Imaging brain-wide subarachnoid and perivascular cerebrospinal fluid flow in aging and Alzheimer's disease

对衰老和阿尔茨海默病中的全脑蛛网膜下腔和血管周围脑脊液流动进行成像

• 批准号: 10722140
• 负责人: Zijing Dong
• 金额: $ 13.39万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722140
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animals; Arachnoid mater; Area; Automobile Driving; Blood Vessels; Brain; Brain Mapping; Brain imaging; Cardiac; Cerebrospinal Fluid; Circulation; Clinical; Communities; Data; Deposition; Elderly; Flowmetry; Foundations; Functional Magnetic Resonance Imaging; Future; General Hospitals; Goals; Grant; Human; Image; Imaging Device; Imaging Techniques; Imaging technology; Impairment; Investigation; Knowledge; Link; Magnetic Resonance Imaging; Maps; Massachusetts; Measurement; Measures; Mentors; Methodology; Methods; Modeling; Morphologic artifacts; Motion; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Outcome Study; Participant; Pathogenesis; Pathway interactions; Patients; Physics; Physiologic pulse; Physiology; Play; Positron-Emission Tomography; Process; Proteins; Protocols documentation; Research; Research Personnel; Resolution; Resources; Respiration; Role; Scanning; Signal Transduction; Spatial Distribution; Specificity; Subarachnoid Space; System; Techniques; Technology; Testing; Therapeutic Intervention; Time; Training; Translating; Translational Research; Transportation; Work; aged; career; career development; cerebrospinal fluid flow; glymphatic system; healthy aging; human study; imaging biomarker; imaging modality; improved; innovation; multidisciplinary; neural; neuroimaging; neuropathology; new therapeutic target; non-invasive imaging; novel; programs; research study; signal processing; skills; spatiotemporal; tau Proteins; tau aggregation; therapeutic development; tool; wasting

PROJECT SUMMARY / ABSTRACT The impaired clearance of neuropathological proteins has been increasingly recognized in Alzheimer's disease (AD). Cerebrospinal fluid (CSF) flow plays an essential role in the waste clearance process of the brain, and disruptions of CSF flow are implicated in AD. However, most of the studies on CSF clearance were conducted in animals, and the CSF flow dynamics and clearance pathways in the human brain remain poorly understood. Most of the human studies on brain CSF flow are only able to investigate flow dynamics in ventricles or in the aqueduct so far due to the lack of sufficient imaging tools, and little is known about CSF flow in the key regions for clearance—subarachnoid space (SAS) and perivascular space (PVS). This poses a major barrier to studying brain-wide CSF flow dynamics and clearance pathways as well as their correlation with aging and AD pathology, which are essential steps toward understanding the clearance process of toxic proteins in AD. To overcome this barrier, the goal of this proposal is to develop the first whole-brain MR CSF flowmetry that extends the imaging area from ventricles to previously inaccessible SAS and PVS, and apply it to investigate the alteration of brain-wide CSF flow in aging and AD, and its correlation with neuropathological protein deposition. The flowmetry technique will provide unparalleled sensitivity, specificity, efficiency, and spatiotemporal resolution to map SAS/PVS CSF flow in the human brain. Using this tool, we will answer key questions about brain-wide SAS/PVS flow dynamics and pathways as well as their driving factors in the human brain. We will then study how CSF flow dynamics change with healthy aging and how they are disrupted in AD patients, especially how flow stagnation correlates with amyloid-beta and tau deposition using MR flowmetry combined with PET imaging. The outcome of this study will significantly advance our knowledge of brain clearance in aging and AD, and lay the foundation for future investigation of CSF-flow-based imaging biomarkers and therapeutic interventions for AD to improve clinical outcomes. The candidate has in-depth training in neuroimaging, MR physics and state-of-the-art MR methodology, and signal processing. He is seeking additional training in Alzheimer's disease, translational research skills, and multi-model imaging analysis from this grant mechanism, to achieve his long-term career goal to become an independent investigator in neuroimaging of neurodegenerative diseases, and establish research programs that develop innovative neuroimaging technologies, apply them to advance our understanding of aging and neurodegeneration, and translate these technologies to facilitate the discovery of non-invasive imaging biomarkers and aid in the development of therapeutic interventions of Alzheimer's disease and related dementias. He will work with a multi-disciplinary team of mentors and collaborators who are world-renowned experts in their respective fields, and leverage the exceptional resources at Massachusetts General Hospital to achieve his scientific and career development goals.

项目摘要/摘要 在阿尔茨海默病中，神经病理蛋白的清除受损已越来越多地被认识到。 疾病（AD）。脑脊液（CSF）流动在大脑的废物清除过程中起着重要作用， 并且CSF流动的中断与AD有关。然而，大多数关于CSF清除率的研究 在动物中进行，并且人脑中的CSF流动动力学和清除途径仍然很差 明白大多数关于脑CSF流动的人体研究只能研究脑室中的流动动力学 由于缺乏足够的成像工具，到目前为止， 间隙区-蛛网膜下腔（SAS）和血管周围间隙（PVS）。这是一个主要的障碍， 研究全脑CSF流动动力学和清除途径以及它们与衰老和AD的相关性 病理学，这是了解AD中毒性蛋白质清除过程的重要步骤。 为了克服这一障碍，本提案的目标是开发第一个全脑MR CSF流量计 将成像区域从心室扩展到以前无法到达的SAS和PVS，并将其应用于研究 增龄和AD全脑脑脊液流量变化及其与神经病理蛋白的相关性 证词流量计技术将提供无与伦比的灵敏度，特异性，效率， 空间时间分辨率来映射人脑中的SAS/PVS CSF流。使用此工具，我们将回答关键 关于全脑SAS/PVS流动动力学和途径以及人类驱动因素的问题 个脑袋然后，我们将研究CSF流动动力学如何随着健康老龄化而变化，以及它们在AD中如何被破坏。 患者，特别是使用MR血流测定法，血流停滞与淀粉样蛋白β和tau沉积的相关性 结合PET成像。这项研究的结果将大大推进我们对大脑的认识 清除衰老和AD，并为未来研究基于CSF流的成像生物标志物奠定基础 和AD的治疗干预以改善临床结果。 候选人在神经影像学，MR物理学和最先进的MR方法学方面接受过深入的培训， 和信号处理。他正在寻求在阿尔茨海默病，转化研究技能， 多模式成像分析从这个资助机制，实现他的长期职业目标，成为一个 神经退行性疾病神经影像学的独立研究者，并建立研究计划， 开发创新的神经成像技术，应用它们来促进我们对衰老的理解， 神经变性，并将这些技术转化为促进非侵入性成像的发现 生物标志物，并帮助开发阿尔茨海默病和相关痴呆症的治疗干预措施。 他将与一个由导师和合作者组成的多学科团队合作，他们是世界知名的专家， 各自的领域，并利用特殊的资源在马萨诸塞州总医院，以实现他的 科学和职业发展目标。