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

描述(申请人提供)：这是一份K23指导患者导向研究职业发展奖的申请书。该提案的总体目标是为候选人提供关键技能集以及作为一名独立的、翻译的临床医生研究员的广泛经验和能力发展。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规课程工作相结合，并在临床研究中积累经验，以实现成为一名独立研究人员的长期目标，研究重点是基于生物标记物的早期神经退行性疾病(例如，AD)的识别，从而有针对性地预防精神错乱。具体的培训目标包括：(1)进行纵向研究和高级教学培训，分析纵向数据；(2)深入了解围术期风险因素和评估妄想和功能状态的方法；(3)深入了解与脑脊液生物标记物相关的测量和标准化问题，以及它们与非痴呆AD病理受试者的神经病理学的关系。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，研究AD、淀粉样β蛋白(A�42)和tau(总tau和p tau181)脑脊液生物标记物与接受髋部骨折修复的非痴呆症患者术后精神错乱的发生和严重程度、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)之间的关系。在初步数据中，较低的脑脊液A�42和较高的tau水平提示潜在的AD病理与更严重的精神错乱有关，这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，而精神错乱可能是基本病理的临床表现。建议的项目将被纳入NIH资助的正在进行的项目“减少老年患者术后妄想的策略”(R01AG033615)，这是一项关于髋部骨折修复患者术后妄想的研究。在非痴呆症患者的腰麻期间采集脑脊液，研究AD、淀粉样β蛋白(A�42)和tau(总tau和p tau181)的脑脊液生物标志物与下列因素的关系：(1)术后精神错乱的发生和严重程度，(2)术后1个月和6个月的长期功能结果，(3)住院时间和护理水平的变化(例如，从家里到辅助生活设施或疗养院) 术后1个月和6个月)。这项拟议项目的结果将证明，无痴呆症的老年人术后精神错乱部分地反映了早期(临床前，轻度认知障碍)AD。该项目还将导致及早确定 术后精神障碍高危患者，便于针对性的精神障碍干预。它 也可能导致未来的研究，在早期治疗潜在的AD可能导致较低的妄想症发生率和更好的术后结果。

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.