Glymphatic and cognitive impairment of aging and diabetes

衰老和糖尿病导致的类淋巴和认知障碍

• 批准号: 9428053
• 负责人: QUAN JIANG
• 金额: $ 285.9万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9428053
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Birth; Blood Vessels; Brain; Cerebrospinal Fluid; Cerebrovascular Disorders; Cerebrum; Characteristics; Cognitive deficits; Confocal Microscopy; Data; Development; Diabetes Mellitus; Diagnostic; Dimensions; Disadvantaged; Exhibits; Fluorescence; Functional disorder; Gadolinium DTPA; Hippocampus (Brain); Human; Hyperglycemia; Hypothalamic structure; Impaired cognition; Impairment; Intercellular Fluid; Investigation; Kinetics; Laser Scanning Confocal Microscopy; Learning; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Memory; Metabolic Clearance Rate; Methodology; Microscopic; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Patients; Prognostic Marker; Publishing; Rattus; Reporting; Residual state; Role; Severities; Sleep; Surface; Techniques; Testing; Thrombosis; Time; Tracer; Traumatic Brain Injury; Vascular Diseases; abeta accumulation; base; brain parenchyma; cognitive development; cognitive testing; diabetic; fluorescence imaging; glymphatic system; imaging biomarker; imaging modality; in vivo; indexing; insight; interest; interstitial; middle age; morris water maze; novel; older patient; prognostic; solute; success; two-photon; wasting

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.

抽象的 该应用的目的是调查进展过程中的糖性损害和认知防御能力 患有和不糖尿病的衰老。新兴数据1-5表明大脑中的子糖系统介导 脑脊液（CSF） - 间隙（ISF）的交换和可溶性清除率与脑实质的清除率。 然而，尽管在开发过程中，糖基体系的功能障碍 神经退行性疾病，仍然没有报道的研究重点是糖基体系的作用 在患有2型糖尿病（DM）衰老期间认知障碍和衰老期间的认知障碍中。使用非 - 在中年控制和2型中研究脑可溶性废物清除的侵入性MRI方法 糖尿病（DM）大鼠，我们发现糖糖系统的损害增加，如降低所示 在脑实质中的间隙GD-DTPA清除，主要在海马和下丘脑中 大鼠（图2和3）6。同时，荧光示踪剂的大脑范围分布的3D共聚焦显微镜分析 揭示了DM大鼠海马和下丘脑中ISF的延迟清除增加（图2和3）6。 DM大鼠中糖系统的损害被证明与认知缺陷高度相关 通过一系列认知测试来衡量，包括用于海马相关学习的莫里斯水迷宫（MWM） 和内存。重要的是，组织病理学分析表明，间质解的延迟清除率是 高血糖后2个月，与海马偶发的脑微血管血栓形成有关 （从出生起15个月），而大量的微血管血栓形成和β- 淀粉样蛋白（Aβ）在诱导高血糖后4个月（距出生后17个月）在4个月后检测到，这表明 糖基系统的损害导致Aβ积累。总的来说，我们的初步数据是第一个 时间，证明非侵入性MRI方法可以检测到DM诱导的早期损害 与海马相关的学习和记忆功能障碍高度相关的胶状系统。 根据我们新的初步数据，我们将采用MRI和3D共聚焦显微镜评估和 在衰老进展过程中，定量测量的糖基系统的动力学清除参数 并且没有DM（AIM 1）。然后，我们将调查：性糖系统预测的损害是否认知 功能障碍，糖浆系统损伤之间的敏感性和关联，大脑的发作 血管功能障碍和认知在衰老期间有和没有DM（AIM 2）。从中生成的数据 应用将提供有关糖脂衰老和年龄匹配的DM相关损害的新见解 系统以及血糖系统与血管和认知功能障碍的关系。