Predicting post-transplant mortality and global functional health based on pre-transplant functional status in liver transplantation

项目总结 肝硬变的特征是一系列神经认知障碍，通常被诊断为单一的 肝硬变特有的实体，“肝性脑病”，被认为是完全可逆的肝移植。但 虽然公开的精神状态变化通常会在移植后几天内得到改善，但我们的初步数据显示 18%的肝移植受者至少表现出轻微的认知障碍，这是阿尔茨海默氏症的先兆 疾病和相关痴呆(ADRD)，在移植后6个月，尽管肝功能正常和 平均年龄只有58岁。这增加了一些认知障碍在肝硬变中的可能性。 事实上，不可逆，并可能代表未诊断的ADRD和/或ADRD风险增加。但在 目前，肝移植患者中ADRD的患病率既不清楚，也没有相关因素。 在这一人群中导致ADRD风险的因素已被确定，排除了关于后 移植ADRD和开发降低风险的干预措施。肝移植患者存在多重风险 增加ADRD风险的因素，包括潜在的慢性肝病的贡献，高 与ADRD相关的合并症(如高血压、糖尿病)和低教育水平的比率。ADRD面临的风险是 移植后由于高比例的精神错乱和长期免疫抑制的使用而进一步恶化。最后， 脆弱，一种与ADRD事件相关并与ADRD共享共同生物学途径的状态，是 在肝硬变中高度流行，并在移植后长期存在。总而言之，这些高风险因素提供了科学 我们假设肝移植患者有很高的ADRD患病率和风险。这个 我们的母公司R01AG059183的首要目标是调查肝移植对全球 身体虚弱和残疾等经典老年学概念所定义的功能性健康。这个 拟议的行政补充扩展了这一目标，扩大了我们对全球功能健康的定义 从身体功能到认知功能，目的是识别那些患有ADRD或有ADRD风险的人。要做到这一点， 我们提出了一个两步过程，包括最初的筛查/检测，然后通过 专家(按照NIA AD诊断指南的建议)。具体地说，使用我们强大的多中心 研究基础设施，我们的目标是：1)表征认知障碍的患病率并确定临床预测因素 在不同的队列中使用新的、有效的脑健康评估来评估肝移植后的损伤 5个地点的350名肝移植受者≥60岁(因为年龄是一个强烈的不良反应风险因素)，以及2) 在一个子集中进行详细的认知表型分析(通过全面的神经学测试和神经成像) 在15名认知障碍患者中确定ADRD的临床诊断和病因 会导致认知障碍。影响：这项研究将建立一个肝移植受者队列 基线认知评估作为未来提案的平台，以调查以下方面的纵向变化 在这一高危人群中，认知功能、进展到ADRD，以及可修改的ADRD危险因素。

PROJECT SUMMARY Cirrhosis is characterized by a spectrum of neurocognitive impairments that is often diagnosed as a single cirrhosis-specific entity, “hepatic encephalopathy”, and considered fully reversible with liver transplantation. But while overt mental status changes often improve within days of transplant, our preliminary data revealed that 18% of liver transplant recipients displayed at least mild cognitive impairment, a precursor for Alzheimer's disease and related dementias (ADRD), at 6 months after transplant, despite normal liver function and an average age of only 58 years. This raises the possibility that some cognitive impairments in cirrhosis are, in fact, not reversible, and potentially represent undiagnosed ADRD and/or elevated risk for ADRD. But at the current time, the prevalence of ADRD in liver transplant patients is neither known nor have the factors contributing to ADRD risk in this population been identified, precluding discussions about risks of post- transplant ADRD and development of risk-reducing interventions. Liver transplant patients have multiple risk factors that increase their risk for ADRD, including contributions from underlying chronic liver disease, high rates of ADRD-related co-morbidities (e.g., hypertension, diabetes), and low education level. Risk for ADRD is further exacerbated after transplant by high rates of delirium and use of long-term immunosuppression. Lastly, frailty, a state that is associated with incident ADRD and shares common biological pathways with ADRD, is highly prevalent in cirrhosis and persists long after transplant. Together, these high-risk factors offer scientific premise for our hypothesis that liver transplant patients have a high prevalence of and risk for ADRD. The overarching goal of our parent R01AG059183 is to investigate the impact of liver transplantation on global functional health as defined by classical geriatric constructs such as physical frailty and disability. The proposed administrative supplement expands this goal by broadening our definition of global functional health from physical to cognitive function, with the intent to identify those with or at risk for ADRD. To accomplish this, we propose a 2-step process involving initial screening/detection followed by ADRD evaluation/diagnosis by a specialist (as recommended by the NIA AD Diagnostic Guidelines). Specifically, using our robust, multi-center research infrastructure, we aim to: 1) characterize the prevalence of and identify clinical predictors of cognitive impairment after liver transplantation using the novel, efficient Brain Health Assessment in a diverse cohort of 350 liver transplant recipients ≥60 years old (since age is a strong ADRD risk factor) across the 5 sites, and 2) conduct detailed cognitive phenotyping (with comprehensive neurologic testing and neuroimaging) in a subset of 15 individuals with cognitive impairment to establish a clinical diagnosis of ADRD and etiologic factors contributing to cognitive impairment. IMPACT: This study will establish a cohort liver transplant recipients with baseline cognitive assessments as the platform for future proposals to investigate longitudinal changes in cognitive function, progression to ADRD, and modifiable ADRD risk factors in this high risk population.