Transcript Manganese Toxicity - University of Texas School of Public

The Epidemiology of
Parkinson’s disease
Samuel M. Goldman, MD, MPH
Parkinson’s Institute
Sunnyvale, California, USA
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
Parkinsonism:
• Akinesia/Bradykinesia
A Clinical Syndrome
•
Cogwheel rigidity
•
Postural reflex impairment
• Resting tremor
Parkinson’s disease pathology:
loss of pigmented neurons
Parkinson’s disease pathology:
Lewy Body
What Causes PD?
Is the disease inherited?
OR
Is it due to something in the
environment?
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
This debate was brought
into sharp focus in the
th
closing decades of the 20
Century by two discoveries
MPTP – Induced Parkinsonism
BBB
Complex I
Dopamine
Transporter
Substantia
Nigra DA
Neuron
Mitochondrion
Similar to
Parkinson’s
Disease
•Cardinal signs of PD
•L-dopa benefit
•Progressive in some
BUT
•Acute onset
•No Lewy bodies
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
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 monogenetic forms of parkinsonism
In the 2000s:
 More environmental associations; better animal models
 Several genetic forms of parkinsonism identified
Epidemiology
The study of the distribution
and determinants of
diseases in populations
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
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
Part 1:
Descriptive Epidemiology
Distribution of disease
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)
Finland
17.2
(Kuopio et al, 1999)
Age-Specific PD Incidence
Kaiser STUDY, 2003 (n = 442)
200
PD Incidence per 100,000
180
160
Male
Female
140
120
100
80
60
40
20
0
30-39
40-49
50-59
60-69
Age
70-79
80+
Ethnicity-specific PD Incidence
Kaiser Study, 2003
18
16
14
12
10
8
6
4
2
0
Hispanic
non-Hispanic
White
Asian
Age- and Gender-Adjusted Incidence, per 100,000
Black
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 9th decade
Men more frequently affected than women
Risk may be related to ethnicity or geography
Unclear if incidence is increasing over time
Part 2:
Analytic Epidemiology
Searching for the Cause
in the ENVIRONMENT
Association  Causation
Are you sure about this? It seems odd that a pointy head and long beak is what makes birds fly.
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
Relative risks from case
control and cohort studies
of smoking and PD *
* Hernan et al,
Ann Neurol 2002;
52:276-284
•1
0
•1
1
Relative risks
2
3
Smoking and PD: Hypotheses
Nicotine neuroprotective in several
animal models
Upregulation of hepatic detoxifying
enzymes
MAO inhibition
Other compounds in smoke?
Occupations associated with increased
risk of PD in case-control studies
Agriculture work
Pesticides?
Rural
Well
residence?
water?
Other?
Teaching and Healthcare
Infection?
Pre-morbid
personality?
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
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
Pesticides & PD: Hypotheses
Mitochondrial Complex 1 inhibition
Rotenone
animal model
Oxidative Stress/Redox cycling
Paraquat
animal model
Potentiation of -synuclein fibrillization
Proteosomal inhibition
Is the increased risk of Parkinson’s
disease associated with farming or rural
residence due to pesticide exposure?
An Alternative Hypothesis
Could the increased risk be due to a common soil pathogen?
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 (b-N-methylamino-L-alanine) from cyanobacteria
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)
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)
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:
 Coffee or Caffeine
 Dose-response
 Effect
magnitude similar to that of smoking
 Nuts & legumes
 Niacin
gradient
Part 3
Genetic Epidemiology of
Parkinson’s disease
Genes linked to familial PD
Locus
Protein
Inherit
LB
Frequency & Possible Mechanism
PARK1
-Synuclein
AD
+
Rare. Missense or genomic duplication.
Protein aggregation.
PARK2
Parkin
AR
-
25 - 50% of young onset cases (< 40).
Ubiquitin-protein ligase loss of function.
PARK5
UCH-L1
AD
?
Rare. Ubiquitin-proteosome loss of fxn.
Some polymorphisms may be protective.
PARK6
PINK1
AR
?
Rare. Mitochondrial kinase loss of fxn.
May h proteosomal vulnerability.
PARK7
DJ-1
AR
?
Mutant protein misfolds, may sensitize
mitochondria to oxidative stressors.
PARK8
LRRK2
AD
+/-
Common? Penetrance? Typical onset
age. Quite variable clincally; synuclein/
tau pathology. Toxic gain of fxn.
Family 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 Studies
Compare concordance for PD in monozygotic (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
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
Part 4
Genes AND Environment?
Exposure of the brain to environmental toxins is controlled
by enzymes and transporters in lung, intestine, liver, kidney
and blood brain barrier.
Toxicant
MDR1
MRP1,2
MDR1
OCT1
MRP2
MDR1
OCT1
Circulation
OCT2
MRP2
CYP2D6
NAT
GST
Conclusions
Parkinson’s disease and monogenic or toxicantinduced 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
Acknowledgements
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