1 / 20

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.

Download Presentation

Parkinson’s Disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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 fibrilformation • 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.* 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

  11. 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

  14. 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

  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). 0.08 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

  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

  17. 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

  18. 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

  19. 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

More Related