Title: The effect of air pollution on aggravation of neurodegenerative diseases
Description: Background: Air pollution is one of the leading environmental issues in the world today. In 2015, pollution-related diseases accounted for 16% of all deaths worldwide — that is an estimated 9 million premature deaths were linked to air pollution. In addition to the substantial effects on human health, air pollution-related diseases result in productivity losses that reduce countries’ gross domestic product. Although air pollution disproportionately affects middle- and low-income countries, it is still a major issue in high-income countries, such as the United States, where 25% of Americans breath air with pollutant levels above the national regulatory standards. Fine particle matter (particles with diameter ≤ 2.5 μm, PM₂.₅ ) is the most extensively studied air pollutant and it has been causally linked with a wide range of adverse health outcomes, including cardiovascular and pulmonary disease, myocardial infarction, hypertension, congestive heart failure, arrhythmias, chronic obstructive pulmonary disease, and lung cancer.

Moreover, recent scientific evidence suggests that PM₂.₅ affects the nervous system and possibly contributes to the development and exacerbation of neurodegenerative diseases. This is increasingly relevant as populations are aging and the number of adults living with neurodegenerative diseases increases, negatively affecting families, communities, and health-care systems around the world. Although millions of people suffer from neurodegenerative diseases, there is currently no treatment that slows the progression of these conditions and no known cure or cause. Thus, determining whether a link exists between air pollution and neurodegenerative diseases is a goal of increasing importance. Objective: The research presented in this dissertation has two main objectives: (1) to characterize the relationship between long-term exposure to PM₂.₅ and disease aggravation in two of the most prevalent neurodegenerative diseases worldwide: Alzheimer’s (AD) and Parkinson’s disease (PD), as well as in the rare and devastating neurodegenerative motor disorder amyotrophic lateral sclerosis (ALS); (2) to identify the specific PM₂.₅ chemical components that are associated with disease aggravation in PD.

Methods: We used data from the New York Department of Health Statewide Planning and Research Cooperative System from 2000–2014 to identify patients’ first hospitalization with a primary or secondary diagnosis of AD, PD, or ALS. With these data, we constructed annual AD, PD, and ALS first hospitalization county counts (total and sex- and age-stratified) for all of New York State (NYS). A patient’s first hospital admission was used as a surrogate for disease aggravation, indicating the crossing point into a more severe stage of the disease. We used prediction estimates from well-validated models that incorporate satellite information and ground-based monitoring data to estimate annual PM₂.₅ and PM₂.₅ chemical component (nitrate, sulfate, organic matter, sea salt, black carbon, and soil) concentrations across NYS at a high spatial resolution. In Chapter 2, we used outcome-specific (AD, PD, or ALS) mixed quasi-Poisson models with county-specific random intercepts to assess the relationship between long-term exposure to PM₂.₅ and disease aggravation.

In Chapter 3, we used a multi-pollutant mixed quasi-Poisson model with county-specific random intercepts to identify specific PM₂.₅ components associated with disease aggravation in PD. In all analyses, we evaluated potential nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders. Results: We observed a total of 264,075 AD, 114,514 PD, and 5,569 ALS first admissions between 2000 and 2014. The hospitalization annual average counts per county were 284, 131, and 6 for AD, PD, and ALS, respectively. In Chapter 2, we found a nonlinear association between total PM₂.₅ exposure and PD hospitalizations, which plateaued at higher concentrations of PM₂.₅ (> 13 μg/m³, RR=1.08, 95% CI: 1.04–1.13 for a PM₂.₅ increase from 8 to 10 μg/m³, Figure 2.3). We also found that patients with a first PD hospitalization at age 70 or younger are at slightly higher risk for disease aggravation at lower PM₂.₅ concentrations relative to those age >70. In the case of AD, we observed evidence of a potential association between annual increases in PM₂.₅ exposure and disease aggravation, but only in a sensitivity analysis aiming to decrease outcome misclassification.

We found no association for ALS in the main analysis, but we observed an unexpected negative association in those <70 years in the stratified analysis. We found no evidence of effect modification by sex for any of the outcomes. In Chapter 3, we observed a linear association between disease aggravation in PD and long-term exposure to the PM₂.₅ components nitrate (RR = 1.05, 95%CI: 1.02–1.09 per one standard deviation (SD) increase) and organic matter (RR = 1.05, 95%CI: 1.02– 1.07 per one SD increase), and a nonlinear association for black carbon with a negative association above the 96th percentile of the BC concentration distribution (Figure 3.4). We found no evidence of an association with sulfate, sea salt or soil. Conclusion: Overall, our studies provide an analysis of the potential association between long-term exposure to PM₂.₅ , both as an overall pollution mixture and by chem- ical composition, and disease aggravation in AD, PD, and ALS. Our findings suggest that annual increases in county-level PM₂.₅ concentrations are associated with disease aggravation in PD and possibly AD.

We found that the PM₂.₅ components organic matter and nitrate are particularly harmful in the association between PM₂.₅ and dis- ease aggravation in PD. Additionally, our results indicate that current national PM₂.₅ standards may not be strict enough to safeguard the population’s neurological health. Specifically, in Chapter 2, we observed that the PM₂.₅ –PD association has a steeper slope at lower concentrations that are well below the current annual National Ambient Air Quality Standards for PM₂.₅ . Thus, our findings warrant further investigation into the potential link between long-term PM₂.₅ exposure and disease aggravation, particularly in the context of PD. Our results also indicate that the chemical composition of PM2.5 affects its neurotoxicity. Further research into how PM₂.₅ composition influences the overall PM₂.₅ adverse effects is needed to fully understand the mechanisms that underlie the association between exposure to PM₂.₅ and aggravation of neurodegenerative diseases.