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: 10387988
• 负责人: Marisa Nicole Denkinger
• 金额: $ 4.27万
• 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/10387988
• 关键词: Affect; Age; Aging; Albumins; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Appearance; Area; Atrophic; Blood; Blood - brain barrier anatomy; Blood Tests; Blood Vessels; Brain; Brain region; Clinical; Cognition; Cognitive; Communication; Cross-Sectional Studies; 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 (Brain); Home; Homeostasis; Human; Impaired cognition; Impairment; Inferior; Institutes; Lead; 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; Patients; Performance; Positron-Emission Tomography; Postdoctoral Fellow; Proteins; Research; Research Personnel; Research Project Grants; Research Training; Role; Sampling; Secure; Students; Symptoms; Temporal Lobe; Testing; Tracer; Training; Vascular Diseases; abeta accumulation; abeta deposition; age related; base; 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; in vivo; innovation; insight; multimodal neuroimaging; neuroimaging; neurotoxic; neurovascular; normal aging; novel; pharmacokinetic model; protein aggregation; skills; statistics; tau Proteins; tau aggregation; theories; therapy development; treatment strategy; 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.

项目总结