P: 33 In Vivo Longitudinal 1H MRS Study of Hippocampal, Cereberal and Striatal Metabolic Changes in the Adult Brain Using an Animal Model of Chronic Hepatic Encephalopathy

Abstract

BACKGROUND: Chronic hepatic encephalopathy (CHE) is a severe complication of chronic liver disease (CLD) characterized by cognitive and motor deficits. The diseased liver fails to metabolize toxins from the blood (ammonium, bilirubin etc.) which accumulate in the blood and brain.1 There is evidence that ammonium uptake rate differs among the brain regions.2 Since the CHE patients present various symptoms with different severity, the susceptibility to CHE and the mechanisms causing the damage may depend on the brain region. The aim of this study was to investigate, for the first time, potential metabolic differences between hippocampus, cerebellum and striatum as key brain regions implicated in manifestation of CHE. METHODS: Hippocampus (n = 7), cerebellum (n = 8) and striatum (n = 4) of adult male Wistar rats were scanned longitudinally using in-vivo 1H-MRS (SPECIAL sequence-TE = 2.8 ms,3 quantification with LCModel) at 9.4T before (week 0) and after bile duct ligation (BDL-CHE model4). Scans and blood tests were performed every two-weeks till week 8. RESULTS: All BDL rats showed an increase in plasma bilirubin and blood ammonia validating the presence of CLD. Increase in brain Glutamine (Gln) was observed for all brain regions being the most pronounced in cerebellum (+134%-week 8) (Figure 1c). Furthermore, this increase showed a strong correlation with blood ammonia for all three brain regions (Figure 1b). The main brain organic osmolytes (Inositol, Taurine, Creatine and total-Choline) displayed a similar decreasing trend in concentration as a response to Gln increase (osmoregulation) for both hippocampus and cerebellum, always having a stronger change for cerebellum. Interestingly, despite the smallest Gln increase, striatum showed more pronounced decrease in concentration of osmolytes than hippocampus (Figure 1d,e). Also, trend towards a decrease in NAA and PE was observed uniquely for striatum (data not shown). A tendency of increase in Lactate was observed being the strongest for cerebellum (+84%-cerebellum, +8%-hippocampus, +5%-striatum) indicating a possible energy metabolism perturbation (Figure 1f). Brain regions displayed different antioxidant response with a decrease in Ascorbate being stronger in cerebellum (data not shown). CONCLUSIONS: This is the first study showing in-vivo longitudinal analysis of neurometabolism in three different brain regions in a model of CHE. Hippocampus and cerebellum displayed similar trends in metabolite changes during the course of disease, while the changes were much more pronounced in cerebellum. Striatum showed differences in metabolic response when compared to the other brain regions. Clinical relevance of these findings remain to be determined. We conclude that different brain regions are differentially susceptible to the metabolic consequences of CLD, a field which warrants further study.