Interesting Rich. We just need more money don't we? I believe the original paper suggested increased rates of oxidative stress which I would think fits into the GSH depletion scenario. I don't know if the possibly increased lactic acid levels in the brain found by the CFIDS Association researcher have anything to do with this? Anyone know?
Eric can those microvascular tears be picked up by brain imaging?
Sunny, I wish you were in that study! I'm trying to get into touch with the Georgetown CFS team again. I'll send along your email.
Yes, money is a big help, if it is spent wisely. Unfortunately, it seems to me that too often the money that is allocated for CFS is not spent on hypothesis-driven research. As a result, it is spent measuring backwater or downstream phenomena that have nothing to do with identifying the root issues or figuring out how to treat them. Conference after conference, people report on measuring something they like to measure a little better than they did the last time, but it still is no more useful in shedding real light on the causes of CFS than it was the first time they measured it. It's just that these are "safe" things to measure. They know they will be able to get some numbers to report so that they can publish another paper and thus have a basis to get their grant renewed for the next year. The root issues in CFS are in the basic metabolism, not in the immune system, or the endocrine system, or the neurological system. These systems are downstream victims of the problems in the basic metabolism. The basic metabolism is not considered a "sexy" topic for research these days. It's already in the textbooks. But that's where CFS starts, and that's where we need to look. I probably sound like a sycophant, but I have been trying to draw the attention of the CFS "power structure" to this for a very long time, without much success.
Yes, glutathione depletion in the brain will result in oxidative stress there, and by putting a partial block in the Krebs cycle in the mitochondria, it will also raise lactic acid. There are also several other things observed in the brain in CFS that this hypothesis will explain:
One is the slow processing speed, which is the best-documented brain-related phenomenon in CFS. The speed of transport of nerve impulses in the axons of the neurons depends on having good myelin around them. At least three components of myelin require methylation for their synthesis, at least partially: myelin basic protein, phosphatidylcholine, and some plasmalogens. Put a partial block in the methylation cycle and you will not be able to keep the myelin maintained in good condition.
Another is the excitotoxicity that produces anxiety, hypersensitivity and insomnia, and probably also brain fog. Glutathione depletion will place a partial block in the Krebs cycle, lowering the rate of production of ATP. ATP is needed to power the membrane ion pumps, and they are what maintain the electrical potential across the cell membrane of the neurons, which in turn establishes the threshold for firing nerve impulses. When the membrane potential drops, it is easier to trigger these impulses, and the result is excitotoxicity. Piling onto this is depletion of taurine and intracellular magnesium, which are also consequences of glutathione depletion and the methylation cycle block. Furthermore, the draining of folates from the cells, which is a consequence of the methylation cycle block, removes molecules that normally bind glutamate, thus raising the glutamate to GABA ratio, which also contributes to excitotoxicity.
Another is the loss of methylation from the dopamine D4 receptors, which affects the ability to focus and maintain attention. This is based on the work of Prof. Deth and his group.
Another is the loss of choline to make acetylcholine, a neurotransmitter that is important in the brain for memory. Methylation is necessary to make phosphatidylcholine from phosphatidylethanolamine, and acetylcholine is derived at least in part from phosphatidylcholine. There have been magnetic resonance spectroscopy studies that have concluded that choline is high rather than low in the brain in CFS. However, I believe that this was based on a wrong assumption, i.e. they saw an increase in the ratio of choline to creatine, and assumed that creatine was the same as in healthy normals, so choline must be higher. However, creatine also requires methylation for its synthesis, so it was actually decreased as well, and moreso than choline, so that the ratio of choline to creatine went up, but both were actually lower in absolute terms. The same thing happens in urine testing with creatinine. It is customary to ratio everything else to creatinine to compensate for different dilutions of the urine by water, the assumption being that the creatinine level depends only on the lean muscle mass, and doesn't change in CFS. However, creatinine is the breakdown product of creatine, which requires methylation for its synthesis. So this again is basing conclusions on shifting sands.
Low creatine in the brain will affect the energetics there, too, because creatine is an energy storage and tranport molecule, interacting intimately with ATP. This may account for the "mental fatigue" people report.
Oxidative stress due to glutathione depletion likely damages the blood-brain barrier, allowing toxins into the brain that would ordinarily be excluded.
I suspect that there are quite a few more. The brain and the gut in CFS have the most things wrong with them, it seems, of all the organs. Unfortunately a lot of problems converge on these two organs, and they all start at the methylation cycle block, which is coupled to glutathione depletion and draining of folates from the cells. I think that everything in CFS at its root can be tied to that combination by very specific and detailed biochemical mechanisms. XMRV may turn out to be a significant factor, but I suspect that the response of the immune system to it is going to be influenced by glutathione depletion, the methylation cycle block, and the draining of the folate metabolites, because all of these impact the immune system.