Glucose Variability as a Digital Biomarker for Preclinical AD Risk in Prediabetes.

项目摘要 需要可靠的诊断数字化工具来早期检测认知功能障碍和分层。 2型糖尿病（T2 DM）风险的老年人中的早期阿尔茨海默氏痴呆症（AD）风险。T2 DM是一种... 已知的认知能力下降和AD风险的加速因素：T2 DM与情景记忆功能障碍有关， 执行功能，并提供2至4倍的AD风险增加。糖尿病前期阶段可能是 理解这种加速老化，因为它可以提供一个最佳的窗口，进入最初的病理生理学 引发认知功能障碍和AD的变化。然而，不确定性围绕高血糖症的作用 在糖尿病前期阶段，可能是因为仅使用单个时间点零星地评估葡萄糖峰值 像血红蛋白A1 c（HbA 1c）和空腹血糖这样的测量结果， 未经检查这些局限性使得更精确地测量精神障碍将产生一种可能性。 更明确地了解T2 DM病理生理学改变认知功能的机制 和AD风险，这是目前未知的。我们将成为第一个利用尖端动态葡萄糖 监测（CGM）技术，以调查精神障碍，认知功能， 和关键的AD生物标志物。CGM允许精确评估 葡萄糖水平的波动，以显示高血糖和低血糖的个性化模式，这是一个主要的 空腹血糖或HbA 1c中未反映的代谢障碍成分。因为CGM技术几乎 专门用于诊断为T2 DM的人群，检查T2 DM风险人群是一种创新。我们 建立了多学科研究团队，具有行为医学，内分泌学，老年医学， 神经心理学和神经病学，以及多年的合作临床研究经验，是很好的- 定位于检查40名有T2 DM风险的老年人（a）血糖波动与 情景记忆和执行功能的认知功能障碍，这些关键领域显示出 在AD轨迹的早期和前驱糖尿病中，以及（B）首次探索血糖与糖尿病的相关性。 与早期AD风险的成熟生物标志物的波动。这些基于血浆的AD tau生物标志物 磷酸化和淀粉样蛋白负担是具有成本效益的，需要微创抽血， 血液中脑特异性蛋白的量，用于超灵敏免疫测定。通过利用精确， 评估早期血糖波动的可扩展技术，以及早期AD风险的敏感筛查工具， 创新的建议，使科学和技术的进步，在老龄化和AD风险研究。 支持我们的假设将引入具有成本效益的，用户友好的CGM技术作为一种新颖的，敏感的， 数字生物标志物用于早期检测认知功能障碍和AD风险分层，最终帮助 老年人的认知功能会保留到晚年。

PROJECT ABSTRACT Reliable diagnostic digital tools are needed for the early detection of cognitive dysfunction and stratification of early Alzheimer’s Dementia (AD) risk among older adults at risk for Type 2 diabetes (T2DM). T2DM is a well- known accelerator of cognitive decline and AD risk: T2DM is linked to dysfunction in episodic memory and executive functions, and proffers a 2- to 4-fold increased risk for AD. The prediabetes stage may be key to understanding this accelerated aging as it could provide an optimal window into the initial pathophysiological changes that trigger cognitive dysfunction and AD. However, uncertainty surrounds the role of hyperglycemia in the prediabetic stage, perhaps because only assessing peaks in glucose sporadically using single time-point measurements like hemoglobin A1c (HbA1c) and fasting glucose leaves key aspects of dysglycemia unexamined. These limitations open the possibility that more precise measurement of dysglycemia will yield a more definitive understanding of the mechanisms by which T2DM pathophysiology modifies cognitive function and AD risk, which are presently unknown. We will be the first to leverage cutting-edge Continuous Glucose Monitoring (CGM) technology to investigate the precise associations between dysglycemia, cognitive function, and key AD biomarkers in older adults with at risk for T2DM. CGM allows for the precise assessment of fluctuations in glucose levels to show individualized patterns of hyper- and hypoglycemia over days- a major component of dysglycemia not reflected in fasting glucose or HbA1c. Because CGM technology has almost exclusively been used by people with a T2DM diagnosis, examining those at risk for T2DM is innovative. Our established multidisciplinary research team, with expertise in behavioral medicine, endocrinology, geriatrics, neuropsychology, and neurology, and numerous years of collaborative clinical research experience, is well- positioned to examine among 40 older adults at risk for T2DM (a) the association of glycemic fluctuations with cognitive dysfunction in episodic memory and executive functions, key domains that show decrements both early in the AD trajectory, and in prediabetes, and (b) explore, for the first time, the association of glycemic fluctuations with well-established biomarkers of early AD risk. These plasma-based AD biomarkers of tau phosphorylation and amyloid burden are cost-effective, require minimally invasive blood draws, and minute amounts of brain-specific proteins in blood for use with ultrasensitive immunoassays. By leveraging precise, scalable technology to assess early glycemic fluctuations, and sensitive screening tools for early AD risk, this innovative proposal stands to make both scientific and technological advances in aging and AD risk research. Support for our hypotheses would introduce cost-effective, user-friendly CGM technology as a novel, sensitive, digital biomarker for the early detection of cognitive dysfunction and stratification of AD risk, ultimately, helping older adults preserve cognitive function into later life.