AS252 - Environmental determinants of cognitive aging in WHIMS
Investigator Names and Contact Information
Jiu-Chiuan` (JC) Chen
Introduction/Intent
Specific Aims
Accumulating neuroscientific and toxicological data have provided the pathophysiological and neurobiological basis of the hypothesized link of cognitive aging with ambient air pollution, supporting its role in the development and progression of neurocognitive disorders. Various in vivo experiments with exposures to ozone, particulate matter (PM), or particles-ozone mixtures have collectively presented a constellation of pertinent effects on central nervous system (CNS) in different animal models 1-14. These studies demonstrate not only the direct effect on memory impairment, but also the enhanced or selective neurotoxicity of air pollution on the hippocampus (the neuroanatomical target of Alzheimer's disease), the characteristic histopathological lesions (e.g., plaques formation, β-amyloid accumulation, neurofibrillary triangles) indicative of neurodegeneration, and pathophysiological processes (neuroinflammation, central oxidative stress, activation of stress axis) as well as molecular pathways (e.g., increased activities of neurodegenerative protease calpain, neurochemical disturbance) involved in the neurobiology of cognitive aging and pathogenesis of dementia. No previous human studies have examined the effects of ambient air pollutants on cognitive impairment and dementia in the elderly.
The primary goal of this research project is to investigate ambient air pollutants as novel environmental determinants of neurocognitive disorders in elderly women. We will leverage on the high-quality longitudinal data sources developed in the Women's Health Initiative Memory Study (WHIMS) and addresses this critical knowledge gap in a cost-efficient manner. Specifically, using geocoded residential information of all participants in WHIMS (including the subset of these participants enrolled in the Women's Health Initiative Study of Cognitive Aging – WHISCA and the Women's Health Initiative Magnetic Resonance Imaging Study – WHIMS-MRI), we will link their outcome data (cognitive declines, mild cognitive impairment [MCI], dementia, and MRI measures of ischemic lesion volumes and regional brain volumes) with environmental characteristics of residential neighborhoods to assess the adverse neurocognitive effects of long-term exposures to ambient air pollutants, with primary focus on PM10, PM2.5 (PM with aerodynamic diameter ≤10 and 2.5 μm), diesel exhaust particles (DEP) and ozone. The proposed investigation of neurodegenerative effects of long-term exposures to ambient air pollutants is in accord with the National Research Council's recommendation that "studies to determine the potential of PM to have long-term effects on the CNS in both healthy and susceptible people are needed." 15 To this end, we submit the following specific aims:
1. Ambient air pollution and incidence of all-cause dementia and mild cognitive impairment
Investigate whether long-term exposures to ambient air pollutants (PM10/PM2; DEP; ozone) increase the risk for all-cause dementia and mild cognitive impairment (MCI) in a geographically-diverse population of elderly women, adjusting for potential confounders.
Hypothesis 1: (H1) Residing in places with high exposures to ambient air pollutants is associated with increased risks for all-cause dementia and MCI, adjusting for spatial variability, individual demographics, socioeconomic positions, personal biophysical and psychosocial attributes, and other potential confounders.
2. Ambient air pollution and cognitive function
Examine whether long-term exposures to ambient air pollutants (PM10/PM2; DEP; ozone) correlate with cognitive function (global and within specific domains) and predict cognitive declines in elderly women, adjusting for potential confounders.
Hypothesis 2: (H2) Estimated residence-specific exposures to ambient air pollutants averaged over 1-year are negatively associated with global and specific cognitive function at baseline and follow-up and positively associated with cognitive declines, adjusting for spatial variability, individual demographics, socioeconomic positions, personal biophysical and psychosocial attributes, and other potential confounders.
**3. Ambient air pollution and radiographic neuropathology of cognitive aging **
Examine whether long-term exposures to ambient air pollutants (PM10/PM2; DEP; ozone) correlate with ischemic lesion volumes and regional brain volumes measured by MRI in elderly women, adjusting for potential confounders and total intracranial volume.
Hypothesis 3: (H3) Residing in places with high exposures to ambient air pollutants is associated with larger ischemic lesion volumes and lower regional volumes, adjusting for spatial variability, individual demographics, socioeconomic positions, personal biophysical and psychosocial attributes, total intracranial volume and other potential confounders.
4. Determinants of population susceptibility to adverse neurocognitive effects of air pollution
Investigate the population variability in the associations of all-cause dementia, MCI, and declines of global cognitive function with long-term exposure to ambient air pollution. Identify susceptible population subgroups defined by individual's cardiovascular risk profiles and hematological biomarkers, adjusting for potential confounders.
Hypothesis 4: (H4) Elderly women with indicators of population susceptibility (histories of stroke, diabetes mellitus, or hypertension; obesity; high while blood cell count) are more likely to have adverse neurocognitive effects of to ambient air pollution than those without these characteristics.
