Multimodal NIRS-MRI reveals cortical hypoperfusion, hypoxia, and mitochondrial changes in a mouse model of autoimmune...

Abnormal oxidative metabolism and tissue hypoxia could exacerbate multiple sclerosis. Research in both animal models and people with multiple sclerosis shows increased inflammation, reduced cerebral blood flow, damage to mitochondria, and loss of myelin. Understanding such abnormalities is crucial for developing effective treatments. In this study, we apply a multimodal imaging approach-combining near-infrared spectroscopy (NIRS) with 9.4T MRI-to investigate the cortical gray matter of the experimental autoimmune encephalomyelitis (EAE) mouse model of autoimmune inflammatory diseases. Female C57BL/6J mice (n = 42) were used. EAE mice (n = 13) were induced using MOG_35-55 peptide emulsified in complete Freund's adjuvant (CFA) and pertussis toxin (PTX). Control groups were naïve (n = 15, no interventions), and CFA/PTX mice (n = 14, given CFA and PTX injections). We used NIRS-MRI to simultaneously monitor cerebral oxygenation, mitochondrial function (cytochrome c oxidase content and oxidation state), cerebral blood flow, and metabolic rate for oxygen consumption in the mice cortex at approximately peak disease. Both CFA/PTX and EAE groups showed reduced perfusion and tissue oxygenation (hypoxia), while the metabolic rate of oxygen did not change. The concentration of cytochrome c oxidase was lower with a higher oxidation state in EAE mice than naïve and CFA/PTX groups. Histology showed cortical gray matter microgliosis, but no obvious neuronal death or demyelination in EAE at peak disease. As reduced blood flow, hypoxia, and high oxidation state were observed in both CFA/PTX and EAE, it is possible that inflammation is causing these changes. Mitochondrial dysfunction appears in EAE mice, but increased oxygen extraction fraction and oxidation of cytochrome c oxidase compensate, allowing no change in the metabolic rate of oxygen consumption. Inflammation, damaged mitochondria, hypoxia, and inefficient energy production could exacerbate gray matter pathology in multiple sclerosis. By revealing cortical disruptions in oxygen delivery and consumption, the multimodal NIRS-MRI approach provides a powerful imaging tool for identifying potential biomarkers of disease physiology and progression.