Particulate matter from vehicular exhaust in the setting of chronic cerebral hypoperfusion

2015-11-05The 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, very little is known about underlying pathophysiology or putative mechanisms. Our preliminary experimental data suggests an association between PM exposure and white matter injury in the corpus callosum of mice. Cerebrovascular disease may affect this process. Experimental studies examining the effects of air pollution in the setting of cerebrovascular disease are lacking. The proposed investigation utilizes an experimental murine model to address theses 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 BBB permeability. Urban PM will be collected with a particle sampler situated near the CA 110 Freeway in Los Angeles. Collected aerosols represent a mix of fresh PM, predominantly from vehicular traffic. These samples will then be distilled to nanoparticles and re-aerosolized for administration to mice through exposure chambers. The principal investigator has refined a Bilateral Carotid Stenosis model of CCH which generates reproducible white matter injury and behavioral deficits. A factorial design will be used to assess the independent and combined effects of PM exposure and CCH on white matter injury and neurocognitive decline. When administered together, we expect these exposures to exhibit synergy. Putative mechanisms of injury including inflammation, oxidative stress and blood-brain barrier breakdown, will be examined. The proposed research program utilizes nanoparticulate matter exposures sampled from a near-roadway traffic source, representing real world, multi-pollutant exposures. Scientific knowledge obtained from this study will advance our understanding of the relationship between PM exposure and white matter injury and neurocognitive decline. Insight into the role of underlying cerebrovascular disease will be gained. Results could 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