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.

项目摘要 越来越多的共识，环境因素会影响阿尔茨海默氏病和阿尔茨海默氏症的风险 与疾病相关的痴呆症（AD/ADRD）。与这一假设，参与者的认知轨迹一致 加州大学戴维斯分校阿尔茨海默氏病研究中心（UCD ADRC）纵向多样性队列（LDC）不同 地理上。这些地理差异可能来自环境的差异暴露 污染物。在这项翻译研究中，我们将测试我们的中心假设，即超细问题 （UFPM）进入暴露个人的大脑，并增加认知能力下降和事件AD/ADRD的风险。 人类和动物研究主要集中在PM2.5上 AD/ADRD风险<2.5 µm）。 UFPM是PM2.5的子集。由于其尺寸较小（<0.1 µm），因此吸入的UFPM 可以跨越生物学障碍，以进入包括大脑在内的多个器官。我们先前的工作找到了UFPM 在暴露于交通相关的空气污染（陷阱）但没有过滤的空气控制的大脑中，表明UFPM 可能是脑损伤的机制。迄今为止，没有人类研究和少数动物研究专门研究 在AD/ADRD中的UFPM上。与大多数相对均匀均匀的空气污染物不同，UFPM更多 集中在污染物来源附近，因此它们在地理上是离散的。为了检验我们的假设，我们将利用 UCD独有的资源：（1）LDC已经在北加州的500个人处于地理编码 与相关的纵向认知措施的人口普查水平； （2）一些神经病理样本 这些人，（3）UFPM暴露模型，该模型量化了特定空气污染物的水平和来源 从2000年到2019年的最不发达国家捕获区； （4）来自暴露于未改变环境的大鼠的UFPM的大脑 实时陷阱； （5）用于表征化学成分的高光谱和拉曼光谱 大鼠和人脑中UFPM的of of评估大脑分布并进一步告知来源。使用这些资源， 我们将解决以下目的：1。确定暴露于陷阱的TGF344-AD大鼠大脑中UFPM的来源 并评估大鼠大脑中UFPM与与AD相关的神经病理学的空间关系。 2。确定是否 人类对UFPM的暴露与（a）事件认知障碍和AD/ADRD有关，并且（b）加速 认知能力下降的速度。 3。在人类AD/ADRD脑样本中启动探索性研究，以确定是否是否 LDC个体的精选大脑区域中的UFPM与AD病理有关。该项目的数据将识别 与UFPM相关的AD/ADRD相关神经病理学，这是开发机械假设的第一步 可以在以后的研究中进行测试。此外，该项目解决了（1）生物合理性和临床 UFPM在空气污染中的相关性是修改AD/ADRD计划的环境因素 并为人类的AD/ADRD大鼠模型做出贡献 暴露于污染空气中的UFPM； （3）支持公共卫生和监管所需的数据 控制与AD/ADRD相关的UFPM关键来源的策略。