CNS and Plasma Amyloid--Beta Kinetics in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是痴呆症的最常见原因，目前没有疾病修饰治疗或简单准确的诊断测试。几种靶点已被确定为AD病理生理学的贡献者（例如A？、tau、炎症），目前大多数治疗方法靶向淀粉样蛋白-β（A？）。然而，A？病理生理学尚未完全理解。淀粉样蛋白假说提出，淀粉样蛋白-β过度产生或清除不足导致常见的病理生理学，导致级联事件，其最终导致神经元死亡并表现为阿尔茨海默型的进行性临床痴呆。因此，在治疗试验中，在轻度至中度痴呆阶段治疗AD可能为时已晚，因为50%的AD特异性神经元已经死亡。因此，更好地了解A？的病理生理学和基于A？病理生理学的生物标志物是提供抗A？治疗策略成功的最佳机会所必需的。该项目的总体目标是确定AD中A？代谢发生的变化，并对A？在人类中枢神经系统（CNS）和外周中的产生、转运、代谢和清除进行建模，以改善临床试验设计。为了理解A？为了研究AD病理生理学中的代谢动力学，申请人将使用稳定同位素标记动力学（SILK）对人CNS中的蛋白质进行代谢标记和定量。具体目的是：1）确定稳态输注标记血液中A <$亚型的产生和清除率，2）测量AD和对照受试者中脉冲口服标记SILK方案的血液和CSF A <$SILK。在SA 1中，血液A？动力学将与CSF A？动力学进行比较，并利用多室和结构模型进行组合，以确定转运和分解的方向和幅度。SA 2中的口服标记方案将提供关于A？动力学的额外信息，并可能更好地区分AD与对照。来自SA 2的结果将与来自SA 1和正在进行的研究的结果一起纳入补充模型，以提供脑、CSF和血液隔室内和之间的A？产生、运输和分解的测量。拟议的工作建立在先前的开创性方法的基础上，该方法影响了对A？在淀粉样蛋白假说和AD病理生理学原因中的作用的理解。该方法已扩展到显着改进的技术，新颖的标签协议，和尖端的建模方法。总之，这些研究将提供血液中A？动力学的首次人体测量，开发A？代谢的综合模型，并确定AD中A？代谢的变化，这将导致更好的临床试验设计和潜在的AD血液生物标志物。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia and currently has no disease modifying treatments or simple accurate diagnostic tests. Several targets have been identified as contributors to AD pathophysiology (e.g. A¿, tau, inflammation), with most current therapeutic approaches targeting amyloid- beta (A¿). However, A¿ pathophysiology is not fully understood. The amyloid hypothesis proposes that amyloid-beta over-production or under-clearance leads to a common pathophysiology resulting in a cascade of events which culminate in neuronal death and manifest as progressive clinical dementia of the Alzheimer's type. Therefore, treatment of AD during the mild to moderate stage of dementia in therapeutic trials may be too late as 50% of AD specific neurons are already dead. Thus, a better understanding of the pathophysiology of A¿ and biomarkers based on A¿ pathophysiology are necessary to offer anti-A¿ therapeutic strategies their best chance of success. The overall goal of this project is to determine the changes that occur in A¿ metabolism in AD and model the production, transport, metabolism and clearance of A¿ in the human central nervous system (CNS) and periphery to improve clinical trial designs. In order to understand A¿ kinetics in the pathophysiology of AD, the applicant will use Stable Isotope Labeling Kinetics (SILK) to metabolically label and quantify proteins in the human CNS. The specific aims are 1) to determine A¿ isoform production and clearance rates in steady state infusion labeled blood, and 2) to measure blood and CSF A¿ SILK from a pulse oral labeled SILK protocol in AD and control participants. In SA1, blood A¿ kinetics will be compared to CSF A¿ kinetics and combined utilizing multi-compartment and structural models to determine the direction and magnitude of transport and breakdown. The oral labeling protocol in SA2 will provide additional information on A¿ kinetics and potentially better distinguish AD from controls. Results from SA2 will be incorporated into complimentary models with results from SA1 and ongoing studies to provide measures of A¿ production, transport, and breakdown within and between the brain, CSF and blood compartments. The proposed work builds on the prior pioneering approach that has influenced the understanding of A¿'s role in the amyloid hypothesis and pathophysiological causes of AD. The approach has been extended with significantly improved techniques, novel labeling protocols, and cutting-edge modeling approaches. In summary, these studies will provide the first human measurements of A¿ kinetics in blood, develop comprehensive models of A¿ metabolism, and determine changes of A¿ metabolism in AD that will lead to better clinical trial designs and potentially a blood biomarker for AD.