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

项目摘要 1)目标：我们将确定PM2.5和金属暴露的关联和途径 有助于痴呆症相关神经病理(DAN)、偶发痴呆症和认知功能。我们会做的 因此，通过利用成人思维变化(ACT)研究的资源，正在进行的前瞻性队列 研究登记时认知完好的老年人的大脑老化和痴呆症。每两年一次 自1994年以来，ACT收集了关于痴呆症、其他脑健康指标、身体健康、生活方式、 超过5000名参与者的药物和居住史，跟踪他们直到事件痴呆症或死亡。 在每个时间点，ACT使用认知能力筛查仪(CASI)和 采用DSM-IV标准进行共识诊断。AD还根据NINCDS标准进行评估。对于参与者 同意尸检的人(~25%)，ACT对他们的大脑进行神经病理检查，包括 确认痴呆症诊断。我们的研究将以这些数据和资源为基础，实现三个主要目标 目的：(1)描述嗅球(OB)、嗅束(OT)内PM2.5和金属的浓度。 约140名人类捐赠者的脑组织以确定OB是否是空气污染物的途径 到达大脑；(2)研究OB作为DAN在这些捐赠者的OB和大脑中的途径；以及 (3)评估PM2.5、金属与偶发性痴呆症的关联--包括病理定义的AD， μVBI、LBD和混合性痴呆--和认知功能、关键混杂因素的控制和效果检查 按性别、种族/族裔、社会经济和健康状况进行调整，并按健康状况进行调解。 2)方法：我们将遵循多学科方法测试我们的目标，该方法依赖于(1)我们详细的 同意的ACT参与者的大脑和OB颗粒、金属和DAN指标的分析 尸检和(2)我们对长期环境PM2.5与金属相关性的流行病学分析 在整个ACT队列和子组中，暴露于事件痴呆、AD、μVBI和LBD 神经病理学证实了痴呆症的诊断。对于两者，我们将利用ACT丰富的临床和 功能性健康测量、行为和居住史。例如，我们将使用住宅 评估每个ACT参与者的长期环境PM2.5和相关金属暴露的历史记录，使用 新的时空模型。我们还将使用健康和行为数据来控制关键混杂因素和 评估污染物-痴呆症关联的修改和调解的预测因素和健康数据。 3)预期结果：我们将提供新的证据，证明空气中金属对偶发痴呆症构成的风险 以及空气中金属造成损害的途径。在此过程中，我们的研究结果将有所帮助 确定有针对性的干预措施，按类型阻断痴呆症的途径，并缓解严重和不断增长的 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.