GENETIC AND ENVIRONMENTAL INFLUENCES ON THE PATHOGENESIS OF PARKINSON'S DISEASE: YOUNG ADULT BRAIN AND BEHAVIORAL RISK INDICATORS

Multiple environmental studies (Wang et al., 2014) have demonstrated an association between organophosphate (OP) insecticide exposure and Parkinson's disease (PD), yet many questions regarding this association remain unanswered. There is a clear need for prospective cohort studies, including biomarkers of exposure, to substantiate a cause-effect relationship between OP insecticides and the development of PD over time (Pezzoli and Cereda, 2013). We have access to a unique community sample, an urban minority birth cohort that has been followed for 18+ years, with a prenatal blood biomarker of exposure to a common OP pesticide, chlorpyrifos (CPF), genotyping, and regular assessments of motor and cognitive development. In this cohort, we have already shown that prenatal CPF exposure is associated with motor delays at 2-3 years of age (Rauh et al., 2004), and persistent brain, behavioral, and motor effects (mild tremor) through 11-12 years of age (Rauh et al., 2015). We now have a rare opportunity to study the emergence of preclinical/pre-motor indicators of PD in an environmentally at-risk sample. We propose the novel hypothesis that prenatal CPF exposure may have long-term motor consequences, as measured by early indicators for PD or PD-like manifestations, and that there may be differences in individual susceptibility. Exploring this hypothesis in a well-described prospective cohort will increase significantly our understanding of the link between toxic exposures, genetic susceptibility, and the emergence of PD risk, prior to the identification of clinically confirmed symptoms/diagnosis. We aim to conduct a full battery of neurological, neuropsychological, and genetic assessments for the purpose of documenting the very earliest potential indicators of PD in this population with well-documented biomarkers of exposure and genetic variants. Specifically, we hypothesize that: (1) subjects with higher prenatal CPF exposure as compared to those with lower exposure will demonstrate significantly more signs of early PD risk, as indicated by (a) higher prevalence of extrapyramidal motor dysfunction, including dystonia, bradykinesia, and tremor; (b) higher prevalence of non-motor symptoms, including REM sleep behavior disorder, cognitive and autonomic dysfunction (heart rate variability), and olfactory deficits; (2) early signs of PD risk identified in (1a) and (1b) will be significantly inter-correlated; (3) early signs of PD risk measured in (1a) and (1b) will be significantly more likely among subjects with specific PON1 polymorphisms.We will enroll 200 eligible individuals as they reach the age of 18 years, beginning with the oldest cohort participants. Allowing for 10% refusal rate (consistent with recent years in the larger cohort study), we anticipate that we will reach our target sample size 6 months prior to the end of the study period. We will conduct a single 45- to 60-minute wave of assessment (at the average rate of 1-2 children per week over a 30-month period), including clinical neurological examination, self-reported behavioral questionnaires, and physiological measures. Our final 6 months will be devoted to data analysis, interpretation, and dissemination. Guided by hypotheses, we will conduct preliminary analyses to calculate summary statistics and describe the distribution of outcome variables, CPF, and PON1 genotype. A regression approach will be used for formal modeling of main and interactive CPF effects on olfactory performance, sleep disturbance symptoms, and heart rate variability, adjusting for relevant covariates and correcting for multiple comparisons. Covariates will include age, sex, and exposure to active smoking and environmental tobacco smoke (current and previous).This application is responsive to the focus area 'Genetic stratification of suspected environmental factors that are quantifiable on the risk of developing Parkinson's disease.' While most cohorts exploring at-risk PD populations focus on people with genetic risks or family history of PD, this innovative study focuses on individuals with carefully documented environmental exposure. Understanding the role of the environment in the emergence and pathogenesis of PD is critically important given the high cost to society. A major strength is the prospective cohort design with biomarkers of exposure and regular prospective assessment, yielding an enormous amount of data for current and future hypothesis-testing. By sharing subjects with an ongoing cohort study, we have access to these previously collected data at no cost to the proposed study, providing a unique opportunity to analyze prospective longitudinal hypotheses at a fraction of its actual cost. If we were to find associations between CPF exposure, genotype, and early PD signs, such results would enable us to better understand the developmental emergence of PD, susceptibility, and the origins of the pathological neurodegenerative process, possibly providing an opportunity for early intervention.