CSF predictors of postoperative delirium in non-demented hip fracture patients

描述（由申请人提供）：这是一份申请K23指导患者导向研究职业发展奖的申请。该提案的总体目标是为候选人提供关键技能集和广泛发展的经验和能力，作为一个独立的，转化的，临床研究人员。候选人提出了一个全面的培训计划，将导师的教学培训与正式的课程工作相结合，并在临床研究中积累经验，以实现成为一名独立研究者的长期目标，研究重点是基于生物标志物的早期神经退行性疾病（如AD）的识别，从而有针对性地预防谵妄。具体的培训目标包括：(1)进行纵向研究和纵向数据分析的高级教学培训；(2)深入了解谵妄和功能状态评估的围手术期危险因素和方法；(3)深入了解与脑脊液生物标志物相关的测量和标准化问题及其与AD病理非痴呆受试者神经病理学的关联。培训目标将与一组特定的研究项目协调执行，这些研究项目基于候选人的初步数据，这些数据检查了脑脊液生物标志物AD，淀粉样蛋白- β （a¿42）和tau（总tau和p-tau181）与接受髋部骨折修复的无痴呆患者术后谵妄的发生和严重程度，功能变化以及更大的医疗负担（更长的住院时间和护理水平变化）的关联。在初步数据中，提示潜在AD病理的CSF A¿42水平降低和tau水平升高与更严重的谵妄相关，表明这些患者可能更容易受到麻醉、手术和术后护理的压力，谵妄可能是潜在病理的临床表现。拟议的项目将纳入正在进行的NIH资助项目“减少老年患者术后谵妄的策略”（R01 AG033615），这是一项关于髋部骨折修复患者术后谵妄的研究。将在脊髓麻醉期间收集无痴呆患者的脑脊液（CSF），并检查AD，淀粉样蛋白- β （A¿42）和tau（总tau和p- tau181）的脑脊液生物标志物与以下内容之间的关系：(1)术后谵妄的发生和严重程度，(2)术后1和6个月的长期功能结局，(3)住院时间和护理水平变化（例如从家中到辅助生活设施或养老院）

DESCRIPTION (provided by applicant): This is an application for a K23 Mentored Patient-Oriented Research Career Development Award. The overall goal of the proposal is to provide the candidate with critical skill sets and broad development of experience and competence as an independent, translational, clinician researcher. The candidate proposes a comprehensive training plan, combining didactic training by mentors with formal course work, and gaining experience in clinical research, to achieve the long-term goal of becoming an independent investigator with research focus on biomarker-based identification of early stages of neurodegenerative disease (e.g., AD) leading to targeted delirium prevention. Specific training goals include : (1) conducting a longitudinal study and advanced didactic training in analysis of longitudinal data, (2) in-depth understanding of perioperative risk factors and methodologies in assessment of delirium and functional status, (3) in-depth understanding of measurement and standardization issues related to CSF biomarkers and their association with neuropathology of non-demented subjects with AD pathology. The training goals will be executed in coordination with a specific set of research projects that are based upon the candidate's preliminary data which examines the association of CSF biomarkers of AD, amyloid-beta (A¿42) and tau (total tau and p-tau181) with the occurrence and severity of postoperative delirium, changes in function, and greater health care burden (longer hospital stay and level of care change) in patients without dementia who are undergoing hip fracture repair. In the preliminary data, lower CSF A¿42 and higher tau levels suggestive of underlying AD pathology were associated with more severe delirium, demonstrating that these patients may be more vulnerable to the stresses of anesthesia, surgery, and post-operative care, and delirium may be the clinical manifestation of underlying pathology. The proposed project will be incorporated into an on-going NIH funded project "A Strategy for Reduction of Postoperative Delirium in Elderly Patients" (R01 AG033615), a study of postoperative delirium in hip fracture repair patients. Cerebrospinal fluid (CSF) will be collected during spinal anesthesia from patients without dementia, and the association between CSF biomarkers of AD, amyloid-beta (A¿42) and tau (total tau and p- tau181) and the following will be examined: (1) occurrence and severity of postoperative delirium, (2) long-term functional outcomes at 1 and 6 months after surgery, (3) and length of hospital stay and level of care change ( e.g. from home to assisted living facility or nursing home placement) at 1 and 6 months after surgery. The results from this proposed project will demonstrate that postoperative delirium in older adults without dementia in part reflects early (preclinical, mild cognitive impairment) AD. This project will also lead to early identification of patients at high risk for postoperative delirium, and facilitate targeted delirium intervention. It may also lead to future studies where treatment of underlying AD in the early stages may result in lower incidence of delirium and better postoperative outcomes.