Neurovascular dysfunction in delirium superimposed on dementia

摘要 普通外科手术后的认知功能受损是一个日益令人担忧的问题，特别是在5岁以上的人群中 美国有数百万人患有痴呆症，包括阿尔茨海默病(AD)，因此 骨折风险增加3倍，需要手术修复。骨科手术后，骨盆的剧烈变化 认知功能，通常被称为术后精神错乱，发生在高达%的既往患者 痴呆症，预后较差，一年内死亡的风险比 没有痴呆或精神错乱的患者。我们的长期目标是定义手术背后的机制- 诱发的认知功能障碍，并提供安全有效的方法来潜在地减少这种情况 具有毁灭性的复杂性。在这项拟议的研究中，我们将模拟术后精神错乱叠加在 使患有阿尔茨海默病患者常见的大脑淀粉样血管病变(CAA)的小鼠患上痴呆 整形外科(胫骨骨折)。我们的总体目标是确定血-脑界面的作用 (内含神经血管单位和血脑屏障)和血管β-淀粉样蛋白沉积 慢性再生障碍性贫血小鼠骨科手术后的认知功能。中心假设是手术诱导的 BBB/NVU功能障碍在CAA存在时恶化，这可能可以通过以下方法预防 调节小胶质细胞的功能，进而影响术后的认知结果。这一假设是 基于申请者实验室获得的初步数据，并将通过进行3个具体的测试 目的：1)分析骨科手术后CAA小鼠模型的BBB/NVU功能障碍；2)确定 慢性再生障碍性贫血小鼠全身炎症和单核细胞浸润对小胶质细胞功能的影响 骨科手术；以及3)确定MLK3抑制剂对小胶质细胞功能、血管β的影响。 骨科手术后慢性再生障碍性贫血小鼠的淀粉样蛋白沉积和认知功能。这些模式的可行性和 技术已经掌握在申请者手中。在这种创新的方法中，实时体内大脑 影像和尸检分析将与神经血管系统和新颖的无偏见的侧写相结合 定义易患痴呆症小鼠的神志不清类变化的行为分析。建议的理由是 研究表明，成功完成手术将促进和扩大我们对手术如何影响 血-脑界面，并将提供与精神错乱，神经退行性变， 和衰老。这种知识非常重要，因为它有可能改善手术结果和 美国数百万易受伤害的老年患者的生活质量。

ABSTRACT Impaired cognitive function after common surgical procedures is a growing concern especially among over 5 million people in the United States who suffer from dementia, including Alzheimer's disease (AD), and thus have a 3-fold increased risk for fracture requiring surgical repair. After orthopedic surgery, acute changes in cognitive function, often referred to as postoperative delirium, occur in up to 89% of patients with preexisting dementia, and associate with poorer prognosis and even 2-fold greater risk for 1-year mortality compared to patients without dementia or delirium. Our long-term goal is to define the mechanisms that underlie surgery- induced cognitive dysfunction, and to provide safe and effective approaches to reduce this potentially devastating complication. In the proposed study, we will model postoperative delirium superimposed on dementia by subjecting mice with cerebral amyloid angiopathy (CAA), which is common in AD patients, to orthopedic surgery (tibial fracture). Our overall objective is to determine the role of the blood–brain interface (the neurovascular unit (NVU) and the blood-brain barrier (BBB) within) and vascular β-amyloid deposition in cognitive function after orthopedic surgery in CAA mice. The central hypothesis is that surgery-induced BBB/NVU dysfunction is worsened in the presence of CAA, and that this is potentially preventable by regulating microglial function, which in turn, can impact postoperative cognitive outcomes. This hypothesis is based on preliminary data acquired in the applicants' laboratories, and will be tested by pursuing 3 specific aims: 1) Analyze BBB/NVU dysfunction in a CAA mouse model after orthopedic surgery; 2) Define the extent to which systemic inflammation and monocyte infiltration impact microglial function in CAA mice after orthopedic surgery; and 3) Determine the effects of an MLK3 inhibitor on microglial function, vascular β- amyloid deposition, and cognition in CAA mice after orthopedic surgery. 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 unbiased profiling of the neurovasculature and novel behavioral assays to define delirium-like changes in dementia-prone mice. The rationale for the proposed research is that successful completion will advance and expand our understanding of how surgery affects the blood-brain interface, and will provide new molecular mechanisms of relevance to delirium, neurodegeneration, and aging. Such knowledge is highly significant because it has the potential to improve surgical outcome and quality of life for millions of elderly vulnerable patients in the United States.