Relationships between blood-brain barrier breakdown, Alzheimer's disease pathology, and memory in aging

项目摘要 阿尔茨海默病（AD）的主要病因理论是β-淀粉样蛋白的沉积，然而， 不清楚衰老如何影响淀粉样蛋白的积累，也不清楚为什么在淀粉样蛋白缺失的情况下会发生认知能力下降。证据 表明神经血管功能障碍，如血脑屏障（BBB）的破坏，与 神经变性和认知障碍，这种关系可能独立于淀粉样蛋白发生。 然而，BBB破坏和AD生物标志物以及认知之间的直接关系还没有得到证实。 在人类中进行了彻底的研究。本研究的目的是使用一种新的多模态成像设计来检查 人类的血脑屏障破坏如何与萎缩、淀粉样蛋白和tau蛋白以及认知的AD生物标志物相关。BBB 使用动态对比增强磁共振成像（DCE-MRI）在体内定量分解， 其允许检测人脑中细微的BBB渗漏。tau和Aβ均将在 分别使用正电子发射断层扫描（PET）示踪剂[18 F] Flortaucipir和[11 C] PiB体内。 神经退行性病变将通过结构MRI和情景记忆测量， 神经心理学测验得分。目标1将确定BBB崩溃是否随年龄增长而增加， 在正常衰老过程中更脆弱的区域。目标2将检查颞叶中的BBB是否崩溃 与更大的全球Aβ和区域tau蛋白有关。此外，还将确定BBB击穿是否与 具有更大的回顾性纵向Aβ和tau累积。最后，目标3将确定BBB是否击穿 大脑颞叶的体积较小，记忆力也较差。关系 BBB崩溃和记忆表现的回顾性纵向变化之间的关系，独立于淀粉样蛋白 和tau，也将被检查。这项研究的结果将有助于揭示AD的基本机制 发病机制在人类大脑中，这对早期发现和新的发展具有重要意义。 AD的治疗策略拟议的研究项目将实现申请人的培训目标， 包括（1）发展多模式成像技能，（2）高级统计和数据分析培训，（3）培训 在AD的临床损伤和病理生理学方面，（4）发展教学和指导技能，（5） 提高有效的科学沟通技能;（6）职业发展。加州大学伯克利分校的海伦·威尔斯 神经科学研究所拥有尖端研究人员网络和世界一流的成像设施。的 该项目的发起人William Jagust博士在应用多模式神经成像方法方面处于最前沿， 研究衰老和AD的问题。他还成功地指导了许多学生在过去，谁有 成为该领域的领导者。共同发起人Suzanne Baker博士是神经成像优化方面的专家 PET和MRI的定量以及药代动力学建模。无论是拟议的研究和 培训计划将为申请人提供技能，以确保有竞争力的博士后奖学金和 成功的研究事业，研究衰老和AD。

Project Summary The major theory of causation for Alzheimer’s disease (AD) is deposition of the protein β-amyloid, however it is unclear how aging influences amyloid accumulation or why cognitive decline can occur in its absence. Evidence suggests that neurovascular dysfunction, such as the breakdown of the blood-brain barrier (BBB), is related to neurodegeneration and cognitive impairment, and that this relationship may occur independently of amyloid. However, the direct relationship between BBB breakdown and AD biomarkers, as well as cognition, has not been thoroughly investigated in humans. The aim of this study is to use a novel multi-modal imaging design to examine how BBB breakdown in humans is related to AD biomarkers of atrophy, amyloid and tau, and cognition. BBB breakdown will be quantified in vivo using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which allows for the detection of subtle BBB leakage in the human brain. Both tau and Aβ will be measured in vivo using the positron emission tomography (PET) tracers [18F] Flortaucipir and [11C] PiB, respectively. Neurodegeneration will be measured with structural MRI and episodic memory with a composite neuropsychological test score. Aim 1 will determine if BBB breakdown increases with age and if there are specific regions that are more vulnerable during normal aging. Aim 2 will examine if BBB breakdown in the temporal lobe is related to greater global Aβ and regional tau. In addition, it will be determined if BBB breakdown is associated with greater retrospective longitudinal Aβ and tau accumulation. Finally, Aim 3 will determine if BBB breakdown in the temporal lobe is related to smaller temporal lobe volumes and worse memory performance. Relationships between BBB breakdown and retrospective longitudinal change in memory performance, independent of amyloid and tau, will also be examined. The findings from this study will help unravel fundamental mechanisms of AD pathogenesis in the human brain, which has vital implications for early detection and the development of new treatment strategies for AD. The proposed research project will achieve the applicant’s training goals, which include (1) developing skills in multimodal imaging, (2) advanced statistics and data analysis training, (3) training in clinical impairment and pathophysiology of AD, (4) development of teaching and mentoring skills, (5) improvement of effective scientific communication skills, and (6) career development. UC Berkeley’s Helen Wills Neuroscience Institute is home to a network of cutting-edge researchers and world-class imaging facilities. The sponsor of the project, Dr. William Jagust, is at the forefront in applying multimodal neuroimaging methods to study questions of aging and AD. He also has successfully mentored numerous students in the past, who have become leaders in the field. The co-sponsor, Dr. Suzanne Baker, is an expert in optimization of neuroimaging quantification for both PET and MRI, as well as pharmacokinetic modeling. Both the proposed research and the training plan will provide the applicant with the skillset to secure a competitive post-doctoral fellowship and a successful research career studying aging and AD.