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ME/CFS: A disease at war with itself
We can all agree that ME/CFS is a nasty disease, particularly in its severe form, but there are abundant nasty diseases in the world. What is unique and particularly confounding about our disease is that so much controversy surrounds it, and not only surrounds it, but invades it too.
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Article: Proteins on the Brain': A Breakthrough for ME/CFS?

Discussion in 'Phoenix Rising Articles' started by Phoenix Rising Team, Apr 2, 2010.

  1. Phoenix Rising Team

    Phoenix Rising Team

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  2. gracenote

    gracenote All shall be well . . .

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    This is fascinating. Thank you Cort.
  3. Cort

    Cort Phoenix Rising Founder

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    For me this is just another very, very interesting area of work in ME/CFS. We don't have a lot of researchers working for us, but by God, we've got some really good ones probing some really intriguing areas. I love the connections between the blood vessels and the autonomic nervous system; basically anything focused on the autonomic nervous system is a big hit with me.

    The only problem with the studies is that they take soooo looong. This study is due to end in 2011. I don't think they ever thought it would take this long. I think its entirely due to the fact that they've had a lot of trouble getting healthy controls do the spinal tap. When I was there they told me that they'd had CFS patients flying across the country on their own dime to take part in the study but they were getting almost no healthy controls on board. They wanted to do 75 and I heard several months ago this was still a big big problem for them.
  4. gracenote

    gracenote All shall be well . . .

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    I wonder if there is a way to entice healthy controls.

    Offer to give them a Phoenix Rising Hero Award.
    Make a YouTube video about them and give them their 15 minutes of fame.
    Promise that 50 ME/CFS patients will send them thank you cards. ​

    There's got to be something we can do to persuade more healthy controls to volunteer.
  5. Countrygirl

    Countrygirl Senior Member

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    Thank you Cort for this. I found it very interesting and look forward to learning more. It makes sense, but what triggers this problem? Are there any theories?

    Thanks for your very valued hard work. It is greatly appreciated.

    Warmest wishes,
    C.G.
  6. shrewsbury

    shrewsbury member

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    maybe we could - grant membership to Dr Yes's church?

    maybe we could tap the S&M market. Wonder if there's a hospital fetish group?

    maybe........... I should stop now!
  7. Cort

    Cort Phoenix Rising Founder

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    No please do go on IslandFinn...I'd like to see where this ends up. :cool::cool:
  8. SunnyGal

    SunnyGal Senior Member

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    Fascinating stuff, Cort. Thanks for posting. I need to read it a few more times to really understand it. :Retro smile:

    On a somewhat related note, it was in the news recently of a link between Alzheimer's and Down syndrome. People with Down syndrome all get Alzheimer's at a much younger age than the typical population. The new thing they discovered is that some brain cells of patients with Alzheimer's have three copies of the 21st chromosome (known as trisomy 21 or T21) in them. People with Down syndrome have T21 in all their cells, including brain cells, of course.

    Well, interestingly, it's the 21st chromosome that contains the beta amyloid gene. So, with 3 copies of the 21st chromosome (T21) you produce more beta amyloid.

    Here's the article:

    http://www.scienceblog.com/cms/stud...isease-down-syndrome-and-atherosclerosis.html

    My doctor recently had me take Buluoke, a special form of lumbrokinase, and I had a severe reaction to the first capsule (rage, depression, very suicidal, and seizures). My doctor said this meant I had a lot of plaque build up in my brain. So, a lot of amyloid protein, and I wonder if that means I have some brain cells with 3 copies of the 21st chromosome (T21)? And is that part of the cognitive issues in CFS?

    Sunny
  9. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    > several proteins suggesting small amounts of bleeding in the brain could be caused by the aggregation of proteins (amyloids) in the blood vessesl

    That kind of thing has been found in neuropsychiatric lupus, on autopsy - not amyloids necessarily, but micro-infarcts. For example:

    "Multifocal cerebral cortical microinfarcts, associated with microvascular injury, were documented in 4 patients and in our study constituted the predominant histopathologic abnormality attributable to SLE. Changes of a healed vasculitis in medium sized leptomeningeal vessels were seen in 1 case."

    The same things are sometimes found in lupus patients not meeting the clinical definition of neuropsych lupus.
  10. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    No controls? Money talks. I wonder if the review board sets a max compensation -- I think they tend to feel guiltier about people volunteering for dough than for honor, sometimes. Or maybe the group's grant is just limited.
  11. richvank

    richvank Senior Member

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    Hi, Countrygirl.

    My hypothesis to explain Dr. Baranuik's observations is that number 1 in his list of possibilities is correct, i.e., the proteins are not properly folded when they are initially synthesized.

    Folding proteins into their proper tertiary structure depends to a large degree on formation of disulfide bonds between the appropriate partner cysteine residues in the amino acid chain of the protein. This in turn depends on preventing formation of disulfide bonds until the proper stage of the synthesis of the protein molecule in the endoplasmic reticulum of the cell. This in turn depends on having a high enough concentration of glutathione in the cytoplasm of the cell that is making the protein, and also a high enough ratio of reduced to oxidized glutathione. So in my hypothesis, this faulty synthesis of proteins is one more consequence of glutathione depletion, which in turn is maintained in a vicious circle involving a partial block in the methylation cycle, and this stable vicious circle is what makes CFS chronic.

    I suggested this hypothesis to Dr. Baranuik several years ago at an AACFS conference, after he first found misfolded proteins in the spinal fluid in CFS and GWS patients. He said he would consider it. But then he lost his NIH funding for a few years, and I don't know if he ever looked into it.

    As you may know, not long ago there was a magnetic resonance spectroscopy paper in CFS published by Puri et al., which did not find depletion of glutathione in the brain. However, in the study that was reported, the standard deviation of the data was larger than the mean, so the results were not conclusive. Prof. Puri agreed with me that the study lacked sufficient statistical power to determine whether glutathione is depleted in the brain in CFS or not. I was surprised that this paper was published, because it really was not able to reach any conclusion one way or the other.

    I'm hopeful that future MRS research will be more definitive in this regard. It's not easy to measure glutathione in the brain with this method, because there is a larger peak that obscures the glutathione peak in the spectrum that is measured.

    I also want to say thank you to Cort for doing this interview and writing this report for us.

    Rich
  12. Cort

    Cort Phoenix Rising Founder

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    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.
  13. richvank

    richvank Senior Member

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    Hi, Cort.

    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.

    Best regards,

    Rich
  14. Eric Johnson from I&I

    Eric Johnson from I&I Senior Member

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    > Eric can those microvascular tears be picked up by brain imaging?

    In lupus? I'm fairly sure that they cannot be.
  15. Wayne

    Wayne Senior Member

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    Great article Cort. Also, great comments Rich. So much information packed together in one place.

    Helps give perspective for those of us with ME/CFS. Also, if a person were just starting to learn about ME/CFS, this article alone, along with Rich's comments, would give them a great introduction.

    Wayne
  16. Cort

    Cort Phoenix Rising Founder

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    I agree. I can't believe how many frigging papers on cortisol I've seen!

    I was just talking about this with someone -about problems breathing and tight diaphragm, etc. being due to reduced nerve transmission to that area. Its so interesting how uncoordinated I seem to get after too much 'exercise'. This is from a paper I did a few years ago; it describes studies that have suggested reduced rates of nerve transmission to the muscles during exercise - exciting stuff - yet those studies were never replicated as far as I know. They were successful but were never followed up on..... Amazing

    http://www.aboutmecfs.org/Rsrch/CentralFatigueCFS.aspx

    I love this explanation

  17. InvertedTree

    InvertedTree Senior Member

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    Wow-this is exciting news! This isn't a popular opinion right now but I think this makes more sense to me than XMRV does in terms of explaining my own particular set of symptoms.

    I wonder if stem cell therapy is a viable option for treatment given this hypothesis?

    This was fascinating. Thanks for another great write up!
  18. pth11246

    pth11246 Guest

    what is so new about this spinal tapping study??

    this spinal tapping story has been around for 20 more year
    and we found that all !! of cfs/me had high pressure of spinal fluids
    that was the reason why we used the diamox for the foggy head ,headache in cfs/me patients

    also I have presented in many cfs/me conferences about inflammation of microvascular system
    in the brain and spinal cord, that was main reason the IVIG is the only reasonable treatment
    of this cfs/me,which we(myself and DR.PETERSON) ALWAYS USE THIS IVIG.!!




    :Retro mad:
  19. starryeyes

    starryeyes Senior Member

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    This is interesting. I remember reading about protein misfolding in CFS years ago in the NCF newsletters. They have many articles on it.
  20. Cort

    Cort Phoenix Rising Founder

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    Yes, there have been several hints in the literature that something like this could be happening.

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