Locus Coeruleus Biomarker Development for Early Detection of Alzheimers Disease in Humans

项目摘要 测量蓝斑结构的神经影像方法的出现 诚信引起了关注阿尔茨海默氏症的科学领域的浓厚兴趣 疾病(AD)、精神障碍以及基础认知神经科学。信用证是 大脑是神经调节剂去甲肾上腺素(NE)的主要生成器，是 大脑中第一个积累过度磷酸化tau蛋白的区域，这是一个标志 阿尔茨海默病的病理因素。使用磁共振(MR)成像进行评估的能力 LC完整性为最早检测疾病加速开辟了令人兴奋的可能性， 并且还可以提供捕获关于个人的信息的MR测量 神经化学功能的差异。在体内研究神经化学系统的能力 对人体的影响有限，使用放射性示踪剂的成像方法是最多的 已建立(例如正电子发射断层扫描(PET))。然而，由于要承担 主题，以及基础设施的挑战，PET成像并不是一种很多工具 尽管NE等神经调节系统在BASIC中发挥着核心作用，但研究人员仍在使用 认知和疾病。我们将采取初步步骤来测试LC MR的有效性 通过检查两个变量之间的对应关系来预测NE函数的方法 神经黑色素敏感的磁共振测量LC完整性和PET测量 儿茶酚胺(去甲肾上腺素/多巴胺)合成能力([18F]氟-L-m-酪氨酸 (FMT)在健康的年轻人和老年人的受试者中(目标1)。积累证据 在健康老龄化、AD和帕金森病中，儿茶酚胺系统 对受伤做出反应，并表现出补偿能力。接下来，我们将检验这一假设 随着年龄的增长，儿茶酚胺的合成增加(目标2)。最后，为了测试 LC神经成像测量作为tau病理进展的预测工具的作用， 我们将探索神经黑色素敏感的MR和[18F]FMT是否可以预测 用tau敏感的[18F]氟他西平研究tau在内侧颞叶的蓄积 成像(目标3)。总之，这项研究在建立MR方面采取了关键步骤 对神经化学功能敏感的方法，研究了有趣的机制 神经化学补偿，并提供了病理模型的经验测试 传播于公元后。

Project Summary The advent of neuroimaging methods for measuring locus coeruleus (LC) structural integrity has generated intense interest from scientific fields focused on Alzheimer’s disease (AD), psychiatric disorders, as well as basic cognitive neuroscience. The LC is the brain’s primary generator of the neuromodulator norepinephrine (NE) and is one of the first brain regions to accumulate hyperphosphorylated tau protein, a hallmark pathological agent in AD. The ability to use magnetic resonance (MR) imaging to assess LC integrity opens up exciting possibilities for earliest detection of disease acceleration, and may also provide an MR measure that captures information about individual differences in neurochemical function. The ability to study neurochemical systems in vivo in humans is limited, with imaging approaches using radioactive tracers being the most established (e.g. positron emission tomography (PET)). However, due to the burden to subjects, as well as the infrastructural challenges, PET imaging is not a tool many researchers use despite the central role neuromodulatory systems like NE play in basic cognition and disease. We will take initial steps towards testing the validity of LC MR measures for predicting NE function by examining the correspondence between a neuromelanin-sensitive MR measure of LC integrity and a PET measure of catecholamine (norepinephrine/dopamine) synthesis capacity ([18F]Fluoro-l-m-tyrosine (FMT)) within subject in healthy young and older adults (Aim 1). Accumulating evidence in healthy aging, AD, and Parkinson’s disease suggests the catecholamine system responds to injury and shows compensatory capacity. Next, we will test the hypothesis that with advancing age, catecholamine synthesis goes up (Aim 2). Finally, to test the utility of LC neuroimaging measures as forecasters of the advancement of tau pathology, we will explore whether neuromelanin-sensitive MR and [18F]FMT predict the accumulation of tau in the medial temporal lobe using tau-sensitive [18F]flortaucipir imaging (Aim 3). Together, this research takes critical steps in establishing MR approaches as sensitive to neurochemical function, examines intriguing mechanisms of neurochemical compensation, and provides empirical testing of models of pathological spread in AD.