Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses, 2022, Tate et al.

Discussion in 'ME/CFS research' started by Jaybee00, May 25, 2022.

  1. Jaybee00

    Jaybee00 Senior Member (Voting Rights)

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    https://www.frontiersin.org/articles/10.3389/fneur.2022.877772/full

    Hypothesis

    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation.

    What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address.

    We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur.

    By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection.

    The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.
     
    Last edited by a moderator: May 25, 2022
  2. Jaybee00

    Jaybee00 Senior Member (Voting Rights)

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    “chronic relapse recovery cycles”. Still waiting for my recovery cycle.
     
  3. duncan

    duncan Senior Member (Voting Rights)

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    I want to agree with these guys, but it's a bit theory-heavy, and therefore kind of a house of cards.

    Besides, they lost me with the relapsing thing. It suggests to me somewhat of a misunderstanding of daily life with ME/CFS. If this is their way of speaking to PEM, no, that won't cut it. To be fair, I could not get through the entire paper.
     
  4. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Not that I am aware of.

    I don't see the point of trying to explain something that we do not yet know is there and may well not be.
     
  5. JemPD

    JemPD Senior Member (Voting Rights)

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    I do wish researchers, biomedical as well as BPS, would stop declaring things 'have been shown' - as if its established scientific fact. Patients/advocates tend to unwittingly repeat such statements because they sound good but its so unhelpful if its not backed up by evidence
     
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  6. InitialConditions

    InitialConditions Senior Member (Voting Rights)

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    Yep. Seen a lot of this recently in the more vocal parts of the LC community. It's not helpful.

    I like this sentence from John Ioannidis. One study does not establish scientific fact. It's the start of the journey, not the end.
     

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  7. Midnattsol

    Midnattsol Moderator Staff Member

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    I think a problem is we are taught to write this way at university, to "tell a story". The whole "present the background in a nuanced manner" is not really cutting it, readers won't bother. It's boring. Also don't overstate the limitations, you wouldn't want anyone to think what you did was useless? Experiences may vary between universities/courses.
     
  8. Creekside

    Creekside Senior Member (Voting Rights)

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    An immune activating event somehow triggers some neurological changes, and some sort of feedback mechanism keeps the body locked into this abnormal state. I figured that out many years ago, without a medical degree. I don't have any solid evidence of the mechanisms involved ... and neither do these researchers. Isn't publishing that sort of baseless paper a bit embarrassing?
     
  9. Ravn

    Ravn Senior Member (Voting Rights)

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    This team has done a handful of studies in recent years and this looks to be an attempt to fit the results together into an overarching hypothesis.

    The individual studies themselves appear to be well conducted - as far as I can tell, they're pretty technical - but have very small cohorts (limited funding). The findings are interesting and I would be very happy for this or another team to try and replicate them on a larger scale.

    I'm less enthusiastic about the hypothesis building attempts, they give too much credence to findings that don't strike me as sufficiently solid (as yet). This premature faith in certain findings may be why the section on testing the hypothesis appears a little light in that it doesn't address how to test many of the assumptions the hypothesis is based on, the assumptions are just taken as given. I do agree with their call for more longitudinal studies to try and catch 'relapses', and for studies using more and better high-tech scanning technology to sort out the question of 'neuro-inflammation'.

    Which brings me to the language used which is problematic, too, because terms are not sufficiently defined and are likely to be misinterpreted by people not intimately familiar with ME. Some terms are just confusing full stop. Just 3 examples but there are more in the paper:
    • What exactly are acute and chronic phases of ME?
    • What is a relapse recovery cycle? Does relapse equal PEM or a more prolonged crash? And recovery presumably only means return to pre-PEM/crash/relapse baseline rather than actual recovery to no symptoms?
    • What is meant by neuro-inflammation? As far as I recall the different studies used as references here all use different or equally vague definitions (but haven't gone back to check).
    I know there's a lot of lived ME experience in this team, either directly or through having affected family members, and a lot of pwME contact them with their stories as well. So they have a wide range of experiences to draw on. Yet - and I can't quite put my finger on it - but somehow I'm increasingly getting a sense of some sort of echo chamber effect going on here where pieces of the puzzle get squished to fit and everybody agrees with everybody else how nicely they fit. I hope I'm wrong but maybe it's time for some adversarial collaborations* in the ME field?

    https://en.wikipedia.org/wiki/Adversarial_collaboration
     
  10. Hutan

    Hutan Moderator Staff Member

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    Members' comments here are spot on I think.

    There's definitely a breathless naivety in the way preliminary findings are stacked up to support what is a pretty vague and handwavy sort of hypothesis. Really it isn't much advanced on the typical circular diagrams the BPS people so often add to their vague handwavy sort of hypotheses.

    For example, here's part of the diagram illustrating the hypothesis:

    Screen Shot 2022-05-26 at 7.13.25 pm.png

    All the usual suspects get taken for a walk. Apparently there is a 'chronic stress response'. Here's just a sample of the references to the idea.


    So, never mind that there is no evidence for anything pathological in cortisol levels in people with ME/CFS, in this paper the levels are reported as being low. And apparently the ME/CFS response to the low levels is the same (or even greater) than in controls. Umm, so wouldn't that mean that the outcome ends up being the same? And what is the reference provided for this crucial link in their vicious cycle hypothesis?
    Yes, that Cort's blog.
    And reference 107 is a 1991 paper. There have been numerous studies since that time that have not provided evidence for this idea that cortisol levels are somehow wrong or there is cortisol sensitivity.
    We need researchers to get beyond what reads like a Year 1 university essay that was done with not enough time to properly read the papers referenced. There's very much a sense of 'oh, this reference is saying what we want it to say, that will do the job'.
     
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  11. Hutan

    Hutan Moderator Staff Member

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    Some more examples of what I'm talking about:

    ANZMES. ANZMES Preliminary survey findings. (2021). Available online at: https://anzmes.org.nz/ (accessed February, 2022).
    This statement gives the impression that one in 4 people with ME/CFS suffer severe ongoing impacts as a result of being vaccinated. This is just not true; also the source is a voluntary survey that must surely have a high level of selection bias.


    This suggests that therapeutic options are in fact benefiting some patients, while they do not benefit others. I don't think we have any good evidence of there being any therapeutic options benefitting some patients.


    I don't think the use of the microclot finding to support a hypothesis is going to age well. Certainly it should not be presented as bolstering the hypothesis without some words suggesting uncertainty at this time.
     
    Last edited: May 26, 2022
  12. Hutan

    Hutan Moderator Staff Member

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    Here's another example - this statement is used to support the idea that the gastrointestinal system may be contributing to the neuroinflammation.
    The reference given is: Wang J, Song Y, Chen Z, Leng SX. 2018 Connection between systemic inflammation and neuroinflammation underlies neuroprotective mechanism of several phytochemicals in neurodegenerative diseases.
    The paper makes a whole lot of claims for cucurmin, resveratrol, propolis, PUFAs and ginsenosides. It only makes one reference to the myricitrin, green tea and mulberry mentioned in the Tate paper - and that's in the Introduction. Here is the entire relevant paragraph:
    The referenced paper therefore provides no convincing evidence relevant to the argument made in the Tate et al paper. Following the references back, the Wang et al paper references
    Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases, a 2013 review article that talks about animal models and promise. It mentions green tea is an inhibitor of acetylcholinesterase - which incidentally is what the neurotoxin sarin gas does, rather more permanently. With sarin gas being implicated as a, perhaps the, cause of Gulf War Illness, .... perhaps green tea isn't ideal. ...Or perhaps ingested green tea doesn't have the same impact as when it is applied directly to rat synapses in a Petri dish.

    I mean, I'm a fan of green tea, I drink at least several cups of it a day. As far as I can tell, it makes no discernible difference to my illness. Throwing the suggestion about the healing properties of green tea and mulberry and a particular flavone into this hypothesis paper seems speculative, diversionary and grasping at straws.
     
    Last edited: May 26, 2022
  13. Hutan

    Hutan Moderator Staff Member

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    It appears that Warren Tate is primarily responsible for this paper, building on the work he did with Angus Mackay. I've no doubt that Warren is a brilliant biochemist and certainly motivated to help people with ME/CFS, but, in my view, this hypothesis paper would have benefited from much more review. I've got a page more of notes jotted down that I haven't addressed. I don't think the editor or reviewers provided the necessary critical review.

    I'm sure the reviewers are busy, and what incentive would a busy researcher have to spend half a day checking references and generally making the paper of someone who is not in their team great? I was talking to a journal editor the other day and he was saying how hard it is to find peer reviewers, and when they do get someone, they might just spend half an hour reading the paper and writing a quick response, because that is all they have time for. But, a person with ME/CFS on the other hand has an enormous incentive to make sure things are right. I can think of plenty of members here who could provide good-natured useful feedback on trial designs and draft papers and hypotheses, members who have a very good knowledge of the ME/CFS literature. I think we could help researchers make break-throughs more quickly, and cause less harm to patients in the process.

    So, why is it so hard for these researchers to take on wider input? I expect some of the ideas set out in papers like these don't help. I mean, if I was a researcher, I wouldn't be lining up to work with people who have issues with memory and mood, who are liable to fall apart in the face of every day emotional and psychological stressors
    The unfair accusations of the BPS people about angry irrational patients stick too. I don't recognise myself in those descriptions, or my son. We can think and remember well at least some of the time. We, and many of the members of this forum, deal calmly with stressors that many healthy people can not begin to imagine. 'Stress' is an unhelpfully vague term.

    I'm sure all the researchers who contributed to this hypothesis paper are smart and want to help people with ME/CFS, but I think this paper is counter-productive.
     
    Last edited: May 26, 2022
  14. Trish

    Trish Moderator Staff Member

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    Thanks for taking a thorough look at the paper, Hutan. I've just started reading it and am already having arguments with it. Even the description of the illness feels incomplete and unbalanced. Nothing about muscle fatiguability and pain, no mention of PEM, instead a confusing reference to relapsing and recovery which makes no sense to me. And why 'poor response to even small stresses' without specifying what is meant by 'small stresses' - sensory sensitivity? psychological problems???
     
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  15. Charles B.

    Charles B. Senior Member (Voting Rights)

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    One of the principle critiques of the biomedical approach to ME, emanating from BPS quarters, is that much of the research constitutes “biobabble.” I believe one of psychiatrists, maybe Santhouse, used this term in a well received book not too long ago. If we can’t decimate papers that eschew BPS language and philosophy, then we lose credibility when dismantling BPS literature. I’m glad this forum stands for such consistency.
     
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  16. Trish

    Trish Moderator Staff Member

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    I don't have the energy to read it all so I skipped to a few bits:

    There's an assumption all the way through, as far as I can see, that the core explanation of ME is brain inflammation. I don't think that should be presented with such certainty.

    They seem very keen to describe PEM as a stress reaction. I don't think there's any evidence to support that.

    There's also a lot about excess serotonin which would surely suggest that SSRI's would be useful but they're not. They also describe the tryptophan and IDO2 metabolic trap hypothesis which as far as I know isn't established as anything but an idea, so not really appropriate to include in a paper building hypothesis on hypothesis.

    I give up. Hutan has done a much more thorough review than I have.
     
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  17. Hutan

    Hutan Moderator Staff Member

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    No, I haven't. I just picked out a few mostly minor issues, because it was easy to illustrate the problems with them. But I agree with those two big issues you identified - the idea of brain inflammation, specifically in the paraventricular nucleus, and HPA axis dysfunction - as lacking evidence.

    I think perhaps attitudes about people with ME/CFS held by the researchers (e.g. that they are delicate flowers wilting in the face of everyday stresses) are making it difficult for them to get past the idea of 'problems processing stress' and move on to ideas that are more specific and helpful. Is it a lack of energy to deal with things? Is it difficulty filtering sensory inputs? Is it orthostatic intolerance? I mean it all gets a bit ridiculous when brushing your teeth is an 'external life stressor'- it really calls for a bit of finessing around what is meant and exactly what the process is.

    I find the circular diagrams (Figures 1 and 4) which are the core of the hypothesis little better than BPS circular diagrams.

    Another issue is the uncritical acceptance of the idea of an early stage and late stage of ME/CFS, seemingly based on the findings (I think) by Hornig, Lipkin and Montoya who couldn't differentiate people with ME/CFS from healthy controls on the basis of the cytokines. So, they made subsets based on illness duration and did find some differences. But it wasn't very convincing, and I don't think there has been much replication of the result.
     
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  18. hibiscuswahine

    hibiscuswahine Senior Member (Voting Rights)

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    I have heard Prof Tait (who is a biochemist) talking in conjunction with Dr Vallings (GP with special interest in ME). They have worked together for years exchanging theories and information. She was/is our leading ME “expert”. They are using medical terminology (which I often use with my illness and from my clinical practice as I never got used to the words crash/flare up/PEM etc as this was not even understood or recognised by medicine 30 years ago when I was diagnosed)

    I think they are still stuck in the “stress model” of ME which was prevalent in the 80’s-90’s. He has identified some oxidative “stress” problems in the mitochondria but too little is known about the illness and psychological stressors always pop up in their conversations to pwME using brain development and often then “trauma” is mentioned and epigenetic codes.

    So they are still conceptualising ME on old models of describing the ‘illness continuum’ within any particular individual but they have little ability to predict the course of the illness for the individual.

    There are so many different illness experiences: some have gradual onset and no clear pathogenic trigger before meeting criteria. There is the clear bacterial/viral infection trigger and post infectious syndrome where PEM and all the criteria are readily apparent and I suppose could be described as an acute pattern but when does the chronic label become applied? Some don’t “recover” at all and get worse.

    Relapse is a loss of function and return of previous symptoms (that appear to have settled by whatever means) but often new ones appear and the relapse itself causes loss of function even if symptoms resolve in my experience. So the model is not fit for purpose for me.
     
    Last edited: May 27, 2022
  19. Ravn

    Ravn Senior Member (Voting Rights)

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    For those who don't want to read the whole article, IIRC part of this talk relates to the paper here (video link originally posted in the New from NZ thread so some of you may have already seen it).

    https://www.youtube.com/watch?v=2C6IUamf_eI


     
  20. Tom123

    Tom123 New Member

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    I liked the paper- seemed to play nicely with this recent similarly styled paper on glia and the brain’s immune system (summary here)

    It’s also great that you guys are able to critique the heck out of it- that’s science :) hats off to you all, who seem to have a much more nitty gritty understanding of the research than me.

    on being theory heavy- i think it’s good to have some of these types of papers, that try to make sense of the big picture. They may be wrong, but isn’t it great that there’s so many papers finally coming in that there’s even a need for these types of review?
     

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