Glymphatic and cognitive impairment of aging and diabetes

摘要 本申请的目的是研究进展期间的胶质淋巴损伤和认知缺陷 有无糖尿病的衰老过程。新出现的数据1 -5表明，大脑中的胶质淋巴系统介导 脑脊液（CSF）-间质（ISF）交换和溶质从脑实质中清除。 然而，尽管胶质淋巴系统的功能障碍在发展中得到了很好的描述， 神经退行性疾病，仍然没有报道的研究，重点是胶质淋巴系统的作用 在衰老和2型糖尿病（DM）衰老过程中认知障碍的发展。使用非- 研究中年对照者和2型糖尿病患者大脑溶质废物清除的侵入性MRI方法 在糖尿病（DM）大鼠中，我们已经发现胶质淋巴系统的损伤增加，如由减少的 糖尿病患者脑实质（主要是海马和下丘脑）间质Gd-DTPA的清除率 大鼠（图2&3）6.同时，荧光示踪剂全脑分布的3D共聚焦显微镜分析 显示了DM大鼠海马和下丘脑中ISF的延迟清除增加（图2和3）6。 糖尿病大鼠胶质淋巴系统的损害与认知缺陷高度相关， 通过一系列认知测试测量，包括用于海马相关学习的Morris水迷宫（MWM 和记忆重要的是，组织病理学分析表明，间质溶质的延迟清除是 与高血糖后2个月海马区散发性脑微血管血栓形成相关 (15出生后数月），而广泛的微血管血栓形成和血管旁β- 在诱导高血糖后4个月（出生后17个月）检测到淀粉样蛋白（Aβ），这表明 胶质淋巴系统的损伤导致Aβ积聚。总的来说，我们的初步数据， 时间，证明非侵入性MRI方法可以检测DM诱导的早期损伤， 胶质淋巴系统与海马相关的学习记忆功能障碍高度相关。 基于我们新的初步数据，我们将采用MRI和3D共聚焦显微镜来评估和 定量测量在老化过程中胶质淋巴系统的动力学清除参数， 不含DM（目标1）。然后，我们将研究：胶质淋巴系统的损伤是否预示着认知能力的下降。 功能障碍，敏感性和胶质淋巴系统受损之间的关联，脑 血管功能障碍和认知缺陷在老龄化与糖尿病（目的2）。由此产生的数据 应用将为衰老和年龄匹配的DM相关胶质淋巴细胞损伤提供新的见解。 系统以及胶质淋巴系统与血管和认知功能障碍的关系。

ABSTRACT The objective of this application is to investigate glymphatic impairment and cognitive deficits during progression of aging with and without diabetes. Emerging data1-5 indicate that the glymphatic system in the brain mediates the cerebrospinal fluid (CSF)-interstitial (ISF) exchange and solute clearance from the brain parenchyma. However, despite the well-described dysfunction of the glymphatic system in the development of neurodegenerative conditions, there is still no reported study that focuses on the role of the glymphatic system in the development of cognitive impairment during aging and aging with type-2 diabetes (DM). Using non- invasive MRI methodologies to investigate cerebral solute waste clearance in middle-age control and type-2 diabetic (DM) rats, we have found increased impairment of the glymphatic system, as indicated by reduced clearance of interstitial Gd-DTPA in brain parenchyma, primarily in the hippocampus and hypothalamus in DM rats (Fig.2&3)6. In parallel, 3D confocal microscopic analysis of the brain-wide distribution of fluorescent tracers revealed increased delayed clearance of ISF in the hippocampus and hypothalamus from DM rats (Fig.2&3)6. Impairment of the glymphatic system in DM rats was shown to be highly correlated with cognitive deficits as measured by an array of cognitive tests including the Morris Water Maze (MWM) for hippocampal related learning and memory. Importantly, histopathological analysis shows that delayed clearance of interstitial solutes is associated with sporadic cerebral microvascular thrombosis in the hippocampus 2 months after hyperglycemia (15 months from birth), while extensive microvascular thrombosis and para-vascular accumulation of beta- amyloid (Aβ) are detected at 4 months after induction of hyperglycemia (17 months from birth), suggesting that the impairment of the glymphatic system leads to Aβ accumulation. Collectively, our preliminary data, for the first time, demonstrate that non-invasive MRI methodologies can detect DM-induced early impairment of the glymphatic system which is highly correlated with hippocampal related dysfunction of learning and memory. Based on our novel preliminary data, we will employ MRI and 3D confocal microscopy to evaluate and quantitatively measure kinetic clearance parameters of the glymphatic system during progression of aging with and without DM (Aim 1). We will then investigate: whether impairment of the glymphatic system predicts cognitive dysfunction, the sensitivity and association between impairment of the glymphatic system, the onset of brain vascular dysfunction, and cognitive deficits during aging with and without DM (Aim 2). Data generated from this application will provide new insights into aging and age-matched DM associated impairment of the glymphatic system and the relationship of the glymphatic system with vascular and cognitive dysfunction.