Tracking tau spread through functional connectivity networks in aging

跟踪衰老过程中 tau 蛋白通过功能性连接网络的传播

• 批准号: 10022085
• 负责人: Jenna Nicole Adams
• 金额: $ 2.23万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022085
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Animals; Brain; Clinical; Cognitive; Communication; Deposition; Development; Disease; Early Diagnosis; Early Intervention; Educational process of instructing; Elderly; Episodic memory; Evidence based treatment; Fellowship; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Growth; Human; Impairment; Individual; Institutes; Intervention; Investigation; Lead; Literature; Magnetic Resonance Imaging; Measures; Medial; Mediating; Memory; Memory Loss; Memory impairment; Mentors; Methods; Modeling; Neocortex; Nerve Degeneration; Neurons; Neuropsychological Tests; Neurosciences; Pathologic; Pathology; Pattern; Performance; Positron-Emission Tomography; Postdoctoral Fellow; Process; Research; Research Personnel; Research Training; Rest; Role; Sampling; Seeds; Stereotyping; Structure; Synapses; System; Temporal Lobe; Time; Tracer; Training; Work; base; beta amyloid pathology; career; design; entorhinal cortex; follow-up; in vivo; innovation; insight; memory process; multimodality; neuroimaging; normal aging; pre-clinical; prevent; relating to nervous system; skills; spatiotemporal; student mentoring; tau Proteins; tau aggregation

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.

项目摘要 tau蛋白的高磷酸化形式是阿尔茨海默氏病（AD）中的病理剂，也是 在认知正常的老年人中发现。 tau首先积聚在内嗅皮层（ERC）中，然后扩散 通过跨突触和活动相关的刻板印象空间时间模式通过大脑通过大脑 机制。这些发现表明，ERC功能连接性（FC）的模式可能对 了解tau在人类中传播的最初进展，尽管这种关联尚未 调查。此外，以前的文献表明FC和Tau蔓延之间存在双向关系， 因此，尽管强大的足球俱乐部最初可能会驱动tau蔓延，但高水平的TAU最终可能会破坏FC网络。 当前的项目将在人类中首次调查tau差异是否与FC相关 在认知正常的老年人中使用创新的多模式神经影像学方法的ERC网络 （OA）。 TAU将使用极性发射断层扫描（PET）示踪剂[18F] Flortaucipir在体内进行定量。 ERC FC网络将使用种子到体voxel FC分析从静止状态功能MRI得出。 另外，将使用[11C] PIB-PET，结构MRI的神经退行性变性和情节测量Aβ 具有复合神经心理测试评分的记忆。在AIM 1中，我们将调查提议的 OA受试者的横截面设计中Tau扩展与ERC FC网络之间的双向模型。在 AIM 2，我们将在OA受试者中评估基线时的ERC FC强度是否可以预测纵向tau 1.5-2年后的后续沉积，以及这些因素是否也可以预测纵向发作 记忆力下降。这项研究的结果将有助于解释tau通过人脑传播的模式， 为干预措施提供了一个关键目标，以减少或防止Tau在衰老和AD中的传播。另外， TAU对内侧临时叶记忆系统的影响将进一步表征，从而可以预测 记忆力下降要识别。拟议研究的完成将实现申请人的培训 目标，包括（1）宠物，fMRI和SMRI中神经影像学技能的发展，（2） AD的临床病理生理学，（3）提高科学沟通技巧和（4）教学的增长 和心理技能。加州大学伯克利分校的海伦·威尔斯神经科学学院提供了创新的网络 神经科学的研究人员和世界一流的神经影像学设施。赞助商威廉·贾古斯特（William Jagust）博士是 将多模式神经影像学方法应用于衰老和AD的领导者，并具有良好的轨道 成功心理学生的记录。拟议的研究和培训计划的结合将 为申请人提供全面的基础，以建立成功的博士后奖学金 以及使用多模式神经影像学来研究衰老和疾病的记忆障碍的研究职业。