1. 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

2. 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

3. 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???

4. PD causation: Metals? Metals –Manganese—miners, welder, smelters –Mercury—case-control study –Lead—Gorell study: population case- control, occupational exposure to lead—OR of 5.24 (95%CI: 1.59-17); exposure rated by IH blinded to case- control status Mechanism –Catalyzation of Fenton reaction generating reactive oxygen species –Synergy with iron?

5. 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 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 Health- Mexico` Funding: NIEHS, NHLBI, EPA, CDC, ATSDR, NIOSH, March of Dimes

6. 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 lead’s 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.* 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Lowest quartile Highest quartile Odds of developing hypertension

10. Cheng et al. (Am J Epi, 2001). Bone lead and prospective rate ratio of developing hypertension in the Normative Aging Study.* 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Low bone lead High bone lead Rate ratio of hyperension

11. Cheng et al. (Am J Cardiology, 1998). Bone lead and EKG conduction in the NAS.* 0 0.05 0.1 0.15 0.2 0.25 QT interval (ms) QRS interval Low bone lead High bone lead

12. Korrick et al. (Am J Public Health, 1999). Bone lead and hypertension in nurses.* 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Lowest quartile Highest quartile Odds of developing hypertension

13. Payton et al., 1998 (Neurotox and eratology) Bone lead and cognition in the NAS 0 1 2 3 4 5 6 7 8 9 10 Constructional Praxis Score Pattern Memory, Seconds to Complete Low bone lead High bone lead

14. Kamel et al., 2002 (Epidemiology): Case Control study of ALS and Lead 0 0.5 1 1.5 2 2.5 3 3.5 4 OR for developing ALS Low bone lead High bone lead

15. 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 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 1st Qtr ALAD 1-1 ALAD 1-2/2-2

16. 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

18. 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

19. 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 < 10 yrs

20. 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