Transcript Parkinson`s Disease

Parkinson’s 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 >75yo
Parkinson’s 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
PD causation
 Twin
studies: must be mostly
environmental or gene-env >50yo
 Environment
– IVDA exposed to MPTP
– Pesticides
• Paraquat—induces oxygen free radicals
leading to lipid peroxidation in neurons
• Heptachlor, rontenone, dieldrin—may
accelerate alpha-synuclein fibril formation
– Solvents—n-hexane, toluene
– Smoking (inverse)
– Metals???
PD causation: Metals?
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Metals
– Manganese—miners, welder, smelters
– Mercury—case-control study
– Lead—Gorell study: population casecontrol, occupational exposure to
lead—OR of 5.24 (95%CI: 1.59-17);
exposure rated by IH blinded to casecontrol status
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Mechanism
– Catalyzation of Fenton reaction
generating reactive oxygen species
– Synergy with iron?
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, Brigham&Women’s, HMS
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Collaborations:
– Boston: Boston VA Hospital, Normative Aging
Study, BU Neuro, Children’s Hospital, Mass Coll
of Pharmacy
– Outside: UC-Santa Cruz, NIEHS, U. Pittsburgh,
Brookhaven Nat’l Lab, Nat’l Inst. Public HealthMexico`

Funding: NIEHS, NHLBI, EPA, CDC, ATSDR,
Lead as cause of PD

High population exposures with longlived 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
Our relevant prior research
We have developed and used a new
biological marker of cumulative lead
dose to elucidate lead’s impact on
chronic disease
 We have also examined other leadgene interactions
 Examples…

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)
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
0.6
0.4
0.2
0
Odds of
developing
hypertension
Lowest
quartile
Highest
quartile
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
lead
lead
Rate ratio of
hyperension
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
interval interval
(ms)
Low bone lead
High bone lead
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
Lowest Highest
quartile quartile
Odds of developing
hypertension
Payton et al., 1998
(Neurotox and eratology)
Bone lead and cognition in the NAS
10
9
8
7
6
5
4
3
2
1
0
Low
bone
lead
High
bone
lead
Constructional
Praxis Score
Pattern Memory,
Seconds to Complete
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
developing
ALS
Low bone lead
High bone lead
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
0
1st Qtr
ALAD 1-1
ALAD 1-2/2-2
Candidate genes for gene-metal
interactions and Parkinson’s
 HFE—hemochromatosis
(C282Y, H63D)
– Increases intracellular iron that can
• catalyze reactions to produce
toxic-free radicals
• promote the Fenton reaction
environmental exposure
(lead, pesticide, copper, etc.)
oxidative toxicity
damage to dopamine neurons
in substantia nigra
(increased by H2O2 & autooxidation of dopamine)
initiation of Fenton reaction
C282Y or H63D
hemochromatosis mutation
facilitated transport of Fe+2 across
blood-brain barrier & into neuronal cells
increased unbound Fe+2
content in substantia nigra
Fe+2 potentiates Fenton reaction,
lipid peroxidation, and cellular injury
dopaminergic
neuronal cell death
loss of neurons beyond functional threshold
clinical
Parkinson's Disease
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 (n=1,233) + new
PD patients (n=1,080)
 Critieria: PD sx<10y, meet case def,
within 2 hrs drive
 Controls: spouses and in-laws
Case definition
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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 < 10 yrs
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
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