Association of glycemia and related factors and complications with cognitive impairment and AD/ADRD biomarkers

血糖及相关因素和并发症与认知障碍和 AD/ADRD 生物标志物的关联

• 批准号: 10507635
• 负责人: Dana Dabelea
• 金额: $ 14.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507635
• 关键词: Advanced Glycosylation End Products; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Beta Cell; Biological Markers; Blood Pressure; Brain; Brain Pathology; Brain imaging; Buffers; Classification; Clinical; Cognition Disorders; Cognitive; Collaborations; Coronary Arteriosclerosis; Data; Defect; Dementia; Dyslipidemias; Education; Educational Background; Ethnic Origin; Functional disorder; Genetic Risk; Glial Fibrillary Acidic Protein; Goals; Impaired cognition; Impairment; Infarction; Inflammation; Insulin Resistance; Investigation; Kidney Diseases; Lead; Light; Magnetic Resonance Imaging; Measures; Mediating; Microvascular Dysfunction; Myocardial Infarction; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Outcome Study; Participant; Pathologic; Peripheral; Persons; Plasma; Positron-Emission Tomography; Prediabetes syndrome; Predictive Factor; Prevention strategy; Race; Recording of previous events; Retinal Diseases; Risk; Risk Factors; Severities; Stroke; Structure of beta Cell of islet; Syndrome; Thick; Thinness; Time; White Matter Hyperintensity; adjudicate; adjudication; apolipoprotein E-4; cognitive reserve; cognitive testing; diabetes mellitus genetics; diabetes prevention program; endothelial dysfunction; extracellular vesicles; genetic risk factor; high risk; imaging biomarker; insulin signaling; literacy; macrovascular disease; mild cognitive impairment; modifiable risk; neurofilament; neuroimaging; neuropathology; neurophysiology; novel; predictive modeling; sex; sociodemographic factors; tau Proteins; treatment strategy; vascular contributions; vascular factor

The goal of Project 2 is to study the associations of type 2 diabetes (T2D) related factors with risk for cognitive decline, mild cognitive impairment (MCI), dementia, and related neuropathologies, among persons with pre- diabetes (PreD) and type 2 diabetes (T2D) in the Diabetes Prevention Program Outcomes Study (DPPOS). T2D related factors include dysglycemia, its determinants, insulin resistance (IR) and pancreatic β-cell dysfunction, and downstream markers of pathophysiology including advanced glycation end products (AGE), as well as peripheral vascular factors (endothelial dysfunction, inflammation, blood pressure, dyslipidemia), microvascular (retinopathy, neuropathy, nephropathy) and macrovascular (non-fatal myocardial infarction, coronary artery disease) complications, ascertained longitudinally over 20 years in DPPOS. A vast body of evidence supports T2D as a significant modifiable risk factor for cognitive impairment. However, it is not clear that T2D related factors cause cognitive impairment in T2D. Few studies have investigated the temporal changes of T2D related factors in people with PreD and T2D in relation to cognitive syndromes and neuropathology. As described in the Cognitive Assessment and Adjudication Core, cognitive impairment syndromes will include amnestic and non- amnestic cognitive decline, MCI, and dementia. As described in the Biomarker Core we will examine trajectories of plasma biomarkers of neuropathology including amyloid (Aβ42/Aβ40 ratio), tau (ptau-181), neurofilament light (NfL), and Glial Fibrillary Acidic Protein (GFAP) in all participants. In collaboration with Project 1, we will additionally examine brain insulin signaling from plasma-derived neuronal extracellular vesicles as a novel plasma biomarker of T2D related dysregulated neurophysiology. Among those participants with brain imaging, we will use imaging biomarkers of neuropathology including brain Aβ via PET, cortical thickness, and white matter hyperintensity volume (WMHV) and infarcts on MRI to explore brain pathology. Finally, among those with a cognitive syndrome, we will explore pathologic classification as being AD continuum or non-AD pathologic change using the plasma biomarkers (see Neuroimaging and Plasma Biomarkers Core) and vascular contribution to impairment or dementia (VCID) measured via adjudicated stroke by the Clinical Core. Our aims are: (1) Examine the associations of trajectories of dysglycemia, IR, β-cell dysfunction, and AGE with risk of cognitive syndromes, biomarkers of neuropathology, and brain insulin signaling; (2) Examine the associations of trajectories of vascular factors and history of micro- and macrovascular complications with risk of cognitive syndromes and biomarkers of neuropathology; (3) Build prediction models of cognitive syndromes in persons with PreD or T2D using T2D related factors (Aims 1 and 2), sociodemographic factors (sex, race/ethnicity, education), and genetic risk factors (APOE-e4 and diabetes genetic risk scores); Exploratory aims: Aims 1 and 2 will explore sex, race/ethnicity, and measures of cognitive reserve (e.g., education level and literacy) as moderators of the hypothesized associations.

项目2的目标是研究2型糖尿病（T2D）相关因素与认知风险的关系