Systemic and dietary advanced glycation end products in type 2 diabetes-related cognitive decline and incident dementia: effects on Alzheimer's pathology and cerebrovascular disease

摘要 治疗阿尔茨海默病(AD)和认知功能减退是我们老龄化人口和 尤其是患有2型糖尿病(T2D)的老年人，他们患上这些疾病的风险很高。引人入胜 小规模研究表明，高水平的饮食和血清晚期糖基化终末产物(AGEs)，a 一组葡萄糖衍生化合物，在T2D中慢性升高，导致认知障碍和 老年阿尔茨海默病和血管性脑病理的增加。然而，大规模的纵向稀缺。 对患有T2D的特征良好的老年人的研究使获得饮食和T2D之间联系的证据变得困难 血清AGEs与T2D老年人认知损害的关系以及血清AGEs是否起到调节认知功能的作用 饮食年龄与认知。这些知识上的差距阻碍了基于年龄的治疗方法的发展 减轻阿尔茨海默病日益加重的负担和认知功能衰退。 为了填补这些空白，这项提议的总体目标是检验饮食和循环年龄的假设 与AD相关和脑血管相关的T2D老年人认知损害相关 神经病理学。为了实现这些目标，我们将招收921名非痴呆症社区居住的T2D老年人 来自以色列糖尿病和认知衰退研究(IDCD；R01 AG034087)的成年人，每年接受 认知测试。这项研究建议对饮食和血清AGEs水平进行全面评估。在255年 IDCD参与者我们将量化血脑屏障(BBB)功能障碍(使用新的对比增强MRI)， 脑血流量(CBF；通过ASL-MRI)、脑血管反应性(经颅多普勒)、颈动脉斑块 体积负荷(通过三维超声)和淀粉样蛋白(通过PET)。这项全面的大规模研究将1) 提供证据表明饮食和血清AGEs水平与老年痴呆和认知功能减退有关 患有T2D的老年人，2)确定与饮食和血清AGEs有关的关键神经病理指标 3)检验血清AGE是否调节饮食年龄与认知和 神经病理学。这些数据对于开发针对老年T2D相关年龄的治疗至关重要 认知障碍。因此，这些数据有可能减轻日益增长的认知负担 在我们老龄化的人口中，数以百万计的人受到损害并影响大脑健康。

ABSTRACT Treatments for Alzheimer's disease (AD) and cognitive decline is a health priority in our aging population and especially in elderly with type 2 diabetes (T2D) who are at high risk of developing these conditions. Compelling small scale studies suggest that high dietary and serum levels of Advanced Glycation End products (AGEs), a group of glucose-derived compounds, chronically elevated in T2D, contribute to cognitive impairment and increased AD and vascular brain pathology in old age. However, there is scarcity of large scale longitudinal studies of well-characterized older adults with T2D making it difficult to obtain evidence linking dietary and serum AGEs with impaired cognition in T2D elderly and whether serum AGEs mediate the associations of dietary AGEs with cognition. These gaps in knowledge impede the development of treatments based on AGEs to decrease the growing burden of AD and cognitive decline. To fill these gaps, the overall goal of this proposal is to test the hypothesis that dietary and circulating AGEs are related to impaired cognition in T2D elderly through an association with AD-related and cerebrovascular neuropathologies. To achieve these aims, we will enroll 921 non-demented community-dwelling T2D older adults from the Israel Diabetes and Cognitive Decline Study (IDCD; R01 AG034087) who undergo annual cognitive testing. This study proposes a comprehensive assessment of dietary and serum AGEs levels. In 255 IDCD participants we will quantify blood brain barrier (BBB) dysfunction (using novel contrast-enhanced MRI), cerebral blood flow (CBF; via ASL-MRI), cerebrovascular reactivity (with Transcranial Doppler), carotid plaque volume burden (via 3D ultrasound), and amyloid (via PET). This comprehensive large-scale study will 1) provide evidence that dietary and serum AGEs levels are related to incident dementia and cognitive decline in older adults with T2D, 2) identify the key neuropathological indices linking dietary and serum AGEs with cognition and 3) test if serum AGEs mediate the association of dietary AGEs with cognition and neuropathology. These data are crucial for developing treatments targeting AGEs for late-life T2D-related cognitive impairment. Thus, these data have the potential to decrease the growing burden of cognitive impairment and affect the brain health of millions in our aging population.