonism likely have common induced parkinsonism likely have common pathogenic mechanismspathogenic mechanisms

Typical disease is likely due to the interaction of Typical disease is likely due to the interaction of multiple environmental and genetic risk factorsmultiple environmental and genetic risk factors

Specific causes may be different in different Specific causes may be different in different individualsindividuals

Collaboration of epidemiologists, clinicians and Collaboration of epidemiologists, clinicians and laboratory scientists is criticallaboratory scientists is critical

Parkinson’s disease and monogenic or toxicant-Parkinson’s disease and monogenic or toxicant-induced parkinsonism likely have common induced parkinsonism likely have common pathogenic mechanismspathogenic mechanisms

Typical disease is likely due to the interaction of Typical disease is likely due to the interaction of multiple environmental and genetic risk factorsmultiple environmental and genetic risk factors

Specific causes may be different in different Specific causes may be different in different individualsindividuals

Collaboration of epidemiologists, clinicians and Collaboration of epidemiologists, clinicians and laboratory scientists is criticallaboratory scientists is critical

AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

Parkinson’s InstituteParkinson’s InstituteCaroline TannerCaroline TannerBill LangstonBill LangstonDino Di MonteDino Di MonteKathleen ComynsKathleen ComynsMonica KorellMonica KorellCheryl MengCheryl MengAnjali GuptaAnjali GuptaGrace BhudikanokGrace BhudikanokSauda YerabatiSauda Yerabati

NIEHSJane HoppinFreya Kamel

Parkinson’s InstituteParkinson’s InstituteCaroline TannerCaroline TannerBill LangstonBill LangstonDino Di MonteDino Di MonteKathleen ComynsKathleen ComynsMonica KorellMonica KorellCheryl MengCheryl MengAnjali GuptaAnjali GuptaGrace BhudikanokGrace BhudikanokSauda YerabatiSauda Yerabati

NIEHSJane HoppinFreya Kamel

Stanford UniversityStanford UniversityLorene M. NelsonLorene M. NelsonNeil RischNeil Risch

Pacific Health Pacific Health Research InstituteResearch InstituteWeb RossWeb Ross

Kaiser PermanenteKaiser PermanenteStephen Van Den EedenStephen Van Den Eeden

UCSFUCSFPatricia QuinlanPatricia QuinlanSarah JewellSarah Jewell

Stanford UniversityStanford UniversityLorene M. NelsonLorene M. NelsonNeil RischNeil Risch

Pacific Health Pacific Health Research InstituteResearch InstituteWeb RossWeb Ross

Kaiser PermanenteKaiser PermanenteStephen Van Den EedenStephen Van Den Eeden

UCSFUCSFPatricia QuinlanPatricia QuinlanSarah JewellSarah Jewell