Manganese Toxicity by fft92177

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									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?


Is it due to something in the
          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
closing decades of the 20 th

Century by two discoveries
           MPTP – Induced Parkinsonism

 BBB                     Transporter

     Complex I
                 Nigra DA

Similar to         •Cardinal signs of PD
                                           BUT   •Acute onset
Parkinson’s        •L-dopa benefit               •No Lewy bodies
Disease            •Progressive in some
Alpha synuclein mutation (chromosome 4q)
       PARK 1 (Polymeropoulos et al, 1996)

 Autosomal dominant
   < 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 mono-
 genetic forms of parkinsonism

In the 2000s:
   More environmental associations; better animal models
   Several genetic forms of parkinsonism identified

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
   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                          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)
PD Incidence per 100,000

                                      Male     Female







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

Ethnicity-specific PD Incidence
                    Kaiser Study, 2003

     Hispanic      non-Hispanic       Asian               Black

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

                                      Relative risks
                             0    1         2          3
Smoking and PD: Hypotheses

Nicotine neuroprotective in several
 animal models
Upregulation of hepatic detoxifying
MAO inhibition
Other compounds in smoke?
Occupations associated with increased
  risk of PD in case-control studies

Agriculture work
    Rural   residence?
    Well   water?

Teaching and Healthcare
    Pre-morbid      personality?
        Pesticides and PD Risk
Pesticide use at work or
 home associated with
 PD in >20 case-control
 studies in US, Europe,

However, specific
 compounds are rarely
               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,
    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
    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)

   Trichloroethylene case reports, rodent model (Guehl, 1999)
   Acute/subacute parkinsonism case reports
   Long term exposure case-control study (McDonnell, 2003)
                Metals & PD
   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     gradient
      Effect   magnitude similar to that of smoking
   Nuts & legumes
   Niacin
       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/    Odds       Population
                       Controls   Ratio

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 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
 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.

                                OCT1     MRP2
Toxicant                                 MDR1         NAT
                                         OCT1         GST

MDR1                        Circulation
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
Collaboration of epidemiologists, clinicians and
 laboratory scientists is critical
Parkinson’s Institute   Stanford University
  Caroline Tanner         Lorene M. Nelson
  Bill Langston           Neil Risch
  Dino Di Monte
  Kathleen Comyns       Pacific Health
  Monica Korell
  Cheryl Meng             Research Institute
  Anjali Gupta
                          Web Ross
  Grace Bhudikanok
  Sauda Yerabati
                        Kaiser Permanente
NIEHS                     Stephen Van Den Eeden

  Jane Hoppin
  Freya Kamel
                          Patricia Quinlan
                          Sarah Jewell

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