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 轻度认知功能障碍(MCI)、痴呆症及相关神经病理改变 糖尿病预防计划结果研究(DPPOS)中的糖尿病(PRED)和2型糖尿病(T2D)。T2D 相关因素包括血糖异常及其决定因素、胰岛素抵抗(IR)和胰腺β细胞功能障碍。 和下游的病理生理标记物，包括晚期糖基化终产物(AGE)，以及 外周血管因素(内皮功能障碍、炎症、血压、血脂异常)、微血管 (视网膜病变、神经病变、肾病)和大血管(非致命性心肌梗死、冠状动脉 疾病)并发症，在DPPOS中纵向确定超过20年。大量证据支持 T2D是认知损害的一个重要的可改变的危险因素。然而，目前还不清楚T2D与 影响T2D儿童认知功能障碍的因素。很少有研究研究与T2D相关的时间变化 PRED和T2D患者的因素与认知综合征和神经病理学的关系。如中所述 认知评估和裁决核心，认知障碍综合征将包括遗忘性和非遗忘性 遗忘性认知衰退、MCI和痴呆症。正如在Biomarker Core中所描述的，我们将检查轨迹 血浆神经病理生物标志物包括淀粉样蛋白(Aβ42/Aβ40比率)、tau(ptau-181)、神经丝光 (NFL)和胶质纤维酸性蛋白(GFAP)。与项目1合作，我们将 此外，还研究了来自血浆来源的神经元细胞外小泡的脑胰岛素信号作为一种新的 T2D相关神经生理学失调的血浆生物标志物。在那些接受脑部成像的参与者中， 我们将使用神经病理的成像生物标记物，包括经正电子发射计算机断层扫描的脑Aβ、皮质厚度和白质 在MRI上显示物质高信号体积(WMHV)和脑梗塞，以探讨脑病理。最后，在那些拥有 一种认知综合征，我们将探讨AD的病理分类为AD连续体或非AD病理 使用血浆生物标记物(参见神经成像和血浆生物标记物核心)和血管的变化 对损害或痴呆(VCID)的贡献(VCID)由临床核心通过判定的中风来衡量。我们的目标 主要研究内容包括：(1)研究血糖紊乱、胰岛素抵抗、β细胞功能障碍和年龄与糖尿病风险的关系。 认知综合征、神经病理的生物标记物和脑胰岛素信号；(2)检查 有认知风险的微血管和大血管并发症的血管因素轨迹和病史 神经病理学的证候和生物标志物；(3)建立人的认知证候预测模型 使用T2D相关因素(目标1和2)的PRED或T2D、社会人口因素(性别、种族/民族、 教育)和遗传风险因素(载脂蛋白E-e4和糖尿病遗传风险评分)；探索目标：目标1和 2将探讨性别、种族/民族和认知储备的衡量标准(例如，教育水平和识字) 假想协会的主持人。