UCLA

Parkinson’s disease (PD), a neurodegenerative disease, is characterized by the accumulation of Lewy bodies in the substantia nigra and the loss of dopaminergic neurons. Currently, roughly one million people are living with PD in the U.S., and it is projected to increase to 1.6 million by 2037. Therefore, it is important to understand the risk factors that impact the prognosis of these patients and improve their quality of life. PD patients usually develop motor symptoms, which include tremors, rigidity, slowness of movement, and non-motor symptoms, which include depression, pain, cognitive impairment, and eating and sleep disorders. Symptoms get worse as the disease progresses. In addition, type 2 diabetes mellitus (T2DM) is one of the most common comorbidities among PD patients, and therefore, research is needed for uncovering the possible link between the two diseases. Pesticide exposure has been consistently linked to the onset of PD and yet, there is little study on its association with symptom progression. In addition, evaluating the cost and effectiveness of regulating these pesticides in reducing PD is also lacking in the existing literature. In this dissertation, we investigate the influence of pesticides on the progression of Parkinson’s disease, the molecular link between diabetes mellitus (DM) and PD using metabolomics, and the cost-effectiveness analysis of regulating pesticides that are associated with PD onset. We first identified 53 pesticides that were associated with PD onset based on data collected from a community-based case-control study in Central California. PD patients from the case-control study were followed up for assessment of their symptoms including motor decline, cognitive dysfunction, and depression. Based on PD patients’ reported residential and occupational addresses, we linked these addresses to the California Pesticide Use Reports database and calculated the amounts of pesticides applied at participants’ reported addresses from 1974 to the year of their PD diagnoses. We then performed censoring weighted time-to-event regression models to estimate effects. Ten pesticides were associated with faster symptom progression. Sulfate (pentahydrate) and 2-methyl-4-chlorophenoxyacetic acid (dimethylamine salt) were associated with all three progression endpoints. We then investigated the metabolic disturbance in the serum metabolome associated with type 2 DM among 636 PD patients and 253 non-PD elder participants through non-targeted metabolomics-wide association analysis (MWAS). Following MWAS, we performed pathway analysis to identify dysregulated pathways. We identified several amino acids, nucleic acid, and fatty acid metabolism pathways that were only associated with T2DM in the PD patient group. These pathways were often involved in energy metabolism, nitrogen balance, mitochondrial dysfunction, and oxidative stress. Finally, we investigated the cost-effectiveness of regulating 7 insecticides that were associated with PD onset as well as multiple pesticide exposures. We used a cohort-based state of transition/Markov model to model a homogeneous cohort of the 65- and 66-year-old population for 20 years. We simulated 7 single insecticide exposure and 4 pesticide mixture exposure scenarios and one scenario where no pesticides were present. We then calculated the total cost and quality-adjusted life years obtained from each scenario and used the no-pesticide exposure scenario as the reference group to calculate the incremental cost-effectiveness ratio. Our results suggested regulating these insecticides was a cost-effective approach compared to scenarios where these insecticides were not regulated even when we considered the potential cost of crop loss and pest management from not using these insecticides. All of the studies suggest the possible target, whether it’s pesticide or dysregulated pathways shared by T2DM and PD, in better understanding the pathogenesis and progression of PD. Since pesticide exposure was associated with both PD onset and progression, regulating pesticides is of top priority for governmental agencies and our study provided an assessment tool that incorporates the public health perspective in assessing the cost and effectiveness of regulating pesticides.