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联 患有前期疾病的人会出现衰退、轻度认知障碍 (MCI)、痴呆和相关的神经病理学症状 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、其决定因素、胰岛素抵抗（IR）和胰腺β细胞功能障碍， 和病理生理学下游标志物，包括晚期糖基化终末产物 (AGE)，以及 周围血管因素（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（非致命性心肌梗塞、冠状动脉 疾病）并发症，在 DPPOS 中纵向确定了 20 多年。大量证据支持 T2D 是认知障碍的一个重要的可改变危险因素。然而，尚不清楚 T2D 相关 导致 T2D 认知障碍的因素。很少有研究调查 T2D 相关的时间变化 PreD 和 T2D 患者中与认知综合征和神经病理学相关的因素。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症和非记忆症 遗忘性认知衰退、MCI 和痴呆。正如生物标记核心中所述，我们将检查轨迹 神经病理学血浆生物标志物，包括淀粉样蛋白（Aβ42/Aβ40 比率）、tau (ptau-181)、神经丝光 (NfL) 和所有参与者的胶质纤维酸性蛋白 (GFAP)。与项目 1 合作，我们将 另外还检查了来自血浆源性神经元细胞外囊泡的脑胰岛素信号传导作为一种新的方法 T2D 相关神经生理学失调的血浆生物标志物。在进行脑成像的参与者中， 我们将使用神经病理学的成像生物标志物，包括通过 PET 检测的大脑 Aβ、皮质厚度和白细胞 MRI 上的物质高信号体积 (WMHV) 和梗塞，以探索大脑病理学。最后，在那些有 认知综合征，我们将探讨 AD 连续性或非 AD 病理性的病理分类 使用血浆生物标志物（参见神经影像和血浆生物标志物核心）和血管进行改变 通过临床核心判定的中风来测量对损伤或痴呆 (VCID) 的影响。我们的目标 是： (1) 检查血糖异常、IR、β 细胞功能障碍和 AGE 的轨迹与以下风险之间的关联： 认知综合征、神经病理学生物标志物和脑胰岛素信号传导； (2) 检查关联性 血管因素的轨迹以及具有认知风险的微血管和大血管并发症的历史 神经病理学的综合征和生物标志物； (3) 建立人体认知综合症的预测模型 使用 T2D 相关因素（目标 1 和 2）、社会人口因素（性别、种族/民族、 教育）和遗传风险因素（APOE-e4 和糖尿病遗传风险评分）；探索性目标：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率）： 假设关联的主持人。