Spectrum of Neuro-Cognitive Impairment in Cirrhosis

描述（由申请人提供）：肝性脑病（HE）是肝硬化的一种神经认知并发症，分为临床上明显的显性HE （OHE）和轻度HE (MHE)，需要进行认知测试。MHE与生活质量差（QOL）、驾驶技能受损和OHE发展的高风险有关。用于将肝硬化分为正常、MHE和OHE的标准是主观的，不可重复。这种主观性和缺乏与临床相关结果的相关性是我们知识的主要差距。由于HE是一个连续体，一个更有效的方法可能是使用连续的测量来量化它，将患者定位在肝硬化神经认知障碍的范围内（SONIC）。这种方法可以定量评估肝病进展后的认知变化，以及对肝移植（LT）反应的改善。我们的中心假设是：在肝硬化受试者中，神经认知功能损害的程度和恶化的速度可以预测(1)显性肝性脑病的发展(2)肝性脑病相关的医学和社会心理结果以及(3)肝移植后神经认知过程的可逆性。具体目的包括：(1)建立SONIC模型来预测肝硬化中he相关的医学和心理社会结局。300名没有OHE的肝硬化患者将接受多维认知电池、驾驶史、社会经济地位和生活质量的测试。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终点。假设是，多维认知模型将提供一种敏感而具体的量化SONIC的方法，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的损害。(2)明确肝移植对SONIC的影响，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例患者将在肝移植前、肝移植后6个月和12个月进行SONIC检测。还将定义LT前认知功能障碍严重程度和MR评估（MR光谱、弥散张量成像和功能MR）对LT后SONIC可逆性的影响。假设是lt前认知功能障碍的严重程度及其潜在的病理生理学决定了lt后的可逆性程度。这一贡献是重要的，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，从而在肝硬化认知评估中产生范式转变。这样的结果将具有积极的影响，因为它将客观性引入该领域，并定义SONIC移植后的病理生理和认知结果。这将改善肝硬化认知测试的诊断和治疗策略，并改善患者对移植的选择。

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. PUBLIC HEALTH RELEVANCE: The proposed studies will change the way patients with cirrhosis are approached and will replace the current faulty system of categorizing their brain function with a better method of predicting how the effect of cirrhosis on the brain affect patients' medical outcomes as well as their quality of life and ability to work and earn and how much of these defects change after liver transplant. These procedures will then make it easier for doctors to diagnose, predict complications and treat patients with cirrhosis. Thus, the findings are ultimately expected to be applicable in improving the health of patients with cirrhosis, which is one of the leading causes of death.