Translational pharmacoepidemiology: neuroprotection and neurotoxicity of antihypertensives and strong anticholinergics

项目3摘要 药物是生命过程流行病学框架中的一个重要组成部分，它将成年人的变化联系在一起 一起思考(ACT)U19计划。治疗慢性病的药物要分几年服用，通常是 从中年开始，慢性养生法可以达到稳定的血液水平，因此对大脑有毒性或保护性作用 暴露在药物中的可能性是合理的。成人思维变化(ACT)研究是一项令人难以置信的研究 20多年的前沿痴呆症药物流行病学研究资源。我们采取了多方面的 使用一系列与大脑相关的测量方法检查常见药物和大脑健康之间的联系的方法 以加深我们对这些关系和机制的理解。相当可观的 药物流行病学研究中固有的方法学问题因适应症而令人困惑，其中 开出药物的情况与痴呆症有关，而不是药物本身。在这个项目中， 我们采取创新和转换的方法来补充我们现有的药物流行病学方法。 通过部署分子分析，将直接解决指征偏差与基于细胞的模型的混淆 使用来自ACT参与者的人诱导多能干细胞(HiPSC)来源的神经元(hiPSC-NS)。这个 以下目标将通过与所有项目核心直接合作来实现。目标1：部署人类干细胞-- 基于分子分析直接测试抗胆碱类药物(ACHS)和Address的神经毒性机制 有迹象表明令人困惑。我们将部署四种细胞结果的检测方法：AD病理 分子，抗体和ptau；神经毒性；和神经功能。目标2：确定以下各项之间的比较联系 抗高血压药物(AHTS)与痴呆和AD(2A)、神经病理学(2B)和神经成像结果(2C)， 和测试神经保护机制(2D)。我们将检验假设，在控制了它们的影响之后 在血压方面，与Ang-II↑药物相比，接触Ang-II↓药物与较低的风险相关 痴呆症和阿尔茨海默病、神经病理学和神经成像结果。我们将检验Ang-II↑药物的假设 将对细胞结果(即：Aβ和Ptau、神经毒性和神经功能)产生积极影响 使用血管紧张素转换酶II↓药物，使用在目标1中发展出的hIPSC来源的神经元组。 我们的项目具有重要的

PROJECT 3 ABSTRACT Medications are an important exposure in the life course epidemiology framework that ties the Adult Changes in Thought (ACT) U19 Program together. Medications for chronic conditions are taken over several years, often beginning in mid-life, and chronic regimens achieve consistent blood levels, so toxic or protective brain effects of medication exposures are plausible. The Adult Changes in Thought (ACT) study has served as an incredible resource for cutting-edge dementia pharmacoepidemiology research for over 20 years. We take a multifaceted approach to examine links between common drugs and brain health by using an array of brain-related measures in the same cohort to deepen our understanding about these relationships and mechanisms. A considerable methodologic issue inherent in pharmocoepidemiology research is confounding by indication, where the condition for which a drug is prescribed is associated with dementia rather than the drug itself. In this Project, we take an innovative and translational approach to complement our existing pharmacoepidemology methods by deploying molecular assays that will directly address confounding by indication bias with a cell-based model using human induced pluripotent stem cell (hiPSC)-derived neurons (hiPSC-Ns) from ACT participants. The following Aims will be accomplished by working directly with all Project Cores. Aim 1: Deploy a human stem cell- based molecular assay to directly test mechanisms of neurotoxicity from anticholinergics (AChs) and address confounding by indication. We will deploy assays that measure four cellular outcomes: AD pathological molecules, Ab and pTau; neurotoxicity; and neuronal function. Aim 2: To determine comparative associations of antihypertensives (AHTs) with dementia and AD (2A), neuropathology (2B), and neuroimaging outcomes (2C), and test mechanisms of neuroprotection (2D). We will test the hypotheses that after controlling for their effects on blood pressure, exposure to Ang-II↑ drugs compared with Ang-II↓ drugs is associated with lower risk of dementia and AD, neuropathology and neuroimaging outcomes. We will test the hypothesis that Ang-II↑ drugs will have positive effects on cellular outcomes (i.e: Aβ and pTau, neurotoxicity and neuronal function) compared with an Ang-II↓ drug using the group of hiPSC-derived neurons developed in Aim 1. Our Project has important