Amylin as a Diagnostic Test and Potential Treatment for Alzheimers Disease

描述(申请人提供)：由于阿尔茨海默病(AD)人口迅速增长，目前没有针对AD的血液测试，也没有治愈的治疗方法。利用AD小鼠模型，我们开发了一种AD的血液测试，类似于糖尿病患者的葡萄糖耐量测试。由于糖耐量试验仅在给予葡萄糖刺激后的糖尿病患者中显示异常，我们开发了一种在给予胰淀素刺激后测量血液中淀粉样肽(A？)的测试方法。胰淀素是一种可以自由通过血脑屏障(BBB)的多肽，与A竞争结合到同一受体上，并被大脑中的胰岛素降解酶(IDE)降解。阿尔茨海默病患者大脑中的A？水平很高，因此淀粉蛋白的挑战可能会导致A？从大脑中移到可以被检测到的血流中。这项修订的R21提案的目标是进行一项探索性研究，以进一步支持人类胰淀素挑战测试的概念。代替胰淀素，我们建议在人体上使用普拉林肽进行这项挑战性测试，普拉林肽是胰淀素的合成类似物，已经获得FDA批准用于糖尿病，并具有良好的安全性。我们推测，在临床诊断为阿尔茨海默病的患者中，普拉林肽激发引起的血浆A升高会引起血液中A升高。我们期望普拉林肽的挑战有可能通过增加血浆中的A‘来诊断AD和人类的前驱AD。目的1是研究普拉林肽是否能引起AD患者与认知正常者相比血浆Aβ的升高。目的2研究普拉林肽激发试验结果与脑脊液中AD生物标志物的相关性。目的3是在激发试验中检查普拉林肽的安全性。

DESCRIPTION (provided by applicant): As the Alzheimer's disease (AD) population is growing rapidly, currently there are no blood tests for AD and no cure treatments. Using the AD mouse model, we have developed a blood test for AD that is analogous to the glucose tolerance test for diabetics. As the glucose tolerance test shows abnormalities only in diabetic patients after the challenge of glucose is given, we have developed a test that measures amyloid-¿ peptide (A¿) in the blood after the challenge of amylin. Amylin is a peptide that freely passes through the blood brain barrier (BBB) and competes with A¿ to bind to the same receptor and be degraded by the insulin-degrading enzyme (IDE) in the brain. Patients with AD have high levels of A¿ in the brain, so an amylin challenge probably results in a removal of A¿ from the brain to the blood stream where it can be detected. The goal of this revised R21 proposal is to conduct an exploratory study to further support the concept of the amylin challenge test in humans. Instead of amylin, we propose to conduct this challenge test in humans using pramlintide, a synthetic analog of amylin, which already has FDA approval for diabetes and a favorable safety profile. We hypothesize that an increase of A¿ in plasma induced by the pramlintide challenge will provoke an increase of A¿ in the blood among clinically diagnosed AD patients. We expect that the pramlintide challenge has potential to diagnose AD and the prodromal AD in humans through an increase of A¿ in plasma. Aim 1 is to examine whether pramlintide can induce an increase of plasma A¿ in AD vs. those who have normal cognition. Aim 2 is to study whether the result of the pramlintide challenge test is correlated with the AD biomarkers in cerebral spinal fluid (CSF). Aim 3 is to examine the safety of pramlintide in the challenge test.