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

项目摘要 肝硬化的特征是一系列的神经认知障碍，通常被诊断为单一的 肝硬化特异性实体，“肝性脑病”，认为肝移植完全可逆。但 虽然明显的精神状态变化通常在移植后几天内改善，但我们的初步数据显示， 18%的肝移植受者表现出至少轻度的认知障碍，这是阿尔茨海默氏症的前兆。 疾病和相关痴呆（ADRD），在移植后6个月，尽管肝功能正常， 平均年龄只有58岁。这就提出了肝硬化中的一些认知障碍， 事实上，不可逆，可能代表未诊断的ADRD和/或ADRD风险升高。但与此 目前，肝移植患者ADRD的患病率尚不清楚，也没有相关因素。 在该人群中，已确定导致ADRD风险的因素，排除了关于术后风险的讨论。 移植ADRD和降低风险干预措施的发展。肝移植患者有多种风险 增加ADRD风险的因素，包括基础慢性肝病的贡献， ADRD相关共病的发生率（例如，高血压、糖尿病）和教育水平低。ADRD的风险是 在移植后由于高比率的谵妄和使用长期免疫抑制而进一步恶化。最后， 虚弱是一种与ADRD事件相关的状态，与ADRD共享共同的生物学途径， 在肝硬化中非常普遍，并在移植后持续很长时间。这些高风险因素共同提供了科学 这是我们假设肝移植患者ADRD患病率和风险较高的前提。的 我们的母体R 01 AG 059183的总体目标是研究肝移植对全球 功能性健康，如经典的老年医学概念所定义的，如身体虚弱和残疾。的 拟议的行政补充通过扩大我们对全球功能性健康的定义来扩大这一目标 从身体到认知功能，旨在识别患有ADRD或有ADRD风险的患者。为了实现这一点， 我们提出了一个两步的过程，包括初步筛查/检测，然后通过一个 专家（根据NIA AD诊断指南的建议）。具体来说，使用我们强大的多中心 研究基础设施，我们的目标是：1）表征的患病率，并确定临床预测认知 肝移植后的损伤使用新的，有效的脑健康评估在一个不同的队列 5个研究中心的350例≥60岁的肝移植受者（因为年龄是一个强ADRD风险因素），以及2） 在一个子集中进行详细的认知表型分析（通过全面的神经病学测试和神经成像） 对15名认知障碍患者进行研究，以确定ADRD的临床诊断和病因因素 导致认知障碍影响：本研究将建立一个队列肝移植受者， 基线认知评估作为未来建议的平台，以调查 认知功能、ADRD进展和可改变的ADRD风险因素。

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.