Organochlorine pesticide, PCBs, and Parkinsons
This project studies prospectively whether the risk of Parkinson’s disease (PD) is predicted by plasma levels of organochlorine pesticides, polychlorinated biphenyls (PCBs), and the antioxidant uric acid. This investigation takes advantage of a unique population comprising over 35,000 Finnish men and women who provided blood samples in 1968-72 as part of a health examination survey, and have subsequently been followed for incidence of PD for over 20 years. Between the baseline survey and 1994, 201 new cases of PD have been confirmed in this population. Plasma levels of organochlorine insecticides, PCBs, and uric acid will be assessed among these cases and controls matched by age and gender. Specific hypotheses to be tested include: 1) That higher plasma levels of para, para-dichlorodiphenyl dichloroethene [p,p-DDE], the major metabolite of DDT, dieldrin, hexachlorobenzene (HCB), beta-hexachlorocyclohexane (HCH), heptachlor, heptachlor epoxide, trans-nonachlor, and oxychlordane are associated with increase risk of PD; 2) that higher plasma levels of PCBs (sum of all congeners) are associated with an increased risk of PD; and 3) that higher plasma levels of the antioxidant uric acid are associated with a decreased risk of PD, and exert a protective effect against the deleterious effects of DDE. The proposed investigation is unique and innovative as there are no previous data relating biomarkers of exposure to environmental contaminants and future risk of developing PD. The blood samples were collected at a time of high exposure to both organochlorine insecticides and PCBs as supported by the high mean plasma level of DDE and PCBs that we found in a pilot study. Finally, the long follow-up period will allow the investigation of long-term effects of exposure.
NSAIDS, Inflammation and Parkinson’s Disease
As a part of this study, we are evaluating prospectively whether use of non-steroidal anti-inflammatory drugs (NSAIDs), and particularly selective COX-2 inhibitors, and statins reduces the risk of Parkinson’s disease (PD). A key role of inflammatory and oxidative processes in the degeneration of dopaminergic neurons in PD is supported by experimental and postmortem studies. Further, preliminary findings from prospective investigations suggest that regular use of NSAIDs is associated with lower risk. To address these hypotheses, we propose to extend to the year 2008 the follow-up of PD in the Nurses’ Health Study (NHS), the Health Professional Follow-up Study (HPFS), and the Cancer Prevention Study-ll Nutrition (CPS-IIN), three well-established cohorts that collectively comprise a population of over 335,000 individuals. Participants in these cohorts have provided detailed information on use of NSAIDs, diet, lifestyle, and medical history over the past 14 to 24 years; 50,843 participants have also provided blood samples that have been stored for future analyses. The past occurrence of incident PD in these cohorts has already been documented or is in progress – 415 cases have been confirmed in the NHS and HPFS, and approximately 550 cases are being confirmed in the CPS-IIN cohort. By extending the follow-up we expect to confirm 988 new incident cases. We will be able for the first time to test whether users of selective COX-2 inhibitors and statins (neither was included in previous follow-up) have a lower risk of PD, and to examine dose-response relationships, the effects of duration of use or time since use, differences between individual NSAIDs, and possible interaction with other risk factors, including exposure to pesticides that we have shown in preliminary analyses to be associated with an increased risk of PD and to interact with NSAIDs use. Blood samples collected at different time intervals before the diagnosis will be available. Using these samples, we will examine the novel hypothesis that elevations in plasma levels of alpha-synuclein precede the onset of PD. Lastly, the proposed project will establish a unique resource that will be readily available for future studies on the etiology of PD.
Urate as a predictor of Parkinson’s disease risk and progression
Urate, the end product of purine metabolism, at physiological concentrations is an effective antioxidant and may provide a natural defense against the development of Parkinson’s disease (PD). In previous studies, healthy individuals with higher blood levels of urate were found to have a reduced risk of developing PD. Further, we found that higher blood urate levels in patients recently diagnosed with PD predict a favorable (slower) rate of disease progression, assessed by both clinical and neuroimaging measures. These studies suggest that urate may serve as a robust predictor of the neurodegeneration that leads to PD and its progression, and, because urate and its metabolic pathways are particularly amenable to pharmacological and dietary manipulations, have a potential therapeutic significance. It remains to be established, however, whether this association reflects a neuroprotective effect of urate or its metabolic precursors, or whether it is explained by a still unidentified common factor/confounder. Further, whereas a strong inverse association between blood urate and both PD risk and progression has been established in men, results in women are uncertain, because few women were included in previous studies. Primary purpose of the investigation is to conduct a systematic and in depth analysis of how blood urate and its determinants, including genetic variations in the urate pathway, affect both PD risk and progression in men and women. The investigation will comprise two main components. One is a nested case-control study including 1,492 incident cases of PD (685 women) and 3,316 matched controls to examine: 1) whether blood levels of urate predict risk of PD independently from known or suspected risk factors for PD and from genetic and non-genetic determinants of uricemia, and 2) whether mutations in genes involved in urate metabolism are associated with blood levels of urate and PD risk. The second is a cohort analysis among participants in two previously conducted large randomized trial in patients with early PD. We will examine: 1) whether the previously reported strong inverse associations between serum urate and PD progression are independent of genetic mutations affecting urate metabolism, and 2) whether these genetic mutations predict blood or CSF levels of urate, or PD progression. The combination of an epidemiological (disease risk) and clinical (disease progression) outcome is a novel aspect of this proposal, which is made possible by a close collaboration between PD epidemiologists and clinical investigators.