Brain and Behavioral Indicators of Risk for Parkinsonism among Adolescents with Early Pesticide Exposure

Multiple studies have demonstrated an association between organophosphate (OP) insecticide exposure and Parkinson's Disease (PD) in adults, but virtually no studies have explored signs of the pathogenic process that begins long before the appearance of motor symptoms. There is a clear need for prospective studies, including biomarkers of exposure and brain-based measures, to substantiate a cause-effect relationship and the development of parkinsonism over time. We have access to a well-characterized 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), and regular assessments of neurodevelopment, including multimodal brain scans at 12-14 and 18 years. In this cohort, we have shown that prenatal CPF exposure is associated with motor delay at 2-3 years, and persistent brain, behavioral and subtle motor effects through 11- 12 years of age. We now have a unique opportunity to study the emergence of pre-clinical/non-motor indicators of PD risk at 18-20 years of age in this cohort. We propose to test the novel hypothesis that prenatal CPF exposure has long-term motor consequences, including neurological signs and brain-based biomarkers of PD risk that are measureable early in the pathogenic process, prior to the identification of clinically confirmed symptoms or diagnosis. We aim to: (1) conduct a single wave of neurological and brain imaging assessment (using known indicators of PD risk in adult populations) in a subset of the cohort (n=200) at 18-20 years of age. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly more signs of early PD risk, as indicated by (a) higher prevalence of pre-clinical extrapyramidal motor dysfunction (dystonia, bradykinesia, arm tremor); (b) higher prevalence of non-motor symptoms (REM sleep behavior disorder, autonomic dysfunction, olfactory deficits); and (c) increased prodromal motor markers (gait variability, inconsistent walking pattern, arm swing asymmetry and lower axial rotation smoothness); (2) conduct structural MRI for neuromelanin to identify substantia nigra involvement (a biomarker of PD) in these same subjects. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly greater substantia nigra involvement marked by a greater decrease in neuromelanin content; (3) employ an innovative statistical procedure using a vast number of functional and structural brain characteristics, based on multi-modal imaging data previously collected at 12-14 and 18 years, to determine whether an exposure-related pattern of neural deficits across modalities (a potential biomarker for PD) can be detected in our young cohort. We hypothesize that subjects with higher prenatal CPF levels as compared to those with lower levels will show a distinctive pattern of brain anomalies across modalities and time. This study has the potential to shift the research paradigm from a focus on neurodegenerative processes in PD to incorporate a neurodevelopmental perspective, with potential implications for future interventions.