Chemical exchange saturation transfer imaging in hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) is a common complication in liver cirrhosis and associated with an invasion of ammonia into the brain through the blood-brain barrier. Resulting higher ammonia concentrations in the brain are suggested to lead to a dose-dependent gradual increase of HE severity and an associated impairment of brain function. Amide proton transfer-weighted (APT_w) chemical exchange saturation transfer (CEST) imaging has been found to be sensitive to ammonia concentration. The aim of this work was to study APT_w CEST imaging in patients with HE and to investigate the relationship between disease severity, critical flicker frequency (CFF), psychometric test scores, blood ammonia, and APT_w signals in different brain regions. Whole-brain APT_w CEST images were acquired in 34 participants (14 controls, 20 patients (10 minimal HE, 10 manifest HE)) on a 3 T clinical MRI system accompanied by T₁ mapping and structural images. T₁ normalized magnetization transfer ratio asymmetry analysis was performed around 3 ppm after B₀ and B₁ correction to create APT_w images. All APT_w images were spatially normalized into a cohort space to allow direct comparison. APT_w images in 6 brain regions (cerebellum, occipital cortex, putamen, thalamus, caudate, white matter) were tested for group differences as well as the link to CFF, psychometric test scores, and blood ammonia. A decrease in APT_w intensities was found in the cerebellum and the occipital cortex of manifest HE patients. In addition, APT_w intensities in the cerebellum correlated positively with several psychometric scores, such as the fine motor performance scores MLS1 for hand steadiness / tremor (r = 0.466; p = .044) and WRT2 for motor reaction time (r = 0.523; p = .022). Moreover, a negative correlation between APT_w intensities and blood ammonia was found for the cerebellum (r = -0.615; p = .007) and the occipital cortex (r = -0.478; p = .045). An increase of APT_w intensities was observed in the putamen of patients with minimal HE and correlated negatively with the CFF (r = -0.423; p = .013). Our findings demonstrate that HE is associated with regional differential alterations in APT_w signals. These variations are most likely a consequence of hyperammonemia or hepatocerebral degeneration processes, and develop in parallel with disease severity.

Keywords: Amide proton; Ammonia; CEST; CFF; Critical flicker frequency; Liver cirrhosis.

Graphical abstract

Fig. 1

Mean group atlases of APT_w MTR_asym in healthy controls and HE patients. The rows depict three representative slices including the six selected regions of interests (ROI) (Red: Cerebellum; Yellow: Occipital cortex; Cyan: Putamen; Magenta: Thalamus; Green: Caudate; Blue: White matter). The template of the current study population is depicted in the first column. ROI are illustrated in the second column. The last three columns display the mean atlases of the APT_w imaging of each group (control, minimal HE (mHE), manifest HE (HE)). The signal reduction could either be linked to increased ammonia accumulation or hepatocerebral degeneration.

Fig. 2

APT_w imaging of the cerebellum in healthy controls and HE patients (minimal HE (mHE), manifest HE (HE)). (a) Group boxplots including mean APT_w^T1 MTR_asym values. Asterisks indicate significant differences between groups (p < .05). Correlations between blood ammonia levels (b), psychometric MLS1 score (hand steadiness/tremor) (c), psychometric WRT2 score (motor reaction time) (d), and mean APT_w^T1 MTR_asym. The data suggests a strong cerebellar involvement in HE explaining poor motor performance of HE patients, which could possibly be linked to ammonia accumulation or hepatocerebral degeneration.

Fig. 3

APT_w imaging of the occipital cortex in healthy controls and HE patients (minimal HE (mHE), manifest HE (HE)). (a) Group boxplots including mean APT_w^T1 MTR_asym values. Asterisks indicate significant differences between groups (p < .05). Correlations between blood ammonia levels (b), psychometric MLS2 score (arm/hand precision) (c), psychometric LVT1 score (time per item) (d), and mean APT_w^T1 MTR_asym values. This might explain alterations in visual perception of HE patients with increasing diseases severity due to ammonia accumulation.

Fig. 4

APT_w imaging of the putamen in healthy controls and HE patients (minimal HE (mHE), manifest HE (HE)). (a) Group boxplots including mean APT_w^T1 MTR_asym. Asterisks indicate significant differences between groups (p < .05). (b) Correlation between critical flicker frequency (CFF) and mean APT_w^T1 MTR_asym values. The data suggests the domination of other contrast mechanisms, such as metabolite concertation changes.