GIUV2020-484
Our research focuses on identifying the mechanisms by which chronic liver disease (cirrhosis) leads to cognitive and motor impairment in patients with minimal hepatic encephalopathy (MHE) and on finding new treatments and markers for early diagnosis of MHE. The group has made relevant contributions on MHE, such as: Characterisation of neurological alterations in MHE. We are characterising the earliest neurological alterations in patients with MHE. We found that cirrhotic patients classified by the PHES battery as not having MHE have attention and coordination deficits. We evaluate a wide range of neurological functions using more than 20 tests. 42% of cirrhotic patients have abnormalities that are not detected by PHES. We are studying the usefulness of a new, rapid, objective, reproducible and highly sensitive procedure based on eye movement analysis to diagnose MHE and early cognitive impairment in patients with cirrhotic and fatty liver disease. Characterisation of brain alterations in MHE: We have found that patients with MHE have decreased mismatch negativity (MMN) area, an auditory evoked potential that we analyse by EEG, and that the MMN area is useful for diagnosing...Our research focuses on identifying the mechanisms by which chronic liver disease (cirrhosis) leads to cognitive and motor impairment in patients with minimal hepatic encephalopathy (MHE) and on finding new treatments and markers for early diagnosis of MHE. The group has made relevant contributions on MHE, such as: Characterisation of neurological alterations in MHE. We are characterising the earliest neurological alterations in patients with MHE. We found that cirrhotic patients classified by the PHES battery as not having MHE have attention and coordination deficits. We evaluate a wide range of neurological functions using more than 20 tests. 42% of cirrhotic patients have abnormalities that are not detected by PHES. We are studying the usefulness of a new, rapid, objective, reproducible and highly sensitive procedure based on eye movement analysis to diagnose MHE and early cognitive impairment in patients with cirrhotic and fatty liver disease. Characterisation of brain alterations in MHE: We have found that patients with MHE have decreased mismatch negativity (MMN) area, an auditory evoked potential that we analyse by EEG, and that the MMN area is useful for diagnosing attention deficits. Magnetic resonance imaging (MRI) of the brain has shown a loss of cortical thickness in certain regions that correlates with cognitive impairment. By arterial spin labelling we show that blood flow is increased in the cerebellum, correlates with attention and coordination deficits and allows detection of MHE earlier than PHES. We have observed reduced microstructural integrity of the white matter in MHE that correlates with deficits in attention and mental processing speed and reduced functional connectivity in neural networks involved in attention and executive control processes. Contribution of hyperammonemia and inflammation to MHE. Mechanisms involved. We analysed the presence of cognitive impairment in patients with different degrees of hyperammonaemia and/or inflammation, due to different liver and dermatological diseases and concluded that in patients with liver diseases (cirrhosis, steatohepatitis) cognitive impairment may appear before progression to cirrhosis, if ammonia and inflammation levels are sufficiently high. We found that MHE correlates with an increase in IL6 and IL18, whose serum concentration allows us to discriminate between patients without and with MHE. We hypothesise that the onset of MHE is due to a change in peripheral inflammation that is transmitted to the brain. We analysed the differences in inflammation in patients with and without MHE. We have identified alterations in immunophenotype and inflammation associated with the development of MHE. We are further investigating the mechanisms of these alterations and their transmission to the brain and evaluating which ones are reversed by treatment with rifaximin. Rifaximin treatment reverses immunophenotype alterations and improves cognitive function in some MHE patients but not in others. We are characterising alterations in brain activity by functional MRI before and after rifaximin treatment. Peripheral inflammation may lead to neuroinflammation in patients with MHE, which would mediate cognitive and functional alterations. We have shown that neuroinflammation occurs in the cerebellum in early stages of chronic liver disease, before cirrhosis is reached. Creation of a bioinformatics model of molecular, cellular and intercellular communication events associated with the development of MHE. Using multi-omics bioinformatics analysis, we have identified two biological pathways associated with the development of MHE in cirrhotic patients, related to "adaptive immune response" and "G protein-coupled receptor signalling".
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- Caracterizacion detallada de las alteraciones en EHM y los mecanismos que las producen, y evaluar nuevos procedimientos diagnosticos y terapeuticos
- Creacion de un modelo bioinformatico de eventos moleculares, celulares y de comunicacion intercelular asociados a la aparicion de EHM
- Evaluar la utilidad del analisis de movimientos oculares para el diagnostico temprano del deterioro cognitivo en EHM y en enfermedad hepatica grasa
- Busqueda de biomarcadores que puedan servir para diagnosticar la EHM de forma temprana y predecir la respuesta al tratamiento con rifaximina
- Desarrollo de una nueva metodologia diagnostica simultanea de la Fibrosis e inflamacion Hepatica a partir de Resonancia Magnetica
- Characterization of cognitive, neuropsychological and cerebral alterations in patients with minimal hepatic encephalopathy (MHE).We are better characterising the early neurological and brain alterations associated with MHE and the mechanisms that produce them to identify and evaluate new earlier and more sensitive MHE diagnostic procedures. Line funded by the Carlos III Health Institute (ISCIII) (PI18/00150).
- Assessment of the utility of the analysis of eye movements for early diagnosis of MHE.We evaluate the usefulness of eye movement alterations for the early diagnosis of MHE. This approach is in collaboration with the company AURA Innovative Robotics, which has developed sensitive equipment for the fine analysis of different eye movement parameters.
- To characterise alterations in inflammation, neuroinflammation and brain function associated with the onset of MHE.We characterise the changes in immunophenotype and inflammation associated with the onset of MHE. We analyse the microRNA and protein content of exosomes and their usefulness for diagnosing MHE. We analysed alterations in neuronal connectivity by functional MRI. Funded by: ISCIII (PI18/00150).
- Identification of biomarkers Identification and modelling of molecular and cellular events of the immune response associated with the development of MHE in cirrhotic patients.We are characterising inflammatory processes in detail to create a bioinformatic model of molecular, cellular and intercellular communication events associated with the development of MHE. We will evaluate its usefulness in predicting the onset of MHE. Funded by the Ramón Areces Foundation.
- Evaluation of the effects of rifaximin treatment and the mechanisms involved.We are evaluating the effects of treatment of patients with MHE with rifaximin on neurological, cerebral, immunological, metabolic and exosome alterations. Line funded by the ISCIII (PI18/00150).
- Study of neurological, cerebral and biochemical alterations in patients with fatty liver disease. Molecular and cellular mechanisms.We are studying whether patients with fatty liver disease present neurological, cerebral and biochemical alterations, in order to characterise them and look for biomarkers of cerebral alterations in steatohepatitis. Funded by: Agencia Valenciana de la Innovación (Valencian Government).
- Study of the microbiota in patients with cognitive impairment associated with chronic liver disease: cirrhosis and non-alcoholic steatohepatitis.The aim of this study is to search for biomarkers of cognitive impairment associated with liver disease by characterising the salivary and faecal microbiota in cirrhotic patients and in patients with non-alcoholic steatohepatitis.
- Study of cognitive, immunological and biochemical alterations in patients with morbid obesity and fatty liver disease. Molecular and cellular mechanisms.The objectives of this study are 1) To study whether patients with morbid obesity, NAFLD or NASH carriers, have cognitive and motor impairments. 2) To characterise the changes in the immunophenotype and inflammation associated with the appearance of cognitive impairment in patients with morbid obesity and NASH. 3) To analyse the microRNA and protein content of exosomes and their usefulness in diagnosing NASH-associated cognitive impairment. 4) Evaluate if there is an improvement in cognitive and motor skills and blood parameters after bariatric surgery for the treatment of morbid obesity.Characterisation of these alterations could provide biomarkers for NASH-associated cognitive impairment. Furthermore, some of the parameters identified could be a good biomarker to predict progression from steatohepatitis to cirrhosis.
| Name | Nature of participation | Entity | Description |
|---|---|---|---|
| MARIA DEL CARMEN MONTOLIU FELIX | Director | Universitat de València | |
| Research team | |||
| M DESAMPARADOS ESCUDERO GARCIA | Member | Universitat de València | |
| TERESA CONSUELO SAN MIGUEL DIEZ | Collaborator | Universitat de València | |
| MARIA AMPARO URIOS LLUCH | Collaborator | FUNDACION PARA LA INVESTIGACION DEL HOSPITAL CLINICO DE LA COMUNIDAD VALENCIANA (FUNDACION INCLIVA) | researcher |
| Adelaida Rodrigo Sanbartolomé | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| Juan Fermín Ordoño Domínguez | Collaborator | Hospital Arnau de Vilanova_GVA | head of section/service |
| Salvador Benlloch Pérez | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| JUAN JOSE GALLEGO ROIG | Collaborator | Universitat de València - Estudi General | UVEG PhD student |
| Nicolás Peñaranda Sarmiento | Collaborator | Hospital Clínico Universitario de Valencia | phisician |
| Roberto Aliaga Méndez | Collaborator | Hospital Clínico Universitario de Valencia | researcher |
| Pilar Aguilar Santaisabel | Collaborator | Hospital Clínico Universitario de Valencia | technical officer |
| Lucía Durbán Serrano | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| Mª Pilar Ríos Peset | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| MARIA PILAR BALLESTER FERRE | Collaborator | FUNDACION PARA LA INVESTIGACION DEL HOSPITAL CLINICO DE LA COMUNIDAD VALENCIANA (FUNDACION INCLIVA) | researcher |
| Cristina Montón Rodríguez | Collaborator | Hospital Clínico Universitario de Valencia | phisician |
| Alessandra Fiorillo | Collaborator | Universitat de València - Estudi General | UVEG PhD student |
| Maria Encarnación Rueda Soriano | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| Cristina Ipiens Escuer | Collaborator | Hospital Clínico Universitario de Valencia | phisician |
| Felipe Ordoño Domínguez | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| Laura Puchades Lanza | Collaborator | Hospital Clínico Universitario de Valencia | technical officer |
| Gabriel Villanueva Barco | Collaborator | Hospital Arnau de Vilanova_GVA | phisician |
| Paula Cases Bergón | Collaborator | Hospital Clínico Universitario de Valencia | head of section/service |
| FRANC CASANOVA FERRER | Collaborator | Universitat de València - Estudi General | UVEG PhD student |
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- Pathology
- encefalopatía hepática mínima; cirrosis; deterioro cognitivo leve; test psicométricos
- encefalopatía hepática mínima; movimientos oculares; sacadas; antisacadas
- encefalopatía hepática mínima; inflamación; inmunofenotipo; resonancia magnética funcional; microARNs; exosomas
- encefalopatía hepática mínima; modelo bioinformático; diagnóstico precoz; inmunofenotipo; inflamación; exosomas
- encefalopatía hepática mínima; rifaximina; inflamación; inmunofenotipo; resonancia magnética funcional
- enfermedad hepática grasa; esteatohepatitis; deterioro cognitivo; biomarcadores; inflamación; inmunofenotipo; resonancia magnética
- microbiota; encefalopatía hepática mínima; esteatohepatitis; biomarcadores
- alteraciones cognitivas, inmunológia, obesidad mòrbida, enfermedad grasa del hígado.
