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

十分之一的65岁及以上的美国人（10%）患有阿尔茨海默病（AD）。2型糖尿病患者中 (DM)患者中，近70%随着年龄的增长而发展为AD。许多研究支持糖尿病与 AD. AD是一种缓慢进展的、不可逆的神经退行性疾病，具有长的临床前阶段，持续至 到20岁; AD在DM中的患病率在以后几年增加。糖尿病是血管疾病的已知危险因素 并且与微血管系统中的弥漫性硬化有关。这两种疾病之间的关系， 将它们联系在一起的机制还不完全清楚，但DM患者的胶质淋巴清除较慢， 预计将发挥重要作用。大脑中glymphatics的概念是由Negergaard开创的，他 确定了一个系统，通过该系统，可溶性蛋白质和代谢物从中枢神经系统中消除 通过脑脊髓液（CSF）和间质液（ISF）在血管旁空间交换。研究支持 其重要性在正在进行研究中继续得到扩展和验证，主要是在啮齿动物中。睡眠和 据报道，体力活动可加速胶质淋巴清除。在睡眠期间， 已经观察到由细胞外空间的膨胀和收缩引起的大鼠脑废物的清除。 其他研究表明，胶质淋巴清除率随着年龄的增长而下降，但可以增加 短暂的老年小鼠自愿轮运行演习。最近，在人类中，使用钆- 通过鞘内注射的基于造影剂（GBCA）允许观察胶质淋巴清除作为示踪剂， 尽管是在很长一段时间内。然而，这种方法受到其侵入性和细胞的未知作用的限制。 GBCA示踪剂对胶质淋巴清除的体内时间过程的影响。据报道，体育锻炼可以改善 大鼠脑Aβ清除率。最近的小动物研究表明，GBCA在间隙中的清除速度减慢， 在糖尿病大鼠的海马中增加了三倍。DM大鼠也表现出认知功能下降， 非DM大鼠。尽管这些研究表明，胶质淋巴清除率降低对认知功能的影响很重要， 糖尿病大鼠的下降，解释受到糖尿病和非糖尿病大鼠之间可能的潜在变化的限制， GBCA对CSF清除率的影响。使用一种新的，非侵入性的，非对比MRI技术，我们建议， 研究了DM和非DM人脑中硬脑膜淋巴清除， 人类脑膜的矢状旁硬脑膜（PSD）和蛛网膜颗粒（AG）液体。我们的挑战包括 识别PSD和AG并测量脑膜处硬膜淋巴液清除的细微变化。 为了克服这些挑战，我们将开发MR技术来阐明i）PSD、AG和上级的解剖结构 矢状窦，ii）确定硬膜淋巴液的详细清除途径; iii）获得硬膜淋巴液 灌注测量; iv）评估健康受试者中的年龄和运动效应;以及v）比较硬脑膜 糖尿病患者与年龄、性别匹配的健康成人的淋巴灌注。我们认为硬膜淋巴管 与健康的老年受试者相比，灌注测量将是不同的，并且随着运动而改变。

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.