Immunoprofiling postoperative delirium during aging and neurodegeneration

衰老和神经变性期间术后谵妄的免疫分析

• 批准号: 10301230
• 负责人: HARRIS A GELBARD
• 金额: $ 23.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301230
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; American; Amyloid; Animal Model; Automobile Driving; Bar Codes; Biological; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; CCL2 gene; Cells; Cerebrospinal Fluid; Cytometry; Data; Delirium; Dementia; Development; Elderly; Evolution; Female; Foundations; Fracture; Functional disorder; Future; Genetic; Harvest; Health Care Costs; Human; Human Amyloid Precursor Protein; Immune; Immune Targeting; Immune response; Immune signaling; Immune system; Immunity; Immunophenotyping; Impaired cognition; Impairment; Individual; Inflammaging; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Isotopes; Liquid substance; Maps; Mediating; Memory impairment; Metals; Modeling; Morbidity - disease rate; Morphology; Mus; Nerve Degeneration; Neuraxis; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; PTPRC gene; Palladium; Pathogenesis; Pathologic; Pathologic Processes; Patients; Perioperative complication; Peripheral; Phagocytosis; Pharmaceutical Preparations; Population; Postoperative Period; Procedures; Public Health; Quality of life; Research; Risk; Risk Factors; Rodent; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Stains; Synapses; TNF gene; Techniques; Testing; Transgenic Organisms; Trauma; advanced dementia; age difference; aged; aging population; base; brain tissue; chemokine; clinically relevant; cohort; cytokine; experience; experimental study; high dimensionality; high reward; high risk; inflammatory marker; insight; male; mortality; mouse model; mutant; nervous system disorder; neuroinflammation; neurovascular injury; neurovascular unit; new therapeutic target; normal aging; older patient; postoperative delirium; presenilin-1; preservation; prevent; repaired; response; sham surgery; spatiotemporal; systemic inflammatory response; trafficking; traumatic event; validation studies; young adult

This R21 application uses the high risk, high reward technique of mass cytometry (abbreviated as CyTOF) to identify immune cell subsets that mediate neuroinflammation in the central nervous system (CNS) in a well- established orthopedic mouse model of postoperative delirium (POD). Dysregulated immunity is a hallmark of normal aging; it is also recognized as a key feature of many neurological disorders including dementia and perioperative complications like delirium. POD is common, occurring in up to 50% of older patients after a fracture repair. The strongest risk factors for POD are advanced age and dementia. Interestingly, the postoperative emergence of delirium may presage dementia. In fact, delirium superimposed on dementia (DSD) contributes to a faster trajectory of cognitive decline as well as significant mortality. This is significant because of the millions of elderly patients that routinely undergo orthopedic or other surgeries every year. The biologic mechanisms that drive POD and DSD during aging are unknown and without approved drugs to treat or prevent it. We have pioneered a clinically-relevant orthopedic surgery murine model that displays systemic inflammation, alters microglial activation, and causes memory deficits in mice. In our model, surgery mobilizes discrete immune cell populations with pro-inflammatory signaling responses that mediate damage to the blood-brain barrier, damage the neurovascular unit (NVU) and impair normal synaptic transduction. Translationally, similar immune signatures with the same pro-inflammatory markers have now been described in fluid biomarkers of delirious patients. However, current immunophenotyping is limited to selected non-specific cytokines and pro- inflammatory molecules such as TNF, IL-1, IL-6, MCP-1 and S100b in brain tissue (rodents) and cerebrospinal fluid (humans). No study has yet attempted to unbiasedly profile the immune subset specific response to orthopedic surgical trauma in the CNS. We propose two specific aims: (1) to define how age differences between young adult (6mos) and elderly (22mos) male and female mice modulate immune cell subsets in the CNS and blood after orthopedic surgery; and (2) to determine the impact of Alzheimer’s (AD)-like pathologic features using 5xFAD transgenic male and female mice at 6mos of age (when AD and postoperative neuroinflammation become pathologically significant) on immune cell subsets in the CNS and blood after orthopedic surgery. The ability to resolve immune cell subsets and align them with discrete repertoires of pro-inflammatory signaling molecules with CyTOF will be key to understanding whether POD results from neuroinflammation due to peripherally migrating and/or CNS-resident immunocytes. These experiments will provide the foundation for future RO1 studies in which we pursue key findings focused on dysfunction of the NVU associated with neurodegeneration in Alzheimer’s disease as sought by NOT-AG-19-033. We expect our findings to have an important positive impact on the ADRD field to reduce the impact of delirium and dementia in the aging population by helping identify patients at greater risk for developing POD and DSD.

该R21应用程序使用高风险、高回报的质谱细胞计数技术（缩写为CyTOF）， 鉴定在中枢神经系统（CNS）中介导神经炎症的免疫细胞亚群， 建立骨科手术后谵妄（POD）小鼠模型。免疫失调是一个标志性的 正常衰老;它也被认为是许多神经系统疾病的关键特征，包括痴呆症和 围手术期并发症如谵妄POD很常见，发生在骨折后高达50%的老年患者中 修复. POD的最大危险因素是高龄和痴呆。有趣的是，术后 谵妄的出现可能预示着痴呆。事实上，谵妄叠加痴呆（DSD）有助于 认知能力下降的速度更快，死亡率也更高。这一点意义重大，因为 老年患者每年例行接受骨科或其他手术。生物学机制， 在老化过程中驱动POD和DSD是未知的，也没有批准的药物来治疗或预防它。 开创了一种临床相关的整形外科小鼠模型，显示全身炎症，改变 小胶质细胞激活，并导致小鼠记忆缺陷。在我们的模型中，手术动员了离散的免疫细胞， 具有介导血脑屏障损伤的促炎信号应答的人群， 神经血管单位（NVU）和损害正常的突触转导。翻译，类似免疫 具有相同促炎标记物的特征现在已经在谵妄的流体生物标记物中描述， 患者然而，目前的免疫表型仅限于选定的非特异性细胞因子和促细胞因子。 脑组织（啮齿类动物）和脑脊液中的炎性分子，如TNF、IL-1、IL-6、MCP-1和S100 b 流体（人类）。尚未有研究试图无偏地描述免疫亚群特异性应答， 中枢神经系统的整形外科创伤。我们提出了两个具体目标：（1）确定年龄之间的差异 年轻成年（6个月）和老年（22个月）雄性和雌性小鼠调节CNS中的免疫细胞亚群， 骨科手术后的血液;和（2）使用确定阿尔茨海默病（AD）样病理特征的影响 6个月龄的5xFAD转基因雄性和雌性小鼠（当AD和术后神经炎症 变得具有病理学意义）对骨科手术后CNS和血液中免疫细胞亚群的影响。的 能够分辨免疫细胞亚群并将其与促炎信号的离散库对齐 具有CyTOF的分子将是理解POD是否由神经炎症引起的关键， 外周迁移和/或CNS驻留免疫细胞。这些实验将为 未来的RO 1研究中，我们追求的关键发现集中在NVU相关的功能障碍， 如NOT-AG-19-033所寻求的阿尔茨海默病中的神经变性。我们希望我们的发现能对 对ADRD领域产生重要的积极影响，以减少老年人群中谵妄和痴呆的影响 通过帮助确定患者在发展POD和DSD的风险更大。