Oral Glucose Tolerance Test for Alzheimer's Disease Biomarker Development

描述(申请人提供)：本申请中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，以增强血浆淀粉样β蛋白(A？)作为阿尔茨海默病(AD)生物标志物的效用。目前，有许多关于AD潜在治疗的临床试验正在进行中。因此，重要的是能够在早期阶段确定哪些AD患者将是这些治疗的理想候选者。血浆A将是诊断AD不同阶段的一种廉价和非侵入性工具，以及用于监测A？修改疗法。然而，大多数涉及血浆A的横断面研究都不能显示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”认知正常、轻度认知障碍(MCI)和早期AD(AD)个体之间的差异。我们还建议证明，这一效应可能是由于OGTT导致GLP-1释放减少所致。在一项横断面研究中，我们将对遗忘型MCI(AMCI)、阿尔茨海默病(AD)和认知正常对照组的每一组个体进行OGTT。在不同的时间点采集血浆样本，并用酶联免疫吸附试验(ELISA)定量检测A？42和GLP-1。然后，我们将在单个时间点比较三组OGTT下A？42动力学曲线下的面积(AUC)，并将其与记忆测试中的表现相关联。我们还将比较OGTT时血浆GLP-1动力学的AUC，并与血浆A？42动力学的AUC相关。这项探索性研究的结果将提供有关OGTT调节的血浆A？42作为MCI和AD的诊断生物标志物以及疾病严重程度的生物标志物的潜在用途的数据。它还将提供GLP-1与血浆A？42水平之间对OGTT反应的潜在关系的数据。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，以展示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。 公共卫生相关性：本申请中的研究建议开发一种简单的口服葡萄糖耐量试验作为一种有意义地评估血浆淀粉样蛋白水平的工具。随着阿尔茨海默病(AD)的发病率攀升，这种疾病的生物学和认知后果变得更加虚弱，早期干预的重要性是巨大的。开发一种简单、非侵入性的可靠生物标志物将使早期识别有AD风险的个人，并可能使更早的治疗成为可能。

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.