Differential metabolic and cellular brain regional susceptibility in adult rats with chronic liver disease

Patients with type C hepatic encephalopathy (HE) present diverse symptoms, indicating disease-associated effects in multiple brain regions. While identifying the distinct metabolic and cellular changes in these regions could help explain the clinical variability of HE, this remains challenging. By leveraging the non-invasive capabilities of in-vivo ¹H-MR Spectroscopy (9.4T) and complementary ex-vivo histological assessments, we analyzed, longitudinal neurometabolic and morphological changes in the hippocampus, striatum, and cerebellum during the progression of chronic liver disease, induced type C HE in the bile duct ligated rat model (n = 41). We showed that while brain regions share common metabolic and cellular responses such as acute glutamine increase, glial activation, and neuronal alterations, they also display unique characteristics. The most striking difference was in the cerebellum, where the highest glutamine load (+ 134%) was associated with elevated lactate and reduced Purkinje soma surface, while the striatum showed the strongest osmolyte decrease despite having the lowest glutamine increase among the studied regions. Based on the early rise of glutamine across regions, we highlight glutamine as one of the molecular drivers of a cascade of metabolic and cellular abnormalities, together with ¹H-MRS as a valuable modality to investigate region-specific brain alterations in HE both in animal models and humans.