| Summary: | 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.
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