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

血脑屏障破坏、阿尔茨海默病病理学和衰老记忆之间的关系

• 批准号: 10799538
• 负责人: Marisa Nicole Denkinger
• 金额: $ 4.42万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799538
• 关键词: Affect; Age; Aging; Albumins; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Appearance; Area; Atrophic; Blood; Blood - brain barrier anatomy; Blood Tests; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain region; Clinical; Cognition; Cognitive; Communication; Data Analyses; Deposition; Detection; Development; Diagnosis; Disease; Early Diagnosis; Early Intervention; Educational process of instructing; Elderly; Episodic memory; Etiology; Event; Extravasation; Fellowship; Functional disorder; Goals; Hippocampus; Home; Homeostasis; Human; Impaired cognition; Impairment; Inferior; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Mediating; Memory; Mentors; Methods; Multimodal Imaging; Nerve Degeneration; Neuronal Injury; Neuropsychological Tests; Neurosciences; Outcome; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Performance; Positron-Emission Tomography; Postdoctoral Fellow; Proteins; Research; Research Personnel; Research Project Grants; Role; Sampling; Secure; Students; Symptoms; Temporal Lobe; Testing; Tracer; Training; Vascular Diseases; abeta accumulation; abeta deposition; age related; blood-brain barrier disruption; blood-brain barrier permeabilization; career; career development; cerebral atrophy; contrast enhanced; design; early detection biomarkers; healthy aging; imaging biomarker; imaging facilities; imaging modality; improved; in vivo; innovation; insight; multimodal neuroimaging; neuroimaging; neurotoxic; neurovascular; normal aging; novel; novel therapeutic intervention; pharmacokinetic model; protein aggregation; skills; statistics; tau Proteins; tau aggregation; theories; therapy development; vascular injury; young adult

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.

项目摘要 阿尔茨海默氏病（AD）的主要理论是蛋白质β-淀粉样蛋白的沉积，但是它是 尚不清楚衰老如何影响淀粉样蛋白的积累，或者为什么在不存在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，例如血脑屏障的崩溃（BBB），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。 但是，BBB崩溃与AD生物标志物以及认知之间的直接关系并非 在人类中进行了彻底的调查。这项研究的目的是使用新型的多模式成像设计来检查 人类中的BBB分解与萎缩，淀粉样蛋白和tau以及认知的AD生物标志物有关。 BBB 通过动态对比增强的磁共振成像（DCE-MRI），分解将在体内量化， 这允许检测人脑中细微的BBB泄漏。 Tau和Aβ都将在 分别使用二极子发射断层扫描（PET）示踪剂[18F] Flortaucipir和[11c] Pib的体内。 神经变性将通过结构MRI和情节记忆测量 神经心理学测试评分。 AIM 1将确定BBB分解是否随着年龄的增长而增加，并且是否有特定 在正常衰老期间更脆弱的地区。 AIM 2将检查临时叶中的BBB分解是否 与更大的全局Aβ和区域tau有关。此外，将确定是否关联BBB分解 具有更大的回顾性纵向Aβ和TAU积累。最后，AIM 3将确定BBB是否故障 在临时叶中，叶片与较小的临时叶量和较差的内存性能有关。关系 在BBB崩溃和回顾性记忆性能的纵向变化之间，独立于淀粉样蛋白 和Tau，也将进行检查。这项研究的发现将有助于阐明AD的基本机制 人脑的发病机理，对早期发现和新的发展具有至关重要的意义 AD的治疗策略。拟议的研究项目将实现应用程序的培训目标，这将 包括（1）在多模式成像中发展技能，（2）高级统计和数据分析培训，（3）培训 在AD的临床障碍和病理生理学中，（4）教学和心理技能的发展，（5） 提高有效的科学沟通技巧和（6）职业发展。加州大学伯克利分校的海伦·威尔斯 神经科学研究所是尖端研究人员和世界一流成像设施网络的所在地。这 该项目的赞助商威廉·贾格斯特（William Jagust）博士在将多模式神经影像学方法应用于 研究衰老和广告的问题。过去，他还成功地推荐了许多学生 成为该领域的领导者。共同发起人Suzanne Baker博士是神经影像优化的专家 PET和MRI的定量以及药代动力学建模。拟议的研究和 培训计划将为申请人提供技能，以确保有竞争性的博士后奖学金和 成功的研究职业研究衰老和广告。