Evaluating microtubule binding as a potential imaging biomarker for Alzheimer's disease

项目概要/摘要 由于tau蛋白过度磷酸化导致的神经元微管损伤涉及 包括阿尔茨海默病（AD）、帕金森病和其他神经系统疾病在内的许多疾病病理 紊乱但 技术. （PET） 指示 神经变性 方式 没有可靠的非侵入性方法来量化微管使用临床成像 一个尚未回答的关键问题是，正电子发射断层扫描的定量性质是否 用来测量体内微管的浓度。越来越多的科学证据 微管稳定剂提供保护性益处以抵抗 治疗AD。然而，量化这些保护效益是困难的，因为没有 直接探测它们与微管的相互作用。 一 可以 的 我们的目标是开发微管的体内成像 使用我们的新型PET探针，在AD进展的所有阶段。因此，我们提出了三个具体目标，根据我们的 强有力的初步数据在目标1中，我们将确定微管完整性和淀粉样蛋白之间的关系 通过用[11 C]MPC-6827和淀粉样蛋白对微管进行纵向microPET/CT成像的β病理学 在两种AD小鼠模型中使用[11 C]PiB进行β成像。在目标2中，我们将定量和表征微管， 使用[3 H]/[11 C]MPC-6827在相同的AD鼠模型的脑中的摄取。我们将在体外进行 生物分布，体外放射自显影和组织病理学测定，以将微管密度与 常规的神经生物标志物。在目标3中，我们将确定和建立微管成像摄取的依赖性， 淀粉样蛋白β和/或tau水平。我们将执行microPET/CT图像， 相同的两种AD鼠模型，在标准治疗方案之前、期间和之后， 降低淀粉样蛋白β和/或tau水平的治疗剂。在这个项目中，由早期研究人员领导，我们 假设我们可以扩大微管支架作为潜在的体内成像剂，不仅 在早期诊断AD，但也要遵循治疗的治疗效用。pet成像数据 可能是临床医生评估AD进展和治疗的几个阶段的有价值的工具。 该项目是第一个提出在AD中对微管进行体内成像的项目。如果成功，这项工作将提供 一个新的范例，直接探测微管在体内真实的时间。我们的工作可以显著提高 用于治疗AD和其他神经退行性疾病的药物方法。

Project Summary/Abstract Impairment of neuronal microtubules resulting from hyper-phosphorylation of the tau proteins is implicated in many disease pathologies including Alzheimer's disease (AD), Parkinson disease and other neurological disorders. However, there techniques. (PET) indicates neurodegeneration way are no reliable noninvasive methods to quantify microtubules using clinical imaging key unanswered question is whether the quantitative nature of Positron Emission Tomography harnessed to measure in vivo concentrations of microtubules. Increasing scientific evidence microtubule stabilizing agents provides protective benefits against the deleterious effects of in treating AD. However, quantifying these protective benefits is difficult, since there is no to directly probe their interactions with microtubules. A can be that Our goal is to develop in vivo imaging of microtubules using our novel PET probes, at all stages of AD progression. Thus we propose 3 Specific Aims based on our strong preliminary data. In Aim 1, we will determine the relationship between microtubule integrity and amyloid β pathology by performing longitudinal microPET/CT imaging of microtubules with [11C]MPC-6827 and amyloid β imaging with [11C]PiB in two murine models of AD. In Aim 2, we will quantify and characterize microtubule uptake in brains of the same murine models of AD using [3H]/[11C]MPC-6827. We will perform ex vivo biodistribution, in vitro autoradiography and histopathological assays to correlate microtubule density with routine neurobiomarkers. In Aim 3, we will determine and establish dependency of microtubule imaging uptake to amyloid β and/or tau levels after therapeutic interventions. We will perform microPET/CT images in the same two murine models of AD, before, during and after the standard treatment protocols with potential therapeutic agents reducing amyloid β and/or tau levels. In this project, led by an Early Stage Investigator, we hypothesize that we can expand the microtubule scaffold as potential in vivo imaging agents, not only to diagnose AD at an early stage, but also follow the therapeutic utility of the treatments. The PET imaging data generated could be a valuable tool for clinicians to assess AD in several stages of progression and treatment. This project is the first to propose the imaging of microtubules in vivo in AD. If successful, this work will provide a new paradigm to directly probe microtubules in vivo in real time. Our work could markedly enhance precision medicine approaches for treatment of AD and other neurodegenerative diseases.