Plasma Amyloid-Beta, Insulin, and Cognitive Decline

血浆β淀粉样蛋白、胰岛素和认知能力下降

• 批准号: 7127601
• 负责人: FRANCINE GRODSTEIN
• 金额: $ 60.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127601
• 关键词: Alzheimer' s disease; amyloid proteins; apolipoprotein E; clinical research; cognition disorders; diagnosis design /evaluation; gender difference; human subject; insulin; neural degeneration; pathologic process; patient oriented research

DESCRIPTION (provided by applicant): Cerebral accumulation of amyloid beta (Abeta) protein is a pathological hallmark of Alzheimer disease (AD), and likely plays a fundamental role in its pathogenesis. Research has focused on Aa manipulation as a mechanism for reducing or treating AD, but the clinical utility of findings is limited by lack of a simple way to identify early those at high risk of AD; Abeta levels in the CSF have been measured in some settings, but are impractical for widespread clinical applications. Abeta appears in circulating plasma, and a central aim of this proposal is to investigate the value of plasma Abeta as an early indication of AD risk by exploring its relation to cognitive decline, an early stage in the path of AD development. An additional aim of this proposal is to explore the function of insulin in cognitive decline, and its interaction with Abeta; irecent research has established that insulin modulates levels of Abeta in vitro and in vivo, however, little work has examined the long-term effects of insulin on cognition, or the possibility of different effects in subgroups of the population. This proposal represents a collaboration between basic scientists and epidemologists to test novel hypotheses in men and women regarding plasma Abeta levels, insulin levels, and insulin secretion (as measured by c-peptide) in non-diabetics and their ability to predict development of cognitive decline. The investigation will be conducted within the Nurses' Health Study, including women currently aged 70- 81 years and followed since 1976, and the Physician's Health Study II including men aged 65 years and older and followed since 1982. From each cohort, we will select 2,000 subjects with stored plasma samples collected at two points over 10 years, and with serial tests of cognitive function (3 repeated interviews by telephone, at 1.5-year intervals). The test battery measures general cognitive status, verbal memory, executive function, speed of processing, and working memory; we have conducted extensive demonstrations of the validity and reliability of the telephone method compared to in-person assessments, and have previously detected strong relations with numerous established risk factors for decline. Thus, these two established populations provide a highly cost-efficient setting in which to examine biomarkers of early cognitive decline, and gender and genetic interactions.

描述（由申请人提供）： β淀粉样蛋白（Amyloid beta，Abeta）在脑内的沉积是阿尔茨海默病（Alzheimer disease，AD）的一个重要病理标志，在AD的发病机制中起着重要作用。研究集中在Aa操纵作为减少或治疗AD的机制，但由于缺乏一种简单的方法来识别早期AD高危人群，研究结果的临床实用性受到限制;在某些情况下测量了CSF中的Abeta水平，但对于广泛的临床应用来说是不切实际的。Abeta出现在循环血浆中，该提案的中心目的是通过探索其与认知下降（AD发展路径的早期阶段）的关系，研究血浆Abeta作为AD风险早期指标的价值。该提案的另一个目的是探索胰岛素在认知能力下降中的功能及其与Abeta的相互作用;最近的研究已经确定胰岛素在体外和体内调节Abeta的水平，然而，很少有工作研究胰岛素对认知的长期影响，或者在人群亚组中产生不同影响的可能性。该提案代表了基础科学家和神经病学家之间的合作，以测试男性和女性关于非糖尿病患者血浆Abeta水平，胰岛素水平和胰岛素分泌（通过c肽测量）的新假设，以及他们预测认知能力下降的能力。 调查将在护士健康研究中进行，包括目前年龄在70- 81岁的女性，自1976年以来进行随访，医生健康研究II包括65岁及以上的男性，自1982年以来进行随访。从每个队列中，我们将选择2,000名受试者，在10年内的两个时间点收集储存的血浆样本，并进行认知功能的系列测试（通过电话重复进行3次访谈，间隔1.5年）。测试组合测量一般认知状态，非文字记忆，执行功能，处理速度和工作记忆;我们已经进行了广泛的演示的有效性和可靠性的电话方法相比，在人的评估，并已检测到强关系与许多既定的风险因素下降。因此，这两个已建立的人群提供了一个高度成本效益的环境，在其中检查早期认知能力下降的生物标志物，以及性别和遗传相互作用。