Determine the role of atmospheric particulate matter pollutants in contributing to Lewy Body Dementia

确定大气颗粒物污染物在路易体痴呆症中的作用

• 批准号: 10662930
• 负责人: Pengfei Liu
• 金额: $ 229.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662930
• 关键词: Accounting; Address; Aerosols; Affect; Air Pollutants; Air Pollution; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Anatomy; Animal Behavior; Animals; Anxiety; Area; Atmosphere; Autopsy; Behavioral Symptoms; Biomass; Blood; Braak' s hypothesis; Brain; Brain region; Central Nervous System; Chemicals; China; Clinical; Cognition; Collection; Complex; Consensus; Data; Dementia; Dementia with Lewy Bodies; Elderly; Environmental Pollutants; Epidemiologist; Epidemiology; Etiology; Exclusion; Exhibits; Exposure to; Family; Gases; Gastrointestinal tract structure; Generations; Goals; Histology; Hospitalization; Impaired cognition; In Vitro; Incidence; Individual; Knowledge; Laboratories; Lewy Body Dementia; Lung; Mass Spectrum Analysis; Memory impairment; Mental Depression; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurologic; Neurologic Effect; Nose; Parkinson' s Dementia; Particulate Matter; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Play; Policy Making; Pollution; Positioning Attribute; Prevention strategy; Recombinants; Research; Risk; Risk Factors; Role; Sampling; Site; Smog; Source; Spectrometry; Speed; Stereotyping; Time; Toxic Environmental Substances; Transgenic Organisms; Translations; Water; Wild Type Mouse; air pollution control; alpha synuclein; anthropogenesis; biological systems; brain pathway; environmental stressor; epidemiology study; experimental study; fine particles; genome-wide; mood symptom; mouse model; neuroinflammation; neuropsychiatry; neurotoxicity; novel; olfactory bulb; particle; pollutant; pre-formed fibril; prion-like; response; socioeconomic disparity; stressor; success; synucleinopathy; transcriptomic profiling; treatment strategy

Project Summary There is a consensus that environmental pollutants are a risk factor for Alzheimer's Disease Related Dementias (ADRD). Emerging evidence has shown that environmental stressors (e.g., urban and roadside air pollution) contribute to dementia. Our supporting epidemiological results have determined that annual mean particulate matter (PM) pollution in the USA is significantly associated with an increased risk of first hospital admission with ADRD. We found strong evidence of linearity in concentration-response relationship at PM concentration less than 16 μg/m3 (95th percentile of the PM distribution). PM pollutants can target the central nervous system (CNS). However, what specific PM pollutants are associated with dementia and the underlying mechanisms are poorly known. One of the most common dementia is called “Lewy Body Dementia (LBD)” with the typical hallmark of αS pathology, including Dementia with Lewy body (DLB) and Parkinson's Disease with Dementia (PDD). Patients with LBD suffer from cognition and memory dysfunction, behavioral and mood symptoms (e.g., depression, anxiety, and etc.), affecting 1.4 million individuals and their families in the USA. Furthermore, 30% of the Alzheimer's disease (AD) subjects with αS pathology generally exhibit a more rapid rate of cognitive decline than subjects with AD alone. Substantial postmortem studies by Braak et al. showed the presence of αS pathology was initialized in the olfactory bulb (OB) and gastrointestinal tract, and spread to the brain following stereotypical anatomical stages, resulting in autonomic, neuropsychiatric, and cognitive dysfunction. In addition to clinical observations, emerging evidence has shown pathogenic αS spreading is a master trigger to cognitive impairment (CI) by using inoculation of recombinant αS preformed fibrils (PFF). The majority cases of αS-related dementia (LBD and ⅓ AD) are sporadic and have many causes. Braak's theory well supports the hypothesis that αS-related dementia may begin when foreign stressor (e.g., PM pollutants) enter the body via the nose/gut, induce αS aggregation and subsequent prion-like pathology spreading into the CNS, which results in ADRD. While epidemiological studies demonstrating an association of ADRD with air pollutants are relatively abundant, there is a clear unmet need for more mechanistic research. This knowledge is critical for achieving a complete understanding of the etiology of LBD and the translation of such knowledge to novel prevention and treatment strategies. This is especially important for understanding the causes of socioeconomic inequities in ADRD, and importantly, environmental toxicant risk factors are potentially modifiable.

项目摘要 有一个共识，即环境污染物是阿尔茨海默病相关痴呆症的危险因素 （ADRD）.新出现的证据表明，环境压力因素（例如，（市区及路边空气污染） 会导致痴呆我们的支持流行病学结果已经确定， 在美国，PM污染与首次入院的风险增加显著相关， ADRD。我们发现了强有力的证据，浓度-响应关系的线性在PM浓度小于 低于16微克/立方米（PM分布的第95百分位数）。PM污染物可以靶向中枢神经系统（CNS）。 然而，具体什么样的PM污染物与痴呆症相关，其潜在机制尚不清楚 知道的最常见的痴呆症之一被称为“路易体痴呆症（LBD）”，其典型特征是： αS病理学，包括路易体痴呆（DLB）和帕金森病痴呆（PDD）。 患有LBD的患者患有认知和记忆功能障碍、行为和情绪症状（例如， 抑郁、焦虑等），影响了美国140万人及其家庭。此外，30% 的阿尔茨海默病（AD）患者的αS病理学通常表现出更快的认知速度， 比单独患有AD的受试者下降。Braak等人进行的大量尸检研究表明， 病理开始于嗅球（OB）和胃肠道，并在 刻板的解剖学阶段，导致自主神经，神经精神和认知功能障碍。此外 从临床观察来看，新出现的证据表明致病性αS传播是认知障碍的主要触发因素， 通过接种重组αS预形成的原纤维（PFF）来检测损伤（CI）。大多数α S相关病例 痴呆（LBD和假性AD）是散发性的并且有许多原因。布拉克的理论很好地支持了这一假设 与α S相关的痴呆症可能开始外来压力源（例如，PM污染物）通过鼻子/肠道进入人体， 诱导αS聚集和随后朊病毒样病变扩散至CNS，导致ADRD。 虽然证明ADRD与空气污染物相关的流行病学研究相对丰富， 对更多的机械研究的需求显然没有得到满足。这些知识对于实现一个完整的 了解LBD的病因，并将这些知识转化为新的预防和治疗方法 战略布局这对于理解ADRD中社会经济不平等的原因尤为重要， 重要的是，环境毒物风险因素是可以改变的。