Tracking tau spread through functional connectivity networks in aging

项目摘要 过度磷酸化的tau蛋白是阿尔茨海默病(AD)的病原体，也是 在认知正常的老年人中发现。Tau首先聚集在内嗅皮层(ERC)，然后扩散 在跨突触和相关活动的驱动下，以刻板的时空模式通过大脑 机械装置。这些发现表明，ERC功能连接(FC)的模式可能对 了解tau在人类中传播的最初进展，尽管这种联系尚未被 调查过了。此外，以前的文献表明Fc和tau扩散之间存在双向关系， 因此，虽然强大的FC最初可能会推动tau传播，但高水平的tau最终可能会扰乱FC网络。 目前的项目将首次在人类中调查tau传播是否与FC有关 在认知正常的老年人中使用创新的多模式神经成像方法的ERC网络 (办公自动化)。Tau将在体内使用正电子发射断层扫描(PET)示踪剂[18F]Flortaucipir进行量化。 ERC FC网络将从使用种子到体素FC分析的静息状态功能磁共振获得。 此外，β将用[11C]PIB-PET测量，神经退行性变用结构磁共振测量，发作期 记忆与综合神经心理测试分数。在目标1中，我们将调查建议的 在OA受试者的横截面设计中Tau扩展和ERC FC网络之间的双向模型。在……里面 目标2，我们将评估在骨性关节炎受试者中，基线时的ERCFC强度是否可以预测纵向张量 1.5-2年后随访时的沉积，以及这些因素是否也是纵向发作的预测因素 记忆力衰退。这项研究的发现将有助于解释tau在人脑中的传播模式， 为减少或防止tau在老龄化和阿尔茨海默病中的传播提供一个关键的干预目标。此外， Tau对内侧颞叶记忆系统的影响将进一步表征，允许预测 记忆力下降，无法识别。完成拟议的研究将实现申请者的培训 目标，包括(1)发展PET、fMRI和sMRI的神经成像技能，(2)在 阿尔茨海默病的临床病理生理，(3)科学沟通能力的提高，(4)教学的成长 和指导技能。加州大学伯克利分校的海伦·威尔斯神经科学研究所提供了一个创新网络 神经科学研究人员和世界一流的神经成像设备。赞助商威廉·雅格斯特博士是一位 在将多模式神经成像方法应用于衰老和阿尔茨海默病研究方面处于领先地位，并具有成熟的跟踪记录 成功辅导学生的记录。拟议的研究和培训计划的结合将 为申请者提供一个全面的基础，在此基础上建立成功的博士后奖学金 以及使用多模式神经成像来研究衰老和疾病中的记忆障碍的研究生涯。

Project Summary Hyperphosphorylated forms of the tau protein are pathological agents in Alzheimer's disease (AD) and also found in cognitively normal older adults. Tau first accumulates in the entorhinal cortex (ERC) and then spreads through the brain in a stereotypical spatiotemporal pattern driven by trans-synaptic and activity related mechanisms. These findings suggest that patterns of ERC functional connectivity (FC) may be critical to understanding the initial progression of tau spread in humans, though this association has not yet been investigated. Additionally, previous literature suggests a bidirectional relationship between FC and tau spread, such that while strong FC may initially drive tau spread, high levels of tau could eventually disrupt FC networks. The current project will investigate for the first time in humans whether tau spread is associated with FC networks of the ERC using an innovative multimodal neuroimaging approach in cognitively normal older adults (OA). Tau will be quantified in vivo using the positron emission tomography (PET) tracer [18F] Flortaucipir. ERC FC networks will be derived from resting-state functional MRI using seed-to-voxel FC analyses. Additionally, Aβ will be measured with [11C] PiB-PET, neurodegeneration with structural MRI, and episodic memory with a composite neuropsychological test score. In Aim 1, we will investigate the proposed bidirectional model between tau spread and ERC FC networks in a cross-sectional design in OA subjects. In Aim 2, we will assess within OA subjects whether ERC FC strength at baseline is predictive of longitudinal tau deposition at follow-up 1.5-2 years later, and whether these factors are also predictive of longitudinal episodic memory decline. Findings from this study will help explain patterns of tau spread through the human brain, providing a key target for interventions to reduce or prevent the spread of tau in aging and AD. Additionally, the impact of tau on the medial temporal lobe memory system will be further characterized, allowing predictors of memory decline to be identified. Completion of the proposed research will achieve the applicant's training goals, including (1) development of neuroimaging skills in PET, fMRI, and sMRI, (2) conceptual training in the clinical pathophysiology of AD, (3) improvement of scientific communication skills, and (4) growth of teaching and mentoring skills. The Helen Wills Neuroscience Institute at UC Berkeley provides a network of innovative neuroscience researchers and world-class facilities for neuroimaging. Dr. William Jagust, the sponsor, is a leader in applying multimodal neuroimaging methods to the study of aging and AD, and has a proven track record of successfully mentoring students. The combination of the proposed research and training plan will provide the applicant with a comprehensive foundation on which to build a successful post-doctoral fellowship and research career using multimodal neuroimaging to study memory impairment in aging and disease.