The Adenosine - Phosphatidic Acid Hypothesis

[necessary8]

So, I think wed have to know the cause of th preload failure to know why the hypoperfusion is delayed or why it's effects are delayed.

Okay but then I don't think we can say preload failure explains PEM. Not by itself. I can perhaps see it being part of a larger mechanism, but until I see how it explain the delay, this is just one of dozens upon dozens of mechanisms that can cause exercise intolerance. So I don't really see much argument that this is the correct one, over any of the others, in ME/CFS specifically. Not until it actually explains the strange, difficult to explain features about PEM, like the delay. Right?

 

[frozenborderline]

I'm not convinced the delay is that hard to explain. It's similar to other forms of exertion intolerance/fatiguability just on a longer scale.

I think it's possible that the preload failure induced hypoperfusion and /or some other cause of hypoperfusion like neural strain, cause metabolic changes that are adaptations to low oxygen environments, and that's why people get sicker long term after exertion.

 

[pattismith]

This is an interesting idea. You could probably explain fatigue with it. But I don't think you could explain PEM. Right? Also, do we have any data showing SFN in CFS already? I know studies on it are underway but do we have results yet?

a study looking for SFN in fibro patients found half of them affected. I think the testing was a skin biopsy.
But I wonder if a SFN affecting muscle small fibers only would be detected in skin biopsy.
I've not read about muscle biopsy to look for small fibers, but it would be more relevant;
I'm ill for 30 years, with progressive evolution. Sensory skin symptoms of SFN only happened late in the course of my disease (this year), whereas my muscle pain is from the start. But I'm convinced the two are related, (together with my autonomic symptoms).

 

[necessary8]

I'm not convinced the delay is that hard to explain. It's similar to other forms of exertion intolerance/fatiguability just on a longer scale.

Idk man, I've seen very few hypotheses that can actually explain this. And most of them are mine. People always gloss over it, because it actually doesn't fit with many things.

I think it's possible that the preload failure induced hypoperfusion and /or some other cause of hypoperfusion like neural strain, cause metabolic changes that are adaptations to low oxygen environments, and that's why people get sicker long term after exertion.

I can't comment on this because this statement is too vaugue and non-specific.

a study looking for SFN in fibro patients found half of them affected. I think the testing was a skin biopsy.

Hm, yeah, upon googling, the support for this in fibro is actually pretty significant. I just don't know about CFS. If a study on SFN in CFS does come out, definitely tag me.

 

[pattismith]

@necessary8 ,

many studies found brain hypoperfusion in ME, and this latest one is interesting:

https://www.sciencedirect.com/science/article/pii/S2467981X20300044

"Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia"

Brain vasculature depends on autonomic nervous system, and we seem to have dysregulation in this area.

Peripheral small autonomic fibers, also concerned by SFN, probably plays a role here as well.

 

[necessary8]

many studies found brain hypoperfusion in ME

I think I've seen them all, but the thing is, hypoperfusion can be mediated by many, many possible mechanisms. And I don't think SFN is anywhere near the top of that list. Like, for example, oxidative damage to erythrocytes can explain all of this sufficiently (yes, even in light of the study you linked), and we have really solid, direct data from many angles showing that it is in fact happening in ME/CFS, as opposed to the SFN angle which as far as I know has only speculation backing it at the moment (in CFS, not in fibro). I'm not trying to say it's not an angle worth exploring, but at the moment I don't see it either being proven to happen in most CFS patients nor have I seen a good hypothesis that would explain how it mediates the weird, hard to explain features of CFS. If that ever changes, do tell me. Or if I'm wrong in my assumptions, feel free to correct me, this is good discussion.

 

[wastwater]

Dr Alan Light stated that 12 percent of patients in a study had HSP6A defect I’m likely to have this as it’s a target gene of FOXC1

 

[Snow Leopard]

Like, for example, oxidative damage to erythrocytes can explain all of this sufficiently (yes, even in light of the study you linked), and we have really solid, direct data from many angles showing that it is in fact happening in ME/CFS

Do we know that?

Loss of erythrocytes cannot explain the 2 day CPET findings, namely a reduction in performance at the ventilatory threshold, but not necessarily any change in VO2Peak and blood volume. This rules out loss of erythrocytes as a cause, and likewise 'preload failure'. It surprises me how many people (interested scientists and intelligent patients) have read about the ventilatory threshold CPET findings, but have no idea what it means neurologically, because they have not bothered to read the research by exercise physiologists trying to uncover what it means...

Therefore when examining hypoperfusion hypotheses, it is important to point out that it cannot be a generalised hypoperfusion that is occurring, but hypoperfusion at peripheral capillaries, where the kinetics of the activity that is inhibiting flow needs to reflect the overall symptom kinetics.

This is really interesting as well. When I talked with Alan Light about this a few years back, he was saying that the aabs in CFS cause gain of receptor function, not loss. I guess he was wrong.

I remember discussion about that a few years back and I remember being skeptical that there was a gain of receptor function, given the evidence provided...

 

[Learner1]

Some thoughts on all of this, rereading everything in this thread, with what I've learned since then.

• Many of us have AMPD1 SNPs, resulting in higher levels of adenosine, which would result in feeling sleepy, particularly after exercise.
• Some of the doctors are having patients try MOTS-C peptides, a once a week injection, which stimulates AMPK. It can lower blood sugar and improve brown fat, but can apparently interfere with folate metabolism.
• Phosphatidyl choline can be depleted for other reasons. People with PEMT and SOD2 SNPs or who are making peroxynitrites (lots of us, as increased oxidative and nitrosative stress has been noted by researchers) are prone to this. PC supplementation can help rebuild damaged mito membranes and it can increase acetylcholine (as Mestinon and Huperzine A do) to help POTS.
• I no longer get PEM. At all. I skiied 2 days back to back recently, with no hit to my energy after day 1 or 2. This is due to the many significant interventions I've made over the past 3 years. The one problem I am still fighting is a very low anaerobic threshold, where arms and legs drain of energy, I feel dizzy, and need to sleep 5 to 20 minutes before recovering to continue my activity. It happens when I increase pace or intensity. I am trying promoting AMPK and a couple of other things. It may have something to do with burning fat vs glucose.

 

[pattismith]

I think I've seen them all, but the thing is, hypoperfusion can be mediated by many, many possible mechanisms. And I don't think SFN is anywhere near the top of that list.

Autonomic dysfunction may be on the top of the brain hypoperfusion mechanism list, why not?

SFN is an autonomic disorder (+ sensory disorder) and autonomic disorders alter brain blood pressure regulation, don't you think so?

https://forums.phoenixrising.me/thr...ebral-blood-flow-in-post-lyme-syndrome.79374/

;;;

 

[necessary8]

Autonomic dysfunction may be on the top of the brain hypoperfusion mechanism list, why not?

"Autonomic dysfunction" can be a lot of things so I can't address that because it's too unspecific. SFN is not at the top of the list because we have no evidence of it happening in ME/CFS, where as for other mechanisms, like say decreased erythrocyte deformability, or dysfunctional adrenergic receptors, we do.

 

[Learner1]

SFN is not at the top of the list because we have no evidence of it happening in ME/CFS,

My well known ME/CFS specialist has a lot of patients with SFN, and he typically tests for it. There are many patients with it. And, as we have repeatedly been told, there are subsets of patients with various pathologies and comorbidities.

 

[necessary8]

My well known ME/CFS specialist has a lot of patients with SFN, and he typically tests for it. There are many patients with it. And, as we have repeatedly been told, there are subsets of patients with various pathologies and comorbidities.

Then he should publish, I would love to see actual numbers. Also, do you happen to know how he tests it?

 

[pattismith]

"Autonomic dysfunction" can be a lot of things so I can't address that because it's too unspecific. SFN is not at the top of the list because we have no evidence of it happening in ME/CFS, where as for other mechanisms, like say decreased erythrocyte deformability, or dysfunctional adrenergic receptors, we do.

SFN has not been investigated in ME, I do agree.
The standard test for SFN is the skin biopsy….But what if the affected small nerve fibers are not in the skin but only in the gut or in the heart or in the muscles? You will just miss it by looking into the skin only.

This 2019 review says "The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition."


In this great 2018 paper by Dr Todd Levine, "Even within diseases that affect purely small fibers, we now understand that this can present as purely sensory disruption such as pain, purely autonomic dysfunction, or in some patients a combination of both sensory and autonomic."
;;;
"patients with SFN can present with either autonomic or somatic symptoms, or both. Symptoms are potentially numerous and can include allodynia, burning, lower thermal sensation, hyperesthesia, paresthesia, numbness in the lower extremities with potential to affect limbs and trunk, restless leg syndrome, dry eyes and mouth, abnormal sweating, bladder control issues, gastric issues, skin discoloration, and cardiac symptoms.3 Cardiac symptoms include syncope, palpitations, and orthostatic hypotension."

Note that ME/CFS is a known comorbidity of Dry eyes syndrome (an autonomic alteration), as shown in this study, as well as IBS.

General Hospital have made a groundbreaking discovery that could ease symptoms for millions of people suffering from conditions such as chronic fatigue, fibromyalgia and irritable bowel syndrom.

Dr. Anne Louise Oaklander says a good proportion of patients diagnosed with those health issues may actually have a disease called small fiber polyneuropathy, SFPN.

In this paper about Dr Oaklander's great work:

"General Hospital have made a groundbreaking discovery that could ease symptoms for millions of people suffering from conditions such as chronic fatigue, fibromyalgia and irritable bowel syndrom.

Dr. Anne Louise Oaklander says a good proportion of patients diagnosed with those health issues may actually have a disease called small fiber polyneuropathy, SFPN."

I have experienced in my own body and brain what Levine and Oaklander have understood by studying CFS/ME and Fibro and IBS and SFN on their patients.

The autonomic system of my gut and muscles was affected first in the course of my SFN/ME/fibro, years before my neuropathic pains, and many years before any skin sensory symptoms show up (about 30 years!). It's only when I had the typical skin sensory symptoms that I understood that my disease is a SFN, but I am convinced it was my only and real disease from the start....

I am not convinced that any scientist will find the answer to the ME/CFS mystery by looking at it with a nanoneedle, I am convinced they need to take samples of our affected organs and to look at our small nerve fibers density (sudoriferous glands or lacrymal glands or gut or muscles, etc)

 

[necessary8]

I feel like this discussion is kinda pointless until we see a study examining SFN in CFS because for now I'm skeptical of notions standing on shaky grounds and we're just arguing how shaky the grounds are because you think that they're less shaky than I do. Which ultimately doesn't matter. In the end this is an angle that needs to be explored more and that's all there is to it. None of us know what is the mechanism of this disease right now. That's why pursuing multiple different angles is important.

 

[pattismith]

I feel like this discussion is kinda pointless until we see a study examining SFN in CFS because for now I'm skeptical of notions standing on shaky grounds and we're just arguing how shaky the grounds are because you think that they're less shaky than I do. Which ultimately doesn't matter. In the end this is an angle that needs to be explored more and that's all there is to it. None of us know what is the mechanism of this disease right now. That's why pursuing multiple different angles is important.

I do agree with you on that point of course!
But the first problem is that SFN is yet poorly understood by most neurologists and mainly underdiagnosed.
Apart from Dr Levine, very few neurologists really know what SFN is about, and there is no way that .
I read some french papers by the neurologists that are supposed to teach SFN to others in my country and was mostly disappointed with it. SFN is considered a rare disease here, but it's wrong. It's the neurologists able to diagnose it that are rare!