Jarred Younger’s face lit up in a recent YouTube video when he talked about a recent study long-COVID study: “Reduced Adenosine Triphosphate-to-Phosphocreatine Ratios in Neuropsychiatric Post-COVID Condition: Evidence From 31P Magnetic Resonance Spectroscopy“.
This is the first long-COVID study to actually measure energy availability in the brain. No similar ME/CFS or FM studies have been done.
The study used, for the first time in long COVID (or ME/CFS), a technique that measures energy availability in the brains of long-COVID patients.
Where did this paper come from? Not the US! No, No! It came from Germany – which has become a seedbed of innovation.
It’s potentially a big deal. The brain is easily the most energy-intensive organ in the body. Clocking in at about 2% of body weight, it consumes about 20% of the body’s total energy. Even at rest, it still consumes more energy than any other organ of the body.
Reduced brain energy production in long COVID and ME/CFS has been inferred using a variety of techniques that measure cerebral blood flows (MRI, SPECT, transcranial Doppler ultrasound), metabolites (proton magnetic resonance spectroscopy, glucose uptake (FDG-PET), and oxygen uptake (MRI; near-infrared spectroscopy; oxygen-15 PET).
The phosphorus-31 magnetic resonance spectroscopic imaging (31P—MRS) technique used doesn’t tell us how much ATP the mitochondria are producing or if the brain is consuming more ATP than normal. Its superpower is its ability to determine how much actual energy is available to the brain.
It does this by measuring the phosphorus metabolites that play a major role in energy production. ATP (adenosine triphosphate) – the premier energy producer of the cell – contains a base (adenine), a sugar (ribose), and three phosphate groups. The energy in ATP lies in the bonds between the phosphate groups. When those bonds are broken, energy is released.
The authors focused on something called the ATP/phosphocreatine ratio (ATP/PCr) to measure energy availability. When ATP is used up, it gets depleted to ADP (adenosine diphosphate). ATP is revived when phosphocreatine donates a phosphate to ADP and creates ATP (adenosine triphosphate).
ATP doesn’t efficiently move about in the cell, though. Particularly in high energy cells like the brain and the muscles, something called the creatine kinase (CK) shuttle is needed to quickly get ATP to where it’s needed.
The CK shuttle takes ATP from the mitochondria and then adds creatine to it to create phosphocreatine (PCr), which moves around the cell much more efficiently. Once phosphocreatine gets to the part of the cell that needs more ATP, the CK shuttle adds the phosphocreatine to ADP that’s floating around, and voilà, the cell has ATP. (More about the shuttle later.)
Phosphocreatine, then, is kind of the secret sauce that keeps the energy flows in the cell moving. Without it, ATP has a hard time getting from the mitochondria to where it’s needed in the cell, and things bog down.
Small Blood Vessel Focus
In their introduction, the authors focused on the very small blood vessels, or microvasculature, as they made the case for their decision to assess the energy availability in the brain.
The authors proposed that damaged small blood vessels and clotting could be causing energy deficits in the brain.
They proposed that inflammation, increased clotting (hypercoagulation), and autonomic nervous system problems were damaging the small blood vessels, causing low oxygen levels (hypoxia), and hurting the mitochondria. Plus, they noted evidence that a leaky brain barrier may be allowing pro-inflammatory cytokines into the brain.
They referenced a VanElzakker/Loggia long-COVID study which found that blood vessel dysfunction (fibrinogen, sL-selectin) was correlated with neuroinflammation. (Fibrinogen can actually trigger immune cells in the blood to enter the brain.) The study found evidence of neuroinflammation “across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles.”
In conclusion, there are many ways that the fragile but oh-so-important brain may be getting tweaked in long COVID, and in ME/CFS (which has similar findings).
Results
“We present the first direct evidence of deficient high-energy phosphate metabolism in the central nervous system of patients with PCCo (long COVID).” the authors
The sample size was not large (29 people with long COVID; 29 people who had fully recovered from COVID-19) but was larger than many brain imaging studies.
A large energy deficit was found in the cingulate cortex. Jarred Younger believes it plays a key role in these disorders.
The study found a “large, significant cluster of reduced ATP/PCr concentration…centered on the cingulate cortex” in the long-COVID patients. This indicated that this area of the brain was experiencing a significant energy deficit.
The nice high probability value (P < .001) indicated that the finding was solid; i.e., the long-COVID and the recovered COVID-19 patients had very different ratios.
The researchers dug deeper and assessed the phosphorus levels across the three different regions of the cingulate cortex and found reduced levels across all of them.
Lower ATP/PCr ratios in the anterior cingulate cortex were significantly correlated with poorer performance on a cognitive test called MOCA. That suggested that the energy deficit in the ACC may be contributing to the brain fog in long COVID.
Core Brain Region?
Jarred Younger has said that if he could affect any region in the brain in these diseases it would be the cingulate cortex. I asked him in our talk (upcoming) if he thought the cingulate cortex could be a core hub in the brain which causes dysfunctions in other areas of the brain, and he said yes. Problems with the cingulate cortex could make everything more effortful, and the anterior cingulate cortex, in particular, has popped up again and again in ME/CFS and fibromyalgia.
Reduced energy availability in the cingulate cortex was the main finding. The authors did report, though, that reduced ATP levels were found in other areas of the brain.
The Cause – Not the Mitochondria After All
The authors believe that a transport mechanism in the cell called the CK shuttle is failing to deliver energy across the cell. (Image – Richard Krieider, Jun 17, 2017.J Int Soc Sports Nutr)
The authors came up with an intriguing cause for the energy availability problems seen. Their analyses suggested that the reduced ATP/PCr ratio found in the long-COVID patients probably resulted from reduced ATP production.
The authors didn’t believe the reduced ATP production was mainly caused by the mitochondrial problems, however. (That would be too simple (lol).)
If mitochondrial ATP production was simply low, then PCR would have been low too, but PCR was increased relative to ATP. So, it appears that ATP is being produced, but it’s not making it to the part of the cell that needs it.
A low ATP/PCR reading indicated that phosphocreatine is present but is not being readily turned into ATP, and that suggests that an energy transport problem is present. (Other studies have suggested that an energy transport problem may exist with the carnitines).
They fingered the creatine kinase (CK) shuttle, which moves ATP from where it is produced (the mitochondria) to where the cell needs it, as the chief problem.
A number of things could have gone wrong. The creatine kinase enzyme may be less active, the transport system inside the cell may be impaired, the cell may not be using phosphocreatine properly, creatine may not be efficiently getting into the cells, and mitochondrial ATP production may be impaired (to some extent).
Core Physiological Factor?
We’re always searching for core problems, and the key role the CK shuttle plays in cellular energy production certainly fits that bill. Because the shuttle is present in cells across the body, it’s possible that it could be causing problems elsewhere. If it is, it might particularly show up in high-energy areas such as the brain and the muscles.
Because different forms or isoforms of the CK shuttle exist in different parts of the body, some areas might be affected while others are not.
You have to go all the way back to 1992 to find the first skeletal muscle 31P NMR study in ME/CFS, which found rapid exhaustion and reduced intracellular concentrations of ATP. In 1993, Barnes found evidence of reduced phosphocreatine utilization in about a quarter of ME/CFS patients. McCully tried three times, on the other hand, and did not find evidence of prolonged phosphocreatine recovery after exercise. A 2023 NMRS study, which did not assess phosphocreatine (i.e. energy production), nevertheless found reduced creatine levels in the same part of the brain – the anterior cingulate cortex – as the long-COVID paper.
In fibromyalgia, phosphocreatine skeletal muscle abnormalities were not found in three small 1994 studIes, or a small 2000 study, but abnormalities were found in a small 1998 study, a larger 2000 study, in the anterior cingulate of the brain in 2021, and in 2023 in a small study in the thalamus. Interestingly, in the last study, reduced blood creatine levels were associated with neuroinflammation, and the authors proposed that “Low creatinine levels may be the prime peripheral biomarker of neuroinflammation in FM patients”.
On that note, in 2019, Nacul found lower serum creatine kinase levels in people with severe ME/CFS compared to healthy controls.
A small 2014 Gulf War Illness study found it took abnormally long to replenish PCr levels in the muscles after exercise. A larger 2023 long-COVID study found slower phosphocreatine recovery after exercise in calf muscle.
The evidence for skeletal muscle phosphocreatine abnormalities in these diseases is mixed, with some studies finding them and others not. At least three studies, however, have found reduced phosphocreatine levels in the brain.
Treatment Possibilities
A small ME/CFS study suggested that creatine may help.
This study’s findings need to be validated, but an interesting and apparently safe option is creatine supplementation. Creatine, via phosphocreatine, plays a major role in getting ATP from the mitochondria to where it’s needed in the cell.
Whether creatine helps or not depends on where the problem is in the CK shuttle. If the CK shuttle lacks the creatine, it needs to operate properly, then creatine supplementation could help. If the primary problem lies elsewhere (CK enzyme problems including loss, inflammation, low oxygen levels, reduced mitochondrial ATP production), then creatine supplementation might not help.
The long-COVID study’s finding made a small Oxford 2024 ME/CFS creatine supplementation study all the more interesting. While the study did not measure ATP/PCr levels directly, it did find that creatine supplementation (16 g creatine monohydrate) increased brain creatine in cingulate/prefrontal regions and improved fatigue and some cognitive measures.
A small Japanese study also found that creatine and glucose (8 g of creatine monohydrate and 3 g of glucose per day) for 8 weeks reduced several long-COVID symptoms (including body aches, breathing problems, difficulties concentrating, headache, and general malaise).
Check out Courtney Craig’s blog on creatine supplementation in ME/CFS, long COVID, fibromyalgia, etc.
Like any supplement, creatine is probably not going to be the answer. The answer likely requires addressing fundamental factors like inflammation, blood vessel problems, and autonomic nervous system dysregulation.
It might be helpful, however.
Next Steps?
Hopefully, this study will spawn larger, more comprehensive ones. Jarred Younger is getting the tools needed to do one.
Note that Jarred Younger is getting the equipment needed to duplicate this experiment. When I talked to him, I believe he was about a month away from getting the last piece.
I asked Perplexity AI what it recommended for follow-up studies that could: a) determine if this finding is valid and, if it is; b) try to get at the cause.
(1) A larger study that separated out ME/CFS-like patients from other long-COVID patients and used the same technique but added more complete cognitive and symptom assessment to see if the findings track with brain fog, orthostatic intolerance, fatigue, PEM, etc. would be very helpful. Do exertional challenges to see if the ATP/PCr ratio worsens.
(2) Pair the brain 31P-MRS testing with similar assays of cells found in the body such as PBMCs, fibroblasts, or muscle to see if the same energy availability problems are present. Besides assessing CK activity, check out creatine transport, mitochondrial respiration, and coupling efficiency. (3) Do root-cause studies to determine whether the abnormality is driven by inflammation, persistent immune activation, microvascular dysfunction, altered pH regulation, autonomic dysregulation, or, interestingly, sleep disruption.
(4) Measure brain or systemic acid-base handling, lactate/pyruvate balance, and markers of redox stress alongside CK-related endpoints to help determine whether the problem lies in low ATP production or transport problems.
Good for Germany for opening up this intriguing area of research! Brain research is blowing up right now.
- Coming up – David Goldstein’s ME/CFS and long-COVID brain norepinephrine paper
