Reduced Adenosine Triphosphate-to-Phosphocreatine Ratios in Neuropsychiatric Post-COVID Condition: Evidence From 31P Magnetic Resonance Spectroscopy.

BACKGROUND

Post-COVID condition (PCCo) affects 5% to 10% of individuals following SARS-CoV-2 infection, with cognitive disturbances being a major feature. Central hypotheses regarding its pathophysiology include disturbed cell energy metabolism and oxidative stress pointing to mitochondrial dysfunction. However, brain energy metabolism remains unexplored.

METHODS

We investigated cerebral high-energy phosphate metabolism in 27 patients with PCCo and 23 fully recovered control participants using whole-brain 31P-magnetic resonance spectroscopic imaging at 3T. Adenosine triphosphate/phosphocreatine (ATP/PCr) ratios were quantified throughout the brain and analyzed with voxel-based and regional statistics including correlations with neuropsychological performance (Montreal Cognitive Assessment and Trail Making Test Part B). Statistical analysis used voxelwise comparisons with age as covariate, followed by region-of-interest analysis of cingulate cortex subdivisions.

RESULTS

Patients with PCCo showed a significant cluster of reduced ATP/PCr ratios centered on the cingulate cortex. Regional analysis revealed consistent reductions across the anterior cingulate cortex (ACC), midcingulate cortex (MCC), and posterior cingulate cortex. Lower ATP/PCr ratios in the ACC specifically correlated with poorer cognitive performance. Exploratory analyses revealed a trend toward higher intracellular pH in the MCC, with significant negative correlation between pH and ATP/PCr observed only in patients, suggesting disease-specific alterations in pH regulation and bioenergetic homeostasis. Subgroup analysis showed similar metabolic alterations in patients with PCCo who met criteria for myalgic encephalomyelitis/chronic fatigue syndrome.

CONCLUSIONS

Our study provides the first in vivo evidence of impaired brain energy metabolism in PCCo, with anterior cingulate dysfunction directly linked to cognitive impairment. The observed pH-ATP/PCr relationship suggests broader disruption of cellular bioenergetic regulation. These findings support mitochondrial dysfunction as a key pathophysiological mechanism and may inform targeted therapeutic strategies.