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: 7236174
• 负责人: JOSEPH F PODUSLO
• 金额: $ 56.9万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236174
• 关键词: 1 year old; Affinity; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Area; Binding; Blood - brain barrier anatomy; Brain; Brain region; Cell surface; Characteristics; Contrast Media; Coupled; Deposition; Derivation procedure; Development; Doctor of Philosophy; Dose; Early Diagnosis; Gadolinium; Growth; Hippocampus (Brain); Human; Image; Immunohistochemistry; In Vitro; Individual; Injection of therapeutic agent; Label; Life; Magnetic Resonance Imaging; Measures; Modification; Molecular Probes; Mus; Noise; Patients; Permeability; Polyamines; Protein Structure Initiative; Proteins; Putrescine; Relaxation; Research; Research Personnel; Resolution; Seeds; Senile Plaques; Staining method; Stains; Surface; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Weight; amyloid beta-protein (1-40); base; brain tissue; in vivo; intravenous injection; molecular imaging; mouse model; neurotoxic; neurotoxicity; programs; success; time interval

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）： 该项目将测试淀粉样β蛋白（A β）或A β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的假设。这是基于以下观察结果：A13不仅为斑块的形成提供种子，而且还以高亲和力结合预先存在的斑块并促进其生长。将检查A β的各种衍生物并与A β 1-40进行比较，包括A β 1-30，其不包括细胞表面结合结构域（A β 31-34）; A β 1-25，其不包括神经毒性结构域（A β 25-35）;和A β 1-15，其不包括聚集结构域（A β 16-20）。开发无毒的A β衍生物尤为重要。我们已经解决了一个重要的问题，即通过使用多胺修饰的A β在全身给药后递送A β 1-40穿过血脑屏障（BBB），这导致蛋白质在BBB处的渗透系数×表面积乘积（PS）增加。多胺修饰增加了AD脑组织切片中A β与淀粉样蛋白斑块的结合。此外，我们已经证明，多胺修饰的A β 1-40标记斑块在体内静脉注射后，在转基因小鼠模型的AD。我们的初步结果证明了这种分子探针的成功，现在再加上MRI造影剂，钆，除了多胺，腐胺，标记AD淀粉样蛋白斑块在整个皮质，海马，和其他大脑区域的AD转基因小鼠静脉注射后。我们能够使用高场强7特斯拉磁共振成像（MRI）以高分辨率对单个斑块进行成像，并观察探针特异性的T1加权（T1 W）和T2加权（T2 W）弛豫的变化。特定目的反映了该造影剂的进一步开发，用于通过MRI表征和定量AD转基因小鼠中淀粉样蛋白斑块的沉积。虽然这项研究可能会提出许多问题的可行性MR成像的AD斑块在人类中，我们相信，具体的目标列出将有助于这些问题的答案在一个合乎逻辑的方式，通过最大限度地减少神经毒性，通过优化分子探针的目标和结合到AD斑块，并通过优化成像参数在体外和体内的AD转基因小鼠。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造影剂在AD转基因小鼠体内对斑块成像的能力可以实现AD患者的早期诊断，并且还提供了目前正在开发的抗淀粉样蛋白疗法的功效的直接测量。