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.

项目摘要/摘要 现存的文献表明，微血管功能受损，大脑的CSF清除率已经 与脑淋巴系统有关，与ADRD的发病机理无关。累积 证据表明大脑中的微血管和淋巴系统之间的相互作用。流 据信淋巴液的淋巴液主要由小血管的脉动驱动。因此，改变 血流可能导致淋巴清除率受损，这两者都可能导致痴呆的发病机理。 然而，有关这种相互作用的细节尚不清楚，这主要是由于两者中缺乏体内数据 可以在同一主题中捕获的系统。此外，大多数现有的MRI方法用于成像这些MI- 使用多模式的方法（例如组织学），尚未系统地验证CROVESSELS。最后， 这种功能障碍与认知障碍之间的关系及其与病理标志的关系 β-淀粉样蛋白和tau等痴呆症仍然不太了解，尤其是在人类中。该提议是 旨在解决这些知识差距。 PI的实验室一直集中在 非侵入性MRI方法评估人脑中的微血管和淋巴功能。我们的前 使用这些技术的Limary研究表明，有明显的微血管和淋巴结的有力证据 ADRD患者可以检测到态变化。该提议的核心目标是调查 使用新开发的MRI方法的小血液和淋巴管功能障碍的影响 可以同时测量与小血液和淋巴管有关的灌注参数。迄今为止， 大多数成像方法只能分别测量血液或淋巴管。提出的新方法 （AIM 1）建立在我们以前单个MRI技术的工作以测量血液和淋巴管的工作 分别。可以在一次扫描中测量两个系统的方法将提供Sig-的优势 较短的扫描时间和生理变化的混杂效果和信号污染较少 在扫描之间。对于基于对比剂的MRI方法，一种组合方法将减少 每个参与者需要的对比媒体剂量。人类研究将与动物的研究平行 模型，以便可以使用组织学验证MRI方法（AIM 2）。重要的是，在AIM 3中，使用专业 摆姿势的方法，我们将研究与认知缺陷相关的小血液和淋巴管变化 由于Lewy身体痴呆（LBD），一种ADRD和第二常见的进行性痴呆症 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， 80个个体（LBD患者和匹配的对照组）中的认知功能。血液与 淋巴管将在同一受试者中进行研究。综上所述，拟议的研究应 促进我们对LBD中微血管功能和CSF清除率的变化的理解及其对 认知障碍，这可能有助于生物标志物和潜在治疗靶标的发展。