Metabolic Factors in AD

AD 中的代谢因素

• 批准号: 9246405
• 负责人: Meredith Nicole Braskie
• 金额: $ 12.68万
• 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/9246405
• 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; Brain Diseases; Cerebrospinal Fluid; Cholesterol; Cognition; Cognitive; 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; 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; 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; Research; Rest; Risk; Serum; Signal Transduction; Structure; System; Thick; Time; Toxic effect; Vascular resistance; Work; aged; axonal degeneration; cingulate cortex; entorhinal cortex; frontal lobe; functional loss; hippocampal subregions; improved; individualized medicine; innovation; insulin signaling; mild cognitive impairment; multimodality; non-demented; 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.

项目2：代谢因素与阿尔茨海默病 2型糖尿病(T2 DM)使阿尔茨海默病(AD)的风险增加~1.5倍，但其机制 都不清楚。我们专注于两个可能将早期T2 DM与AD联系起来的代谢风险相关机制：胰岛素和 胰岛素样生长因子1与胆固醇转运。在非精神错乱的成年人中，我们将这些代谢联系起来 影响因素1)脑脊液(CSF)AD病理标志物，2)结构和功能脑连接 和选择性易患AD区域的海马区厚度，以及3)在两年内的变化 大脑连通性和记忆力。我们的多模式纵向项目包括多壳扩散张量成像 用一种新型的纤维取向分布工具进行了分析。这些创新提高了我们测量大脑的能力 甚至在存在交叉纤维和白质病变的情况下也是如此。我们还将使用休眠状态 功能磁共振成像(rs-fmri)评估功能连通性，并将评估内嗅觉 皮质和海马CA1区厚度。我们将检查180名无认知障碍或轻度认知障碍的成年人 70-90岁。我们将招募低血管风险、高血压和糖化升高的受试者。 血红蛋白和低高密度脂蛋白胆固醇使用连续测量胰岛素、IGF1、IGF结合蛋白和 来自血液和脑脊液的胆固醇流出能力，我们将评估：1)IGF1和IGFBPs如何相关 由脑脊液ptau181水平介导的神经变性，测量为内嗅皮层和CA1的萎缩 与AD相关区域的功能和结构连接的丧失；2)胰岛素如何 而胆固醇流出能力与AD相关的脱髓鞘和功能连接性缺陷有关 由A�42水平介导的区域；以及3)胰岛素信号肽和胆固醇流出能力是如何 与两年来认知、大脑结构和功能的变化有关。我们期待着更好的理解 了解T2 DM和代谢风险如何导致临床前AD的大脑变化。这对于实现定制至关重要 对特定风险人群的治疗和预防工作。