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大脑功能产生负面影响，尤其是在老年人 患有既往痴呆症的成年人和/或虚弱的患者。对于这些患者来说，一个常见的神经系统并发症是 神志不清，一种急性衰弱的大脑功能变化，预示着不良的预后。的确，病人 发展为痴呆症(DSD)的精神错乱(DSD)的死亡率明显更差。 术后两年的死亡率高达92%，而非痴呆症患者的术后死亡率为7% 或者精神错乱。血脑屏障(BBB)的损伤，血脑屏障是调节神经免疫相互作用的关键界面 在外周和大脑之间，可能在DSD中发挥作用。使用一种临床相关的精神错乱小鼠模型- 就像整形外科手术的结果一样，我们已经确定了先天免疫的突出作用 促进血脑屏障功能障碍和神经炎症的反应。值得注意的是，血脑屏障故障已报告在 许多神经退行性疾病，包括阿尔兹迈尔氏病(AD)以及在衰老过程中通过改变 血源性因子的跨细胞渗透性和向脑实质的运输。然而， 手术影响血脑屏障的机制和血管功能障碍在DSD中的具体作用(S) 未知。我们的总体目标是确定DSD患者术后血脑屏障功能障碍的机制。我们的中央 假设全身性因素损害离散脑血管和血脑屏障的结构和功能 阿尔茨海默病小鼠术后神经炎症、神经退行性变和精神错乱样行为。我们建议两个 具体目标：1)利用芯片上器官来表征术后全身环境对血脑屏障的影响 由μSIM(具有纳米多孔硅膜的微生理系统)组成的技术 2)确定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掌握在申请者手中。在这 创新的方法，芯片上器官技术将补充血管变化的无偏空间成像 在易患痴呆症的小鼠的大脑中，表现出类似神志不清的行为。建议进行这项研究的理由是 成功的完成将扩大我们对手术如何影响血-脑界面的理解，并将 提供与精神错乱和神经退行性变相关的新分子机制。这样的知识是高度的 意义重大，因为它将实施新技术来研究免疫-血管相互作用和信息 限制脆弱患者术后神经认知并发症的安全治疗的进展。

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.