Muscle abnormalities worsen after post-exertional malaise in long COVID, 2023/4, Wüst, van Vugt, Appelman et al

I used to be one (without mentally triggered PEM). Then I recently did a serious mental exertion trying to solve a problem (with a language design and transfer function modeling) for 3 days, something I hadn't been able to do while I was sick. The effect was nearly identical to biking 40 miles or skiing hard for 4 hours: I had to revert to pacing for a week. My take on this was that I hadn't had enough energy to mentally exert hard enough while I was sick, and now I experienced this because I'm "recovered" enough to. (Probably something unique to me rather than universal).

I'd caution on effort to redefine MECFS or PEM, especially if that is to fit outcome of certain studies. They are defined by reviewing/examining thousands of patients, and they should be what they are till an evidence, not anecdotes, points otherwise.

 

Very true, but I wouldn't expect the same person to experience PEM differently post phy or mental triggers. Especially as PEM is usually seen a (body) global issue, not something localised such as muscle pain

This is why I think we new evidence: we know so little about PEM, not least the patient experience of it..

Some initial thoughts on a survey of pwme, or just a couple of questions (maybe using social media or particular networks, no idea).

1. Is your PEM triggered by:
- mental exertion only
- physical exertion only
- both

If both:

2. Are your PEM symptoms
- broadly similar whether triggered by mental or physical activity
- different
- it varies a lot
- don't know/can't tell

3. Overall, does your PEM feel
- broadly the same whether triggered by mental or physical activity
- mostly different
- it varies a lot
- don't know/can't tell

I'm not suggesting we make a survey here, just using this as an example of questions we could ask - ideally of thousands - where I think we currently do not know the answers. It's important, and the answers could help steer biomedical research.

 

You might enjoy this thread @Simon M where some users are expressing their understanding of the "PEM" nomenclature. My impression is still that we often know how PEM feels but that, that is something that hasn't sufficiently been understood or investigated (very similar to how the brain dysfunction that we experience hasn't been characterised well).

 

What purpose of reclassifying PEM would serve? Unless you think that different PEMs are different phenomena caused by different factors, it doesn't. Then you have to search for multiple different causes for, not only different types of PEMS, but also different worsening of symptoms. 3-4 hours of worsening after alcohol ingestion, 2 weeks of worsening after flu shot, month worsening during the pollen season, 1 hour of worsening immediately after physical exertion, 3 hour worsening 2-3 hours after exertion, etc, etc. They all may feel different, but it can easily be explained by PEM being a spectrum (eg, feeling wipe out at one end and total physical/mental disaster on the other end) just like MECFS itself.

The observed muscle anomaly may or may not be true; we'll just have to wait and see if it gets replicated. If/when it is replicated, it is still a correlation, which could be cause, effect or just incidental. There have to be another study to establish the cause/effect relationship after it is replicated. Maybe then we could get serious about questioning the definition of PEM.

 

I agree that PEM remains poorly characterised - and even more poorly operationalised. Even the peculiar delayed start/peak of symptoms - which is well documented - is, in practice, being confused with DOMS by some. As for the more non-specific symptoms, we all know what a confused mess that is.

I also agree that a sharper characterisation of PEM could help focus minds on areas of research more likely to be revealing. Sure, PEM symptoms are most likely a downstream effect, but trying to work your way up from something at least somewhat specific, like the PEM delay, is more likely to bear fruit than doing so from something completely non-specific like fatigue. And knowing whether we should view symptoms after cognitive or physical exertion as same or different is relevant to assessing the value of different proposed mechanistic explanations

But I think achieving a better characterisation of PEM is going to be much harder than asking a few short questions. That's because we've all seen and internalised the memo that all types of exertion can cause all types of PEM symptoms. This may well be correct. Or not. I don't know. And I suggest nobody truly knows. We interpret our experiences in the light of the language and the stories we have at our disposal. We also tend to seize on the most memorable events when trying to establish causality and forget about all the other minor but cumulative exertions we do throughout the day. In the process we can mislead ourselves or others or both. Using my own fallible reasoning as an example (from another thread)

I actually once tested my reaction to purely cognitive exertion with a little experiment which I'm sure I wrote about somewhere in detail but I can't find it now. Briefly, I lay down and listened to some audio in one language and mentally simultaneous-translated until my brain shut down and I didn't even know what language I was hearing anymore. So no physical movement and no orthostatic challenge involved. Just hardcore thinking. I felt wiped out for I can't remember how long but a matter of hours. Next day: fine. No PEM.

This doesn't prove PEM (beyond the immediate and severe fatiguability) from cognitive exertion isn't possible, only that I can't push myself hard enough cognitively to get delayed PEM from cognitive exertion alone. But it illustrates the point that we can attach an incorrect story to our own experiences. Before my experiment I would have answered Simon's questions with 1. both 2. broadly similar and 3. broadly the same. After my experiment, my answers would be quite different

 

Much of the current characterisation of PEM is based on received wisdom, not actual data. So it's very reasonable to put some effort into checking what holds and what, if anything, doesn't.

I don't think anybody is suggesting going into that level of detail, that would indeed be pointless. What we're trying to get at is verifying the existence or otherwise of some potentially highly relevant differences. For example, if on close examination it looks like symptom patterns after mental exertion (sensory, cognitive, social, emotional) are qualitatively different from symptom patterns after physical exertion that would be important to know. If it turns out the patterns are qualitatively the same, then that would be good to have confirmed on a more solid basis.

 

Dr Daniel Griffin, discussing on This Week in Virology ep. 1078 at 47:24 - 58:10.

"We need to be careful. Here's evidence that if you tell your patient with post-exertional malaise to just ramp up that exercise, you can actually be triggering necrosis and more damage."

 

Excellent discussion of the article.

 

I have been looking through fluorescence histochemistry of muscle and the only thing I can find that looks at all like the Thioflavine T staining is CGRP nerve endings. It would every interesting if CGRP nerves were altered in ME but why they should stain for amyloid would be a mystery.

Does anyone have contact with the authors of this study?

 

I'm not sure what the forum rules are regarding posting people's contact details but the two corresponding authors' email addresses are listed at the bottom of the first page of the Nature Comms article.

 

Thanks. Unfortunately, I don't have the energy to tackle another thread. Do you know if it covers research that addresses the issue of PEM after mental triggers vs PEM after physical ones?

 

In case it's helpful

In case it's helpful, here's a transcript of Dr. Griffin's discussion on the Appleman paper
Edited to replace the link with the actual PDF

 

I've been collating a list of ME/CFS provocation studies and there aren't many studies with cognitive challenges. Here's one evaluating autonomic and behavioral changes (e.g. sleep, physical activity) following cognitive or physical challenges. They said they didn't see a difference between the two challenge types in early analyses so they collapsed the two.

Besides for using Fukuda, they only explored a very limited range of the symptoms and other factors (e.g. duration, onset, etc) that are part of PEM so not much help. I'll dig and see if I can find others.

 

From ThT 101: a primer on the use of thioflavin T to investigate amyloid formation (2017, Amyloid)

ThT can bind to DNA (which might be nuclear or mitochondrial in the context of cell breakdown) and acetylcholinesterase.

 

I came here to post about the same paper @SNT Gatchaman

I thought this sentence might be of interest to @Jonathan Edwards (referencing the staining used in the muscle biospy study).

According to Mr. Google

 

Thanks guys, I searched a bit for cross-binding problems but didn't find anything as specific as that.

It would make good sense. The pictures look most like images of CGRP neurons but I haven't seen any images specifically of ACh neurons so they may be the same.

So the first conclusion is that this may not be amyloid at all. Since the findings didn't seem to tie in with Pretorius anyway that may not take us much further.

But if this is staining of cholinesterase there are two possibilities. One is that this is a sampling artefact. Maybe muscle wasting (of which there will be at least some in ME and LC) may mean that nerve endings make up a higher proportion of tissue per cross sectional area and so on.

The other possibility would be much more interesting - that there is actually more cholinesterase around in nerves going to muscle (and arteriole - in muscle at least).

Now that would lead to a really fancy theory!
I like to play S4ME exactly the way we played debating B cells in my lab 25 years ago - throwing out any idea that arrives and then shredding it - until one day an idea wouldn't shred. Trendy ideas get short shrift but sometimes they turn out a bit right.

There is maybe a possibility that the inability to generate action in ME and LC links to a regulatory mechanism that normally after infection kicks in to calm down any too violent return to hunting mammoths. The mechanism might pivot upon regulating cholinesterase. The effect would be a bit like the soft pedal on a piano. You can still make a lot of noise if you really bang the keyboard but it becomes increasingly effortful and soon enough you give up trying. There may also be regulatory mechanism centrally that pick up the effect of the peripheral regulation and turn off neural control even higher to prevent getting into situations where exertion is costly.

This would make ME or LC remarkably analogous to myasthenia graves, where the ACh receptors are blocked. But rather than producing weakness it might tend to produce a failure in follow through that manifest as a rather different form of fatiguability.

The next question would be what made the nerve or muscle cells express more cholinesterase. That would be easy. It could easily be regulated by policing T cells or macrophages primed by T cells. It could also be regulated by painting signalling molecules on to supportive microfibrils such as fibrillin-1. Such processes would take hours or days so would explain delay in PEM.

Now for the shredding.

 

How strong is the evidence that Sarin was the proximate cause of Gulf War Syndrome? I've heard that said before but never actually seen the evidence myself. If that's true then would that tie in with what you are suggesting @Jonathan Edwards. A nerve agent that destroys acetylcholinesterase activity being met with an compensatory mechanism gone awry?

 

It's an idea, although I am a bit sceptical it would work in reality.

On the other hand we have come up with cholinesterase through a completely blind route relating to a chance cross-reactivity and cholinesterase has been implicated in GWS.

 

I guess the same observation could be made about organo-phosphates leading to farmers developing ME/CFS.

 

I hope Rob Wüst and team might join this discussion, or at least read through this thread. @Robert 1973 maybe this question might warrant a reminder. I expect they'll be in discussion with Resia Pretorius and team.

To pin this down one way or the other, perhaps they could use the AmyTracker which might not cross-react this non-amyloid content. If that were still positive it would be good to control AmyTracker against AChE (and cfDNA) to be confident, if not previously established as negative. Presumably they could also look with TEM, cryo-EM and AFM to confirm fibrillar forms in the tissue sample?

---
Further, I don't know if there's any way to isolate these deposits from tissue and do mass spectrometry/proteomics to compare content with those isolated from blood in the original Pretorius papers. If you found things like alpha-2-antiplasmin or vWF in there, that would raise a lot of mechanistic questions about amyloid transfer from blood to tissue. This is an area of active interest, eg —

Spoiler: References

Blood Transfusion and Brain Amyloidosis: Should We Be Worried? (2023, JAMA)

Intracerebral Hemorrhage Among Blood Donors and Their Transfusion Recipients (2023, JAMA)

Potential human transmission of amyloid β pathology: surveillance and risks (2020, The Lancet Neurology)

Infusion of blood from mice displaying cerebral amyloidosis accelerates amyloid pathology in animal models of Alzheimer’s disease (2020, Acta Neuropathologica Communications)

Exploring cerebral amyloid angiopathy: Insights into pathogenesis, diagnosis, and treatment (2023, Journal of the Neurological Sciences)

Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways (2019, Nature Reviews Neurology)