Chronic Alcohol, Dementia, and CNS Fluid Homeostasis

项目摘要/摘要 中年酒精使用障碍(AUD)是老年痴呆的一个重要的独立预测因素，尤其是 血管性认知损害和痴呆(VCID)，包括常见的大脑淀粉样蛋白亚型 以淀粉样蛋白(Aβ，Aβ)沉积于脑血管系统为特征的血管病。在仅仅十年的时间里， 从2005年到2014年，老年人的饮酒率总体上升了20%，只有女性上升了50%。这个 酒精对中枢神经系统(CNS)的毒性作用机制尚不完全 理解，这限制了制定有针对性的战略，以减少或预防重病负担 有或没有CAA VCID的饮酒者。酒精对中枢神经系统的损害的一个潜在原因是 了解中枢神经系统液体动态平衡失调。初步证据表明，与酒精有关的 体液平衡异常表现为脑室增大和脑脊液血流动力学改变。在……里面 特别是人类，这表现为侧脑室扩大，不仅反映了组织丢失，而且还反映了 它本身也会造成组织损伤和认知障碍。我们认为乙醇会破坏 通过减少通过相互连接的淋巴和淋巴的脑脊液流量来实现液体动态平衡的基本原理 系统，通过生化和神经免疫改变，从而直接损害组织。这个 淋巴/淋巴系统功能维持体液平衡，清除体内废物和毒素。 大脑。我们建议的研究包括一系列全面的实验，以定量分析酒精 对正常脑内脑脊液分泌、淋巴和淋巴转运以及脑脊液/淋巴“组学”特征的影响 并患有CAA VCID病理。在目标1中，我们将确定cEtoh如何干扰大鼠的脑脊液分泌 使用一种新的MRI采集方法测量有/无VCID的脉络膜脑脊液分泌以及血液 脉络丛和皮质的灌流。我们还将实施MRI序列来测量大脑 氯乙醇染毒大鼠VCID及脑脊液、脑膜和脑组织的形态计量学研究 病理和生化淋巴因子和炎症因子。在目标2中，我们将评估cEtoh如何影响 淋巴-淋巴转运，脑和脑膜淋巴病理，淋巴废物产量和 有/无VCID大鼠的认知功能我们将使用动态增强MRI和计算流体 测量脑脊液流动动力学、淋巴转运和淋巴排泄的动力学 CEtoh和VCID，以及对CAA病理和认知功能下降的影响。在目标3中，我们将研究cEtoh如何妥协 脑脊液和淋巴中的生化信号和生物物理变化，包括调节液体的蛋白质 体积(肾素-血管紧张素)和在离子转运/信号转导中起作用的蛋白质(电压依赖性钙信号， V型质子ATPase和碳酸酐酶)。我们确定的分子途径可以在以后探索 治疗效果。

Project Summary/Abstract Alcohol use disorder (AUD) in mid-life is a significant, independent predictor of late-life dementia, particularly vascular cognitive impairment and dementia (VCID) that includes the common subtype cerebral amyloid angiopathy (CAA) characterized by deposits of amyloid-β (Aβ) in the cerebral vasculature. In only one decade, from 2005-2014, the rate of alcohol binging among the elderly rose 20% overall and by 50% in women only. The mechanisms underlying alcohol’s toxic effects on the central nervous system (CNS) remain incompletely understood, which limits the development of strategies targeted to reduce or prevent disease burden in heavy drinkers with and without CAA VCID. An underlying cause of alcohol’s damaging effects on the CNS is a poorly understood dysregulation of CNS fluid homeostasis. Preliminary evidence indicates that alcohol-associated abnormal fluid homeostasis manifests as enlarged cerebral ventricles and altered CSF flow dynamics. In humans, specifically, this manifests as lateral ventricular enlargement, and may reflect not only tissue loss but also itself be contributing to tissue damage and cognitive impairment. We propose that ethanol disrupts fundamentals of fluid homeostasis, by reducing CSF flow through the interconnected glymphatic and lymphatic systems, through biochemical and neuroimmune alterations thereby directly damaging the tissue. The functioning of glymphatic/lymphatic system supports fluid homeostasis and clears waste and toxins from the brain. Our proposed studies include a comprehensive series of experiments to quantitatively analyze alcohol’s effects on CSF secretion, glymphatic and lymphatic transport, and CSF/lymph ‘omics’ profiling in normal brain and with CAA VCID pathology. In Aim 1, we will determine how cEtoh interferes with CSF secretion in rats with/without VCID, using a novel MRI acquisition method to measure choroidal CSF secretion, as well as blood perfusion of the choroid plexus and cortex. We will also implement MRI sequences to measure brain morphometry in cEtoh-exposed rats with/without VCID and sample CSF, the meninges, and brain tissue to study pathology and biochemical lymphatic and inflammatory factors. In Aim 2, we will assess how cEtoh affects glymphatic-lymphatic transport, cerebral and meningeal lymphatic pathology, lymphatic waste output and cognition in rats with/without VCID. We will use dynamic contrast-enhanced MRI and computational fluid dynamics to measure CSF flow dynamics, glymphatic transport, and lymphatic waste drainage as affected by cEtoh and VCID, as well on CAA pathology and cognitive decline. In Aim 3 we will study how cEtoh compromises biochemical signaling and bio-physical changes in the CSF and lymph, including proteins that regulate fluid volume (renin-angiotensin) and proteins functioning in ion transport/signaling (Voltage dependent calcium signal, V-type proton ATPase and Carbonic Anhydrase). Molecular pathways that we identify can later be probed for therapeutic benefit.