Parkinsons Disease

1
Parkinsons Disease

• Bradykinesia, tremor, rigidity, postural reflect
  impairment
• Destruction of dopaminergic neurons in the pars
  compacta of the substantia nigra (with Lewy
  inclusion bodies)
• Lifetime risk up to 2 men, 1.3 women rates
  rising among gt75yo

2
Parkinsons Disease and the Environment the
Potential Contribution of Metal-Gene Interactions

• Howard Hu, M.D., M.P.H., Sc.D.
• Professor of Occupational and Environmental
  Medicine
• Harvard School of Public Health

3
PD causation

• Twin studies must be mostly environmental or
  gene-env gt50yo
• Environment
• IVDA exposed to MPTP
• Pesticides
• Paraquatinduces oxygen free radicals leading to
  lipid peroxidation in neurons
• Heptachlor, rontenone, dieldrinmay accelerate
  alpha-synuclein fibril formation
• Solventsn-hexane, toluene
• Smoking (inverse)
• Metals???

4
PD causation Metals?

• Metals
• Manganeseminers, welder, smelters
• Mercurycase-control study
• LeadGorell study population case-control,
  occupational exposure to leadOR of 5.24 (95CI
  1.59-17) exposure rated by IH blinded to
  case-control status
• Mechanism
• Catalyzation of Fenton reaction generating
  reactive oxygen species
• Synergy with iron?

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Metals Epidemiology Research Group

• Director Howard Hu
• Primary base
• Dept. Environ Health, HSPH (also, Depts. Of Epi,
  Biostat, Health and Social Behavior, Maternal and
  Child Health, Cell and Cancer Biology)
• Channing Lab, BrighamWomens, HMS
• Collaborations
• Boston Boston VA Hospital, Normative Aging
  Study, BU Neuro, Childrens Hospital, Mass Coll
  of Pharmacy
• Outside UC-Santa Cruz, NIEHS, U. Pittsburgh,
  Brookhaven Natl Lab, Natl Inst. Public
  Health-Mexico
• Funding NIEHS, NHLBI, EPA, CDC, ATSDR, NIOSH,
  March of Dimes

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Lead as cause of PD

• High population exposures with long-lived body
  stores
• Animal studies lead decreases dopamine
  synthesis, turnover, uptake in the basal ganglia
• Increased spontaneous release of dopamine
  dopamine auto-oxidized to 6-OHDA, facilitating
  Fenton reaction places these neurons at
  increased risk of oxidative toxicity
• Lead also has direct oxidative properties,
  perhaps mediated by ALA

7
Our relevant prior research

• We have developed and used a new biological
  marker of cumulative lead dose to elucidate
  leads impact on chronic disease
• We have also examined other lead-gene
  interactions
• Examples

8
Method for measuring cumulative lead exposure
scanning measurements of bone lead using K-x-ray
fluorescence

• Non-invasive
• Safe (radiation dose in microsieverts)
• Convenient (20-30 minutes/measure)

9
Hu et al. (JAMA, 1996). Bone lead and odds of
hypertension in the Normative Aging Study.
2
1.8
1.6
1.4
1.2
1
0.8
Odds of developing
0.6
0.4
hypertension
0.2
0
Lowest
Highest
quartile
quartile
10
Cheng et al. (Am J Epi, 2001). Bone lead and
prospective rate ratio of developing hypertension
in the Normative Aging Study.
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Low bone
High bone
Rate ratio of
lead
lead
hyperension
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Cheng et al. (Am J Cardiology, 1998).
Bone lead and EKG conduction in the
NAS.
0.25
0.2
0.15
0.1
0.05
0
QT
QRS
Low bone lead
interval
interval
High bone lead
(ms)
12
Korrick et al. (Am J Public Health, 1999). Bone
lead and hypertension in nurses.
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Odds of developing
Lowest
Highest
hypertension
quartile
quartile
13
Payton et al., 1998 (Neurotox and eratology)
Bone lead and cognition in the NAS
10
9
8
Low bone lead
7
6
5
4
High bone lead
3
2
1
0
Constructional
Pattern Memory,
Praxis Score
Seconds to Complete
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Kamel et al., 2002 (Epidemiology) Case Control
study of ALS and Lead
4
3.5
3
2.5
2
1.5
1
0.5
0
OR for
Low bone lead
developing
High bone lead
ALS
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Wu et al., (EHP, 2003). Increase in serum
creatinine (mg/dL) assoc. with bone lead of 40
µg/g, stratified by ALAD genotype (Conclusion
ALAD-2 gene carriers have worse kidney toxicity
from lead).
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
ALAD 1-1
0
ALAD 1-2/2-2
1st Qtr
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Candidate genes for gene-metal interactions and
Parkinsons

• HFEhemochromatosis (C282Y,
  H63D)
• Increases intracellular iron that can
• catalyze reactions to produce toxic-free
  radicals
• promote the Fenton reaction

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Our Study Design Case Control Epidemiologic Study

• NIEHS R01ES10798 to Channing Lab, 5
  yrs
• Major collaboration with the late R. Feldman,
  Marie St-Hilaire, and BU-PDC
• Existing PD patients (n1,233) new PD patients
  (n1,080)
• Critieria PD sxlt10y, meet case def, within 2 hrs
  drive
• Controls spouses and in-laws

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Case definition

• Complete hx and clinical eval by neurol
• 2 of 3 resting tremor, cogwheel rigidity,
  bradykinesia
• Assymetry
• None of supranuclear gaze palsy, postural
  instability, dysautonomia out of proportion for
  PD unexplained cerebellar findings,
  hyperreflexia no response to L-dopa
  nonprogressive MRI or CT with infarcts
• Recent clinical exam, with at least 2 exams
• Sx lt 10 yrs

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Protocol

• Questionnaire (exposures, smoking, diet, etc)
• KXRF measures of bone lead, blood lead
• Toenails for manganese, copper
• Blood for genotyping of HFE status and for future
  genotyping, other studies