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

每10个65岁及以上的美国人中就有一个(10%)患有阿尔茨海默病(AD)。在2型糖尿病中 在糖尿病患者中，近70%的人会随着年龄的增长而患上阿尔茨海默病。大量研究支持糖尿病和糖尿病之间的联系 广告。AD是一种进展缓慢、不可逆转的神经退行性疾病，临床前阶段较长。 至20岁；糖尿病患者AD患病率在晚年呈上升趋势。糖尿病是血管疾病的已知危险因素 并与弥漫性微血管硬化有关。这两种疾病之间的关系和 将它们联系在一起的机制尚不完全清楚，但糖尿病患者的淋巴清除速度较慢 预计将发挥重要作用。大脑中的语音学概念是由尼格加德首创的，他 指从中枢神经系统中清除可溶性蛋白质和代谢物的系统 通过脑脊液(CSF)和间质液(ISF)在血管旁间隙进行交换。学习支持 它的重要性继续得到扩大，并在正在进行的研究中得到验证，主要是在啮齿动物身上。睡眠和 据报道，体育活动可以加速淋巴的清除。在睡眠中，近60%的 已经观察到由于细胞外空间的扩张和收缩而导致的大鼠脑废物的清除。 更多的研究表明，随着年龄的增长，淋巴清除量减少，但可以增加。 通过自愿跑轮运动在衰老小鼠中进行一过性实验。最近，在人类身上，使用了Gd- 通过鞘内注射的基础造影剂(GBCA)允许观察作为示踪剂的淋巴清除， 尽管是在很长一段时间内。然而，这种方法受到其侵入性和 GBCA示踪剂在体内淋巴清除的时程研究据报道，体育锻炼有改善作用。 大鼠脑A-β的清除。最近的小动物研究表明，GBCA在间质中的清除速度减慢 在糖尿病大鼠的海马体中增加了三倍。与糖尿病大鼠相比，糖尿病大鼠的认知功能也有所下降 给非糖尿病大鼠。尽管这些研究表明减少淋巴清除量对认知能力很重要 在DM大鼠中的下降，解释受到DM和非DM大鼠之间可能的潜在变化的限制，以及 银杏叶提取物对脑脊液清除率的影响使用一种新的、非侵入性、非对比度的MRI技术，我们提出了 研究糖尿病和非糖尿病人脑的硬脑膜淋巴清除，运动诱导的清除 人类脑膜矢状面旁硬脑膜(PSD)和蛛网膜颗粒(AG)积液。我们面临的挑战包括 PSD和AGs的鉴别和脑膜淋巴清除量的细微变化测量。 为了克服这些挑战，我们将开发磁共振技术，以阐明i)PSD、AG和SUBERVER的解剖 矢状窦，ii)确定硬脑膜淋巴液的详细清除途径；iii)获取硬膜淋巴液 灌注测量；iv)评估健康受试者的年龄和运动效果；v)比较硬脑膜 糖尿病患者与年龄、性别匹配的健康成年人的淋巴灌流。我们预计硬脑膜淋巴管 与健康的老年受试者相比，血流灌注量会有所不同，并随着运动的进行而改变。

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.