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

2型糖尿病相关认知能力下降和痴呆事件中的全身和饮食晚期糖基化终末产物：对阿尔茨海默病病理学和脑血管疾病的影响

• 批准号: 10532448
• 负责人: Michal Schnaider Beeri
• 金额: $ 6.65万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532448
• 关键词: 3D ultrasound; Adult; Advanced Glycosylation End Products; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Arterial Fatty Streak; Biological; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Pathology; Carotid Artery Plaques; Cell model; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Collaborations; Communities; Core-Binding Factor; Data; Dementia; Diabetes Mellitus; Diagnosis; Diet; Dietary Assessment; Elderly; Endothelium; Enrollment; Functional disorder; Glucose; Goals; Health Priorities; Health Services; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Inflammation; Insulin Resistance; Israel; Knowledge; Lead; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medical center; Memory; Mus; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Pathogenesis; Pathology; Pharmaceutical Preparations; Positron-Emission Tomography; Questionnaires; Registries; Research; Serum; Testing; White Matter Hyperintensity; aging population; base; blood-brain barrier disruption; blood-brain barrier function; brain health; cerebrovascular; cognitive testing; contrast enhanced; dementia risk; dietary; dietary restriction; endothelial dysfunction; gray matter; high risk; human old age (65+); indexing; medical schools; neuropathology; non-demented; novel; therapy development

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.

摘要 阿尔茨海默病（AD）和认知能力下降的治疗是我们老龄化人口的健康优先事项， 特别是在患有2型糖尿病（T2 D）的老年人中，他们处于发展这些病症的高风险中。引人注目 小规模的研究表明，高水平的饮食和血清中的晚期糖基化终末产物（AGEs）， 一组葡萄糖衍生化合物，在T2 D中长期升高，导致认知障碍， 老年AD和血管性脑病变增加。然而，缺乏大规模的纵向 对具有良好特征的老年T2 D患者的研究使得很难获得饮食和 2型糖尿病患者血清AGEs与认知功能损害的关系以及血清AGEs是否介导了 饮食AGEs与认知功能的关系这些知识上的差距阻碍了基于AGEs的治疗方法的发展 以减轻AD和认知能力下降的负担。 为了填补这些空白，本提案的总体目标是检验膳食和循环AGEs 通过与AD相关和脑血管疾病相关，与T2 D老年人的认知受损相关 神经病理学为了实现这些目标，我们将招募921名非痴呆社区居住的T2 D老年人， 来自以色列糖尿病和认知能力下降研究（IDCD; R 01 AG 034087）的成年人， 认知测试本研究提出了一个全面的评估饮食和血清AGEs水平。在255 IDCD参与者，我们将量化血脑屏障（BBB）功能障碍（使用新型对比增强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 容积负荷（通过3D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水平与痴呆和认知能力下降有关， 2）确定饮食和血清AGEs与T2 D相关的关键神经病理学指标， 3）测试血清AGEs是否介导饮食AGEs与认知的关联， 神经病理学这些数据对于开发针对晚期T2 D相关AGEs的治疗至关重要。 认知障碍因此，这些数据有可能减少日益增长的认知负担。 损害并影响我们老龄化人口中数百万人的大脑健康。