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

项目摘要/摘要 Tau蛋白过度磷酸化导致的神经元微管损伤与 许多疾病的病理包括阿尔茨海默病(AD)、帕金森病和其他神经系统疾病 精神错乱。然而，在那里 技巧。 (宠物) 表示 神经退行性变 道路 目前还没有可靠的非侵入性方法来使用临床成像来量化微管 关键的悬而未决的问题是正电子发射断层扫描的定量性质 用来测量体内微管的浓度。越来越多的科学证据 微管稳定剂提供了保护作用，防止有害的影响 治疗阿尔茨海默病。然而，量化这些保护益处是困难的，因为没有 直接探测它们与微管的相互作用。 一个 可 那 我们的目标是开发微管的活体成像 使用我们的新型PET探针，在AD进展的所有阶段。在此基础上，我们提出了三个具体目标 强劲的初步数据。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 用[11C]MPC-6827和淀粉样蛋白对微管进行纵向microPET/CT成像的β病理 两种AD小鼠模型的[11C]PIBβ显像在目标2中，我们将对微管进行量化和表征 使用[~3H]/[11C]MPC-6827的相同AD模型小鼠的脑摄取。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检测微管密度与 常规神经生物标记物。在目标3中，我们将确定并建立微管成像摄取的依赖性。 在治疗干预后恢复到淀粉样蛋白β和/或tau水平。我们将在这里进行microPET/CT成像 相同的两种AD小鼠模型，在标准治疗方案之前、期间和之后具有潜在的 降低淀粉样蛋白β和/或tau水平的治疗剂。在这个由早期调查员领导的项目中，我们 假设我们可以将微管支架扩展为潜在的体内显像剂，而不仅仅是 早期诊断阿尔茨海默病，还要观察治疗的效果。PET成像数据 对于临床医生评估进展和治疗的几个阶段的AD来说，生成的可能是一个有价值的工具。 本项目首次提出了AD患者体内微管的成像。如果成功，这项工作将提供 一种实时直接探测体内微管的新范式。我们的工作可以显著提高精度 治疗阿尔茨海默病和其他神经退行性疾病的医学方法。

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.