Interaction between microvascular function and CSF clearance in Lewy body dementia

路易体痴呆中微血管功能与脑脊液清除之间的相互作用

• 批准号: 10661984
• 负责人: Jun Hua
• 金额: $ 238.71万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661984
• 关键词: Address; Age; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Arteries; Autopsy; Blood Vessels; Blood Volume; Blood flow; Brain; Brain Diseases; Brain region; Cerebrovascular Circulation; Cerebrum; Clinical; Cognitive deficits; Contrast Media; Cross-Sectional Studies; Data; Dementia; Development; Disease; Dose; Foundations; Functional disorder; Future; Goals; Histologic; Histology; Human; Image; Impaired cognition; Impairment; Individual; Knowledge; Laboratories; Lewy Body Dementia; Link; Literature; Lymph; Lymphatic; Lymphatic System; Lymphatic clearance; Lymphatic function; Magnetic Resonance Imaging; Measures; Methodology; Methods; Microvascular Dysfunction; Participant; Pathogenesis; Pathologic; Pathology; Patients; Perfusion; Physiologic pulse; Physiological; Proteins; Research; Resolution; Rodent Model; Scanning; Severities; Signal Transduction; System; Techniques; Time; Validation; Variant; Vascular Endothelium; Vascular System; Wild Type Mouse; Work; arteriole; biomarker development; brain dysfunction; cognitive function; design; drug development; imaging modality; in vivo; interest; lymph flow; lymphatic dysfunction; lymphatic vessel; millimeter; multimodality; novel; preclinical study; tau Proteins; technology development; technology validation; temporal measurement; vascular injury

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.

项目总结/摘要 现有文献表明，受损的微血管功能和CSF从脑中的清除， 与脑淋巴系统相关的神经元参与ADRD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 淋巴液的流动被认为主要是由小血管的脉动性驱动的。因此， 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机制。 然而，关于这种相互作用的细节尚不清楚，主要是由于缺乏两者的体内数据。 可以在相同的主题中捕获的系统。此外，大多数现有的MRI方法成像这些MI- 还没有使用多模态方法如组织学对crovessels进行系统验证。最后 这种功能障碍和认知障碍之间的关系，以及它们与病理标志之间的关系 诸如β-淀粉样蛋白和tau蛋白等痴呆症的发病机制仍然没有得到很好的理解，特别是在人类中。这项建议是 旨在填补这些知识空白。PI的实验室一直专注于开发 用于评估人脑中微血管和淋巴功能的非侵入性MRI方法。我们的预- 使用这些技术的初步研究已经显示出强有力的证据， 在ADRD患者中可以检测到嗜酸细胞的变化。该提案的中心目标是调查 使用新开发的MRI方法对ADRD中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灌注参数。到目前为止， 大多数成像方法只能分别测量血管或淋巴管。提出的新方法 (Aim 1）建立在我们以前的工作的个人MRI技术来测量血液和淋巴管 分别一种可以在一次扫描中测量两个系统的方法将提供信号的优势。 扫描时间明显更短，来自生理变化的混杂效应和信号污染更少 扫描之间。对于基于造影剂的MRI方法，组合方法将减少造影剂的数量。 每名参与者所需的造影剂剂量。人体研究将由动物研究进行补充 模型，以便MRI方法可以使用组织学进行验证（目标2）。重要的是，在目标3中，使用亲- 提出的方法，我们将研究与认知缺陷相关的小血管和淋巴管的变化 由于路易体痴呆症（LBD），一种ADRD类型和第二个最常见的进行性痴呆， 我们我们将研究MRI测量、淀粉样蛋白和tau病理学之间的横截面关系， 和认知功能在80个人（LBD患者和匹配的对照）。血液与 将在相同的受试者中研究淋巴管。总的来说，拟议的研究预计将 提高我们对LBD微血管功能和CSF清除率变化及其对 认知障碍，这可能有助于生物标志物和潜在治疗靶点的开发。