Neurotoxicity of Airborne Particles: Role of Chronic Cerebral Hypoperfusion

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 DESCRIPTION (provided by applicant): The proposed research program seeks to determine the impact of particulate matter (PM) exposure on white matter injury and neurocognitive decline. These associations are further examined in the setting of underlying cerebrovascular disease (chronic cerebral hypoperfusion). Studies have established a strong relationship between PM exposure and atherosclerotic cardiovascular disease. Clinical imaging, epidemiology and pharmacotherapy studies have verified a critical role for cerebral vascular dysfunction in the onset and progression of dementia and cognitive deficits. Investigations suggest a relationship between long-term PM exposure and low cognitive performance, however, little is known about underlying pathophysiology or putative mechanisms. Cerebrovascular disease may affect these processes. Experimental studies examining effects of air pollution in the setting of cerebrovascular disease are lacking. The proposed investigation utilizes an experimental murine model to address these knowledge gaps through the following specific aims: 1) To examine the time course of white matter injury secondary to PM exposure. 2) To examine the effects of PM exposure and chronic cerebral hypoperfusion (CCH) on white matter injury and neurocognition and, 3) To examine the impact of PM exposure and CCH on inflammation, oxidative stress and blood-brain-barrier (BBB) permeability. Urban PM will be collected with a particle sampler near the CA-110 Freeway in Los Angeles. Collected aerosols represent a mix of fresh PM, predominantly from vehicular traffic. Samples will be distilled to nanoparticles (nano) and re-aerosolized for administration to mice through exposure chambers. The Principal Investigator has refined a Bilateral Carotid Stenosis CCH model which generates reproducible white matter injury and behavioral deficits. A factorial design will assess independent and combined effects of PM exposure and CCH on white matter injury and neurocognitive decline. When administered together, the investigators expect these exposures to exhibit synergy. Putative mechanisms of injury including inflammation, oxidative stress and BBB breakdown, will be examined. They have assembled a multidisciplinary team including senior scientists with complementary expertise in air pollution neurotoxicity, vascular biology, neuroinflammation, BBB pathophysiology, neurocognition, environmental health science epidemiology and biostatistics. Expected new knowledge gained from this R01 will greatly advance the understanding of neurovascular toxicity of environmental pollutants. Results can ultimately impact public policies and regulation with respect to cognitive health in a vulnerable population and provide a critical first step towards individual risk assessment and stratification.