Neurovascular dysfunction in delirium superimposed on dementia

摘要 普通外科手术后认知功能受损是一个日益关注的问题，特别是在5岁以上的人群中。 在美国，有100万人患有痴呆症，包括阿尔茨海默病（AD），因此 需要手术修复的骨折风险增加3倍。整形外科手术后， 认知功能障碍，通常被称为术后谵妄，发生在高达89%的患者中， 痴呆症，与预后较差，甚至2倍的风险，1年死亡率相比， 无痴呆或谵妄的患者。我们的长期目标是确定手术的机制- 诱发的认知功能障碍，并提供安全有效的方法，以减少这种潜在的 毁灭性的并发症在拟议的研究中，我们将模拟术后谵妄叠加在 通过使患有脑淀粉样血管病（CAA）的小鼠（这在AD患者中很常见）经历 骨科手术（胫骨骨折）。我们的总体目标是确定血脑界面的作用 (the神经血管单位（NVU）和血脑屏障（BBB）内）和血管β-淀粉样蛋白沉积 CAA小鼠矫形手术后的认知功能。中心假设是手术引起的 BBB/NVU功能障碍在CAA的存在下恶化，并且这可能通过以下方法预防： 调节小胶质细胞功能，这反过来又会影响术后认知结果。这种假设是 根据申请人实验室获得的初步数据，并将通过3个特定的 目的：1）分析CAA小鼠模型在骨科手术后BBB/NVU功能障碍; 2）确定BBB/NVU功能障碍的程度， 全身炎症和单核细胞浸润影响CAA小鼠中小胶质细胞功能， 3）确定MLK 3抑制剂对小胶质细胞功能、血管β-淀粉样蛋白（β-淀粉样蛋白）和血管内皮细胞的影响。 淀粉样蛋白沉积和CAA小鼠矫形手术后的认知。这些模型的可行性和 技术已经在申请人手中建立。在这种创新的方法中， 成像和死后分析将与神经血管的无偏分析相结合， 行为测定来确定痴呆倾向小鼠的谵妄样变化。建议的理由 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，并将提供与谵妄，神经变性， 和衰老。这些知识是非常重要的，因为它有可能改善手术结果， 美国数百万老年弱势患者的生活质量。

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.