Reduced ATP-to-phosphocreatine Ratios in PCS

Prof. Dr. Gabriele Ende talked about phosphorus magnetic resonance spectroscopy (MRS) to investigate in vivo cellular energy metabolism in the brain of post-COVID patients by means of quantifying the ATP-to-phosphocreatine ratios. Phosphorus MRS provides access to intracellular pH estimates, which are tightly coupled to mitochondrial proton gradients and adenosine triphosphate (ATP) production. Subtle shifts in intracellular pH may therefore serve as an additional marker of altered bioenergetic homeostasis in post COVID syndrome. The primary aim of her study was the in vivo investigation of changes in the cerebral energy metabolism in post-COVID syndrome patients, compared to recovered controls using phosphorus MRS. Using a 3D method, the investigation covered the whole brain. The group also investigated the association of cerebral energy metabolism with measures of cognitive performance and disease severity. Additionally, they explored potential alterations in intracellular pH regulation as an additional indicator of disrupted mitochondrial function. The group analysed 27 post-COVID patients four to 45 months post-acute illness and compare them with 23 age-matched recovered controls. Their analytical scheme run similar to that of functional magnetic resonance imaging (fMRI) analysis, including normalisation and smoothing. The results revealed clusters with reduced ATP to phosphocreatine ratios in patients. Since ATP plays a crucial role in the transfer and storage of energy in the cells, reduced neural ATP levels can have a significant impact on various cellular functions and the general health of the brain. In a healthy brain, and also in a healthy muscle, there is a dynamic balance between ATP production and consumption, and the relatively constant ATP pool is maintained to support its complex functions. Disruption in any of these regulatory mechanisms can lead to an energy imbalance and affect cellular health and neurological function. This was found to be the case in the investigated patients as there were significant correlations between cognitive assessment scores and imaging results. Noteworthy, there were no significant differences between post-COVID patients meeting Canadian Consensus Criteria (CCC) and those not meeting CCC. In conclusion, the group found robust evidence for impaired cellular energy metabolism in the brains of patients with post-COVID syndrome, in the form of significantly reduced ATP-to-phosphocreatine ratios. This may be the first direct evidence of deficient high energy phosphate metabolism in the central nervous system of post-COVID syndrome patients. These metabolite alterations correlate with cognitive impairment and likely reflect limitation of energy buffering or intercellular energy transfer, potentially, together with mitochondrial dysfunction. The overall findings contribute to a growing body of evidence suggesting that cellular bioenergetics failure may be a key pathophysiological mechanism in post-COVID syndrome, potentially explaining many of the persistent symptoms experienced by patients.

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