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程序过程中的肾小球损伤和认知缺陷 有或没有糖尿病的衰老。 脑脊液（CSF） - 间隙（ISF）的交换和溶质清除率从bronchyma。 然而，尽管在开发中散发性系统的功能障碍是 神经退行性条件，仍然没有据报道，重点是Gllymphatic System的作用 在使用非 - 侵入性MRI方法学研究中年龄控制和2型中的大脑废物清除 糖尿病（DM）大鼠，我们发现淋巴系统的损伤增加了，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。在平行的3D共聚焦显微镜分析中，荧光示踪剂的大脑分布 揭示了大鼠海马和下丘脑中海马和下丘脑的延迟清除的增加（图2和3）6。 DM大鼠中Gllymphatic系统的损害被抛弃到 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） 和记忆。 与速食2个月后的河马囊肿相关的孢子脑微血管血栓形成 （出生后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 淋巴系统的损害会导致Aβ的积累。 时间，证明非侵入性MRI方法可以检测到DM引起的早期损害 与海马相关的学习和记忆功能障碍相关的Glymphatic系统。 根据我们新的预启示数据，我们将采用MRI MRI和3D共聚焦显微镜评估和 定量测量糖系统的动力学清除参数与随着衰老的形式衰老期间。 没有DM（目标1）。 功能障碍，淋巴系统损伤之间的敏感性和关联，大脑的发作 在有或没有DM的过程中，血管功能障碍和认知缺陷（AM 2）。 应用将在Anto Anto Anto Anto Ange匹配的DM相关损伤中提供新的应用 系统以及淋巴系统与血管和认知功能障碍的关系。