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

评估微管结合作为阿尔茨海默病的潜在成像生物标志物

• 批准号: 10541153
• 负责人: Kiran Solingapuram Sai
• 金额: $ 47.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541153
• 关键词: AD transgenic mice; APP-PS1; Affinity; Aftercare; Age Months; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amyloid beta-Protein; Attention; Autoradiography; Axonal Transport; Binding; Biochemical; Biodistribution; Biological Assay; Biological Markers; Brain; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Cytoskeleton; Data; Dependence; Disease; Disease Progression; Early Diagnosis; Future; Glioblastoma; Goals; Image; Impaired cognition; Impairment; In Vitro; Laboratories; Magnetic Resonance Imaging; Malignant neoplasm of brain; Measures; Methods; Microtubule stabilizing agent; Microtubules; Modality; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Production; Reducing Agents; Reporting; Research; Research Personnel; Signal Transduction; Stabilizing Agents; Stratification; Structural Protein; Tauopathies; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Studies; Time; Tracer; Transgenic Organisms; Treatment Protocols; Tubular formation; Wild Type Mouse; Work; X-Ray Computed Tomography; abeta accumulation; beta amyloid pathology; clinical imaging; clinically relevant; cohort; density; diagnostic biomarker; extracellular; human subject; hyperphosphorylated tau; imaging agent; imaging biomarker; imaging properties; imaging study; improved; in vivo; in vivo imaging; innovation; microPET/CT; mouse model; nervous system disorder; neuroimaging; neuropathology; novel; overexpression; precision medicine; scaffold; small molecule; standard care; targeted treatment; tau Proteins; tau aggregation; tau-1; tool; transgenic model of alzheimer disease; translational potential; treatment strategy; uptake

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.

项目摘要/摘要 tau蛋白高磷酸化引起的神经元微管的损害与 许多疾病病理学，包括阿尔茨海默氏病（AD），帕金森氏病和其他神经系统 疾病。但是，那里 技术。 （宠物） 指示 神经变性 方式 没有使用临床成像来量化微管的可靠无创方法 关键的未解决的问题是正电子发射断层扫描的定量性质是否 利用以测量微管的体内浓度。越来越多的科学证据 微管稳定剂可针对 在治疗广告中。但是，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 可以 那 我们的目标是开发微管的体内成像 在AD进展的各个阶段使用我们新颖的宠物问题。我们提出了3个特定目标 强大的初步数据。在AIM 1中，我们将确定微管完整性与淀粉样蛋白之间的关系 通过使用[11C] MPC-6827和淀粉样蛋白的微管的纵向微型细节/CT成像，β病理 β成像AD的两个鼠模型中的[11C] PIB。在AIM 2中，我们将量化和表征微管 使用[3H]/[11C] MPC-6827在大脑中吸收相同的AD鼠模型。我们将执行Ex Vivo 生物分布，体外自身自显影和组织病理学测定法，以将微管密度与 常规的神经虫标志物。在AIM 3中，我们将确定并确定微管成像吸收的依赖性 治疗干预后，淀粉样蛋白β和/或tau水平。我们将在 在标准治疗方案之前，之中和之后，具有潜力的标准治疗方案前，期间和之后的两个鼠模型 降低淀粉样β和/或tau水平的治疗剂。在这个项目中，由早期调查员领导，我们 假设我们可以将微管支架扩展为体内成像剂的潜力，而不仅仅是 在早期诊断AD，但也遵循治疗方法的治疗效用。宠物成像数据 生成的可能是临床医生在进展和治疗的几个阶段评估AD的宝贵工具。 该项目是第一个提出AD中体内微管成像的成像。如果成功，这项工作将提供 一个新的范式实时直接在体内探测微管。我们的工作可以显着提高精度 药物治疗AD和其他神经退行性疾病的方法。