Neurovascular dysfunction in delirium superimposed on dementia

摘要 在所有新冠肺炎患者中，多达20%-30%的患者在住院期间出现精神错乱，据估计，这一数字还在增加 到60%-70%在那些发展成严重疾病的人。精神错乱是痴呆症的一个公认的危险因素，因此 正在进行的大流行对神经退化的影响将是长期的。特别是，我们假设 新冠肺炎感染将加速阿尔茨海默病相关痴呆的进展和出现 (ADRD)在老年人中通过增加外周和中枢炎症以及降低 肺为大脑提供足够的氧气，以维持正常的认知功能。本附录是对 RO1AG057525《精神错乱叠加痴呆的神经血管功能障碍》寻求建立全身性 炎症，类似于新冠肺炎感染患者的病理报告，对中枢神经的影响 系统(CNS)通过关注神经血管单位(NVU)和精神错乱样行为作为我们 家长助学金。此外，我们最近报道了我们的药物在开发中的保护作用， URMC-099用于患有持续神经变性的小鼠整形外科手术后的NVU。我们处于有利地位 使用为肺损伤建立的方法学方法快速评估肺损伤后这种治疗的效果 我们的父母拨款。本附录的总体目标是确定炎症环境的影响 新冠肺炎简化模型对内毒素吸入后NVU及认知功能的影响 相关的精神错乱。中心假设是吸入内毒素诱导血小板聚集，中性粒细胞黏附， 和神经血管缺氧-新冠肺炎患者的关键病理特征。我们认为，这些 后遗症可通过使用脑穿透性混合血统激酶(MLK)抑制剂URMC治疗来预防。 099.我们的假设是基于申请者实验室获得的初步数据，并将通过 追求2个具体目标：1)实施基于吸入性内毒素的肺损伤模型，以翻译临床 用中性粒细胞、中性粒细胞胞外捕获指数量化系统性新冠肺炎感染的特征 (Net)、血小板和细胞因子释放综合征作为中枢神经系统功能障碍的基础；2)定义炎症 吸入脂多糖和重新定位URMC-099治疗小鼠的NVU事件和相关认知障碍 以防止这些后遗症。这些模型和技术已经在申请者的 举起手来。在这种创新的方法中，实时活体脑成像和身体分析将结合在一起 用新的行为分析来定义小鼠的神志不清的变化。建议进行这项研究的理由是 这一成功的完成将促进我们对新冠肺炎如何影响中枢神经系统功能的理解，并提供 与衰老、神志不清、神经变性和阿尔茨海默病相关的新分子机制 以及相关的在逃的Dementias。这样的知识具有非常重要的意义，因为在此期间新冠肺炎感染 大流行将影响美国数百万老年人和高危患者 神经变性和痴呆症。

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.