In Vivo Investigation on Mitochondrial Dysfunction in Post-COVID Fatigue and Cancer Fatigue.

The clinical manifestations of post-COVID fatigue are comparable with chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) whose clinical features comprise substantial decrease in function persisting for more than 6 months, post-exertional malaise, unrefreshing sleep, cognitive impairment or orthostatic intolerance (Blomberg, 2021; Logue, 2021). From the clinical perspective, there is high plausibility of abnormalities of energy production or mitochondrial function as the etiology of CFS/ME (Tomas, 2017; Filler, 2014). The similar clinical features were observed in other infections such as EBV, Ebola, lime disease, etc., which led to coining a terminology, post-infectious syndrome. Considering the recent study showing SARS-CoV-2 reduces mitochondrial proteins uniquely, known as Complex One, to quiet the cell's metabolic output (Miller, 2021), the etiological relevance of post-COVID fatigue and CFS/ME should be scrutinized. By the way, fatigue is prevalent in cancer survivors even after achieving the complete remission, which is described as "paralyzing" and ensues physical or mental exhaustion that may not reversed by taking rest or sleep. This cancer related fatigue may compound the effect of chemo brain or chemo fog which denotes cancer-related cognitive dysfunction lingering for months or years after cancer treatment. As such, there are many analogous clinical features shared by post-COVID fatigue and cancer fatigue. The comparison of the metabolic changes between post-COVID fatigue and cancer fatigue may provide hints to understand the mechanism of fatigue better.

It has been challenging technically to verify the role of mitochondria in CFS/ME. A commercially available test, e mitochondrial energy score protocol, failed to show the reliability and reproducibility required of a diagnostic test (Thomas, 2019), which implies the practical limitations of in vitro test to evaluate mitochondrial function given the intrinsic and extrinsic factors affecting the test result of target metabolites. That said, proton Magnetic Resonance spectroscopy (MRS) can be a useful tool which detects the major brain metabolites such as N-acetylaspartate (NAA), creatinine (Cr), myo-inositol (MI) and lactate (Kantarci, 2003). The MRS spectra including abnormal positive lactate peaks correlate well with other clinical markers in mitochondriopathies (Lin, 2003). The level of organic acid (including 3-methylglutacoric acid) in urine is associated with compromised mitochondrial energy metabolism (Ikon N, 2016), which will be used as an adjunct index.

To date, little is understood regarding post-COVID fatigue or cancer fatigue though it is known to affect a large proportion of patients (10-70% depending on the population). This study aims to investigate potential mitochondrial function and metabolic changes in brain to provide further information regarding the etiology of these changes leading to fatigue.

This study aims:

1. to determine whether there are changes in the NAA/MI indicating perturbed bioenergetic role in neuronal mitochondrial function in post-COVID fatigue and 2) to prove changes of cerebral blood flow (CBF) assessed by 3D Arterial Spin Labelling (ASL) sequence for brain in post-COVID fatigue.