Learning and Memory Impairments in Patients with Minimal Hepatic Encephalopathy are Associated with Structural and Functional Connectivity Alterations in Hippocampus

Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with alterations in attentional and executive networks. There are no studies evaluating the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system. This study aimed to evaluate verbal learning and long-term memory in cirrhotic patients with (C-MHE) and without MHE (C-NMHE) and healthy controls. We assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system. C-MHE patients showed impairments in learning, long-term memory, and recognition, compared to C-NMHE patients and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in C-NMHE patients and controls. C-MHE patients presented lower FC between the L-presubiculum and L-precuneus than C-NMHE patients. Compared to controls, C-MHE patients had reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in C-MHE patients. This study demonstrates the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients

Cortical networks are disturbed in people with cirrhosis even in the absence of neuropsychometric impairment

OBJECTIVE: Hepatic encephalopathy is a common complication of cirrhosis; it is characterised by neuropsychometric/neurophysiological abnormalities. Its pathophysiology is complex but glial neuronal communication is likely to be disrupted and to impact on oscillatory networks and cortical connectivity. The aim of this study was to use multichannel electroencephalography (EEG) to investigate functional connectivity, as a surrogate for cortical networks, in patients with cirrhosis. METHODS: Resting EEGs were recorded in 98 healthy controls and in 264 patients with cirrhosis characterised psychometrically using the Psychometric Hepatic Encephalopathy Score (PHES). Functional connectivity was calculated using the phase-lag index with stratification into standard EEG frequency bands. The findings were validated in a further cohort of 39 healthy controls and 106 patients with cirrhosis. RESULTS: Widespread disruption in functional connectivity was observed in the patients compared with the controls; connectivity was increased in the theta (4-8 Hz) band and decreased in the delta (1-3.5 Hz), alpha (8.5-13 Hz) and beta (13.5-26.5 Hz) bands. Changes were apparent even in patients who were psychometrically unimpaired compared with healthy controls viz mean ± SEM theta 0.107 ± 0.001 vs. 0.103 ± 0.002 (p < 0.05) and alpha 0.139 ± 0.003 vs. 0.154 ± 0.003 (p < 0.01); more pronounced changes were observed with increasing neuropsychometric impairment. The findings were replicated in the second cohort. CONCLUSIONS: Cortical networks are disturbed in patients with cirrhosis even in the absence of psychometric impairment. SIGNIFICANCE: These findings will facilitate further exploration of the pathophysiology of this condition and provide a robust means for assessing treatment effects in research settings

Ammonia toxicity: from head to toe?

Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction

Emerging Knowledge From Noninvasive Imaging Studies: Is Ammonia Control Enough?

Multiple lines of research suggest that ammonia is harmful to the brain if the levels remain elevated for extended periods of time. Several decades ago, there was no testing or standard of care to monitor the effect of hyperammonemia (HA) on neurological function in urea cycle disorders (UCD), and the timing of HA encephalopathy is still not clear. Magnetic resonance imaging (MRI) was not done routinely, if at all, so it was not known what changes were occurring in the brain, during and after recovery from HA. Decades ago, a diagnosis of a UCD meant severe disability and early death. Earlier diagnosis, improved management, and nitrogen scavenger therapy have improved the lives and life span of patients with UCD. However, many patients suffer from learning difficulties under the umbrella “executive function” which comprises neurologically based skills involving mental control and self-regulation. The general agreement of the core elements of executive functions includes inhibition, working memory, and cognitive flexibility and is necessary in development of skills in reasoning, fluid intelligence, problem-solving, and planning. Our research focuses on the use of noninvasive neuroimaging coupled with neuropsychological testing to understand the complex relationship between ammonia, glutamine, cognitive function, seizures, and specifically impact on development of working memory

Electroencephalogram variability in patients with cirrhosis associates with the presence and severity of hepatic encephalopathy

BACKGROUND & AIMS: The outputs of physiological systems fluctuate in a complex manner even under resting conditions. Decreased variability or increased regularity of these outputs is documented in several disease states. Changes are observed in the spatial and temporal configuration of the electroencephalogram (EEG) in patients with hepatic encephalopathy (HE), but there is no information on the variability of the EEG signal in this condition. The aim of this study was to measure and characterize EEG variability in patients with cirrhosis and to determine its relationship to neuropsychiatric status. METHODS: Eyes-closed, awake EEGs were obtained from 226 patients with cirrhosis, classified, using clinical and psychometric criteria, as neuropsychiatrically unimpaired (n=127) or as having minimal (n=21) or overt (n=78) HE, and from a reference population of 137 healthy controls. Analysis of EEG signal variability was undertaken using continuous wavelet transform and sample entropy. RESULTS: EEG variability was reduced in the patients with cirrhosis compared with the reference population (coefficient of variation: 21.2% [19.3-23.4] vs. 22.4% [20.8-24.5]; p<0.001). A significant association was observed between EEG variability and neuropsychiatric status; thus, variability was increased in the patients with minimal HE compared with their neuropsychiatrically unimpaired counterparts (sample entropy: 0.98 [0.87-1.14] vs. 0.83 [0.75-0.95]; p=0.02), and compared with the patients with overt HE (sample entropy: 0.98 [0.87-1.14] vs. 0.82 [0.71-1.01]; p=0.01). CONCLUSIONS: Variability of the EEG is associated with both the presence and severity of HE. This novel finding may provide new insights into the pathophysiology of HE and provide a means for monitoring patients over time. LAY SUMMARY: Decreased variability or increased regularity of physiological systems is documented in several disease states. Variability of the electroencephalogram was found to be associated with both the presence and severity of brain dysfunction in patients with chronic liver disease

Brain-muscle axis during treatment of minimal hepatic encephalopathy with L-ornithine L-aspartate

Abstract Background: Minimal Hepatic Encephalopathy (MHE) is a fluctuant cognitive deficit, and a common complication of cirrhosis, with significant health and socioeconomic consequences. Oral L-Ornithine L-Aspartate (LOLA) has been proposed to treat MHE but mechanism and efficacy are unknown. This study hypothesises LOLA treatment will correlate with improvements in: 1) Cognitive function (primary endpoints) 2) Relation to Brain-muscle axis (secondary endpoints) Design and methods: This double-blinded placebo-controlled trial included 34 patients (LOLA n=14, placebo n=20) over 12 weeks. All underwent psychometric testing (PHES, CogstateTM, Stroop, Short Form-36). Secondary endpoints included brain volume, white matter microstructure, brain function (proton MR spectroscopy/ functional MRI); muscle power (handgrip strength, 6-minute-walk-test); anthropometry (upper limb skinfold); muscle metabolome (lateral vastus muscle biopsy LC-MS analysis). Results: Significantly more patients receiving LOLA reported improved energy levels, specifically in Vitality (SF36 subdomain). No differences in PHES, Cogstate and Stroop test performance occured. Change-in-biceps skinfold thickness demonstrated significant gain with LOLA compared to placebo, without differences in power. LC-MS experiments were not discriminatory. Whole Brain differences in FA and RD suggested reduced brain oedema (subcortical volume reduction and global white matter changes). No significant group differences in fMRI task/ resting activation were seen. Spectroscopy of ACC showed significantly higher unresolved glutamine-glutamate (Glx) complex levels with LOLA, also correlating with increased PPI use, and may represent LOLA-driven increased Krebs-cycling or a function of altered gut microbiome. Conclusion: No cognitive benefits were demonstrated. Improved quality of life measures maybe a nutritional consequence also relating to increased biceps skinfold thickness with LOLA. Effects on brain oedema are postulated. Future studies need higher powering to allow subanalysis by aetiology, and smaller voxels at basal ganglia are recommended. Attempts to replicate rising ACC Glx with LOLA and regions of interest identified on fMRI subanalysis may be fruitful.Open Acces

Analyzing three different cognitive spheres (memory, reasoning and verbal ability) : an online psychometric battery for the assessment of covert hepatic encephalopathy in patients with cirrhosis

L'encéphalopathie hépatique (EH) est une complication neurocognitive débilitante de la cirrhose qui affecte la qualité de vie et augmente le risque de décès. L'EH est divisée en EH minimale, définie comme subclinique et HE manifeste, diagnostiquée avec des symptômes cliniques. Cette étude vise à effectuer une évaluation des troubles cognitifs chez les patients atteints de cirrhose en évaluant trois domaines cognitifs (mémoire, raisonnement et capacité verbale) et en interprétant les valeurs prédictives de ces tests pour identifier les patients à haut risque de développer leur premier épisode d'EH manifeste dans l'année. Cette étude longitudinale prospective a inclus des patients sans antécédent d'EH, recrutés à la clinique d'hépatologie du CHUM entre janvier et octobre 2021. Chaque patient a complété l'évaluation cognitive en ligne Cambridge Brain Sciences (CBS) au départ, composée de 12 tests neurocognitifs, qui prend 45 minutes. Les scores des patients ont été comparés aux normes CBS appariés pour l'âge, le sexe et les années d'éducation. Les scores moyens des patients (n=34, 61,7% hommes, âge moyen 60,7±8,5 ans) étaient inférieurs à la moyenne des normes dans tous les domaines cognitifs étudiés (p <0,05), ainsi que des scores inférieurs dans 11 des 12 tâches cognitives réalisées. Vingt-deux patients (65%) ont échoué à au moins un test. Jusqu'en janvier 2022, 3 patients ont développé une EH manifeste et 1 patient a terminé l'étude sans développer d'épisodes d'EH. Sur les questionnaires de suivi, tous les 3 ont signalé des troubles du sommeil, de l'attention et de la mémoire, avant l'épisode. De plus, ils avaient des scores inférieurs dans 8 des 12 tests cognitifs au départ. L'évaluation cognitive CBS en ligne est facile à utiliser et réalisable. Il semble être assez sensible car la plupart des patients ont obtenu de mauvais résultats par rapport aux normes. La valeur du CBS réside dans sa capacité à prédire l'EH manifeste chez une population de patients atteints de cirrhose, ce qui permettrait d'identifier les patients à risque nécessitant un traitement et de prévenir de futurs épisodes d'EH manifeste.Hepatic encephalopathy (HE) is a debilitating neurocognitive complication of cirrhosis that impacts quality of life and increases the risk of death. HE is divided into covert, defined as subclinical HE and overt HE, diagnosed with clinical symptoms. This study aims to perform a detailed assessment of cognitive impairment in patients with cirrhosis by evaluating three different cognitive domains (memory, reasoning and verbal ability) and interpreting the predictive values of these tests in identifying patients who are at high risk of developing their first episode of overt HE within one year. This prospective longitudinal study included patients with cirrhosis without a history of HE, recruited from the CHUM hepatology clinic between January to October 2021. Each patient completed the Cambridge Brain Sciences (CBS) online cognitive assessment at baseline, composed of 12 neurocognitive tests, which required 45 minutes. Patient scores were compared to CBS controls matched for age, sex and years of education. The patients (n=34, 61.7% male, average age 60.7±8.5 years) mean scores were lower than the average of the norms in all the cognitive domains studied (p <0.05), as well as lower scores in 11 of 12 cognitive tasks performed. Twenty-two patients (65%) failed at least one test. Up until January 2022, 3 patients developed overt HE and 1 patient completed the study without developing any episodes of overt HE. On follow-up questionnaires, all 3 reported impairments in sleep, attention, and memory, leading up to the HE episode. In addition, they had lower scores in 8 of 12 cognitive tests at baseline. The CBS online cognitive assessment is easy to use and feasible. It appears to be quite sensitive as most patients did poorly compared to controls. The value in the CBS lies within its ability to predict overt HE which would allow to identify patients at risk who require treatment and prevent future episodes of overt HE

Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed

Hepatic encephalopathy : novel insights into classification, pathophysiology and therapy

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed

Ammonia, infection and inflammation in hepatic encephalopathy.

For over a century, we have known that ammonia is important in the pathogenesis of hepatic encephalopathy. Studies in patients with acute liver failure have shown rapid progression to severe encephalopathy in those patients with evidence of a systemic inflammatory response, suggesting a possible link between inflammation and encephalopathy. In view of the growing evidence to support the role of inflammation in increasing the susceptibility of the brain to the effects of hyperammonemia in liver disease, 3 hypotheses were explored: 1: Inflammation and infection are important in hepatic encephalopathy. 2: Inflammation and infection act synergistically with ammonia. 3: Ammonia makes the immune system more susceptible to infection. In the first of 2 clinical studies, inflammation was shown to be an important determinant of the presence and severity of minimal hepatic encephalopathy. In a second study, significant deterioration of neuropsychological test scores in patients with cirrhosis following induced hyperammonemia during the inflammatory state, but not after its resolution, suggested that inflammation may be important in modulating the cerebral effect of ammonia in liver disease, supporting the first hypothesis. Ammonia and inflammation were shown to be synergistic in the bile duct ligated rat which showed increased brain water and astrocyte swelling exacerbated by endotoxin and accompanied by a rise in nitric oxide and brain nitrotyrosine, but not in plasma ammonia, suggesting nitric oxide may play an important synergistic role in the pathogenesis of hepatic encephalopathy. Ammonia was shown to impair neutrophil function by reducing phagocytosis, inducing spontaneous respiratory burst and cell swelling. The p38"MAPK pathway was shown to be important and a p38"MAPK agonist prevented neutrophils from swelling in the presence of ammonia and improved phagocytosis. While cultures of muscle cells were a potentially interesting direction to take to investigate the effect of inflammation on the muscle uptake of ammonia, unfortunately the resulting data demonstrated a low glutamine synthetase activity. In conclusion, these studies illustrate the important factors that modulate the manifestation of symptoms of hepatic encephalopathy in cirrhosis, the most important of which is the synergistic role of inflammation and ammonia. Furthermore, the ammonia-induced impairment of neutrophil function may, in part, account for the increased susceptibility to infection found in patients with cirrhosis