Reduced Adenosine Triphosphate-to-Phosphocreatine Ratios in Neuropsychiatric Post-COVID Condition: Evidence From 31P Magnetic Resonance Spectroscopy.
Weber-Fahr, Wolfgang, Dommke, Sandra, Sack, Markus et al. · Biological psychiatry · 2026 · DOI
Quick Summary
This study looked at how the brain produces and uses energy in people with long COVID and cognitive problems. Using a special brain imaging scan, researchers found that people with long COVID have lower energy levels in a part of their brain called the cingulate cortex, and this energy shortage is linked to thinking and memory problems. The findings suggest that problems with how brain cells produce energy may be a key reason why some people experience cognitive difficulties after COVID-19.
Why It Matters
This is the first direct neuroimaging evidence demonstrating impaired brain energy metabolism in post-COVID condition, providing biological support for mitochondrial dysfunction as a central pathophysiological mechanism. Since energy metabolism dysfunction is also hypothesized in ME/CFS, these findings may help explain cognitive symptoms in both conditions and could guide development of targeted therapies aimed at improving cellular energy production.
Observed Findings
Patients with post-COVID condition showed significantly reduced ATP/phosphocreatine ratios in a brain region cluster centered on the cingulate cortex compared to controls.
Lower ATP/PCr ratios specifically in the anterior cingulate cortex correlated with worse performance on cognitive tests (Montreal Cognitive Assessment and Trail Making Test Part B).
Patients showed a trend toward higher intracellular pH in the midcingulate cortex, with a disease-specific negative correlation between pH and ATP/PCr ratios.
Subgroup analysis of patients meeting ME/CFS criteria showed similar patterns of reduced brain energy metabolism.
Inferred Conclusions
Impaired brain energy metabolism, particularly in the anterior cingulate cortex, is a key biological feature of post-COVID condition and directly contributes to cognitive impairment.
Disrupted cellular pH regulation coupled with reduced ATP availability suggests broader dysfunction in bioenergetic homeostasis specific to the post-COVID disease state.
Mitochondrial dysfunction in brain cells is a probable central mechanism underlying neuropsychiatric symptoms in post-COVID condition.
Remaining Questions
Does the reduced brain ATP cause cognitive symptoms, or is it a consequence of cognitive dysfunction—does causality flow in one direction or both?
What specific triggers or mechanisms lead to mitochondrial dysfunction and impaired brain energy metabolism after SARS-CoV-2 infection?
What This Study Does Not Prove
This study does not prove that mitochondrial dysfunction is the sole cause of cognitive symptoms in long COVID—it demonstrates an association between reduced brain ATP levels and cognitive impairment. The cross-sectional design cannot establish whether energy metabolism changes cause cognitive problems or result from them. Additionally, findings in long COVID may not directly translate to ME/CFS without specific studies in ME/CFS populations, though preliminary subgroup analysis suggests similar patterns.
Could therapies targeting mitochondrial function or cellular energy production improve cognitive symptoms in post-COVID condition, and if so, what would be the most effective approaches?
How do the observed metabolic abnormalities in long COVID brain tissue compare quantitatively and qualitatively to those documented in primary ME/CFS patients?