Oral Glucose Tolerance Test for Alzheimer's Disease Biomarker Development

描述（由申请人提供）：本申请的研究建议开发一种简单的口服葡萄糖耐量试验（OGTT），作为一种工具，以提高血浆淀粉样蛋白- β （a¿）作为阿尔茨海默病（AD）生物标志物的效用。目前，有许多正在进行的临床试验的潜在治疗阿尔茨海默病。因此，能够识别早期AD患者是这些治疗的理想候选者是很重要的。血浆A¿将是一种廉价的非侵入性工具，用于诊断AD的各个阶段，以及监测A¿修饰疗法。然而，大多数涉及血浆A¿的横断面研究无法显示AD患者与对照组之间的差异。在我们的项目中，我们建议通过OGTT调节血浆A¿水平来“揭示”正常认知、轻度认知障碍（MCI）和早期AD （AD）个体之间的差异。我们还提出证明这种效应可能是由于OGTT应答中胰高血糖素样肽-1 （GLP-1）释放降低所致。在横断面研究中，我们将对健忘性MCI （aMCI）、AD和认知正常对照组中的一组个体进行OGTT治疗。将在不同时间点获得血浆样品，并通过ELISA定量检测A¿42和GLP-1。然后，我们将在一个时间点上比较三组a¿42对OGTT反应的曲线下面积（AUC），并将其与记忆测试中的表现联系起来。我们还将比较血浆GLP-1动力学响应OGTT的AUC，并将其与血浆A¿42动力学的AUC相关联。这项探索性研究的结果将提供关于OGTT调节血浆A¿42作为MCI和AD的诊断性生物标志物以及疾病严重程度的生物标志物的潜在效用的数据。它还将提供GLP-1与OGTT反应中血浆A¿42水平之间潜在关系的数据。此外，这项探索性研究的数据将使我们能够收集足够的数据来设计一项纵向研究，以证明OGTT在区分受试者、监测治疗反应和预测疾病进展方面的效用。

DESCRIPTION (provided by applicant): The studies in this application propose to develop a simple oral glucose tolerance test (OGTT) as a tool to enhance the utility of plasma amyloid-beta (A¿) as a biomarker of Alzheimer's disease (AD). Currently, there are many on-going clinical trials for potential treatment of AD. Therefore, it is important to be able to identify AD patients in the earlier stages who would be ideal candidates for these therapies. Plasma A¿ would be an inexpensive and non-invasive tool in diagnosing various stages of AD, as well as for monitoring A¿ modifying therapies. However, most cross-sectional studies involving plasma A¿ have not been able to show differences between individuals with AD compared to controls. In our project, we propose to "unmask" the differences between individuals who have normal cognition, mild cognitive impairment (MCI), and early AD (AD) by modulating the plasma A¿ levels with OGTT. We also propose to demonstrate that this effect may be due to lower glucagon-like peptide-1 (GLP-1) release in response to OGTT. In a cross-sectional study, we will administer OGTT to a group of individuals in each of the amnestic MCI (aMCI), AD and cognitively normal control groups. Plasma samples will be obtained at various time points and quantified for A¿ 42 and GLP-1 by ELISA. Then, we will compare at a single time point, the area under curve (AUC) of A¿ 42 kinetics in response to OGTT across the three groups, and also correlate it to the performance on tests of memory. We will also compare the AUC of plasma GLP-1 kinetics in response to OGTT, and correlate to the AUC of plasma A¿ 42 kinetics. The results of this exploratory study will provide data regarding the potential utility of OGTT modulated plasma A¿ 42 as a diagnostic biomarker of MCI and AD, as well as a biomarker of disease severity. It will also provide data on the potential relationship between GLP-1 to plasma A¿ 42 levels in response to OGTT. In addition, the data from this exploratory study will enable us to gather sufficient data to design a longitudinal study to demonstrate the utility of OGTT in differentiating subjects, monitor therapeutic response and predict disease progression. PUBLIC HEALTH RELEVANCE: The studies in this application propose to develop a simple oral glucose tolerance test as a tool to meaningfully assess plasma amyloid levels. As the incidence of Alzheimer's disease (AD) climbs and the biological and cognitive ramifications of such a disorder become more debilitating, the importance of early intervention is tremendous. Development of a reliable biomarker that is simple and non-invasive would enable early identification of individuals who are at risk for AD, and may allow earlier treatment.