The spectrum of cognitive impairment including Alzheimer’s Disease and Related Dementias after liver transplantation

项目摘要 我们非常成功的多中心肝移植功能评估（FrAILT）研究，由 自2013年以来，NIH已经明确了肝硬化患者接受肝脏治疗时身体虚弱的特征 移植（LT），并通过国家指南为身体虚弱评估提供了基础 用于肝硬化/LT患者管理。当我们缩小了关于身体虚弱的知识差距时，我们发现了一个 LT患者的新差距-认知“脆弱”，或更准确地说，认知障碍的表现。在2个试点 研究发现，30-60%的LT接受者符合认知障碍的标准。然而，目前， LT后认知障碍的研究-从细微的注意力变化到阿尔茨海默病及相关疾病 痴呆症（ADRD）-特征不明确。因此，临床医生不筛选认知障碍， 肝移植后的情况，肝移植患者没有被转介给专家进行及时的诊断/管理。在这 竞争性更新，我们将利用我们的多中心FrAILT研究来解决这一未满足的需求。我们假设 LT患者在LT后经历过早的认知综合征，包括ADRD（相对于一般的 人群），认知障碍影响LT后的整体功能健康，身体虚弱是主要的 LT后认知障碍的预测因素。这些假设有很强的科学前提，因为许多风险 肝硬化的因素与认知障碍有关。这些包括常见的ADRD合并症（例如， 糖尿病、高血压）、酗酒、肝性脑病、LT后谵妄和免疫抑制。 LT患者中普遍存在的身体虚弱本身与ADRD有共同的途径。这项研究的科学目标是 竞争性更新是为了更深入地描述LT后认知功能障碍（包括ADRD）的谱 患者为了实现这一目标，我们将在6个美国研究中心扩展FrAILT研究，并扩展我们的评估方案 在约2,000名LT FrAILT后患者中进行神经认知筛查。此外，我们将建立新的“神经- 肝病学”与我们的5个研究中心的AD研究中心（ADRC）合作， 通过全面的神经认知评估和脑成像，对150名LT后患者进行了分析， 表现出认知障碍具体而言，我们的目标是：1）描述患病率/发病率，并确定 与LT后认知功能障碍相关的因素，并评估其与LT后整体功能的相关性 健康; 2）描述LT后第一年认知功能的轨迹; 3）进行深度认知 分析以区分痴呆症的病因。我们建立的多中心FrAILT研究是独一无二的 准备解决这一巨大的未满足的需求，深入表征LT患者的认知障碍 具有高负担的常规ADRD风险，但传统上被排除在ADRD研究之外。 此外，我们将开发一个具有丰富认知数据的新队列，这些数据可能会对肝脏产生新的见解， 其他（一般，实体器官移植）人群中ADRD的移植相关贡献者。

PROJECT SUMMARY Our highly successful multi-center Functional Assessment in Liver Transplantation (FrAILT) Study, funded by the NIH since 2013, has definitively characterized physical frailty in patients with cirrhosis undergoing liver transplantation (LT) and provided the foundation to codify physical frailty assessment through national guidelines for cirrhosis/LT patient management. As we closed the knowledge gap around physical frailty, we identified a new gap in LT patients—cognitive “frailty”, or more precisely, the manifestation of cognitive impairment. In 2 pilot studies, we found that 30-60% of LT recipients met criteria for cognitive impairment. Yet, currently, the spectrum of post-LT cognitive impairment—from subtle attentional changes to Alzheimer’s Disease and Related Dementias (ADRD)—is not well characterized. As a result, clinicians do not screen for cognitive impairment in the post-LT setting, and LT patients are not referred to specialists for timely diagnosis/management. In this competing renewal, we will leverage our multi-center FrAILT Study to address this unmet need. We hypothesize that LT patients experience premature cognitive syndromes, including ADRD, after LT (relative to the general population), that cognitive impairment impacts post-LT global functional health, and that physical frailty is a major predictor of post-LT cognitive impairment. There is strong scientific premise for these hypotheses, as many risk factors for cirrhosis are linked with cognitive impairment. These include common ADRD comorbidities (e.g., diabetes, hypertension), heavy alcohol use, hepatic encephalopathy, post-LT delirium, and immunosuppression. Physical frailty itself, prevalent in LT patients, shares common pathways with ADRD. The scientific goal of this competing renewal is to deeply characterize the spectrum of cognitive impairment including ADRD in post-LT patients. To accomplish this, we will extend the FrAILT Study at 6 U.S. sites and expand our assessment protocol with neurocognitive screening in ~2,000 post-LT FrAILT patients. Additionally, we will establish new “neuro- hepatology” collaborations with 5 of our sites’ AD Research Centers (ADRC) to conduct deep cognitive profiling—through comprehensive neurocognitive assessments and brain imaging—in 150 post-LT patients who display cognitive impairment. Specifically, we aim to: 1) Characterize the prevalence/incidence of and identify factors associated with post-LT cognitive impairment and evaluate its association with post-LT global functional health; 2) Characterize trajectories of cognitive function in the first year post-LT; 3) conduct deep cognitive profiling to differentiate among the etiologies of dementia. Our established multi-center FrAILT Study is uniquely poised to address this enormous unmet need for deep characterization of cognitive impairment in LT patients who have a high burden of conventional ADRD risks but have traditionally been excluded from ADRD studies. Further, we will develop a novel cohort with rich cognitive data that may yield novel insights into liver- and transplant-related contributors to ADRD in other (general, solid organ transplant) populations.