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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病 (AD) 因果关系的主要理论是 β-淀粉样蛋白的沉积，然而，目前还不清楚衰老如何影响淀粉样蛋白的积累，或者在缺乏证据的情况下为什么会发生认知能力下降。表明神经血管功能障碍，例如血脑屏障（BBB）的破坏，与神经变性和认知障碍，并且这种关系可能独立于淀粉样蛋白而发生。然而，BBB 崩溃与 AD 生物标志物以及认知之间的直接关系尚未得到证实。这项研究的目的是使用一种新颖的多模态成像设计来检查。人类 BBB 分解与萎缩、淀粉样蛋白和 tau 蛋白以及 BBB 等 AD 生物标志物有何关系。将使用动态对比增强磁共振成像（DCE-MRI）在体内量化分解，可以检测人脑中细微的 BBB 渗漏，并且可以测量 tau 蛋白和 Aβ。分别使用正电子发射断层扫描 (PET) 示踪剂 [18F] Flortaucipir 和 [11C] PiB 进行体内检测。神经退行性疾病将通过结构 MRI 和复合情景记忆来测量目标 1 将确定血脑屏障是否随着年龄的增长而增加以及是否存在特定的情况。目标 2 将检查颞叶中的 BBB 是否崩溃。与更大的整体 Aβ 和局部 tau 相关。此外，将确定是否与 BBB 崩溃有关。最后，目标 3 将确定 BBB 是否崩溃。颞叶的体积与较小的颞叶体积和较差的记忆性能有关。血脑屏障破坏与记忆表现的回顾性纵向变化之间的关系，与淀粉样蛋白无关这项研究的结果将有助于揭示 AD 的基本机制。人脑的发病机制，这对于早期检测和新疾病的开发具有重要意义拟议的研究项目将实现申请人的培训目标，其中包括 (1) 发展多模态成像技能，(2) 高级统计和数据分析培训，(3) 培训 AD 的临床损伤和病理生理学，(4) 教学和指导技能的发展，(5) 提高有效的科学沟通技巧，以及 (6) 加州大学伯克利分校的海伦·威尔斯的职业发展。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。该项目的发起人 William Jagust 博士处于应用多模态神经影像方法的前沿他过去还成功指导过许多学生，他们已经研究了衰老和 AD 问题。成为该领域的领导者，苏珊·贝克博士是神经影像优化方面的专家。 PET 和 MRI 的量化以及药代动力学模型。培训计划将为申请人提供获得有竞争力的博士后奖学金和研究衰老和 AD 的成功研究生涯。