CNS TAU KINETICS IN ALZHEIMER'S DISEASE

项目摘要 肌萎缩侧索硬化症是一种具有tau病变的神经退行性疾病，是最常见的病理疾病。 神经退行性疾病的表现，包括进行性皮质基底膜变性(CBD) 核上性瘫痪(PSP)、额颞叶痴呆(FTD)和阿尔茨海默病(AD)，这是 最常见的肌萎缩侧索硬化症，正在达到流行的程度。 近年来，tau靶向治疗在AD研究领域得到了极大的关注。级别 脑脊液(CSF)总tau和磷酸化tau(p-tau)随着AD的增加而增加，这对AD很重要 AD的生物标志物。然而，目前还没有建立适当的方法来测量人类的tau动力学。 目的：评价tau靶向疗法的疗效。令人惊讶的是，最近一项纵向生物标记物研究 显性遗传性AD患者在认知功能衰退开始后脑脊液tau水平下降。这个 结果表明，tau的浓度随着症状性疾病的进展或大脑的进展而降低。 Tau在阿尔茨海默病的大脑中的固存增加。有趣的是，最近对tau正电子发射的研究 脑电地形图(PET)成像显示，只有在认知功能下降之后，tau的沉积才会增加， 与脑脊液tau浓度下降相吻合。因此，对活体tau的更全面的研究 人类中枢神经系统(CNS)中的动力学对于理解糖尿病的病理生理学是至关重要的 以及为什么tau浓度会随着tau聚集性的增加而升高，然后又会下降。 这项建议将利用稳定同位素标记动力学(SILK)方法来阐明tau在 人中枢神经系统中的活体及其在AD中的变化共100名参与者(30名正常对照，30名AD和 40名年龄匹配的对照组)将被招募并静脉注射稳定同位素标记以测量tau 使用新开发的牛丝丝方法进行动力学研究。目标1将测量人体的生理动力学 通过按年龄和比较对参与者进行分层来识别与年龄相关的变化 将在三个不同的年龄段(18-39岁；40-；65岁以上)进行。AIM 2将研究中枢神经系统tau动力学 与认知正常、年龄匹配的迟发性阿尔茨海默病患者相比，tau PET的tau聚集率 控制。此外，为了进一步确定AD病理对人tau的生理动力学的影响。 中枢神经系统、tau丝的数据将与通过PET成像评估的淀粉样蛋白和tau脑病理相关联。 用tau PET成像研究tau丝的结果将有助于阐明人类的动态动力学。 中枢神经系统tau在肌萎缩侧索硬化症的生理学和病理生理学中的作用。牛丝绸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 目标是陶。

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.