Non-invasive visualisation of long-lasting brain metabolic alterations in murine pseudo-infection model using parahydrogen-polarised [1-13C] pyruvate MRI

Abstract

Long-lasting neurological issues, including cognitive impairment, anxiety, and depression, that persist after recovery from acute inflammatory diseases, such as infections, have become a significant social problem, particularly following the coronavirus disease 2019 pandemic. Various diagnostic techniques and biomarkers have been explored to objectively evaluate brain symptoms associated with infection–induced local or systemic inflammatory responses (i.e. immune fatigue); however, their detection capabilities remain limited. Here we investigated whether magnetic resonance imaging (MRI) combined with a quantum-sensed molecule, parahydrogen-polarised [1-¹³C] pyruvate, could detect persistent brain metabolic alterations in a murine pseudo-infection model induced by polyinosinic–polycytidylic acid (Poly(I: C)), a Toll-like receptor 3 ligand. Significant alterations in brain pyruvate metabolism favouring glycolysis were observed in both the acute and late phases of the pseudo-infection model, with a 12.7% and 2.5% decrease in bicarbonate flux, and a 58.4% and 32.2% increase in lactate flux on day 3 and week 2, respectively. These brain metabolic changes were accompanied by diminished dopamine signal markers in the striatum and nigra/ventral tegmental areas and reduced spontaneous nocturnal locomotor activity. A biochemical analysis of energy metabolic markers consistently supported the reprogramming of brain glucose metabolism, showing the suppression of oxidative phosphorylation during the acute phase and promotion of glycolysis during the late phase of Poly(I: C) treatment. Hyperpolarised ¹³C MRI of pyruvate metabolism is a promising non-invasive imaging biomarker for brain issues during the late phase of systemic infections and other neurodegenerative and psychiatric diseases, particularly in conditions lacking discernible morphological abnormalities.