Amylin as a Diagnostic Test and Potential Treatment for Alzheimers Disease

胰淀素作为阿尔茨海默病的诊断测试和潜在治疗方法

• 批准号: 8694671
• 负责人: WEI QIAO Wendy QIU
• 金额: $ 24.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694671
• 关键词: Adverse effects; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Binding; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Glucose; Blood Tests; Blood Vessels; Brain; Cerebrospinal Fluid; Cerebrum; Cognition; Consensus; Development; Diabetes Mellitus; Diagnosis; Diagnostic tests; Enrollment; Etiology; Excision; FDA approved; Failure; Glucose; Glucose tolerance test; Goals; Human; Hypoglycemia; Injection of therapeutic agent; Insulin; Insulinase; Measures; Mus; Paper; Participant; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase III Clinical Trials; Plasma; Population; Pramlintide; Public Health; Recruitment Activity; Reporting; Safety; Sampling; Scanning; Spinal Puncture; Staging; Stream; Subcutaneous Injections; Symptoms; Testing; Transgenic Mice; Transgenic Organisms; amylin receptor; amyloid formation; amyloid imaging; amyloid pathology; amyloid peptide; analog; diabetic; diabetic patient; effective therapy; islet amyloid polypeptide; mild cognitive impairment; mouse model; neurotoxic; non-diabetic; peptide A; pilot trial; pre-clinical; public health relevance; receptor; tau-1

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.

描述（由申请人提供）：随着阿尔茨海默病（AD）人口的迅速增长，目前没有AD的血液检测，也没有治愈治疗。使用AD小鼠模型，我们已经开发了AD的血液测试，其类似于糖尿病患者的葡萄糖耐量测试。由于葡萄糖耐量试验仅在给予葡萄糖激发后在糖尿病患者中显示异常，因此我们开发了一种在胰淀素激发后测量血液中淀粉样肽（A）的试验。胰淀素是一种肽，可自由穿过血脑屏障（BBB），与A？竞争结合相同的受体，并被脑中的胰岛素降解酶（IDE）降解。AD患者的大脑中有高水平的A？，因此胰淀素激发可能会导致A？从大脑转移到血流中，在那里可以检测到A？。修订后的R21提案旨在进行探索性研究，以进一步支持人类胰淀素激发试验的概念。代替胰淀素，我们建议使用普兰林肽（一种胰淀素的合成类似物）在人体中进行这项挑战试验，普兰林肽已经获得FDA批准用于糖尿病，并且具有良好的安全性。我们假设普兰林肽激发诱导的血浆中A <$的增加将引起临床诊断的AD患者血液中A <$的增加。我们预计普兰林肽激发有可能通过血浆中A？的增加来诊断人类AD和前驱AD。目的1是检查普兰林肽是否能诱导AD患者与认知正常者相比血浆A？升高。目的二是研究普兰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是检查普兰林肽在激发试验中的安全性。