The association of selected biomarkers with postoperative delirium (POD) and postoperative cognitive dysfunction (POCD): modelling biomarkers from the PAWEL study (patient safety, cost-effectiveness, and quality of life after elective procedures in older

谵妄是一种神经精神综合征，其特征是注意力、意识和认知的急性障碍，由潜在的医学疾病引起。它与多种短期和长期不良结局相关，包括住院时间延长以及新的机构化，以及发病率和死亡率增加。择期手术后，老年患者发生术后谵妄（POD）和术后认知功能障碍（POCD）的风险增加。尽管识别了临床风险因素并将其整合到预测算法中，但不可能确定地预测个体患者是否会发展POD或POCD。血液生物标志物可以帮助更好地识别高危患者，同时有助于更好地了解POD的致病机制，从而为靶向治疗干预提供信息。最近的研究确定神经炎症和神经退行性生物标志物是最有前途的生物标志物。在PAWEL研究中（PAWEL：Patientensicherosity，Wirtschaftlichkeit und Lebensqualität;患者安全性、成本效益和生活质量，由Innovationsfond资助），我们能够在一项阶梯式楔形分组随机试验中证明跨部门和多模式干预在减少接受不同择期外科手术但不接受心脏手术的老年患者术后谵妄发生率和谵妄天数方面的有效性。独立于主要资金，我们在一项子研究中收集了约350名患者的血液样本，并分析了标志物NFL，GFAP，Abeta 42/40，S100 B，NSE和IL-6。与其他已发表的谵妄生物标志物研究相比，这是最大的样本集之一。该提案的总体目标是更好地了解哪些生物标志物（例如，神经变性对神经炎性）与POD和相关POCD的发作对严重性相关，以便描绘POD和POCD的预测标志物和致病机制。为此，我们计划确定其他神经炎症和神经退行性生物标志物，并采用复杂的统计分析，包括潜在类别回归分析和结构方程建模（SEM）。我们建议表征与谵妄发病机制相关或调节谵妄发病机制的潜在生物标志物类别，以便更好地了解POD的生物学机制，该生物学机制对应于神经退行性和炎症生物标志物的变化，其总体目标是确定潜在的药理学干预靶点。我们还将确定这些生物标志物的水平和变化是否可以改善POCD的临床风险预测评分。我们的研究结果将有助于进一步了解老年患者术后谵妄的机制，最终导致更好的预测和针对谵妄和POCD的干预。

Delirium is a neuropsychiatric syndrome characterized by acute disturbances in attention, awareness and cognition and caused by an underlying medical condition. It is associated with multiple poor short and long-term outcomes, including prolonged hospital stay as well as new institutionalization, and increased morbidity and mortality. After elective surgery, elderly patients are at increased risk of developing postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Despite the identification of clinical risk factors and their integration in predictive algorithms, it is not possible to predict with certainty whether an individual patient will develop POD or POCD. Blood biomarkers could help to both better identify high-risk patients and at the same time help to better understand pathogenic mechanisms of POD and thus inform targeted therapeutic interventions. Recent studies identify neuroinflammatory and neurodegenerative biomarkers as the most promising biomarkers. In the PAWEL-study (PAWEL: Patientensicherheit, Wirtschaftlichkeit und Lebensqualität; patient safety, cost-effectiveness and quality of life, funded by the Innovationsfond) we were able to show in a stepped wedge cluster randomized trial the effectiveness of a cross-sectoral and multimodal intervention to reduce the prevalence of postoperative delirium occurrence and days with delirium in older patients undergoing different elective surgical procedures but not cardiac procedures. Independent of the primary funding, we collected blood samples in a substudy from ~350 patients and already analysed the markers NFL, GFAP, Abeta 42/40, S100B, NSE and IL-6. Compared to other published biomarker studies in delirium this is one of the largest sample sets. The overall aim of this proposal is to gain a better understanding of which biomarkers (e.g., neurodegenerative vs. neuroinflammatory) are associated with the onset versus severity of POD and associated POCD in order to delineate predictive markers and pathogenic mechanisms of POD and POCD. To do so, we plan to determine additional neuroinflammatory and neurodegenerative biomarkers and employ complex statistical analyses including latent class regression analyses and structural equation modelling (SEM). We propose to characterize latent classes of biomarkers associated with or moderating the pathogenesis of delirium in order to gain a better understanding of the biological mechanisms of POD that correspond to changes in neurodegenerative and inflammatory biomarkers with the overall aim of identifying potential targets for pharmacological interventions. We will also determine whether level and change in these biomarkers can improve clinical risk prediction scores for POCD. Our results will help to further understand the mechanisms underlying postoperative delirium in elderly patients, ultimately leading to better prediction and tailored intervention for both delirium and POCD.