Do Atmospheric Ultrafine Particles Lodge in the Brain and Cause Cognitive Decline Leading to Alzheimer's Disease Related Dementias?

大气超细颗粒是否会滞留在大脑中并导致认知能力下降，从而导致阿尔茨海默病相关的痴呆症？

• 批准号: 10591354
• 负责人: Charles DeCarli
• 金额: $ 209.43万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591354
• 关键词: Address; Affect; Air; Air Pollutants; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid; Animals; Area; Biological; Brain; Brain Injuries; Brain region; Caliber; California; Cause of Death; Censuses; Chemicals; Chronic; Clinical; Cognitive; Communities; Consensus; Data; Detection; Environment; Environmental Pollution; Environmental Risk Factor; Exposure to; Female; Funding; Future; Gases; Gasoline; Generations; Geography; Goals; Grant; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Inhalation; Magnetic Resonance Imaging; Measures; Modeling; Natural Gas; Organ; Outcome; Participant; Particle Size; Pathology; Positron-Emission Tomography; Property; Public Health; Raman Spectrum Analysis; Rattus; Research; Resolution; Resources; Risk; Rodent; Sampling; Scanning; Severities; Source; Testing; Time; Transgenic Organisms; Wildfire; Work; air filter; base; clinically relevant; cognitive function; cohort; dementia risk; density; exhaust; experimental study; exposed human population; fine particles; geographic difference; male; neuropathology; particle; pollutant; racial and ethnic disparities; spatial relationship; traffic-related air pollution; translational study; ultrafine particle

Project Summary There is growing consensus that environmental factors influence risk for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Consistent with this hypothesis, cognitive trajectories of participants in the UC Davis Alzheimer’s Disease Research Center (UCD ADRC) Longitudinal Diversity Cohort (LDC) differ geographically. These geographical differences may arise from differential exposures to environmental contaminants. In this translational study, we will test our central hypothesis that ultrafine particulate matter (UFPM) enters the brain of exposed individuals and increases risk of cognitive decline and incident AD/ADRD. Human and animal studies have largely focused on PM2.5 (fine particulate matter with an aerodynamic diameter < 2.5 µm) in AD/ADRD risk. UFPM is a subset of PM2.5. Because of its smaller size (< 0.1 µm), inhaled UFPM can cross biological barriers to gain access to multiple organs, including the brain. Our prior work found UFPM in the brain of rats exposed to traffic-related air pollution (TRAP), but not filtered air controls, indicating UFPM may be a mechanism of brain injury. To date, no human studies and few animal studies have focused specifically on UFPM in AD/ADRD. Unlike most air pollutants that are relatively spatially homogeneous, UFPM are more concentrated near pollutant sources, so they are geographically discrete. To test our hypothesis, we will leverage resources unique to UCD: (1) the LDC, which has already geocoded 500 individuals in Northern California at the census tract level with associated longitudinal cognitive measures; (2) neuropathological samples on some of these individuals, (3) an UFPM exposure model that quantifies levels and sources of specific air pollutants over the LDC capture area from 2000 to 2019; (4) brains containing UFPM from rats exposed to unchanged ambient TRAP in real time; and (5) hyperspectral and Raman spectroscopy for characterizing the chemical composition of UFPM in rat and human brains to assess brain distribution and further inform source. Using these resources, we will address the following Aims: 1. Identify the source of UFPM in brains of TgF344-AD rats exposed to TRAP and assess the spatial relationship of UFPM to AD-relevant neuropathology in rat brains. 2. Determine whether human exposure to UFPM is associated with (a) incident cognitive impairment and AD/ADRD and (b) accelerated rate of cognitive decline. 3. Initiate exploratory studies in human AD/ADRD brain samples to determine whether UFPM in select brain regions of LDC individuals are related to AD pathology. Data from this project will identify AD/ADRD-relevant neuropathology associated with UFPM, a first step in developing mechanistic hypotheses that can be tested in future studies. Additionally, this project addresses (1) biological plausibility and clinical relevance of UFPM in air pollution as an environmental factor that modifies AD/ADRD initiation and progression and contributes to AD/ADRD racial/ethnic disparities; (2) relevance of the AD/ADRD rat model to humans exposed to UFPM in polluted air; and (3) generation of data needed to support public health and regulatory strategies for controlling key sources of UFPM associated with AD/ADRD.

项目总结