Ammonia is a neurotoxic substance primarily produced in the intestine by the metabolism of proteins and amino acids followed by intestinal bacterial degradation. Dysbiosis of the gut microbiota has been shown to increase ammonia production (Kang et al., 2016). Some preclinical studies have demonstrated that dysbiosis is associated with cognitive impairment and hyperammonemia in HE rats (Higarza et al., 2019). Since the elimination of ammonia depends on the liver’s ability to convert ammonia, impairment of liver function due to the lack of glutamine synthetase in the liver can result in the accumulation of ammonia in the body and cognitive changes (Qvartskhava et al., 2015). Elevated blood ammonia can freely pass through the blood–brain barrier, causing inflammation of the nervous system and leading to cognitive impairment (Bobermin et al., 2020; Jaffe et al., 2020)， however, treating HE symptoms can be achieved by reducing central ammonia levels and improving inflammation (Jayakumar et al., 2015; Lu et al., 2020). Ammonia is detoxified by converting it into glutamine by astrocytes in the central nervous system (Jayakumar and Norenberg, 2016), but glutamine has permeability, and its accumulation can cause swelling and functional impairment of astrocytes (Rama Rao and Norenberg, 2014) and brain edema (Cudalbu and Taylor-Robinson, 2019). Although high blood ammonia levels are considered a core factor in causing HE (Aldridge et al., 2015; Hadjihambi et al., 2018), their role in mild cognitive impairment associated with liver disease is not significant and is only observed in MHE patients with increased blood ammonia concentration levels and decreased brain ammonia metabolism (Lockwood et al., 1991). In addition, Higarza et al. (2019) showed that cognitive impairment in NAFLD rats was related to increased blood ammonia levels, but only mild ammonia elevation was observed in NAFLD patients (Felipo et al., 2012).

Neuroinflammation is a common feature of various liver disease-related mild cognitive impairments. The immune cells of the central nervous system are microglia (Sheeler et al., 2020), which can monitor synaptic activity, pathogens, and injuries in the local environment and have phagocytic and synaptic remodeling-promoting functions. Microglial activation is a significant feature of neuroinflammation and is accompanied by an increase in cytokines and chemokines (Sheeler et al., 2020; Woodburn et al., 2021). It has been reported that MHE patients have significantly higher levels of inflammation, such as IL-6 and C-reactive protein, compared to normal individuals (Shawcross et al., 2007). Nonetheless, Shawcross et al. (2004) found that hyperammonemia in cirrhotic patients could only induce cognitive impairment when an inflammatory response occurred. Patients did not have cognitive impairment after the inflammation subsided, indicating that inflammation plays an important role in cognitive impairment in MHE patients. Neuroinflammation is also an important cause of cognitive impairment in NAFLD patients (Kjaergaard et al., 2021). Balzano et al. (2018) showed that NASH patients had neuroinflammatory manifestations such as neuronal loss, microglial and astrocytic activation, and lymphocyte infiltration in the cerebellum. Animal experiments have indicated that the neurological dysfunction of NAFLD is related to neuroinflammation (Veniaminova et al., 2020). Similarly, Bokemeyer et al. (2011) and Pflugrad et al. (2016) observed microglial and astrocytic activation and other neuroinflammatory manifestations in HCV patients. Although there is no evidence of cholestatic liver disease-associated neuropathy, it has been reported that NF-KB is activated in cholestatic liver disease, and NF-KB is associated with neuropathic inflammation and cognitive impairment (Phaw et al., 2021).

The brain has a high energy demand, consuming 20% of the body’s energy despite accounting for only 2% of its weight (Magistretti and Allaman, 2018). Glucose is the brain’s primary source of energy, providing over 95% of its energy needs through the tricarboxylic acid (TCA) cycle in neurons under physiological conditions (Bordone et al., 2019). However, the astrocyte-neuron lactate shuttle hypothesis (Magistretti and Allaman, 2018) suggests that glucose is mainly metabolized to lactate in astrocytes. When neuronal activity increases, the released glutamate can trigger astrocytes to uptake glucose and produce lactate as a supplemental energy source for neurons (Pellerin et al., 2007; Huang et al., 2019).

Elevated brain lactate levels in hepatic encephalopathy (HE) patients are typically regarded as a sign of cerebral energy failure (Bosoi and Rose, 2014). The accumulation of lactate in brain cells can cause cell swelling and brain edema, and interfere with communication, metabolism, and neurotransmission between astrocytes and neurons (Bosoi and Rose, 2014). Jiménez et al. (2010) compared the serum 1H-NMR metabolome of healthy controls (n = 69), cirrhotic patients without minimal hepatic encephalopathy (MHE) (n = 62), and cirrhotic patients with MHE (n = 39), and found that MHE patients had increased glucose and lactate concentration levels. Basic research also suggests that bile duct ligation (BDL) induced HE in rats which results in significant lactate accumulation in the cerebellum, hippocampus, and striatum (Simicic et al., 2019). Additionally, Hadjihambi et al. (2017) demonstrated that hyperammonemia induced by BDL in HE rats can impair the function of lactate transporters and astrocyte-neuron lactate shuttle, leading to neuronal energy metabolism disorders.

Apart from metabolic substrates, adequate oxygen supply is needed for the normal functioning of the brain. The energy metabolism of the brain is regulated by the neurovascular unit (NVU), which consists of neurons, glial cells, and vascular cells (Ahmad et al., 2020). Astrocytes strictly regulate cerebral blood flow through the NVU, thereby regulating the nutrition and oxygen supply of the central nervous system to meet the needs of local neurons (Bélanger et al., 2011). Structural and functional damage to the blood–brain barrier and astrocyte dysfunction can lead to NVU dysfunction, resulting in inadequate oxygen and energy metabolism in brain tissue. Nakanishi et al. (2014) ascertained that non-MHE cirrhotic patients exhibited a sharp and repetitive increase in cerebral oxyhemoglobin during task execution, while MHE patients showed a relatively slow increase, indicating poor task responsiveness to cerebral oxygen concentration levels in MHE patients. Sunil et al. (2012) also reported abnormal cerebral blood flow perfusion in multiple brain regions of MHE patients, and that regional cerebral blood flow in some brain regions was related to patients’ cognitive impairment. Near-infrared spectroscopy measurements of NAFLD (Takahashi et al., 2017) and PBC (Duszynski et al., 2020) patients illustrated cerebral hypoxia in these patients. Moreover, significant decreases in glucose, lactate, and tissue oxygen concentration levels were observed in the cortex of BDL-induced MHE rats (Hadjihambi et al., 2022). In conclusion, these findings indicate that there is energy metabolic dysfunction in mild cognitive impairment associated with liver disease.

Impaired glucose metabolism in the brain not only causes damage to brain energy metabolism but also affects neurotransmitter synthesis. In neuronal cells, glucose generated from glycolysis can not only be metabolized into ATP through the TCA cycle, but its product alpha-ketoglutarate (α-KG) can be synthesized into glutamate (Glu) via aspartate transaminase. Glu released into the synaptic cleft can be retaken up by astrocytes and converted into glutamine (Gln) via glutamine synthetase, and then transferred back to neurons where it is reconverted to Glu via glutaminase, a process known as the glutamate-glutamine cycle (Schousboe et al., 2014). Gln generated by astrocytes is also an important pathway for GABA replenishment. Impairment of the glutamate-glutamine cycle is a major cause of hepatic encephalopathy (Limón et al., 2021).

Magnetic resonance spectroscopy (MRS) of ¹³C-labeled metabolic substrates can provide insights into energy and neurotransmitter metabolism in neurons and astrocytes (Sonnay et al., 2017). Zwingmann et al. (2003) used [1-¹³C] glucose labeling to track neurotransmitter metabolism in rats with acute liver failure (ALF) induced by portacaval anastomosis (PCA), from the early stages of hepatic encephalopathy (HE) to the coma stage. The results showed that, compared to the control group, the total Gln and lactate concentrations in the brains of rats in the early stages of HE increased by 2 to 4.5 times, lactate synthesis (¹³C-labeled lactate enrichment) increased by 2.5 times in rats in the coma stage, Gln synthesis (Gln₂) increased by 10 times in the precoma stage, and Glu synthesis (Glu₄) decreased in the coma stage, while GABA synthesis did not show significant differences at any stage. Furthermore, Bosoi et al. (2014) used [1-¹³C] glucose and lactate labeling to trace neurotransmitter metabolism in the brains of rats with minimal hepatic encephalopathy (MHE) induced by bile duct ligation (BDL) and found that the de novo synthesis of lactate and Gln significantly increased in the brains of MHE rats. These results indicate the presence of neurotransmitter metabolism defects in MHE.

Neuroinflammation can affect the transmission of glutamatergic and GABAergic neurotransmitters (Cabrera-Pastor et al., 2019). Changes in glutamatergic and GABAergic neurotransmission are closely related to cognitive and motor changes in MHE patients (Llansola et al., 2015), and an increase in GABAergic tone in the brain is considered a characteristic of HE. Hassan et al. (2019) used transcranial magnetic stimulation to compare cerebellar inhibition (CBI) in 15 HE patients at different stages with 15 healthy controls. The results showed that CBI was reduced in HE patients at a stimulus interval of 5–7 ms, but the degree of CBI in patients at a stimulus interval of 7 ms was significantly correlated with the severity of HE, indicating an increase in GABAergic neurotransmission in the cerebellum of HE patients and a decrease in GABAergic neurotransmission in the motor cortex. Zöllner et al. (2023) study of 16 healthy controls and 19 MHE patients used edited MRS to measure GABA levels in the right cerebellum, left thalamus, and left motor cortex. The results showed that Gln levels were elevated in all three brain regions in MHE patients, whereas GABA levels were elevated in the cerebellum, and significantly decreased in the motor cortex and highly correlated with the severity of MHE. A clinical study also reported that the GABA-A receptor modulating steroid antagonist golexanolone improved cognition in MHE patients (Montagnese et al., 2021). Overall, these study results imply the important role of changes in the GABAergic system in the cerebellum and motor cortex in MHE.

Besides, neurotransmitter metabolic changes have been reported in patients with liver disease-related mild cognitive impairment. In NASH, rats with cognitive impairment, had decreased dopamine levels in the frontal cortex and the cerebellum and reduced norepinephrine levels in the striatum (Higarza et al., 2019). In patients with chronic hepatitis C cognitive impairment, the choline/creatine ratio in the basal ganglia and posterior cingulate gyrus was significantly increased, while the N-acetylaspartate/creatine ratio was significantly decreased. Cognitive impairment was also significantly negatively correlated with the choline/creatine ratio and positively correlated with the N-acetylaspartate/creatine ratio in the basal ganglia (Abo Hagar et al., 2018). Furthermore, Pflugrad et al. (2019) compared the brain MRS of healthy individuals with LT-related cognitive impairment patients before and after LT and found that after LT, there was an increase in myo-inositol in the thalamus, putamen, and white matter in LT cognitive impairment patients, and a decrease in glutamine/glutamate ratio in the putamen. Patients without cognitive impairment after LT only showed an increase in myo-inositol in the thalamus after LT, and there was no significant difference in brain MRS between transplant-related cognitive impairment patients and those without cognitive impairment.

The liver’s condition is closely intertwined with brain function. A study by Seo et al. (2016) revealed that elevated levels of liver enzymes, specifically aspartate aminotransferase (AST) and alanine aminotransferase (ALT), in patients with NAFLD are associated with impaired cognitive performance. Interestingly, in healthy individuals, plasma levels of ALT and AST not only display a significant negative correlation with memory capacity (Kamada et al., 2016), but also exhibit a noteworthy positive correlation with plasma Glu levels. AST and ALT serve as crucial indicators for assessing liver function biochemically, while also acting as vital enzymes involved in hepatic gluconeogenesis and the regulation of tissue glutamate production (Sookoian and Pirola, 2015). ALT facilitates a reversible transamination reaction between alanine and α-ketoglutarate, leading to the formation of pyruvate and glutamate. Conversely, AST catalyzes the reversible reaction between aspartate and α-ketoglutarate, resulting in the production of oxaloacetate and glutamate (Ellinger et al., 2011).

Notably, decreased ALT levels signify reduced liver metabolic activity and have been linked to a higher risk of dementia (Lu et al., 2021; He et al., 2022). Furthermore, a study by Nho et al. (2019) demonstrated demonstrated that lower serum ALT levels and an elevated AST/ALT ratio in individuals with Alzheimer’s disease (AD) are associated with poorer cognitive abilities, reduced brain glucose metabolism, and the deposition of amyloid-beta (Aβ). These findings suggest that reduced ALT levels may contribute to decreased pyruvate levels, leading to disrupted energy balance, compromised glutamate metabolism, and impaired synaptic transmission in the central nervous system. However, it’s important to note that Ferri et al. (2022) only observed lower serum ALT levels and higher AST/ALT ratios in elderly male dementia patients compared to cognitively normal individuals, with no significant differences observed in elderly females. In contrast, a study by Yokokawa et al. (2022) found a significant correlation between serum levels of brain-derived neurotrophic factor (BDNF) and liver enzymes in middle-aged and elderly females, along with a negative correlation between BDNF and liver fibrosis measured by the Fibrosis-4 (FIB-4) index. Although cognitive function was not assessed in this particular study, previous research has established a link between liver fibrosis and an increased risk of dementia (Weinstein et al., 2019; Solfrizzi et al., 2020; Jeong et al., 2022). Moreover, serum BDNF has been identified as a biomarker not only for cognitive function in elderly females (Komulainen et al., 2008) but also for the decline in cognitive abilities associated with mild cognitive impairment and dementia (Nikolac Perkovic et al., 2023). In addition, a study by Chen et al. (2020) reported that short-term exposure to bilirubin can induce AD-like brain pathology. In summary, while gender differences exist, liver enzymes play a significant role in the underlying mechanisms of dementia.

The liver, as the largest organ responsible for metabolite clearance in the bloodstream, plays a critical role in the peripheral clearance of plasma Aβ. Peripheral clearance of Aβ by the liver potentially facilitates the removal of Aβ from the brain, thus contributing to the treatment of AD (Liu et al., 2015). Impairment in liver function leading to reduced peripheral Aβ clearance is a significant factor in the accumulation of Aβ in the brain and the development of AD (Bassendine et al., 2020). A study by Cheng et al. (2023) revealed elevated plasma Aβ levels in patients with liver cirrhosis, and chronic impairment in hepatic Aβ clearance was found to increase brain Aβ deposition in APP/PS1 transgenic mice, resulting in neurodegeneration and cognitive deficits. These findings suggest that a decrease in hepatic Aβ clearance rate may be a potential factor in AD development. Additionally, Li et al. (2013) reported postoperative cognitive dysfunction in 44% of patients who underwent liver transplantation, which was associated with an increase in postoperative serum biomarkers of dementia, including Aβ, within 24 h after surgery. Moreover, NAFLD exacerbates Aβ plaque accumulation in transgenic AD mice, promoting the progression of AD (Kim et al., 2016). Furthermore, the clearance of peripheral Aβ relies on the transportation of circulating proteins such as albumin and apolipoprotein E, highlighting the significance of lipid metabolism disorders in the liver as contributing factors to Aβ accumulation and cognitive impairment (Cheng et al., 2020).

Furthermore, certain liver-derived factors have the potential to regulate cognition. For instance, Horowitz et al. (2020) reported that an elevated concentration of liver-derived glycosylphosphatidylinositol (GPI)-specific phospholipase D1 in the plasma of mice after exercise can improve hippocampal function and alleviate cognitive impairment in elderly mice. Yan et al. (2022) found that aerobic exercise increases the synthesis of liver methyl donors, leading to enhanced brain RNA N6-methyladenosine levels and exhibiting anti-anxiety effects. These research findings collectively suggest that liver-derived factors play a significant role in mild cognitive impairment associated with liver disease.