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: 10755501
• 负责人: Michal Schnaider Beeri
• 金额: $ 3.26万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10755501
• 关键词: 3D ultrasound; Advanced Glycosylation End Products; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Arterial Fatty Streak; Biological; Blood; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain Pathology; Carotid Artery Plaques; Cell model; Cells; Cephalic; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Collaborations; Communities; Data; Dementia; Diabetes Mellitus; Diagnosis; Diet; Dietary Assessment; Elderly; Endothelium; Enrollment; Glucose; Goals; Health Priorities; Health Services; Hippocampus; Human; Impaired cognition; Impairment; Individual; Inflammation; Insulin Resistance; Israel; Knowledge; 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; blood-brain barrier disruption; blood-brain barrier function; brain health; cerebrovascular; cognitive testing; comparison control; 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.

抽象的 阿尔茨海默病 (AD) 和认知能力下降的治疗是人口老龄化和认知衰退的首要健康问题 尤其是患有 2 型糖尿病 (T2D) 的老年人，他们患这些疾病的风险很高。引人注目 小规模研究表明，膳食和血清中晚期糖基化终末产物 (AGE) 水平较高， 一组葡萄糖衍生化合物在 T2D 中长期升高，导致认知障碍和 老年时 AD 和血管脑病理学增加。但缺乏大规模的纵向研究 对患有 T2D 的老年人进行的研究使得很难获得饮食与 T2D 之间联系的证据 血清 AGEs 与 T2D 老年人认知受损的关系以及血清 AGEs 是否介导 膳食 AGEs 与认知。这些知识差距阻碍了基于 AGE 的治疗方法的开发 减轻 AD 和认知能力下降日益加重的负担。 为了填补这些空白，该提案的总体目标是检验膳食和循环 AGEs 的假设 通过与 AD 相关和脑血管疾病的关联，与 T2D 老年人的认知受损有关 神经病理学。为了实现这些目标，我们将招募 921 名居住在社区的非痴呆 T2D 老年人 来自以色列糖尿病和认知衰退研究（IDCD；R01 AG034087）的成年人每年接受一次 认知测试。本研究提出对饮食和血清 AGE 水平进行全面评估。 255年 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 体积负荷（通过 3D 超声）和淀粉样蛋白（通过 PET）。这项综合性大规模研究将 1) 提供证据表明饮食和血清 AGE 水平与痴呆症和认知能力下降有关 患有 T2D 的老年人，2) 确定饮食和血清 AGE 与 认知和 3) 测试血清 AGE 是否介导膳食 AGE 与认知和认知的关系 神经病理学。这些数据对于开发针对晚年 T2D 相关疾病的 AGE 治疗方法至关重要 认知障碍。因此，这些数据有可能减轻日益增长的认知负担 损害并影响我们老龄化人口中数百万人的大脑健康。