Neurocognitive Effects of Episodic Exposure to Wildfire Smoke: Mechanisms and Patterns of Exposure

This study will explore whether repeated exposure to wildfire smoke contributes to cognitive decline and long-term neurological disease, how its effects compare to other types of air pollution, and which people may be most vulnerable.

Wildfires have grown more frequent and severe in North America in recent years. The fine particulate matter (PM2.5) in wildfire smoke (WFS) can travel thousands of kilometers, crossing international borders and affecting the air quality experienced by tens of millions. As the United States and Canada experience wildfire-driven increases in PM2.5, and communities face changes in the frequency, intensity, and duration of their exposures, it is essential to elucidate the long-term health risks and mechanistic pathways of WFS to inform air quality management and public health policy. 

Epidemiologic evidence to date highlights associations between short-term WFS exposure (i.e., over the course of days) and acute adverse cardiorespiratory effects. Newer studies have also identified both short-term and multiyear WFS exposure as a potential risk factor for adverse cognitive outcomes, with evidence that exposures to WFS-related PM2.5 may differ from exposures to PM2.5 from other sources, with suggestions of more pronounced effects. However, there remain unanswered questions about the ways in which repeated exposure to WFS contributes to chronic neurological conditions, and how these risks compare to non-WFS PM2.5. These questions have direct policy relevance given the different regulatory and air quality management approaches that can be applied towards WFS-related and non-WFS PM2.5.

Complementing the growing body of epidemiologic evidence are toxicological and clinical studies that support neuroinflammatory responses driven by oxidative stress as the likely mechanistic pathways by which WFS affects cognitive health. However, evidence for these biological mechanisms and linkage to chronic disease remains immature, and human studies to buttress animal and cellular models are limited.

Furthermore, the episodic and extreme nature of WFS events presents a unique challenge in understanding WFS’s longer-term health risks and underlying biological mechanisms. To date, most epidemiologic and human studies have failed to adequately capture the effects of WFS-driven peaks in PM2.5 and different patterns of exposure. We therefore propose to combine experiments in our state-of-the-art controlled human exposure facility with a data-rich observational approach, relying on linked administrative health databases and a large, well-characterized aging cohort, to investigate how different durations, frequencies, and intensities of WFS exposure contribute to cognitive decline and chronic neurological conditions from the biological to population levels. This interdisciplinary study will address the following:

Aim 1: Use a controlled human exposure study to identify, across different intensities of WFS exposure:
1.1 Neurocognitive changes relevant to the development of chronic neurological diseases  
1.2 Temporal patterns of onset and resolution in relevant circulating neuro-inflammatory markers 1.3 Sex, age, and genetics as effect-modifying susceptibility factors for the above phenomena 

Aim 2: Use epidemiologic studies to identify, across patterns of multiyear, episodic WFS exposure:
2.1 Associations between WFS exposure, cognitive decline, and chronic neurological diseases
2.2 Neurocognitive effects of WFS-related PM2.5 compared with total and non-WFS-related PM2.5
2.3 Individual- and neighborhood-level risk factors for WFS-related neurocognitive outcomes

We have included common endpoints across Aims 1 and 2 (e.g., specific instruments for cognitive testing and functional magnetic resonance imaging of the brain) to increase alignment and bolster evidence of causal relationships. This proposed study will illuminate how episodic exposure to WFS contributes to the development of chronic neurological outcomes by identifying plausible mechanistic pathways, assessing the effects of WFS-related PM2.5 relative to other sources of PM2.5, elucidating high risk exposure patterns, and identifying susceptible populations. We will leverage our comprehensive knowledge mobilization plan to ensure this evidence both reaches the decision-makers responsible for implementing air quality standards and producing public health guidance and increases awareness in the general population.