Baseline cerebral metabolism predicts fatigue and cognition in Multiple Sclerosis patients

Background: Cerebral metabolic rate of oxygen (CMRO₂), a measure of global oxygen metabolism, reflects resting cellular activity. The mechanisms underlying fatigue and cognitive dysfunction in multiple sclerosis (MS) remain unknown. If fatigue indeed reflects ongoing autoimmune activity and cortical reorganization, and cognitive decline is the result of gray matter atrophy and white matter degeneration, we postulate that changes in CMRO₂ should reflect disease activity and predict these symptoms. Objective: We sought to utilize T₂-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI to measure global CMRO₂ to understand its relationships to white matter microstructure, fatigue and cognitive dysfunction. Methods: We measured venous oxygenation (TRUST) and cerebral blood flow (PC-MRI) in superior sagittal sinus to calculate global CMRO₂ and diffusion tensor imaging (DTI) to evaluate white matter microstructure in healthy controls (HC) and MS patients. Participants underwent neuropsychological examinations including Modified Fatigue Impact Scale (MFIS) and Symbol-Digit-Modalities Test (SDMT). Results: We observed lower CMRO₂ in MS patients compared to HC. After controlling for demographic and disease characteristics (i.e., age, education, disability, lesion volume), CMRO₂ predicted increased fatigue (MFIS) and reduced cognitive performance (SDMT) in MS patients. Finally, MS patients with higher CMRO₂ have reduced FA in normal-appearing white-matter. Conclusion: Altogether, these results suggest that increased CMRO₂ reflects ongoing demyelination and autoimmune activity which plays an important role in both fatigue and cognitive dysfunction.