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 岁及以上的美国人中有十分之一 (10%) 患有 2 型糖尿病中的阿尔茨海默病 (AD)。 (DM) 患者中，近 70% 的人会随着年龄的增长而患上 AD。大量研究支持 DM 与衰老之间的关联。 AD 是一种缓慢进展、不可逆的神经退行性疾病，具有长期的临床前阶段。 20 岁以后，糖尿病中 AD 的患病率会增加，这是已知的血管疾病危险因素。 并与微血管系统的弥漫性硬化有关，这两种疾病之间的关系。 将它们联系在一起的机制尚不完全清楚，但糖尿病患者的类淋巴清除速度较慢 大脑中类淋巴系统的概念是由 Negergaard 提出的，他被认为将发挥重要作用。 确定了一种从中枢神经系统中消除可溶性蛋白质和代谢物的系统 通过血管旁空间的脑脊液（CSF）和间质液（ISF）交换。 其重要性在正在进行的研究中不断得到扩展和验证，主要是在啮齿类动物中。 据报道，体力活动可加速睡眠期间的类淋巴液清除，增加近 60%。 已观察到大鼠脑废物的清除是由细胞外空间的扩张和收缩引起的。 其他研究表明，类淋巴清除率随着年龄的增长而降低，但可以增加 最近，在人类中，使用钆- 通过鞘内注射基于造影剂（GBCA）可以作为示踪剂观察类淋巴间隙， 然而，这种方法因其侵入性以及未知的影响而受到限制。 据报道，GBCA 示踪剂可改善体内类淋巴清除的时间过程。 大鼠脑 Aβ 的清除最近的小动物研究表明，细胞间隙中 GBCA 的清除速度减慢。 与糖尿病大鼠相比，糖尿病大鼠的海马体认知功能也下降了三倍。 尽管这些研究表明类淋巴清除率的降低对于认知能力很重要。 DM 大鼠的下降，解释受到 DM 和非 DM 大鼠之间可能的潜在变化的限制，并且 我们建议使用一种新型、非侵入性、非对比 MRI 技术来研究 GBCA 对 CSF 清除的影响。 研究 DM 和非 DM 人脑中的硬脑膜淋巴清除率，体力活动诱导的清除率 我们面临的挑战包括： 识别 PSD 和 AG，并测量脑膜处硬脑膜淋巴液清除率的细微变化。 为了克服这些挑战，我们将开发 MR 技术来阐明 i) PSD、AG 和高级的解剖结构 矢状窦，ii) 确定硬脑膜淋巴液的详细清除途径；iii) 获取硬脑膜淋巴液； 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； DM 患者的淋巴灌注与年龄、性别匹配的健康成年人的情况一致。 与健康的老龄受试者相比，灌注测量将有所不同并随着运动而改变。

项目成果

Physical Exercise Alters Egress Pathways for Intrinsic CSF Outflow: An Investigation Performed with Spin-labeling MR Imaging.

体育锻炼改变内在脑脊液流出的流出途径：使用自旋标记 MR 成像进行的研究。

• 发表时间: 2024-04-01
• 作者: Miyazaki, Mitsue;Malis, Vadim;Yamamoto, Asako;Kungsamutr, Jirach;McEvoy, Linda K;McDonald, Marin A;Bae, Won C
• 通讯作者: Bae, Won C

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。

• 发表时间: 2024-01-01
• 作者: Malis, Vadim;Bae, Won C;Yamamoto, Asako;McEvoy, Linda K;McDonald, Marin A;Miyazaki, Mitsue
• 通讯作者: Miyazaki, Mitsue