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: 7069982
• 负责人: JOSEPH F PODUSLO
• 金额: $ 57.44万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069982
• 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)： 这个项目将测试这样一个假设，即淀粉样β蛋白(Aβ)的修饰或Aβ的衍生物可以用于阿尔茨海默病(AD)的淀粉样斑块的分子成像。这是基于观察到AI3不仅为斑块的形成提供种子，而且还与先前存在的斑块高亲和力结合并促进其生长。Aβ的各种衍生物将被检测并与Aβ1-40进行比较，包括不包括细胞表面结合结构域的Aβ1-30(Aβ31-34)；不包括神经毒性结构域的Aβ1-25(Aβ25-35)；以及不包括聚集域的Aβ1-15(Aβ16-20)。开发一种无毒的Aβ衍生品尤为重要。我们已经解决了一个重要的问题，即全身给药后通过血脑屏障(BBB)传递Aβ1-40，这会导致蛋白质在血脑屏障处的渗透系数x表面积乘积(PS)增加。多胺修饰增加了Aβ与AD脑组织切片中淀粉样斑块的结合。此外，我们已经证明，多胺修饰的Aβ1-40在体内标记了静脉注射后的斑块，在转基因AD小鼠模型中。我们的初步结果证明，这种分子探针在静脉注射后，除了多胺腐胺外，还结合MRI造影剂Gd，成功地标记了AD转基因小鼠大脑皮质、海马区和其他脑区的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，并观察探头特异性的T1加权(T1W)和T2加权(T2W)弛豫的变化。这些特定的目的反映了这种造影剂的进一步发展，用于通过MRI来表征和定量AD转基因小鼠中淀粉样斑块的沉积。尽管这项研究可能会对人类AD斑块的磁共振成像的可行性提出许多问题，但我们相信，列出的具体目标将通过最小化神经毒性、通过优化靶向和结合AD斑块的分子探针以及通过优化AD转基因小鼠的体内外成像参数，从而促进以合理的方式回答这些问题。所有这些步骤在应用于AD患者之前显然是必要的。这种磁共振造影剂能够在AD转基因小鼠体内对斑块进行成像，这可能使AD患者的早期诊断成为可能，也为目前正在开发的抗淀粉样蛋白疗法的疗效提供了直接测量。