Interaction between glymphatic and vascular systems for waste clearance in brain - Administrative Supplement

类淋巴系统和血管系统之间的相互作用以清除大脑中的废物 - 行政补充

• 批准号: 10399708
• 负责人: JIANI HU
• 金额: $ 20.02万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399708
• 关键词: Achievement; Address; Administrative Supplement; Age; Aging; Alzheimer' s disease pathology; Amyloid beta-Protein; Arachnoid mater; Brain; Brain imaging; Caliber; Cerebrospinal Fluid; Cerebrum; Cognitive; Cytoplasmic Granules; Data; Diabetes Mellitus; Disease; Dose; Drainage procedure; Excision; Flushing; Funding; Image; Intercellular Fluid; Laser Scanning Confocal Microscopy; Lymphatic; Magnetic Resonance Imaging; Measurement; Mediating; Meningeal lymphatic system; Methods; Neurologic; Organism; Pathway interactions; Play; Predisposition; Publishing; Research; Resolution; Rest; Role; Route; System; Testing; Vascular System; Venous; Venous system; Visualization; Water; age effect; aging brain; aqueous; base; brain parenchyma; brain pathway; brain tissue; detection sensitivity; ferumoxtran; fluorescence imaging; glymphatic system; imaging modality; improved; in vivo; in vivo imaging; indexing; insight; interstitial; iron oxide; lymphatic vasculature; macromolecule; minimally invasive; novel; olfactory bulb; solute; superparamagnetism; two-photon; wasting

ABSTRACT The objective of this current proposal is to investigate aging induced changes of brain waste clearance in the meningeal lymphatic and glymphatic systems using superparamagnetic iron oxide (SPIO)-enhanced susceptibility weighted imaging (SWI, SPIO-SWI) and fluorescent imaging. Emerging data indicate that the glymphatic system mediates the cerebrospinal fluid (CSF)-interstitial (ISF) exchange and solute clearance from the brain parenchyma and plays an important role in neurological diseases1-6. However, despite many milestone achievements, conclusive findings on the solute efflux pathways are relatively limited. In our funded RO1 (NS108463), we investigate the effects of diabetes on glymphatic and vascular system cerebral waste clearance. The recently discovered meningeal lymphatics has also been shown to be important for cerebral waste clearance. However, the interaction between the meningeal lymphatic and glymphatic systems on cerebral waste clearance has not been investigated. The paucity of research into the efflux pathways may be attributed, in part, to the technical difficulties of performing minimally invasive in vivo, ultra-high detection sensitivity measurements of influx and efflux pathways, and whole brain imaging. Although MRI can overcome the weak points of two-photon imaging (TPI), to provide non-invasive whole brain in vivo imaging of the glymphatic system, conventional MRI sensitivity is insufficient to investigate microvessels of the meningeal lymphatic and glymphatic systems. During the past funded period we have successfully optimized and validated highly sensitive MRI microvessel measurement. We have identified an optimal TE-dose index to greatly improve visualization of sub-voxel vessels (detecting ~10µm diameter microvessels), and have demonstrated that the parenchymal venous system also plays an important role in cerebral waste clearance7-9. The recently discovered meningeal lymphatics has been proposed to be an important efflux pathway for cerebral waste clearance, and the decrease in cerebral waste clearance mediated by a dysfunctional relationship between the meningeal lymphatics and the glymphatic system during, serves as an aggravating factor for Alzheimer’s disease pathology and age-associated cognitive decline10, 11. However, several critical issues for this important topic have not been addressed. Based on our novel preliminary data, and published studies, we hypothesize that the newly optimized SPIO-SWI method significantly increases detection sensitivity of microvessels in both the meningeal lymphatic and glymphatic systems, and that the efflux pathways of waste clearance can be identified and investigated using this optimized SPIO-SWI method. To test these hypotheses, we will investigate the effects of aging on the interaction between the meningeal lymphatic and glymphatic systems during waste clearance using the optimized USPIO-SWI method and fluorescent imaging. Data generated from this current proposal will provide new insights into the effects of aging on the efflux interactions between the meningeal lymphatic and glymphatic systems.

摘要 本研究的目的是研究衰老引起的脑废物清除的变化， 使用超顺磁性氧化铁（SPIO）增强的脑膜淋巴和胶质淋巴系统 磁敏感加权成像（SWI，SPIO-SWI）和荧光成像。新出现的数据表明， 胶质淋巴系统介导脑脊液（CSF）-间质（ISF）交换和溶质清除， 脑实质，并在神经系统疾病中发挥重要作用1 -6。尽管有许多里程碑 尽管已经取得了一些成就，但关于溶质外排途径的结论性发现相对有限。在我们资助的RO 1中 （NS 108463），我们研究了糖尿病对胶质淋巴和血管系统脑废物清除的影响。 最近发现的脑膜炎也被证明是重要的大脑废物 间隙然而，脑膜淋巴系统和胶质淋巴系统对脑废物的相互作用 没有对清除情况进行调查。 对外排途径的研究很少，部分原因可能是 对流入和流出途径进行微创体内超高检测灵敏度测量， 和全脑成像虽然MRI可以克服双光子成像（TPI）的弱点，但提供 胶质淋巴系统的非侵入性全脑体内成像，常规MRI灵敏度不足以 研究脑膜淋巴和胶质淋巴系统的微血管。在过去的一段时间里，我们 成功优化和验证了高灵敏度的MRI微血管测量。我们已经确定 最佳TE剂量指数，可大大改善亚体素血管的可视化（检测~10µm直径 微血管），并已证明实质静脉系统也起着重要作用， 大脑废物清除7 -9。最近发现的脑膜炎被认为是一种 脑废物清除的重要外排途径，以及脑废物清除介导的 由于脑膜炎和胶质淋巴系统之间的功能失调， 阿尔茨海默病病理学和年龄相关的认知能力下降的加重因素10，11.然而，在这方面， 这一重要专题的若干关键问题尚未得到处理。基于我们新的初步数据， 和已发表的研究，我们假设新优化的SPIO-SWI方法显着增加 脑膜淋巴系统和胶质淋巴系统中微血管的检测灵敏度， 废物清除的途径，可以确定和调查使用这种优化的SPIO-SWI方法。测试 这些假设，我们将研究年龄对脑膜淋巴细胞之间的相互作用的影响， 和胶质淋巴系统在废物清除过程中使用优化的USPIO-SWI方法和荧光 显像从目前的建议产生的数据将提供新的见解老化对流出的影响， 脑膜淋巴和胶质淋巴系统之间的相互作用。