Spectrum of Neuro-Cognitive Impairment in Cirrhosis

描述(申请人提供)：肝性脑病(HE)是一种肝硬变的神经认知并发症，分为临床明显的显性肝性脑病(OHE)或需要认知测试的微小肝性脑病(MHE)。MHE与生活质量差(QOL)、驾驶技能受损和OHE发展的高风险有关。用于将肝硬化症分为正常、MHE和OHE的标准是主观的，不可重复性。这种主观性和缺乏与临床相关结果的相关性是我们知识中的一个主要差距。由于HE是一个连续体，一种更有效的方法可能是使用连续的测量方法来量化它，这些测量将患者定位在肝硬变(SONIC)神经认知障碍的范围内。这种方法将允许对肝脏疾病进展后的认知变化进行定量评估，以及改善对肝移植(LT)的反应。我们的中心假设是：在肝硬变患者中，神经认知功能受损的程度和恶化的速度预测了(1)临床肝性脑病(2)与肝性脑病相关的医学和心理社会结局以及(3)肝移植后神经认知过程的可逆性。具体目标包括：(1)建立声学模型来预测肝硬变患者与HE相关的医疗和心理社会结局。300名没有OHE的肝硬变患者将接受多维认知电池、驾车史、社会经济状况和生活质量的测试。这些将每6个月重复一次，直到OHE发展的主要终点。住院、事故、生活质量和社会经济地位将是次要的终点。我们的假设是，多维认知模型将提供一种敏感而具体的方法来量化SONIC，该方法将(A)预测OHE和住院发展，(B)量化生活质量、驾驶和社会经济地位方面的损害。(2)明确肝移植对Sonic的影响，并确定调节肝移植后认知功能障碍可逆性的病理生理因素：移植名单上的45名患者将在肝移植前、术后6个月和12个月接受Sonic测试。还将确定肝移植前认知功能障碍的严重程度和MR评估(磁共振波谱、弥散张量成像和功能磁共振)对肝移植后SONIC可逆性的影响。假设是肝移植前认知功能障碍的严重程度及其潜在的病理生理决定了肝移植后的可逆性程度。这一贡献意义重大，因为它有望通过整合客观方法来预测医学和心理社会结果，并通过定义移植对认知的影响，从而在评估肝硬变患者的认知方面产生范式转变。这样的结果将产生积极的影响，因为它将把客观性引入这一领域，并定义移植后Sonic的病理生理和认知结果。这将改进肝硬变认知测试的诊断和治疗策略，并改善移植患者的选择。

DESCRIPTION (provided by applicant): Hepatic encephalopathy (HE) is a neuro-cognitive complication of cirrhosis that is divided into the clinically apparent overt HE (OHE), or minimal HE (MHE), which requires cognitive testing. MHE is associated with poor quality of life (QOL), impaired driving skills, and high risk of OHE development. Criteria used to categorize cirrhotics into normal, MHE and OHE are subjective and not reproducible. This subjectivity and lack of correlation with clinically relevant outcomes is a major gap in our knowledge. Since HE is a continuum, a more productive approach may be to quantify it using continuous measures that locate the patient within the spectrum of neuro-cognitive impairment in cirrhosis (SONIC). Such an approach would allow quantitative assessment in cognitive changes following progression of liver disease, as well as improvement in response to liver transplant (LT). Our central hypothesis is: In subjects with cirrhosis, the degree of impairment and the rate of deterioration of neuro-cognitive function, predicts development of (1) overt hepatic encephalopathy (2) hepatic encephalopathy-related medical and psychosocial outcomes and (3) reversibility of neuro-cognitive course after liver transplant. The specific aims include: (1) Develop a model of SONIC to predict the HE-related medical and psycho-social outcomes in cirrhosis. 300 cirrhotics without OHE will undergo testing with a multi-dimensional cognitive battery, driving history, socio- economic status and QOL. These will be repeated every 6 months until the primary endpoint of OHE development. Hospitalization, accidents, QOL and socio-economic status will be secondary endpoints. The hypothesis is that a multi-dimensional cognitive model will provide a sensitive and specific method of quantifying SONIC that will (a) predict OHE and hospitalization development, and (b) quantify impairment in quality of life, driving and socio-economic status. (2) Define the impact of liver transplant on SONIC and to determine patho-physiological factors that modulate reversibility of cognitive dysfunction after liver transplant: 45 patients on the transplant list will undergo SONIC testing prior to, and at six and twelve months post-LT. The impact of pre-LT cognitive dysfunction severity and MR assessment (MR spectroscopy, diffusion-tensor imaging and functional MR) on reversibility of SONIC after LT will also be defined. The hypothesis is that pre-LT cognitive dysfunction severity and its underlying patho-physiology determines the degree of reversibility post-LT. This contribution is significant as it is expected to engender a paradigm shift in the evaluation of cognition in cirrhosis by integrating an objective approach to predict medical and psycho-social outcomes, and by defining the impact of transplant on cognition. Such results will have a positive impact, because it will introduce objectivity into this field and define the patho-physiology as well as cognitive outcome of SONIC after transplant. This would improve diagnostic and therapeutic strategies for cognitive testing in cirrhosis as well as improve patient selection for transplant.