Neurovascular dysfunction in delirium superimposed on dementia

摘要 在所有COVID-19患者中，多达20-30%的患者在住院期间出现谵妄，这一估计增加了 到60-70%的严重疾病。谵妄是痴呆症的一个公认的危险因素，因此， 持续的大流行对神经变性的影响将是持久的。特别是，我们假设， COVID-19感染将加速阿尔茨海默病相关痴呆症的进展和出现 （ADRD）在老年人中通过增加外周和中枢炎症以及降低 肺部为大脑提供足够的氧气，以维持正常的认知功能。这一补充 RO 1AG 057525“谵妄叠加痴呆的神经血管功能障碍”旨在模拟全身性 炎症对中枢神经系统的影响，类似于COVID-19感染患者报告的病理学 通过关注神经血管单位（NVU）和谵妄样行为作为我们的关键终点， 家长补助此外，我们最近报道了我们开发的药物的保护作用， URMC-099在具有持续神经变性的小鼠中在整形外科手术后对NVU的作用。我们处于有利地位 使用已建立的方法学方法快速评估肺损伤后该治疗的效果， 我们的家长格兰特我们对这种补充的总体目标是确定炎症环境的影响 作为COVID-19的简化模型，吸入脂多糖（LPS）后对NVU和认知功能的影响- 相关的精神错乱中心假设是吸入的LPS诱导血小板聚集，中性粒细胞粘附， 和神经血管缺氧--这是在COVID-19患者中发现的关键病理标志。我们认为，这些 后遗症是可以预防的治疗与脑渗透混合谱系激酶（MLK）抑制剂URMC- 099.我们的假设是基于申请人实验室获得的初步数据，并将由 追求2个具体目标：1）实施基于吸入性LPS的肺损伤模型，以转化临床 通过量化中性粒细胞、中性粒细胞胞外陷阱指数来评估系统性COVID-19感染的特征 NET、血小板和细胞因子释放综合征作为CNS功能障碍的基础; 2）定义炎性 用吸入LPS和复位URMC-099治疗的小鼠中NVU事件和相关认知损害 以防止这些后遗症。这些模型和技术的可行性已经在申请人的申请中得到了证实。 手在这种创新的方法中，实时体内脑成像和死后分析将结合起来 通过新的行为分析来确定小鼠的谵妄样变化。拟议研究的基本原理是 成功完成将促进我们对COVID-19如何影响CNS功能的理解， 与衰老、谵妄、神经变性和阿尔茨海默病相关的新分子机制 和相关痴呆症。这些知识非常重要，因为在此期间COVID-19感染 大流行将影响美国数百万老年人和高危患者， 神经变性和痴呆。

ABSTRACT As many as 20-30% of all COVID-19 patients develop delirium during hospitalization, an estimate that increases to 60-70% in those that develop severe illness. Delirium is a well-established risk factor for dementia, thus the impact of the ongoing pandemic on neurodegeneration will be long-lasting. In particular, we hypothesize that COVID-19 infection will accelerate the progression and emergence of Alzheimer’s Disease Related Dementias (ADRD) in the elderly by increasing both peripheral and central inflammation as well as decreasing the ability of the lungs to supply the brain with sufficient oxygen to maintain normal cognitive function. This supplement to RO1AG057525 “Neurovascular dysfunction in delirium superimposed on dementia” seeks to model the systemic impact of inflammation, akin to the pathology reported in patients with COVID-19 infection, on the central nervous system (CNS) by focusing on the neurovascular unit (NVU) and delirium-like behavior as key endpoints from our parent grant. Furthermore, we have recently reported on the protective effects of our drug in development, URMC-099 on the NVU after orthopedic surgery in mice with ongoing neurodegeneration. We are well-positioned to rapidly evaluate the effects of this therapy after lung injury using methodological approaches established for our parent grant. Our overall objective for this supplement is to determine the impact of the inflammatory milieu on the NVU and cognitive function after lipopolysaccharide (LPS) inhalation as a simplified model of COVID-19- related delirium. The central hypothesis is that inhaled LPS induces platelet aggregation, neutrophil adhesion, and neurovascular hypoxia — key pathologic hallmarks found in patients with COVID-19. We contend that these sequelae are preventable by treatment with the brain penetrant mixed-lineage kinase (MLK) inhibitor URMC- 099. Our hypothesis is based on preliminary data acquired in the applicants’ laboratories and will be tested by pursuing 2 specific aims: 1) To implement an inhaled LPS-based lung injury model to translate the clinical features of systemic COVID-19 infection by quantifying indices of neutrophils, neutrophil extracellular traps (NETs), platelets and cytokine release syndrome as the basis for CNS dysfunction; 2) To define inflammatory events at the NVU and related cognitive impairment in mice treated with inhaled LPS and reposition URMC-099 to prevent these sequelae. Feasibility for these models and techniques has been established in the applicants’ hands. In this innovative approach, real-time in-vivo brain imaging and postmortem analyses will be combined with novel behavioral assays to define delirium-like changes in mice. The rationale for the proposed research is that successful completion will advance our understanding of how COVID-19 affects CNS function and provide new molecular mechanisms of relevance to aging, delirium, neurodegeneration, and the Alzheimer's Disease and Related Dementias at-large. Such knowledge is highly significant because COVID-19 infection during this pandemic will impact millions of older adults and at-risk patients in the United States with ongoing neurodegeneration and dementia.