Neuroimaging Biomarkers for Post-Operative Cognitive Decline in Older Adults

描述（由申请人提供）：老年人在大手术后认知能力下降的风险增加，这对神经退行性加速以及术后和长期护理费用有影响。骨科置换手术，如全膝关节置换手术，对老年人的认知能力下降率最高。这是令人担忧的，因为越来越多的老年人寻求关节置换，以减少相关的骨关节炎疼痛和增加活动（即生活质量）。不幸的是，目前还没有针对术后认知功能障碍的特定手术或麻醉机制。然而，来自NIA资助的飞行员培训基金的结果显示，初步证据表明，患者的术前脑完整性是术后预后的重要指标。我们现在试图通过更大的样本量来获得这些标记物的明确证据，并探索术前神经元完整性与特定围手术期变量（如麻醉深度、栓子数量）之间的相互作用。目的1是检查连接额叶和皮层下结构的白质区域的完整性，并假设深部白质完整性较差的患者易患术后执行能力下降。我们进一步假设，这种破坏是由连接背外侧前额叶皮层和尾状核的重要白质回路受到损害所驱动的（子目标1）。目的2是检查内侧颞结构的完整性，以支持手术前海马-内嗅连通性降低的患者易发生术后记忆衰退的假设。在Aim 3中，我们探讨了哪些围手术期变量（如术中栓塞、栓塞性卒中、麻醉时间）与基线神经影像学变量负交互作用。这些目标将由一个具有神经心理学、老年病学、痴呆症、术后认知功能障碍、麻醉学和骨科外科专业知识的多学科团队来实现。我们将对两组进行前瞻性纵向研究：接受全膝关节置换术的老年人（60岁）（n=80）和非手术年龄和教育程度相匹配的骨关节炎患者（n=80）。两组患者均接受基线MRI检查，使用复杂的扩散和功能测量来确定感兴趣的特定神经元区域，并在术前/基线时间点完成认知测试，然后在术后/基线后3周、3个月和1年重复测试。在基线扫描48小时后，参与者还将接受重复MRI检查，以确定大脑结构的变化（即栓塞性中风）。总的来说，这项研究的发现将使我们更接近于理解术后认知功能障碍的神经机制，将有助于对某些老年人进行基本的术前MRI筛查，并帮助我们开发针对神经易感性患者的术中干预措施。

DESCRIPTION (provided by applicant): Older adults are at increased risk for cognitive decline following major surgeries with this having implications for neurodegenerative acceleration as well as post-operative and long-term care costs. Orthopedic replacement surgeries such as total knee replacement surgery have the highest rates of cognitive decline in older adults. This is alarming, for older adults are increasingly seeking joint replacement to reduce associated osteoarthritis pain and increase activity (i.e., quality of life). Unfortunately at present there ae no specific surgical or anesthetic mechanisms for post-operative cognitive dysfunction. Results from our NIA funded pilot training grant, however, show preliminary evidence demonstrating that patients' pre-surgical brain integrity is an important indicator for post-operative outcome. We now seek to acquire definitive evidence for these markers using a larger sample size and also explore the interaction between pre-operative neuronal integrity and specific perioperative variables (e.g., anesthesia depth, emboli number). Aim 1 is to examine the integrity of the white matter regions connecting the frontal to subcortical structures and the hypothesis that patients with less deep white matter integrity will be vulnerable to post-operative executive decline. We further hypothesize that this disruption is driven by compromise to an important white matter circuit connecting the dorsolateral prefrontal cortex to the caudate (subaim 1). Aim 2 is to examine the integrity of the medial temporal structures to support the hypothesis that patients' with reduced pre-surgical hippocampal-entorhinal connectivity are vulnerable to post-operative memory decline. In Aim 3, we explore which peri-operative variables (e.g., intraoperative emboli, embolic stroke, anesthesia duration) interact negatively with baseline neuroimaging variables. These aims will be carried out by a multidisciplinary team with expertise in neuropsychology, geriatrics, dementia, post-operative cognitive dysfunction, anesthesiology, and orthopedic surgery. We will conduct a prospective longitudinal study with two groups: older adults (age > 60 years) having total knee replacement (n=80) and non-surgery age and education matched peers with osteoarthritis (n=80). Both groups will acquire baseline MRI using sophisticated diffusion and functional measures to define specific neuronal regions of interest, and complete cognitive testing at a pre-surgery/baseline time point followed by repeat testing at three weeks, three-months, and one-year post-operative/post-baseline. Participants will also acquire a repeat MRI 48 hours after their baseline scan to identify changes in brain structure (i.e., embolic stroke). Overall, the study's findings will bring us closer to understanding neural mechanisms for post- operative cognitive dysfunction, will help argue for basic pre-operative MRI screening for certain older adults, and assist us in the development of intra-operative interventions for patients with neuronal vulnerabilities.