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

项目摘要/摘要 阿尔茨海默病患者越来越认识到神经病理蛋白的清除受损 疾病(AD)。脑脊液(CSF)流动在大脑的废物清除过程中起着至关重要的作用， 脑脊液流量的中断与AD有关。然而，大多数关于脑脊液清除的研究是 在动物中进行，而人脑中的脑脊液流动动力学和清除途径仍然很差 明白了。大多数人类对脑脊液血流的研究只能研究脑室内的血流动力学。 或者到目前为止，由于缺乏足够的成像工具，在导水管内，对脑脊液在关键部位的流动知之甚少 间隙区-蛛网膜下腔(SAS)和血管周围间隙(PVS)。这构成了一个主要的障碍 全脑脑脊液血流动力学和清除途径及其与衰老和阿尔茨海默病的关系 病理学，这是了解阿尔茨海默病中有毒蛋白质清除过程的必要步骤。 为了克服这一障碍，这项计划的目标是开发第一台全脑mr-csf流量计。 这将成像区域从脑室扩展到以前无法接触到的SAS和PVS，并将其应用于研究 增龄和阿尔茨海默病全脑脊液流量的变化及其与神经病理蛋白的关系 证词。流量测量技术将提供无与伦比的灵敏度、特异度、效率和 绘制人脑中SAS/PVS脑脊液流动的时空分辨率图。使用此工具，我们将回答关键字 关于人类全脑SAS/PVS血流动力学和通路及其驱动因素的问题 大脑。然后，我们将研究脑脊液血流动力学如何随着健康年龄的增长而变化，以及它们在AD中是如何被破坏的 患者，特别是血流停滞与淀粉样β蛋白和tau沉积的相关性 结合PET成像。这项研究的结果将极大地促进我们对大脑的了解 清除衰老和阿尔茨海默病，并为未来脑脊液血流成像生物标志物的研究奠定基础 以及对AD的治疗干预，以改善临床结果。 应聘者在神经成像、磁共振物理学和最先进的磁共振方法学方面接受了深入的培训， 和信号处理。他正在寻求阿尔茨海默氏症的额外培训，翻译研究技能，以及 多模影像分析从这一赠与机制出发，实现了自己的长期职业目标，成为一名 神经退行性疾病的神经成像方面的独立研究员，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和 神经变性，并将这些技术转化为促进非侵入性成像的发现 生物标志物和帮助开发阿尔茨海默病和相关痴呆症的治疗干预措施。 他将与一个由多学科导师和合作者组成的多学科团队合作，这些导师和合作者是世界知名的 并利用马萨诸塞州综合医院的特殊资源来实现HIS 科学和职业发展目标。

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.