The CNS and cirrhosis:psychobiological approaches

中枢神经系统和肝硬化：心理生物学方法

• 批准号: 6730407
• 负责人: CHARMAINE A STEWART
• 金额: $ 7.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730407
• 关键词: arteriovenous shunt surgery; benzodiazepine receptor; benzodiazepines; blood flow measurement; brain circulation; clinical research; cognition; hepatic coma /encephalopathy; human subject; liver cirrhosis; liver disorder diagnosis; liver transplantation; medical complication; neuropsychological tests; patient oriented research; positron emission tomography; receptor binding; serotonin transporter

DESCRIPTION (provided by applicant): Hepatic encephalopathy (HE) is one of the most common manifestations of decompensated cirrhosis. Approximately 70% of patients with cirrhosis also have subacute hepatic encephalopathy (SHE), as demonstrated on neuropsychological testing. The use of transjugular intrahepatic portosystemic shunts (TIPS), which acts as a side-to-side shunt, has become common to manage complications of cirrhosis. However, TIPS are associated with adverse effects, including worsening of existing HE or the precipitation of overt HE and liver failure. Liver transplantation has become the ideal management for patients who have decompensated liver disease. The principal hypothesis of this proposal is that changes of HE and SHE can be determined by neuropsychological testing and changes in cerebral blood flow (CBF). The Specific Aims are the following: (1) Determine the changes in cognitive function in patients with cirrhosis; (2) Identify changes in CBF and neurotransmitter activity, as assessed by central benzodiazepine receptor binding and serotonin transporter binding after TIPS insertion; (3) Identify changes in CBF and neurotransmitter activity, as assessed by central benzodiazepine receptor binding and serotonin transporter binding after liver transplantation; and (4) Correlate the neuropsychological changes with cognitive function and central benzodiazepine receptor binding and serotonin transporter binding. These Specific Aims will be pursued in 60 subjects: group I will be 20 cirrhotics who will undergo TIPS; group II will be 20 cirrhotic patients who are scheduled to undergo liver transplantation; and group III will be 20 age and sex matched cirrhotic controls. All groups will be studied with a battery of neuropsychological tests and stimulated CBF, using 1502 labeled water, while half of groups I and II will be tested with 11C flumazenil PET or (11C)(+)McN5652 positron emission tomography (PET), in order to determine central benzodiazepine receptor binding and serotonin transporter binding, respectively, before and one month after undergoing TIPS or liver transplantation. The control group will be studied with 11C flumazenil PET or (11C)(+)McN5652 PET at baseline and 1 month, thereafter. In aggregate, these studies will provide a platform to elucidate cognitive and biological mechanisms underlying hepatic encephalopathy with the ultimate goal of enhancing diagnosis and management. Additionally, the proposed studies will be guided by a team of mentors and sponsors and supplemented by a didactic curriculum, all to lay the foundation for eventual independent clinical investigator status.

描述（由申请人提供）： 肝性脑病（HE）是失代偿性肝硬化最常见的表现之一。神经心理学测试表明，大约 70% 的肝硬化患者还患有亚急性肝性脑病 (SHE)。经颈静脉肝内门体分流术（TIPS）作为一种侧向分流术，已成为治疗肝硬化并发症的常用方法。然而，TIPS 与不良反应相关，包括现有 HE 恶化或明显 HE 和肝衰竭的沉淀。肝移植已成为失代偿性肝病患者的理想治疗方法。该提案的主要假设是，HE 和 SHE 的变化可以通过神经心理学测试和脑血流量（CBF）的变化来确定。具体目标如下：（1）确定肝硬化患者认知功能的变化； (2) 识别 CBF 和神经递质活性的变化，通过 TIPS 插入后中枢苯二氮卓受体结合和血清素转运蛋白结合进行评估； (3) 通过肝移植后中枢苯二氮卓受体结合和血清素转运蛋白结合来评估，确定 CBF 和神经递质活性的变化； (4) 将神经心理学变化与认知功能、中枢苯二氮卓受体结合和血清素转运蛋白结合相关联。这些具体目标将在 60 名受试者中实现：第一组是 20 名接受 TIPS 的肝硬化患者； II组为20名拟行肝移植的肝硬化患者；第三组是20名年龄和性别匹配的肝硬化对照。所有组都将使用 1502 标记水进行一系列神经心理学测试和刺激 CBF 进行研究，而 I 组和 II 组中的一半将使用 11C 氟马西尼 PET 或 (11C)(+)McN5652 正电子发射断层扫描 (PET) 进行测试，为了分别确定接受 TIPS 或肝移植之前和之后一个月的中枢苯二氮卓受体结合和血清素转运蛋白结合。对照组将在基线和此后 1 个月时使用 11C 氟马西尼 PET 或 (11C)(+)McN5652 PET 进行研究。总的来说，这些研究将为阐明肝性脑病的认知和生物学机制提供一个平台，最终目标是加强诊断和管理。此外，拟议的研究将由导师和赞助商团队指导，并辅以教学课程，所有这些都是为最终的独立临床研究者地位奠定基础。