Metabolic Factors in AD

摘要项目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）风险增加约1.5倍，但其机制 不清楚。我们关注两种可能将早期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（IGF 1）和胆固醇转运。在非痴呆的成年人中，我们将这些代谢 1）AD病理学的脑脊液（CSF）标志物，2）结构和功能性脑连接 和海马亚区厚度的区域选择性易受AD，和3）变化超过2年， 大脑连接和记忆。我们的多模态纵向项目包括多壳层扩散张量成像 分析了一种新的纤维取向分布工具。这些创新提高了我们测量大脑的能力 即使在交叉纤维和白色病变的存在下，也可以保持连接性。我们还将使用静息状态 功能性磁共振成像（rs-fMRI），以评估功能连接，并将评估内嗅 皮质和海马CA 1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; 70-90岁。我们将招募低血管风险、高血压和糖化血红蛋白升高的受试者。 血红蛋白和低HDL-C。使用胰岛素、IGF 1、IGF结合蛋白和 从血液和CSF中获得的胆固醇流出能力，我们将评估：1）IGF 1和IGFBPs如何与 神经变性，由CSF ptau 181水平介导，测量为内嗅皮质和CA 1萎缩 2）胰岛素如何影响海马的功能和结构连接，以及AD相关区域的功能和结构连接的丧失; 和胆固醇外排能力与AD相关的脱髓鞘和功能连接缺陷有关。 区域，由A β 42水平介导; 3）胰岛素信号肽和胆固醇流出能力是如何影响 与认知、大脑结构和功能的2年变化有关。我们期待着更好的理解 T2 DM和代谢风险如何导致临床前AD脑变化。这对于实现量身定制至关重要 为处于特定风险的人提供治疗和预防工作。

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.