Interaction between microvascular function and CSF clearance in Lewy body dementia

项目摘要/摘要 现有的文献表明，微血管功能受损，脑脊液从大脑中的清除一直是 与脑淋巴系统相连，错综复杂地参与了ADRDS的发病机制。积累 有证据表明，大脑中的微血管和淋巴系统之间存在相互作用。流动 淋巴液体的减少被认为主要是由小血管的搏动驱动的。因此，改变 血液流动可能导致淋巴清除受损，这两者都可能导致痴呆症的发病。 然而，关于这种相互作用的细节尚不清楚，这主要是因为缺乏两者的活体数据 可以在同一主题中捕获的系统。此外，现有的大多数MRI方法对这些微血管进行成像。 目前还没有使用组织学等多模式方法系统地验证小血管。最后， 这种功能障碍与认知损害的关系及其与病理特征的关系 对诸如β-淀粉样蛋白和tau等痴呆症的研究仍然不是很清楚，尤其是在人类中。这项建议是 旨在解决这些知识差距。PI的实验室一直专注于开发 用于评估人脑微血管和淋巴功能的非侵入性核磁共振方法。我们的前- 使用这些技术的临床学研究表明，显著的微血管和淋巴管- ADRD患者可检测到不同程度的变化。这项提案的中心目标是调查 应用一种新的MRI方法研究ADRDS患者小血管和淋巴管功能障碍的影响 它可以同时测量与小血管和淋巴管相关的血流参数。到目前为止， 大多数成像方法只能单独测量血管或淋巴管。提议的新方法 (目标1)建立在我们先前的单个核磁共振技术测量血管和淋巴管的工作基础上 分别进行了分析。一种可以在一次扫描中测量两个系统的方法将提供Sig. 显著缩短了扫描时间，减少了生理变化带来的混杂影响和信号污染 两次扫描之间。对于基于造影剂的MRI方法，组合方法将减少 每个参与者都需要一定剂量的造影剂。人体研究将与动物研究并行 模型，以便可以使用组织学来验证MRI方法(目标2)。重要的是，在AIM 3中，使用PRO- 提出的方法，我们将研究与认知障碍相关的小血管和淋巴管的变化 由于路易体痴呆(LBD)，是ADRD的一种，也是世界上第二常见的进行性痴呆 我们。我们将研究MRI测量、淀粉样蛋白和tau病理之间的横断面关系， 对80例LBD患者和对照组的认知功能进行了测试。血液和血液之间的相互作用 淋巴管将在相同的科目中进行研究。综上所述，拟议的研究预计将 加深对LBD微血管功能和脑脊液清除率变化及其对预后影响的认识 认知障碍，这可能促进生物标记物和潜在治疗靶点的发展。

PROJECT SUMMARY/ABSTRACT Extant literature suggests that impaired microvascular function, and CSF clearance from the brain that has been linked with the cerebral lymphatic system, are intricately involved in the pathogenesis of ADRDs. Accumulating evidence has indicated the interaction between the microvascular and lymphatic systems in the brain. The flow of lymphatic fluid is believed to be driven primarily by the pulsatility of small blood vessels. Therefore, a change in blood flow may lead to impaired lymphatic clearance, which may both contribute to the pathogenesis of dementia. Nevertheless, details regarding such interaction is unclear, largely due to the lack of in vivo data of the two systems that can be captured in the same subjects. Besides, most existing MRI methods for imaging these mi- crovessels have not been systemically validated using multi-modality approaches such as histology. Finally, the relationship between such dysfunction and cognitive impairment, and their relationship to pathological hallmarks of dementia such as beta-amyloid and tau are still not well understood, particularly in humans. This proposal is designed to address these knowledge gaps. The PI's laboratory has been focusing on the development of non-invasive MRI approaches for assessing microvascular and lymphatic function in the human brain. Our pre- liminary studies using these techniques have shown strong evidence that significant microvascular and lym- phatic changes can be detected in patients with ADRD. The central goal of this proposal is to investigate the impact from dysfunction of small blood and lymphatic vessels in ADRDs using a newly developed MRI method that can measure perfusion parameters related to small blood and lymphatic vessels simultaneously. To date, most imaging methods can only measure blood or lymphatic vessels separately. The proposed new method (Aim 1) builds upon our previous work of individual MRI techniques to measure blood and lymphatic vessels respectively. An approach that can measure the two systems in one single scan will offer the advantage of sig- nificantly shorter scan time, and less confounding effects and signal contamination from physiological variations between scans. For MRI methods based on contrast agents, a combined method will reduce the number of doses of contrast media needed for each participant. Human studies will be paralleled by studies in animal models so that MRI methods can be validated using histology (Aim 2). Importantly, in Aim 3, using the pro- posed methods, we will study the small blood and lymphatic vessel changes associated with cognitive deficits due to Lewy Body Dementia (LBD), a type of ADRD and the second most common progressive dementia in the US. We will examine the cross-sectional relationship between the MRI measures, amyloid and tau pathology, and cognitive function in 80 individuals (LBD patients and matched controls). Interaction between blood and lymphatic vessels will be studied in the same subjects. Taken together, the proposed studies are expected to advance our understanding of changes in microvascular function and CSF clearance in LBD and their impact on cognitive impairment, which may facilitate the development of biomarkers and potential treatment targets.