Linking long-term air pollution exposure with inflammation, ALS risk, and disease progression

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ABSTRACT Air pollution is an understudied amyotrophic lateral sclerosis (ALS) risk factor. ALS and air pollution cause in- flammation, yet no studies link these two critical ALS topics. The long-term goals are to prevent, slow, or stop ALS progression. The overall objective is to determine how long-term air pollution exposure alters ALS risk, progression, and survival and gain insight into the role of inflammation on the path to neuronal damage. The central hypothesis is that air pollution triggers peripheral immune profiles that are an important pathophysio- logic agent of ALS risk, progression and survival. Guided by preliminary data showing that i) ALS cases have higher particulate matter (PM)2.5 exposure compared to controls, ii) the cases with the highest PM2.5 exposures have increased eosinophils, natural kill cell markers, and cytokine activation, and iii) existing literature connect- ing air pollution exposure to ALS disease severity, the rationale is that linking air pollution to ALS inflammatory profiles will strengthen the association between ALS and air pollution to inform critical and needed preventative strategies, as well as define new disease biomarkers and therapeutic targets. The central hypothesis will be tested by pursuing two specific aims: 1) Characterize air pollution exposures for cases and controls in the Uni- versity of Michigan ALS patient biorepository and determine how these exposures associate with ALS risk, pro- gression, and survival; and 2) Evaluate immune profiles as a mediators of the associations between air pollu- tion exposures and ALS risk, progression, and survival using data from cases and controls in the University of Michigan ALS patient biorepository. In Aim 1a, air pollution exposures for cases and controls are estimated using well-established prediction models for key ambient air pollutants including PM2.5, NO2, and traffic related air pollutants (TRAPs). Exposures will span the years 2000 through 2020 and account for the residential his- tory for all subjects and symptom onset date for ALS cases. Aim 1b will investigate how these exposures asso- ciate with ALS risk and, in Aim 1c, with ALS progression and survival. Aim 2a will determine the immune pro- files that associate with long-term, spatiotemporal, air pollution exposures developed in Aim 1. As the literature links air pollution to inflammation and inflammation is linked to ALS progression and survival, Aim 2b, will in- vestigate whether immune profiles play a role in the causal pathway by performing a mediation analysis be- tween air pollution and ALS risk, progression, and survival. The research proposed in this application is innova- tive, in the applicants’ opinion, because it rigorously develops thorough spatiotemporal air pollution data that captures temporal and spatial air pollution trends and analyzes a deeply phenotyped ALS and control cohort from the industrial Midwest. The proposed research is significant because it will provide critical data on the dis- tinct types of air pollution, immune profiles, and immune pathways associated with ALS risk, progression, and survival. Ultimately, as air pollution is a modifiable risk factor, knowledge from this proposal can guide preven- tion efforts, therapeutic targets, and blood-based biomarkers for use in clinical studies.