Immunovascular interactions in postoperative delirium superimposed on dementia (DSD).

摘要 手术创伤引发的全身性炎症会对脑功能产生负面影响，特别是在老年人中。 成年人和/或患有预先存在的痴呆症的虚弱患者。这些患者常见的神经系统并发症是 谵妄，是一种脑功能的急性衰弱性变化，预示着不良预后。事实上，患者 发生谵妄叠加痴呆（DSD）的患者的死亡率明显更差 手术后两年内高达92%，而非痴呆患者的术后死亡率为7% 或者精神错乱血脑屏障（BBB）受损，这是调节神经免疫相互作用的关键界面 可能在DSD中起作用。使用临床相关的谵妄小鼠模型- 就像整形外科手术导致的行为一样，我们已经确定了先天免疫的重要作用， 促进BBB功能障碍和神经炎症的反应。值得注意的是，BBB破裂已经在 许多神经退行性疾病，包括阿尔茨海默病（AD）以及在衰老过程中， 血细胞渗透性和血液衍生因子向脑实质的运输。然而 外科手术影响BBB的机制和血管功能障碍在DSD中的特定作用仍然存在 未知我们的总体目标是确定DSD中BBB功能障碍的术后机制。我们的中央 假设是系统性因素损害离散脑血管和BBB引导的结构和功能， 神经炎症，神经变性，和谵妄样行为的AD小鼠手术后。我们提出了两 具体目的：1）使用器官芯片表征术后全身环境如何影响BBB 由μSiM（具有纳米多孔硅膜的微生理系统）组成的技术， 人iPSC;和2）确定介导DSD诱导的血管功能障碍的细胞和分子机制 手术后。这些模型和技术的可行性已经在申请人手中确立。在这 创新方法，器官芯片技术将补充血管变化的无偏空间分析 有类似谵妄行为的痴呆倾向小鼠的大脑中。拟议研究的理由是， 成功完成将扩大我们对手术如何影响血脑界面的理解，并将 提供了与谵妄和神经变性相关的新分子机制。这样的知识， 意义重大，因为它将实施新技术来研究免疫-血管相互作用， 安全治疗的进步，以限制脆弱患者的术后神经认知并发症。

ABSTRACT Systemic inflammation triggered by surgical trauma can negatively impact brain function, particularly in older adults and/or frail patients with pre-existing dementia. One frequent neurologic complication for these patients is delirium, an acutely debilitating change in brain function that precedes an adverse prognosis. Indeed, patients that develop delirium superimposed on dementia (DSD) have significiantly worse outcomes with mortality rates as high as 92% two years after surgery, compared to a 7% post-surgical mortality in patients without dementia or delirium. Damage to the blood-brain barrier (BBB), a key interface that regulates neuroimmune interactions between the periphery and the brain, may play a role in DSD. Using a clinically-relevant mouse model of delirium- like behavior as a result of orthopedic surgery, we have identified a prominent role for the innate immune response in promoting BBB dysfunction, and neuroinflammation. Notably, BBB breakdown has been reported in many neurodegenerative conditions, including Alzhemeir’s disease (AD) as well as during aging via altered transcellular permeability and trafficking of blood-derived factors into the brain parenchyma. Yet, the mechanisms by which surgery impacts the BBB and the specific role(s) of vascular dysfunction in DSD remain unknown. Our overall objective is to identify postoperative mechanisms for BBB dysfunction in DSD. Our central hypothesis is that systemic factors impair structure and function of discrete brain vasculature and BBB leading to neuroinflammation, neurodegeneration, and delirium-like behavior in AD mice after surgery. We propose two Specific Aims: 1) to characterize how the postoperative systemic milieu impacts the BBB using organ-on-chip technology comprised of μSiM (microphysiologic system with nanoporous silicon membranes) populated with human iPSCs; and 2) to define cellular and molecular mechanisms mediating DSD-induced vascular dysfunction after surgery. Feasibility for these models and techniques has been established in the applicants’ hands. In this innovative approach, organ-on-chip technology will complement unbiased spatial profiling of vascular changes in the brain of dementia-prone mice with delirium-like behavior. The rationale for the proposed research is that successful completion will expand our understanding of how surgery affects the blood-brain interface, and will provide new molecular mechanisms of relevance to delirium, and neurodegeneration. Such knowledge is highly significant because it will implement new technologies to investigate immune-vascular interactions and inform the advancement of safe therapies to limit postoperative neurocognitive complications in vulnerable patients.