Genetic and Environmental Influences on the Pathogenesis of Parkinson's Disease: Young Adult Brain and Behavioral Risk Indicators

This study addresses several important questions about the causes and progression of Parkinson's disease (PD) over the life course. We are specifically interested in the role of toxic chemical exposures (called organophosphate pesticides) that may contribute to the risk of disease, which only appears as PD many years later. This is a dangerous class of chemicals that were originally developed as a warfare nerve gas, because they attack the nervous system, with serious health consequences. Although some of these chemicals have now been banned for indoor residential use (to control pest infestations), they are still commonly used to spray crops for insects in agricultural communities throughout the world. People living in nearby towns and farm workers and their families have particularly high exposures, while the general public is regularly exposed to residues on the foods produced, including fruits, vegetables, nuts, etc.

To learn more about how these chemicals attack the nervous system, genetic susceptibility to these chemicals, and the long-term consequences of exposure, we propose to study a unique community cohort of urban minority children, who are now reaching 19-20 years of age, many of whom were routinely exposed to indoor and outdoor residential sprays (these chemicals were commonly found in canned sprays, termite control applications, and lawn products prior to the residential ban in 2001). This group has been studied continuously since birth, at which time the levels of chlorpyrifos (CPF), an organophosphate pesticide that was particularly widespread and continues to be used agriculturally, were measured in blood samples. We will invite 200 of these young adults to participate in an examination, including neurological measures of stiffness and gait, cardiac measures, sleep questions, measures of tremor, and other neuropsychological measures. We also have access to genetic information, previously collected on the individuals. The proposed assessment will require about 45-50 minutes, and the participants will be paid $100 and the cost of transportation. The purpose is to try to identify the very earliest signs of risk for later PD that may appear long before clinical and motor symptoms can be seen and to determine who is at greatest risk. We hypothesize that the individuals who were most highly exposed during the prenatal period (based on the blood sample) will be more likely to show pre-motor and preclinical symptoms on these specialized tests, as compared to the individuals who had lower exposure, and that some individuals may be more susceptible to the exposure based on their genetic characteristics.

Currently, there is very little knowledge about how these chemicals inflict nerve damage that results in parkinsonian symptoms, and even less information about how early the non-motor and pre-clinical signs of damage can be seen. Furthermore, our minority population (Hispanic and African American) is under-studied in relation to PD. Because we have access to health, developmental, and genetic information on this group of children for the past 18 years, we do not have to incur the cost of previous exposure and health assessments or wait for the follow-up period. Therefore, this study is a highly efficient, cost-effective approach. This application is responsive to the Department of Defense focus area of genetic stratification of suspected environment factors that are quantifiable on the risk of developing Parkinson's disease. This means that we will seek to identify neurological and behavioral 'changes' that may be early signs of PD risk. Furthermore, we may be able to identify individuals with a genetic profile that makes them even more vulnerable to the harmful effects of chemical exposure at any point over the course of the life span. By identifying signs of risk early in the progression of the disease, we may be able to eventually design interventions that target these neurodegenerative processes much earlier than was previously possible. Such longer-term results would have important implications for public health and the future prevention of neurodegenerative diseases.