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，在老年人中认知能力下降的比率最高。这是令人担忧的，因为老年人越来越多地寻求关节置换以减少相关的骨关节炎疼痛并增加活动（即，生活质量）。不幸的是，目前对于术后认知功能障碍还没有特定的手术或麻醉机制。然而，我们的NIA资助的试点培训补助金的结果显示，初步证据表明，患者的术前大脑完整性是术后结果的一个重要指标。我们现在试图使用更大的样本量来获得这些标志物的确切证据，并探索术前神经元完整性与特定围手术期变量（例如，麻醉深度、栓子数量）。目的1是检查连接额叶和皮质下结构的白色物质区域的完整性，以及以下假设：深度白色物质完整性较低的患者容易出现术后执行能力下降。我们进一步假设，这种破坏是由一个重要的白色物质电路连接背外侧前额叶皮层尾状核（子目标1）的妥协。目的2是检查内侧颞叶结构的完整性，以支持以下假设，即术前大脑皮层-内嗅连接减少的患者易受术后记忆下降的影响。在目标3中，我们探索哪些围手术期变量（例如，术中栓塞、栓塞性中风、麻醉持续时间）与基线神经影像学变量存在负面相互作用。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、麻醉学和整形外科专业知识的多学科团队来实现。我们将对两组患者进行前瞻性纵向研究：接受全膝关节置换术的老年人（年龄> 60岁）（n=80）和非手术年龄和教育程度匹配的骨关节炎患者（n=80）。两组均将使用复杂的扩散和功能测量获得基线MRI，以定义特定的感兴趣神经元区域，并在术前/基线时间点完成认知测试，然后在术后3周、3个月和1年/基线后重复测试。参与者还将在基线扫描后48小时获得重复MRI，以识别大脑结构的变化（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，将有助于为某些老年人进行基本的术前MRI筛查，并帮助我们为神经元脆弱性患者制定术中干预措施。 公共卫生相关性：老年人在接受重大非心脏手术（如全膝关节置换术）后发生急性和长期认知障碍的风险增加。除了年龄的影响外，这种风险没有已知的机制。这是令人担忧的，因为术后认知功能障碍代表了一种可能加速神经退行性过程的不必要的认知下降形式。我们的团队将使用复杂的方法学方法来评估关于术前神经影像学生物标志物对全膝关节置换术后认知功能下降类型的预测价值的假设。将在一项纵向研究中评估患者（n=160）和非手术同行（n=80），检查术后3周、3个月和1年/基线后变化的神经影像学预测因素。我们团队的长期目标是：1）确定增加术后急性和不可逆认知下降风险的术前变量，2）使用这些信息为具有特定神经元风险特征的患者设计围手术期干预措施。

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. PUBLIC HEALTH RELEVANCE: Older adults are at increased risk for experiencing acute and long-term cognitive after major non-cardiac surgery such as total knee replacement. Other than the effect of age alone, there are no known mechanisms for this risk. This is alarming, for post operative cognitive dysfunction represents a form of un-necessary cognitive decline that may accelerate neurodegenerative processes. Our team will use sophisticated methodological approaches to assess hypotheses regarding the predictive value of presurgery neuroimaging biomarkers on type of post-operative cognitive decline after total knee replacement. Patients (n=160) and non- surgery peers (n=80) will be assessed in a longitudinal study examining neuroimaging predictors of change at three-weeks, three-months, and one-year post surgery/post baseline. The long-term goals of our team are to 1) identify preoperative variables that increase risk for acute and irreversible cognitive decline after surgery and 2) use this information to design peri-operative interventions for patients with specific neuronal risk profile.