Metabolic Factors in AD

AD 中的代谢因素

• 批准号: 8850280
• 负责人: Meredith Nicole Braskie
• 金额: $ 12.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8850280
• 关键词: Adult; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid Proteins; Animals; Apolipoprotein E; Atrophic; Binding Proteins; Biological Markers; Blood; Blood Vessels; Brain; Cerebrospinal Fluid; Cholesterol; Cognition; Demyelinations; Diffusion; Diffusion Magnetic Resonance Imaging; Education; Fiber; Functional Magnetic Resonance Imaging; Genetic Risk; Glycosylated Hemoglobin; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hippocampus (Brain); Hyperinsulinism; Hypertension; Hypertriglyceridemia; IGF1 gene; Image Analysis; Impaired cognition; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like Growth-Factor-Binding Proteins; Lead; Lesion; Link; Measures; Medial; Mediating; Memory; Memory Loss; Metabolic; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Patients; Peptide Signal Sequences; Persons; Pilot Projects; Positron-Emission Tomography; Prevention; Pulse Pressure; Recruitment Activity; Relative (related person); Research; Rest; Risk; Serum; Signal Transduction; Structure; System; Thick; Time; Toxic effect; Vascular resistance; Work; abstracting; aged; axonal degeneration; cingulate cortex; entorhinal cortex; frontal lobe; functional loss; hippocampal subregions; imaging biomarker; improved; individualized medicine; innovation; insulin signaling; mild cognitive impairment; novel; pre-clinical; sex; success; tau-1; tool; waist circumference; white matter

ABSTRACT PROJECT 2: METABOLIC FACTORS AND ALZHEIMER DISEASE Type 2 diabetes mellitus (T2DM) increases Alzheimer's disease (AD) risk by ~1.5 times, but the mechanisms are unclear. We focus on two metabolic risk-related mechanisms that may link early T2DM to AD: insulin & insulin-like growth factor 1 (IGF1) and cholesterol transport. In non-demented adults, we relate these metabolic factors to 1) cerebrospinal fluid (CSF) markers of AD pathology, 2) structural and functional brain connectivity and hippocampal subregion thickness in regions selectively vulnerable to AD, and 3) changes over 2 years in brain connectivity and memory. Our multimodal longitudinal project includes multi-shell diffusion tensor imaging analyzed with a novel fiber orientation distribution tool. These innovations improve our ability to measure brain connectivity even in the presence of crossed fibers and white matter lesions. We also will use resting state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity, and will evaluate entorhinal cortex and hippocampal CA1 thickness. We will examine 180 adults with no or mild cognitive impairment; aged 70-90 yrs. We will recruit subjects with low vascular risk, with hypertension, and those with elevated glycated hemoglobin and low HDL-C. Using continuous measures of insulin, IGF1, IGF binding proteins, and cholesterol efflux capacity derived from blood and CSF, we will evaluate: 1) How IGF1 and IGFBPs relate to neurodegeneration, mediated by CSF ptau181 levels and measured as atrophy in the entorhinal cortex and CA1 of the hippocampus and loss of functional and structural connectivity in AD-relevant regions; 2) How insulin and cholesterol efflux capacity relate to demyelination and functional connectivity deficits in AD-relevant regions, mediated by A¿42 levels; and 3) How insulin signaling peptides and cholesterol efflux capacity are related to 2-year changes in cognition, and brain structure and function. We anticipate improved understanding of how T2DM and metabolic risk contribute to preclinical AD brain changes. This is crucial to enabling tailored treatment and prevention efforts to persons at specific risk.

摘要项目 2：代谢因素和阿尔茨海默病 2 型糖尿病 (T2DM) 会使阿尔茨海默病 (AD) 风险增加约 1.5 倍，但其机制 不清楚。我们重点关注可能将早期 T2DM 与 AD 联系起来的两种代谢风险相关机制：胰岛素和 胰岛素样生长因子 1 (IGF1) 和胆固醇转运。在非痴呆成年人中，我们将这些代谢联系起来 1) AD 病理学的脑脊液 (CSF) 标志物，2) 结构和功能性大脑连接的因素 和海马亚区厚度，选择性易患 AD 的区域，以及 3) 两年内的变化 大脑连接和记忆。我们的多模态纵向项目包括多壳扩散张量成像 使用新型纤维取向分布工具进行分析。这些创新提高了我们测量大脑的能力 即使存在交叉纤维和白质病变也能保持连通性。我们还将使用静息状态 功能磁共振成像（rs-fMRI）可评估功能连接性，并评估内嗅 皮质和海马 CA1 厚度。我们将对 180 名没有或轻度认知障碍的成年人进行检查；老年的 70-90岁我们将招募血管风险低、患有高血压和糖化水平升高的受试者 血红蛋白和低 HDL-C。连续测量胰岛素、IGF1、IGF 结合蛋白和 为了评估来自血液和脑脊液的胆固醇流出能力，我们将评估：1) IGF1 和 IGFBP 之间的关系 神经变性，由脑脊液 ptau181 水平介导，测量为内嗅皮层和 CA1 的萎缩 海马体的损伤以及 AD 相关区域功能和结构连接的丧失； 2) 胰岛素如何 胆固醇流出能力与 AD 相关的脱髓鞘和功能连接缺陷有关 由 A¿42 水平介导的区域； 3) 胰岛素信号肽和胆固醇流出能力如何 与认知、大脑结构和功能的两年变化有关。我们期望加深理解 T2DM 和代谢风险如何导致临床前 AD 大脑变化。这对于实现定制化至关重要 针对特定风险人群的治疗和预防工作。