Aging and Exercise Effects of Dural Lymphatic Clearance in Healthy Human and Diabetic Brains

健康人和糖尿病大脑中硬脑膜淋巴清除的衰老和运动影响

• 批准号: 10420651
• 负责人: Mitsue Miyazaki
• 金额: $ 224.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420651
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Anatomy; Animals; Arachnoid mater; Blood Vessels; Brain; Cerebrospinal Fluid; Contrast Media; Cytoplasmic Granules; Data; Diabetes Mellitus; Diffuse Cerebral Sclerosis of Schilder; Disease; Dura Mater; Exercise; Extracellular Space; Gadolinium; Goals; Health Status; Hippocampus (Brain); Human; Impaired cognition; Injections; Intercellular Fluid; Intrathecal Injections; Ionizing radiation; Link; Liquid substance; Lymph; Lymphatic; Lymphatic clearance; Magnetic Resonance Imaging; Measurement; Measures; Meninges; Methodology; Methods; Movement; Mus; Neuraxis; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Perfusion; Phase; Physical Exercise; Physical activity; Play; Prevalence; Rattus; Reporting; Research; Risk Factors; Rodent; Role; Running; Site; Sleep; Superior sagittal sinus; System; Techniques; Testing; Time; Tracer; Vascular Diseases; age effect; age group; aged; aging brain; base; cognitive function; cohort; diabetic; glymphatic clearance; glymphatic dysfunction; glymphatic system; healthy aging; human old age (65+); human subject; improved; in vivo; interstitial; lymphatic vessel; mouse model; nonhuman primate; normal aging; novel; pre-clinical; prevent; protein metabolite; public health relevance; sex; temporal measurement; wasting

One in 10 Americans age 65 and older (10%) has Alzheimer’s disease (AD). Among type-2 diabetes mellitus (DM) patients, nearly 70% develop AD with aging. Numerous studies support the association between DM and AD. AD is a slowly progressive, irreversible neurodegenerative disease with a long preclinical phase lasting up to 20 years; the prevalence of AD in DM increases in later years. DM is a known risk factor for vascular disease and is associated with diffuse sclerosis in microvasculature. The relationship between these two diseases and the mechanisms that link them together are not fully understood, but slower glymphatic clearance in DM patients is expected to play a significant role. The concept of glymphatics in the brain was pioneered by Negergaard, who identified a system by which soluble proteins and metabolites are eliminated from the central nervous system via cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the paravascular space. Studies supporting its importance continue to be expanded upon and validated in ongoing research, primarily in rodents. Sleep and physical activity have been reported to accelerate glymphatic clearance. During sleep, a nearly 60% increase in clearance of rat brain wastes has been observed, caused by expansion and contraction of the extracellular space. Additional studies have shown that glymphatic clearance decreases with increasing age but can be increased transiently in aged mice by voluntary wheel running exercises. More recently, in humans, use of a gadolinium- based contrast agent (GBCA) via intrathecal injection allows for observation of glymphatic clearance as a tracer, albeit over a long period. However, this method is limited by its invasiveness, and by the unknown effect of the GBCA tracer on the in vivo time-course of glymphatic clearance. Physical exercise has been reported to improve clearance of brain Aβ in rats. Recent small animal studies show GBCA clearance in the interstitial space slowed by a factor of three in the hippocampus of DM rats. DM rats also showed decline in cognitive function compared to non-DM rats. Although these studies suggest that reduced glymphatic clearance is important for cognitive decline in DM rats, interpretation is limited by possible underlying changes between DM and non-DM rats, and effects of GBCA on CSF clearance. Using a novel, non-invasive, non-contrast MRI techniques we propose to study dural lymphatic clearance in DM and non-DM human brains, physical activity-induced clearance in parasagittal dura (PSD) and arachnoid granulations (AGs) fluid at meninges in humans. Our challenges include identification of PSD and AGs and measurement of subtle changes in dural lymphatic fluid clearance at meninges. To overcome these challenges, we will develop MR techniques to clarify i) the anatomy of PSD, AG, and superior sagittal sinus, ii) identify the detailed clearance pathway of dural lymphatic fluid; iii) obtain dural lymphatic fluid perfusion measures; iv) evaluate the age and exercise effects in healthy subjects; and v) compare the dural lymphatic perfusion of DM patients with age-, sex-matched healthy adults. We expect that dural lymphatic perfusion measures will be different and altered with exercise, as compared to healthy aging subjects.

65岁及以上（10％）的十分之一美国人患有阿尔茨海默氏病（AD）。 2型糖尿病 （DM）患者，几乎有70％的患有衰老的广告。大量研究支持DM和 广告。 AD是一种缓慢进行的，不可逆的神经退行性疾病，长长的临床前阶段持续 到20年； DM中AD的患病率在以后的几年中增加。 DM是血管疾病的已知危险因素 并与微脉管系统中的弥漫性硬化症有关。这两种疾病与 将它们连接在一起的机制尚不完全了解，但是DM患者的糖性清除较慢 预计将发挥重要作用。尼格尔加德（Negergaard 确定了从中枢神经系统中消除固体蛋白质和代谢物的系统 通过脑脊液（CSF）和间质性液体（ISF）在排行空间中的交换。支持的研究 它的重要性继续在正在进行的研究中扩大并验证，主要是在啮齿动物中。睡觉和 据报道，体育活动可以加速糖浆清除率。在睡眠期间，增长了近60％ 已经观察到大鼠脑废物的清除，这是由于细胞外空间的扩张和收缩引起的。 进一步的研究表明，子糖的清除率随着年龄的增长而降低，但可以增加 通过志愿轮跑运动在老年小鼠中瞬时。最近，在人类中，使用gadolinium- 通过鞘内注射的基于造影剂（GBCA）可以将糖性清除视为示踪剂， 尽管很长一段时间。但是，这种方法受到其侵入性的限制，以及未知的效果 GBCA示踪剂在体内的糖浆清除时间。据报道，体育锻炼可以改善 大鼠大脑Aβ的清除。最近的小动物研究表明，间质空间中的GBCA间隙减慢了 在DM大鼠的海马中，倍于三倍。 DM大鼠的认知功能还显示出下降 致非DM大鼠。尽管这些研究表明，降低糖化清除率对于认知很重要 DM大鼠的下降，解释受到DM和非DM大鼠之间的潜在变化的限制，以及 GBCA对CSF清除率的影响。我们建议使用一种新颖的，无创的，非对比度的MRI技术 研究DM和非DM人大脑中的硬膜淋巴清除，体育活动引起的清除率 人类脑膜的副臂硬脑膜（PSD）和蛛网膜颗粒（AGS）流体。我们的挑战包括 PSD和AGS的鉴定以及脑膜硬化淋巴流体清除率微妙变化的测量。 为了克服这些挑战，我们将开发MR技术来阐明i）PSD，AG和Superior的解剖结构 矢状窦，ii）确定硬脑膜淋巴液的详细清除途径； iii）获得硬脑膜淋巴液 灌注措施； iv）评估健康受试者的年龄和运动影响；和v）比较硬膜 年龄，性别匹配的健康成年人的DM患者的淋巴灌注。我们期望硬脑膜淋巴 与健康的衰老受试者相比，灌注措施将有所不同，并且随着运动而改变。

项目成果

Age-related Decline of Intrinsic Cerebrospinal Fluid Outflow in Healthy Humans Detected with Non-contrast Spin-labeling MR Imaging.

使用非对比自旋标记 MR 成像检测健康人体内固有脑脊液流出量与年龄相关的下降。

• DOI: 10.2463/mrms.mp.2022-0117
• 发表时间: 2024
• 期刊: Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine
• 作者: Malis,Vadim;Bae,WonC;Yamamoto,Asako;McEvoy,LindaK;McDonald,MarinA;Miyazaki,Mitsue
• 通讯作者: Miyazaki,Mitsue