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。已经确定了几个靶点作为AD病理生理的贡献者（例如A¿，tau，炎症），目前大多数治疗方法针对淀粉样蛋白- β （A¿）。然而，A¿病理生理学尚不完全清楚。淀粉样蛋白假说认为，淀粉样蛋白- β的过度产生或清除不足会导致一种常见的病理生理学，从而导致一系列事件，最终导致神经元死亡，并表现为阿尔茨海默氏症型的进行性临床痴呆。因此，在治疗性试验中，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¿的病理生理和基于a¿病理生理的生物标志物是提供抗a¿治疗策略的最佳成功机会所必需的。该项目的总体目标是确定AD中A¿代谢发生的变化，并模拟A¿在人类中枢神经系统（CNS）和外周的产生、运输、代谢和清除，以改进临床试验设计。为了了解AD病理生理学中的A¿动力学，申请人将使用稳定同位素标记动力学（SILK）对人类中枢神经系统中的蛋白质进行代谢标记和量化。具体目的是1)确定稳态输注标记血液中A¿异构体的产生和清除率，以及2)通过脉冲口服标记SILK方案测量AD和对照参与者的血液和CSF A¿SILK。在SA1中，血液A¿动力学将与CSF A¿动力学进行比较，并结合使用多室和结构模型来确定运输和分解的方向和大小。SA2中的口服标记方案将提供关于A¿动力学的额外信息，并可能更好地将AD与对照区分开。SA2的结果将与SA1的结果和正在进行的研究结合到互补模型中，以提供脑、脑脊液和血室内部和之间A¿产生、运输和分解的措施。提出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阿尔茨海默病病理生理原因中的作用的理解。该方法已经通过显著改进的技术、新颖的标记协议和尖端的建模方法进行了扩展。总之，这些研究将提供血液中A¿动力学的首次人体测量，建立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，并可能成为AD的血液生物标志物。

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.