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

描述（由申请人提供）：这是一个K23指导的以患者为导向的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，并广泛发展作为独立、翻译、临床研究人员的经验和能力。候选人提出一个全面的培训计划，将导师的教学培训与正式课程工作相结合，并获得临床研究经验，以实现成为独立研究者的长期目标，研究重点是基于生物标志物的神经退行性疾病早期阶段的识别（例如，AD）导致有针对性的谵妄预防。具体培训目标包括：（1）进行纵向研究和纵向数据分析的高级教学培训，（2）深入了解围手术期风险因素和谵妄和功能状态评估方法，（3）深入了解CSF生物标志物相关的测量和标准化问题及其与AD病理学非痴呆受试者神经病理学的相关性。培训目标将与一组特定的研究项目协调执行，这些项目基于候选人的初步数据，该数据检查了AD，淀粉样蛋白β（A42）和tau蛋白的CSF生物标志物的关联。（总tau和p-tau 181）与术后谵妄的发生和严重程度，功能变化，和更大的医疗保健负担（更长的住院时间和护理水平的变化），在没有痴呆症的病人谁是髋关节骨折修复。在初步数据中，较低的CSF A42和较高的tau水平提示潜在的AD病理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”（R 01 AG 033615），这是一项髋关节骨折修复患者术后谵妄的研究。将在脊髓麻醉期间从没有痴呆的患者中收集脑脊液（CSF），并研究AD，淀粉样蛋白β（A β 42）和tau蛋白的CSF生物标志物之间的关联。（总tau和p-tau 181），并检查以下内容：（1）术后谵妄的发生率和严重程度，（2）术后1个月和6个月的长期功能结局，（3）住院时间和护理水平的变化（例如，从家中到辅助生活设施或疗养院 术后1个月和6个月时的植入物）。该项目的结果将证明，无痴呆的老年人术后谵妄部分反映了早期（临床前，轻度认知障碍）AD。该项目还将导致及早查明 患者术后谵妄的高风险，并促进有针对性的谵妄干预。它 也可能导致未来的研究，其中在早期阶段治疗潜在的AD可能导致更低的谵妄发生率和更好的术后结局。

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.