CNS TAU KINETICS IN ALZHEIMER'S DISEASE

项目摘要 tau蛋白病是具有tau病理学的神经退行性疾病，并且是最常见的病理性疾病。 在神经退行性疾病中的表现，包括皮质基底节变性（CBD）、进行性 核上性麻痹（PSP）、额颞叶痴呆（FTD）和阿尔茨海默病（AD）， 最常见的tau蛋白病，并达到流行病的比例。 近年来，tau蛋白靶向治疗在AD研究领域获得了极大的关注。水平 脑脊液（CSF）总tau蛋白和磷酸化tau蛋白（p-tau）随着AD的增加而增加， AD的生物标志物。然而，尚未建立测量人类中tau动力学的适当方法 以评估靶向tau的治疗剂的功效。令人惊讶的是，最近的一项纵向生物标志物研究， 显性遗传的AD患者显示在认知衰退开始后CSF tau水平降低。的 结果表明，tau蛋白浓度随着症状性疾病的进展而降低， AD脑中tau的隔离增加。有趣的是，最近对tau正电子发射的研究 局部解剖（PET）成像表明只有在认知能力下降之后， 与CSF tau浓度降低一致。因此，更全面的体内tau蛋白研究 人类中枢神经系统（CNS）的动力学对于理解 AD和为什么tau浓度升高，后来可能随着tau聚集的增加而降低。 本提案将利用稳定同位素标记动力学（SILK）方法阐明tau蛋白的动力学， 在人CNS中的体内表达及其在AD中的改变。共100名参与者（30名正常对照，30名AD和30名AD患者）， 40名年龄匹配的对照）将被招募并用稳定同位素静脉内标记以测量tau 使用新开发的tau SILK方法进行动力学分析。目标1将测量以下的生理动力学： CNS中的人类tau蛋白，并通过按年龄和比较对参与者进行分层来识别年龄相关的变化 将在三个不同的年龄组（18-39岁; 40-64岁; 65岁以上）进行。目标2将检查CNS tau动力学 与认知正常、年龄匹配的AD痴呆患者相比， 对照此外，为了确定AD病理学对人tau蛋白的生理学动力学的影响， CNS、tau SILK数据将与通过PET成像评估的淀粉样蛋白和tau脑病理学相关。 使用tau PET成像进行的这项tau SILK研究的结果将有助于阐明人类肿瘤的动态动力学。 CNS tau蛋白在tau蛋白病的生理学和病理生理学中的作用。Tau SILK方法将促进未来的努力 评估tau靶向治疗的疗效，并帮助有效地设计未来的临床试验， 目标tau。

Project Summary Tauopathies are neurodegenerative diseases with tau pathology, and are the most common pathological manifestation in neurodegenerative diseases, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD), and Alzheimer's disease (AD), which is the most common tauopathy and is reaching epidemic proportions. Recently, tau-targeted therapies have gained significant attention in the AD research field. Levels of cerebrospinal fluid (CSF) total tau and phosphorylated tau (p-tau) are increased with AD and are important biomarkers for AD. However, proper methods to measure tau kinetics in humans have not been established to evaluate the efficacy of tau-targeted therapeutics. Surprisingly, a recent longitudinal biomarker study in dominantly inherited AD patients showed that CSF tau levels decrease after cognitive decline begins. The results suggest that tau concentrations decrease with symptomatic disease progression, or brain sequestration of tau is increased in the AD brain. Interestingly, recent studies of tau positron emission topography (PET) imaging indicate increasing tau deposition only after the time of cognitive decline, coinciding with decreasing CSF tau concentrations. Thus, a more comprehensive study of in vivo tau dynamics in the human central nervous system (CNS) is critical to understanding the pathophysiology of AD and why tau concentration is elevated and later may decrease with increasing tau aggregation. This proposal will utilize the Stable Isotope Labeling Kinetics (SILK) method to elucidate tau kinetics in vivo in the human CNS and its alteration in AD. A total of 100 participants (30 normal controls, 30 AD and 40 age-matched controls) will be recruited and labeled intravenously with a stable isotope to measure tau kinetics using the newly developed tau SILK method. Aim 1 will measure the physiological kinetics of human tau in the CNS and identify age-related changes by stratifying participants by age and comparisons will be made across three different age groups (18-39; 40-64; 65+). Aim 2 will examine CNS tau kinetics and tau aggregation by tau PET in late-onset AD dementia compared to cognitively normal, age-matched controls. Further, to determine the impact of AD pathology on the physiological kinetics of human tau in the CNS, tau SILK data will be correlated to amyloid and tau brain pathology assessed by PET imaging. Results from this tau SILK study with tau PET imaging will help elucidate the dynamic kinetics of human CNS tau in physiology and pathophysiology of tauopathies. The tau SILK method will facilitate future efforts to evaluate the efficacy of tau-targeted therapies and help effectively design future clinical trials which target tau.