Magnetic Resonance Imaging of Alzheimer's Amyloid Plaque

阿尔茨海默病淀粉样斑块的磁共振成像

• 批准号: 6752087
• 负责人: JOSEPH F PODUSLO
• 金额: $ 56.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752087
• 关键词: Alzheimer' s disease; aging; amyloid proteins; bioimaging /biomedical imaging; blood brain barrier; brain imaging /visualization /scanning; cerebral cortex; contrast media; gadolinium; genetically modified animals; high performance liquid chromatography; hippocampus; histology; immunocytochemistry; laboratory mouse; magnetic resonance imaging; membrane permeability; molecular probes; neuritic plaques; protein binding; putrescine

DESCRIPTION (provided by applicant): This project will test the hypothesis that modifications of amyloid-beta protein (A beta) or derivatives of A beta can be used for the molecular imaging of amyloid plaques in Alzheimer's disease (AD). This is based on the observation that not only does AI3 provide the seed for the formation of plaques, but it also binds to pre-existing plaques with high affinity and facilitates their growth. Various derivatives of A beta will be examined and compared to A beta 1-40, including A beta 1-30, which excludes the cell surface binding domain (A beta 31-34); A beta 1-25, which excludes the neurotoxic domain (A beta 25-35); and A beta 1-15, which excludes the aggregation domain (A beta 16-20). It is particularly important to develop a derivative of A beta that is non-toxic. We have solved an important problem regarding the delivery of A beta 1-40 across the blood-brain barrier (BBB) after systemic administration by using polyamine-modified A beta, which results in an increase in the permeability coefficient x surface area product (PS) of the protein at the BBB. Polyamine modification increases the binding of A beta to amyloid plaques in AD brain tissue sections. Furthermore, we have demonstrated that polyamine-modified A beta 1-40 labels plaques in vivo following intravenous injection in a transgenic mouse model of AD. Our preliminary results document the success of this molecular probe, now coupled with an MRI contrast agent, gadolinium, in addition to the polyamine, putrescine, to label AD amyloid plaques throughout the cortex, hippocampus, and other brain regions of AD transgenic mice following intravenous injection. We are able to image individual plaques using high-field-strength 7-Tesla magnetic resonance imaging (MRI) with high resolution and observe alterations in T1-weighted (T1W) and T2-weighted (T2W) relaxation that are probe specific. The Specific Aims reflect the further development of this contrast agent for characterizing and quantifying the deposition of amyloid plaques in AD transgenic mice by MRI. Although this research may raise numerous questions concerning the feasibility of MR imaging of AD plaques in humans, we believe that the specific aims listed will facilitate answers to these questions in a logical manner by minimizing neurotoxicity, by optimizing the molecular probe for targeting and binding to AD plaques, and by optimizing imaging parameters both ex vivo and in vivo in the AD transgenic mouse. All of these steps are clearly necessary before application to the AD patient. The ability of this MR contrast agent to image plaques in vivo in the AD transgenic mouse may enable early diagnosis of the AD patient and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed.

描述（由申请人提供）： 该项目将测试以下假设：β 淀粉样蛋白 (Aβ) 或 Aβ 衍生物的修饰可用于阿尔茨海默病 (AD) 中淀粉样斑块的分子成像。这是基于以下观察：AI3 不仅为斑块的形成提供种子，而且还以高亲和力与预先存在的斑块结合并促进其生长。将检查Aβ的各种衍生物并与Aβ1-40进行比较，包括Aβ1-30，其不包括细胞表面结合结构域（Aβ31-34）； A beta 1-25，不包括神经毒性结构域（A beta 25-35）；和 A beta 1-15，不包括聚合域（A beta 16-20）。开发无毒的Aβ衍生物尤为重要。我们通过使用多胺修饰的 Aβ 解决了全身给药后 Aβ1-40 穿过血脑屏障 (BBB) 的重要问题，这导致 BBB 处蛋白质的渗透系数 x 表面积乘积 (PS) 增加。多胺修饰增加了 AD 脑组织切片中 Aβ 与淀粉样斑块的结合。此外，我们还证明，在 AD 转基因小鼠模型中静脉注射后，多胺修饰的 A beta 1-40 可在体内标记斑块。我们的初步结果证明了这种分子探针的成功，现在除了多胺、腐胺之外，现在还与 MRI 造影剂钆结合，在静脉注射后标记 AD 转基因小鼠整个皮层、海马和其他大脑区域的 AD 淀粉样斑块。我们能够使用高分辨率的高场强 7 特斯拉磁共振成像 (MRI) 对单个斑块进行成像，并观察探针特异性的 T1 加权 (T1W) 和 T2 加权 (T2W) 松弛的变化。具体目标反映了这种造影剂的进一步开发，用于通过 MRI 表征和量化 AD 转基因小鼠中淀粉样斑块的沉积。尽管这项研究可能会提出许多关于人类 AD 斑块 MR 成像可行性的问题，但我们相信，所列出的具体目标将通过最大限度地减少神经毒性、优化用于靶向和结合 AD 斑块的分子探针、以及优化 AD 转基因小鼠的离体和体内成像参数，以合乎逻辑的方式促进这些问题的答案。在应用于 AD 患者之前，所有这些步骤显然都是必要的。这种 MR 造影剂能够对 AD 转基因小鼠体内的斑块进行成像，从而可以对 AD 患者进行早期诊断，并且还可以直接测量目前正在开发的抗淀粉样蛋白疗法的疗效。