Research group on Laboratory of Neurological Impairment

Description

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".

Goals CT

Detailed characterisation of the alterations in MHE and the mechanisms that produce them, and evaluation of new diagnostic and therapeutic procedures.
Creation of a bioinformatics model of molecular, cellular and intercellular communication events associated with the development of MHE.
Evaluate the usefulness of eye movement analysis for early diagnosis of cognitive impairment in MHE and fatty liver disease.
Search for biomarkers that can be used to diagnose MHE early and predict response to treatment with rifaximin.
Development of a new simultaneous diagnostic methodology for fibrosis and liver inflammation based on Magnetic Resonance Imaging.

Research lines

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).
Evaluación de la utilidad del análisis de movimientos oculares para el diagnóstico temprano de MHE
We are evaluating the usefulness of eye movement abnormalities for early diagnosis of MHE. This is being addressed in collaboration with AURA Innovative Robotics, which has developed sensitive equipment for fine analysis of various parameters of eye movements.
Characterisation of cognitive, neuropsychological and brain 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 in order to identify and evaluate new, earlier and more sensitive diagnostic procedures for MHE. Line funded by the ISCIII (PI18/00150).
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.
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.