Non-invasive identification of brain signatures of acute liver injury.

Abstract

In many disorders, metabolic and inflammatory derangements that originate in peripheral organs have a deleterious impact on the brain. Brain functional impairment, defined asis one of the main diagnostic criteria for acute liver failure (ALF), a severe complication of acute liver injury (ALI). While brain inflammation (neuroinflammation) and metabolic alterations significantly contribute to hepatic encephalopathy, their non-invasive evaluation remains challenging.To address this limitation, we utilized dual radiotracer [F]-fluoro-2-deoxy-2-D-glucose ([F]FDG) and [C]-peripheral benzodiazepine receptor ([C]PBR28) microPET imaging followed by conjunction analysis and metabolic connectivity mapping. We applied this advanced methodology in mice with high dose acetaminophen (N-acetyl-p-aminophenol, APAP)-induced ALI, which can progress into ALF.We observed hepatocellular damage, liver and systemic inflammation, and increased density of hippocampal microglia in mice with ALI. MicroPET imaging analysis characterized the presence of brain region-specific neuroinflammation and altered brain energy metabolism in mice with ALI. We also identified both gains and losses in connectivity, as well as a dual role of neuroinflammation. These results revealed brain "neuroinflammetabolic" signatures of ALI.These findings provide a platform for non-invasively diagnosing early signs of hepatic encephalopathy with the goal of informing timely diagnoses and targeted therapies. Our approach can be further utilized in non-invasive brain assessments in liver diseases and other disorders classically characterized by peripheral immune and metabolic dysregulation.