Airborne metals, neurodegeneration, and dementia in the Adult Changes in Thought study

项目摘要 1)目标：我们将定义暴露于PM2.5和金属的关联和途径 有助于痴呆相关的神经病理学（DAN）、偶发性痴呆和认知功能。我们将尽 因此，通过利用来自成人思想变化（ACT）研究的资源， 在老年人中进行的脑老化和痴呆的研究，这些老年人在登记时认知完整。每两年 自1994年以来，ACT收集了关于痴呆症、其他大脑健康指标、身体健康、生活方式 药物治疗和居住史超过5000名参与者，跟踪他们直到发生痴呆或死亡。 在每个时间点，ACT使用认知能力筛查工具（CASI）评估痴呆， 使用DSM-IV标准的共识诊断。AD也根据NINCDS标准进行评估。为与会者 同意尸检的人（约25%），ACT对其大脑进行神经病理学检查，包括 痴呆症诊断的确认。我们的研究将建立在这些数据和资源，以实现3个主要的 目的：（1）表征嗅球（OB）、嗅道（OT）和嗅鞘（OT）内PM2.5和金属浓度， 大约140名人类捐赠者的脑组织，以确定OB是否是空气污染物通过的途径。 （2）研究OB作为这些供体OB和大脑内DAN的途径;以及 (3)评估PM2.5、金属与痴呆事件的相关性-包括病理学定义的AD， μVBI、LBD和混合型痴呆和认知功能，控制关键混杂因素并检查影响 按性别、种族/民族、社会经济和健康状况进行修改，并按健康状况进行调解。 2)方法：我们将采用多学科方法来测试我们的目标，该方法依赖于（1）我们详细的 对同意接受ACT治疗的参与者的大脑和OB进行颗粒、金属和DAN指标分析， 尸检和（2）我们对长期环境PM2.5和金属之间关系的流行病学分析 对于整个ACT队列和具有以下特征的子集， 神经病理学证实了痴呆诊断对于这两者，我们将利用ACT丰富的临床和 功能性健康指标、行为和居住史。例如，我们将使用住宅 历史来估计每个ACT参与者的长期环境PM2.5和相关金属暴露， 新颖的时空模型。我们还将使用健康和行为数据来控制关键混杂因素， 预测因子和健康数据，以评估污染-痴呆关联的修改和调解。 3)预期结果：我们将提供新的证据，证明空气中的金属对痴呆症的风险 以及空气中的金属造成损害的途径。这样做，我们的研究结果将有助于 确定有针对性的干预措施，以阻止痴呆症的类型，并减轻严重和日益增长的 AD和其他痴呆症的负担。

Project Summary 1) Objectives: We will define associations and pathways through which exposure to PM2.5 and metals contribute to dementia-associated neuropathology (DAN), incident dementia, and cognitive function. We will do so by leveraging resources from the Adult Changes in Thought (ACT) study, an ongoing, prospective cohort study of brain aging and dementia in older adults who are cognitively intact at enrollment. Every two years since 1994, ACT has collected vetted data on dementia, other brain health measures, physical health, lifestyle, medications, and residential history for over 5000 participants, following them until incident dementia or death. At each timepoint, ACT assesses dementia using the Cognitive Abilities Screening Instrument (CASI) and consensus diagnosis using DSM-IV criteria. AD is also assessed based on NINCDS criteria. For participants who consent to autopsy (~25%), ACT performs a neuropathological examination of their brains, including confirmation of dementia diagnoses. Our study will build on these data and resources to achieve 3 primary aims: (1) to characterize PM2.5 and metal concentrations within the olfactory bulb (OB), olfactory tract (OT), and brain tissues of ~140 human donors to establish whether the OB is a pathway through which air pollutants reach the brain; (2) to investigate the OB as a pathway for DAN within the OBs and brains of these donors; and (3) to assess the association of PM2.5, metals with incident dementia - including for pathologically-defined AD, μVBI, LBD, and mixed dementia – and cognitive function, controlling for key confounders and examining effect modification by sex, race/ethnicity, socio-economics, and health conditions and mediation by health conditions. 2) Approach: We will test our aims following a multi-disciplinary approach that relies on (1) our detailed analysis of brains and OB for particles, metals and DAN indicators for ACT participants who consented to autopsy and (2) our epidemiological analyses of the association of long-term ambient PM2.5 and metal exposures with incident dementia, AD, μVBI, and LBD for the entire ACT cohort and for the subset with neuropathology confirmed dementia diagnoses. For both, we will leverage ACT’s rich database of clinical and functional health measures, behaviors, and residential histories. We, for example, will use the residential histories to estimate long-term ambient PM2.5 and associated metal exposures for each ACT participant using novel spatio-temporal models. We will also use health and behavioral data to control for key confounders and predictors and health data to assess modification and mediation of the pollutant-dementia associations. 3) Expected Results: We will provide new evidence of the risks posed by airborne metals to incident dementia and of the pathways through which airborne metals cause damage. In so doing, results from our study will help identify targeted interventions to block pathways to dementia by type and mitigate the severe and growing burden of AD and other dementias.