Ammonia‐weighted imaging by chemical exchange saturation transfer MRI at 3 T

Abstract

Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT-weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations.

Chemical exchange saturation transfer imaging in hepatic encephalopathy

“…At physiological pH levels, ammonia remains invisible to the classical CEST approach, due to its high exchange rate. Nevertheless, our recent study could demonstrate a link between ammonia concentration and APT w MTR asym protein signal (Zöllner et al, 2018).…”

“…In vitro, the contrast mechanisms were mainly driven by an induced protein denaturation through ammonia, while contrast mechanisms remained unclear in the in vivo cases (Zöllner et al, 2018). Our data describes APT w signal reductions in the cerebellum and the occipital cortex of HE patients, including correlations with blood ammonia levels and psychometric test scores.…”

“…Besides, a 3 T system does not have a high sensitivity to depict changes in either glutamate or glutamine (Lee et al, 2016), but showed sensitivity to ammonia load in protein based solutions (Zöllner et al, 2018). Hence, the underlying mechanisms in the putamen remain unclear, but are likely to be linked to HE disease severity.…”

“…Starting from APT w imaging, we adapted our saturation parameters in two ways (Zöllner et al, 2018). In in vitro experiments, the saturation parameters were selected to maximize the contrast gained from the effect of ammonia on the protein signal.…”

“…In our recent in vitro study, we were able to link increasing ammonia concentrations to a decreasing APT w CEST signal through protein denaturation (Zöllner et al, 2018). We could also apply this finding to example cases of HE patients.…”