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: 10533259
• 负责人: Michal Schnaider Beeri
• 金额: $ 73.17万
• 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/10533259
• 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.

摘要