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

项目摘要 测量蓝斑（LC）结构的神经影像学方法的出现 诚信引起了专注于阿尔茨海默氏症的科学领域的强烈兴趣 疾病（AD）、精神疾病以及基础认知神经科学。述LC 脑中神经调节剂去甲肾上腺素（NE）的主要产生者， 大脑中最先积累过度磷酸化tau蛋白的区域， AD中的病理因子。使用磁共振（MR）成像评估 LC完整性为疾病加速的最早检测开辟了令人兴奋的可能性， 并且还可以提供捕获关于个体的信息的MR测量 神经化学功能的差异。研究活体神经化学系统的能力 在人类中是有限的，使用放射性示踪剂的成像方法是最 建立（例如正电子发射断层扫描（PET））。然而，由于负担， 主题，以及基础设施的挑战，PET成像是不是一个工具，许多 尽管NE等神经调节系统在基础免疫中发挥着重要作用， 认知与疾病我们将采取初步措施，测试LC MR的有效性 通过检查A与B之间的对应关系来预测NE功能的措施 神经黑色素敏感的LC完整性MR测量和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））在健康年轻人和老年人中的受试者（目标1）。越来越多的证据 在健康老龄化、AD和帕金森病中， 对损伤作出反应并显示出补偿能力。接下来，我们将测试假设 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病理学进展的预测者的效用， 我们将探讨神经黑素敏感的MR和[18 F]FMT是否能预测 使用tau-敏感的[18F]flortaucipir在内侧颞叶中的tau积累 成像（Aim 3）。总之，这项研究采取了关键步骤，建立MR 方法敏感的神经化学功能，检查有趣的机制， 神经化学补偿，并提供病理模型的实证检验 在AD中传播。

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.