Parkinson's Disease (PD) is well known for its motor manifestations: the characteristic tremor, the slowness of movement, and stiffness. Less attention has been paid to nonmotor symptoms, which can be incredibly disabling and cause substantial loss of health-related quality of life. These nonmotor symptoms include, but are not limited to, cognitive dysfunction, neuropsychiatric symptoms, and alterations in the function and contents of the gut, influencing a classic non-motor finding in PD, i.e., constipation. More recent evidence highlights the importance and the complexity of the gut dysfunction in PD, implicating differences in the bacterial composition of the gut (the so-called "gut microbiome") and the body's immune responses to these bacterial changes as potentially major contributors to the disease risk and/or progression. In turn, the diet has major impact on the gut microbiome. We also know through careful epidemiologic work that pesticide exposure is a risk factor for PD and a subset of those pesticides appear to have a disproportionate effect on the nonmotor symptoms, especially cognition. Intriguingly, exposure to pesticides can also affect microbiome composition.

In this proposal, we will bring together three distinct approaches and sets of expertise to better understand the interplay between environmental factors such as pesticides, the gut microbiome and their respective influences on cognitive change in PD and the health of neurons involved in cognition. The main goal of this work is to better understand environmental factors that contribute to the cognitive changes in PD and how they do it, whether it be direct effects of certain pesticides, the gut microbiome (and the substances produced by the specific gut bacteria), or the potential changes in immune responses caused by the interactions between the gut microbiome and the pesticide exposure, all affecting the health of the nervous system. A particular strength of the study is our ability to utilize real-world data from two separate unique human studies:

(1) A Spanish family that suffers from a genetic form of PD with dementia from which we have compiled extensive clinical data, biospecimens, cell biopsies, and microbiome samples from. Some family members have a history of pesticide exposure, allowing us to make a cell model of PD and dementia in a dish.

(2) The Parkinson's Environment and Genes (PEG) study, which has generated environmental, clinical, biospecimen, and microbiome data from a much larger population-based study. This gives us the ability to assess whether pesticides and lifestyle exposures have deleterious effects on the cognitive function in PD progression and correlate with the gut microbiome changes.

We will use sophisticated PD patient stem cell-based models "in a dish" representing cognitive and motor neuron systems affected in this disease and determine their sensitivity to specific pesticides identified in the PEG population study. Next, we will select specific gut bacteria in pesticide-exposed PD patients from the PEG cohort and determine if they can influence the immune cells normally responsible for safekeeping the brain equilibrium. Complementing the above analyses, we will carefully examine the impact of the pesticide exposures on microbiome and neuronal health in a mouse model of PD. With the environmental data already collected for more than two decades in hundreds of study participants, we will expand the microbiome collection and perform a large longitudinal pesticide wide association study to better understand the pesticide and microbiome impact on cognitive decline in PD.

Nonmotor symptoms such as dementia are very common in Parkinson's disease, with 75% or more patients affected. Therefore, we expect insights gathered from this research to impact the vast majority of patients with this disease. There are multiple clinical applications from our work. First, additional data linking pesticide exposure to cognitive and non-motor outcomes in PD reinforces the importance of establishing better regulation and safety measures for workers and the public who are exposed to these pesticides. Second, an understanding of the mechanisms of cortical neuron death and dysfunction from the in vitro studies has potential to identify targets for therapeutics and neuroprotection. Third, the potential to alter the microbiome through diet or other interventions also holds promise for impacting patient health in the near term as detrimental or beneficial bacteria or bacterial byproducts are identified. Pesticide regulations likely have the longest lag time given that changes to policy today would likely take decades to impact PD incidence and severity. While the microbiome can be modified, the lag time between exposure to factors detrimental to the gut microbiome and disease onset remains unclear. Finally, other aspects of this work which attempt to understand important pathways in neuron death and neuroinflammation, can guide selection of therapeutics on a shorter time scale -- 5 to 15 years depending on whether lead compounds already exist that influence important pathways and can be repurposed for therapeutic use in PD.