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?  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  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  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 Constructional Praxis Score Pattern Memory, Seconds to Complete Low bone lead High bone lead 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  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 