Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease, 2024, Khalid A. Hanafy

I really appreciate you pointing it out, it is my misguided assumption that the researchers would have a good understanding of the basics but I can see how that is certainly not always the case. It seems like researchers use neuroinflammation in a reasonably specific but non standard way. It certainly makes it confusing when two people use that term and are referring to different processes.

Do you agree that we haven't had the tools to image what glial cells are doing in humans with any decent resolution? There are certainly some conditions like migraine, schizophrenia and depression that have some brain pathology that we have historically struggled to image. Surely more specific PET tracers which have not been in development for long will provide a better understanding of the mechanisms behind these conditions.

One question and I don't know if this is the right thread to ask, but if ME/CFS is not driven by some central process how would we get PEM, light and noise sensitivity and other symptoms simply by excess concentration/mental exertion. I am right to think that the main impact of metal exertion is on the production of some metabolites in the brain?

 

We do not have good methods for detecting glial behaviour in living brains. However, for decades we have had excellent histological techniques for looking at glia past-mortem. If glia were behaving abnormally then I would expect someone to have picked it up in autopsies. I appreciate that these days autopsy is rare but not so long ago it was commonly performed.

If we go to the animal models that are supposed to mimic human illnesses abnormal glial activity and distribution is very easily seen on histology. So it is not as if we are expecting the changes to be subtle and invisible on histology.

When the Nakatomi study came out I was a bit sceptical but radiology experts advised me that it looked reasonably plausible. My impression is that the findings have not been confirmed.

I very much agree with that argument. The process may not need to be primarily driven by a central process if some peripheral immunological process sensitises the brain through hypothalamic sensors (as in flu). But yes, I think some central process must then mediate light sensitivity etc. But I think that could be entirely neural signalling and vascular responses. The 'metabolites' may be neurotransmitters.

The situation with acute febrile illness suggests that sever symptoms can be rapidly reversible within hours. You may feel dreadful at lunchtime and much better by the evening. That does not seem likely to be due to any major shift in glial numbers or activation status.

And if microglia were really going berserk and BBB was leaky MRI would show it up very nicely. So I am not sure that I think it very likely that glial goings on are relevant to ME. In most other conditions the glial activity is secondary to some other cell misbehaviour in the brain, as in MS.

 

That makes sense to someone who has it all the time due to autism. Changes in intensity are related to the number of stressors, so a sound that's uncomfortable one day will cause meltdown on another if it's compounded by visual overload or tiredness.

The experience of autistic overload is hard to distinguish from that brought on by illness, just as the experience of PEM is hard to distinguish from the onset of a virus.

 

Do you have any theories that would explain how ME symptoms can completely switch off over a period of minutes, and then switch back to full on again over a similar period? That's how my temporary remissions were, and I use that to judge any ME theories. I think it's not unreasonable for glial cells to change that rapidly. I suppose vascular properties can change that rapidly too.

 

Perhaps the act of death has a large impact on glial cells such that autopsies mightn't be the best way to study them. Apparently we can see large changes in glial activity in animal models of MS https://www.frontiersin.org/articles/10.3389/fncel.2020.00269/full but that wouldn't necessarily translate to ME/CFS. Unfortunately we can't create an animal model of ME/CFS and since we shouldn't go probing people's brains it seems tough to figure out if this is an issue in ME/CFS. I completely agree that there are other processes that may be drivers of a central process though so it doesn't make sense to focus on one area.

I haven't been able to find any other good published PET studies in ME/CFS since then, although there are one or two in long Covid. There are a few studies currently underway seeking to address this question in a larger sample sizes but it is sure taking a while. Very frustrating that it takes years and years to run some people through a scanner to put this to bed once and for all.

Absolutely, and even if we did find that glial cells were activated I'm not sure that would even mean that they are causing the issue. Some other peripheral or vascular issue may very well be the driving force behind it all even if glial activation is contributing to the symptoms. It could even be the case that activated glial cells are trying to help and we would be worse off if we de-activated them. I don't know what neural signaling really means but I definitely see how vascular changes could cause issues.

 

I'd be interested in whether other PwME have experienced such momentary remissions I never heard of such fast ones before (not suggesting anything by that, just curious)

 

I did in the earlier years of M.E. I had short periods of feeling almost recovered for 4-6 weeks, but I wasn't experiencing delayed PEM during those years of PVFS.

 

Other people have reported them. It's like flipping a switch. That tells me that ME (at least my ME) rules out a bunch of theories that involve slow-changing processes. A mechanism involving brain cells fits, and even better--one that involves a small region of the brain (hypothalamus or wherever). Maybe a homeostatic communication molecule that is produced for the wrong set point, and some other factors (prednisone, cuminaldehyde, T2) can temporarily alter those levels, until something else adapts to return to the wrong set point.

I think the rapid switching of state is an important clue for understanding ME. Not everyone experiences it, so research ignores it.

 

I am not sure what glial functions could change in that time other than ion flux - maybe calcium - which I would tend to lump in with neural function. Functions of macrophage-like microglia implicated in 'inflammation' are likely to change over longer periods, even responses to cytokines with activation of NF-kB etc.. And it would be hard to see why the cytokines, coming from elsewhere, would change that quickly. Cytokine shifts in febrile illness often shift up and down twice a day but not much quicker than that.

Blood flow can shift in minutes in brain but it is hard to see that being relevant. There would need to be an explanation for the shift in vessel calibre. If it happens quickly it is likely to be neurally driven (but unconscious autonomic neural).

Neural responses can of course shift in a second or less. Triggering neural pathways can do remarkable things to symptoms. If you have sprained an ankle or had a bee sting or hit your finger with a sledge hammer stimulating spinothalamic temperature sensitive fibres with ice can more or less completely abolish pain in 500msec. Getting your head into some fresh air after suffocating in a hot room can alter ones mental state in the same time frame.

 

But of course, because the brain is falling apart with cells attacking myelin. And of course they are being looked at post mortem. Glial changes are easily seen in human brains where there is pathology to respond to.

Just the brain nerves sending signals to each other and every part of the body - controlling lifting your arm, your thoughts of lunch, your heart rate, your mood, your blood sugar, pretty much everything.

 

I agree. And then there is the paradox that there are also long time frame changes like PEM. Which brings us back to maybe both a central neural pathway and a peripheral immune or endocrine pathway, in sequence.

 

very ineresting, i was aware of longer 'short term' remissions (lasting a few days/wks), and that they were like flicking a switch, but not heard of ones that only last minutes before flicking back again. Most interesting.

PEM although delayed, is very fast when it comes on though, at least for me. Its not a gradual development of symptoms/worseing. I can go from my best to my worst in space of a minute or 2. - One of the reasons its never safe for me to leave the house alone in a powered wheelchair, even on the rare occasions i well enough - strangers think i collapsed due to serious illness/stroke etc & call an ambulance.

 

How many hours is your delay time?

If I go over my energy limits the day before I'll continue to function fine, sleep well and wake feeling my 'normal self", eat breakfast et over 13-15 hours, and then within a minutes the sensation of PEM comes over me and continues to worsen. I also have lows and peaks of PEM during that time period for the next 3 days until I return back to baseline.

 

It varies, it can be anything from 12 hrs (rarely) to 3days (also rarely), its most often 24-48hrs. The delay has got longer through illness duration, i'd never had a 3 day delay until quite recently (20-22yrs in)

 

If it is the same study by Nakatomi/Watanabe that I'm thinking (one that came out of Japan about 10 years ago?), it failed to get replicated. I think a team in Europe tried and failed. It wasn't exactly the same though. I think the cohort or something was a little different.

 

actually thinking about it, thats not strictly accurate... its often a 'light switch type thing, but sometimes it does get gradually worse over days. I think the difference is that the former very quick onset is when the overexertion has been fuelled by a surge in adrenaline due to some major anxiety/anger/urgent issue (which are usually the things that cause a major pacing deviation), and the adrenaline kind of holds the PEM at bay... until either the overexrtion becomes so far over my limits that no amount of stress hormones can keep me going, or i calm down and my ANS rapidly reverts to parasympathetic mode - both of which result in a startlingly abrupt crash/collapse.

Whereas the gradually worsening type of PEM is where there is no emotional upset/adrenaline involved in holding it 'at bay' & where day 1 is bad, day 2 is worse and day 3 is horrendous & then it levels off.

 

What worried me about the Nakatomi images was that they looked like physiological patterns rather than pathological patterns. That made it more likely that apparent differences were due to chance or artifactual differences in individual image calibration.

 

I will add that that study used a PET radiotracer that was developed in the 1980s and isn't as specific as the second generation ones that have been developed recently. I don't know how much of an impact that has on the results but it certainly provides a less clear picture. I would love to get your perspective on this study https://www.biorxiv.org/content/10.1101/2023.10.19.563117v1.full.pdf if you have a chance to glance at it.

 

My temporary remissions didn't last only minutes; they tended to last "until the next morning". I can't recall now whether any switched off during a day, but I think it did. The time from full ME to full non-ME, and from full non-ME to full ME again were IIRC just a few minutes. My PEM, and other triggers, would also typically have me go from "Uh oh, I think I'm starting to feel worse" to full severity over a space of minutes. At the start of this nightmare, when it seemed to be a standard type IV food sensitivity, my symptoms, including oral temperature would flare up over the space of minutes, 48 hrs (+/- a few minutes) after eating the food. Whatever mechanism is responsible for these flu-like symptoms, it flares up rapidly.