Webinar - ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study - Jarred Younger

[Trish]

I didn't think aerobic processes generated lactate. I thought they generated CO2 and water through the Krebs cycle.

I'm floundering a bit here, but I think his idea is that there's not enough oxygen getting to the cells for the krebs cycle to happen so much, so glycolysis is used instead, ie anaerobic respiration of glucose that results in lactate buildup.

I speculate that an alternative explanation rather than lack of oxygen could be the stuff about pyruvate dehydrogenase that Fluge and Mella and others have postulated that means people with ME may be relying more on glycolysis and less on the krebs cycle so only partially breaking down glucose and ending up with more lactate.

I agree that the idea of it being the microglia rather than the neurons that may be inflamed in those areas of the brain doesn't seem to be explained. He did say in answer to a question about why the microglia might be inflamed in these areas of the brain that he doesn't know the cause.

My take away from all this is that there is something interesting being found that distinguishes ME patients from those with RA and healthy controls, but no one knows what or why.

 

[Sasha]

If all this is happening in the brain, though, and JY's model is that this is the cause of ME/CFS, what about the findings in the muscles (or aren't there any we can trust) and the CPET results?

 

[Inara]

I came across heat shock proteins, and found this interesting:

One obvious explanation for thermal injury at the cellular level is direct heat damage (53). However, this cellular damage is likely due in part to functional impairment of a tissue or organ (e.g., reductions in blood flow) and the possible impact of systemic factors such as endotoxin-mediated cytokine production.

https://www.physiology.org/doi/full/10.1152/japplphysiol.01267.2001

 

[unicorn7]

Form what I understood from the video, they measured 4 different chemicals in different spots in the brain and the conclusions he draws are from the different levels of those chemicals and the temperature.

Choline was high in ME/cfs and choline is a marker for rapid cell turnover (happens in neuroinflammation).

N-acetylaspartate was normal and is a marker for neuronal health, so the conclusion is that it's not the neurons (nothing neurodegenerative, like MS), but the glial cells.

Lactate is high in ME/cfs in lots of regions in the brain, that's a sign of anaerobic activity. There should not be lactate in the brain, because you can never have more activity there than you have oxygen, so this is always pathological. It could also be that you don't get enough bloodsupply, but they ruled that out with another test, so they concluded that lactate is caused by higher (pathological) activity (neuroinflammation).

A lot of the spots where lactate was high, there was also high temperature. He does say that a higher temperature is a marker for inflammation.

Myo-inositol was not very much different in ME/cfs, he didn't say much about it, just showed that it was high in people with brain damage.

I was just thinking about that study that just came out of Van Campen et al. that showed that there is less blood-supply to the brain in ME/cfs patients? So that seems to contradict Jarred's idea that the blood-supply is normal.

 

[adambeyoncelowe]

If all this is happening in the brain, though, and JY's model is that this is the cause of ME/CFS, what about the findings in the muscles (or aren't there any we can trust) and the CPET results?

The peripheral symptoms could be secondary. For instance, if central signalling problems are shutting the body down, it might have a knock-on effect elsewhere.

Younger suggests that beta endorphin release, which is usually a positive experience for healthy people, might actually aggravate chronically activated microglia even more. This would then trigger a cascade of worsening symptoms.

But it's possible there are multiple things going on that produce the symptoms we recognise as ME. Some may be central, whereas others may take place in other parts of the body.

The other two main theories of PEM that I'm aware of are that a) it's bacteria crossing into the bloodstream from a leaky gut with dysbiosis, and from there causing an immune reaction throughout the body; or b) that mitochondria are depleting their stores of ATP faster than they can make more, using a shortcut that makes more lactic acid, resulting in delayed recovery while glucose is converted to D-ribose, which is in turn used to make more ATP. The latter would fit with the CPET studies.

There could be other biomedical theories I'm unaware of. There was a BPS theory that posited patients were hyperventilating during exercise, which was why they worsened after exertion, but the results disproved this (although that hasn't deterred some researchers from continuing to examine this line of enquiry).

 

[adambeyoncelowe]

Huh. So I just read Wikipedia, and there, under 'neuroinflammation', it says:

Chronic inflammation is the sustained activation of glial cells and recruitment of other immune cells into the brain.

Link: https://en.m.wikipedia.org/wiki/Neuroinflammation (under 'causes')

So Younger is using the term right.

ETA: The article also says exercise is being researched as a tool for dampening microglia. I wonder how that's gonna work out.

 

[Trish]

If all this is happening in the brain, though, and JY's model is that this is the cause of ME/CFS, what about the findings in the muscles (or aren't there any we can trust) and the CPET results?

I don't think he's saying it's the cause of ME, I think he's saying it could explain a lot of the symptoms of ME eg the 'sickness response' which caused flu like malaise. He did say he doesn't know the cause of the inflammation.

Form what I understood from the video, they measured 4 different chemicals in different spots in the brain and the conclusions he draws are from the different levels of those chemicals and the temperature.

Thank you. A much clearer explanation than mine.

 

[Jonathan Edwards]

A lot of the spots where lactate was high, there was also high temperature. He does say that a higher temperature is a marker for inflammation.

I think this is the problem. High temperature is unlikely to be a sign of inflammation in the brain. It is a sign of inflammation elsewhere. In fact that is what inflammation means - flaming - or hot and red. But in the brain the heat flow in relation to blood is reversed.

So Younger is using the term right.

My grouse is that although glial activation is a component of the inflammatory process in brain in general, what people now call 'neuroinflammation' is often just glial activation, without any recruitment of other immune cells. From my perspective it would be better simply to call it glial activation. That would bring in no unwanted inferences and be more precise.

 

[unicorn7]

So where does the heat come from?

It could be higher activity from cells in that area ( which correlates with lactate found in the same places).

Or it could be from lower circulation? But he specified that he didn’t find that (although other studies did find that).

Higher cell activity and lactacte forming is something that also might be happening in the cells in the body, so it might correlate with there being something wrong with the cell metabolism in the whole body.

 

[Lidia]

My understanding is that body temperature is set by the hypothalamus in response to various triggers, including immune response.

 

[alex3619]

I'm surprised at the increased brain temperature, when so many of us have distinctly lower body temperature. See https://forums.phoenixrising.me/ind...s-your-body-temperature-rethinking-98-6.1454/

Compensatory mechanism? Its the blood that cools the brain, so if you are cold you cool it better.

 

[alex3619]

another low dose drug I've forgotten

He never mentioned the name, only its a Naltrexone variant. Its not been tested on humans. Its specific, supposedly, for microglia or something. This is actually the big news for me, the rest is pending till after publication. Its big because an existing drug, even if not proven effective yet, could cut five years off the 10-20 year development cycle, presuming it works. That would make it a 5-15 year development cycle. I might even live long enough to try it. 20 years is pushing my probable life expectancy.

 

[alex3619]

The counter argument is that our problems with energy production in isolated blood cells shows a strong peripheral mechanism, mediated by blood. This does not run counter to the idea of central inflammation, but rather shows that central inflammation is not by itself a complete argument. For this to be causal then you would need a blood transmitted factor being produced that is shutting down metabolism. Presuming of course that the blood finding is correct.

 

[DokaGirl]

Excellent idea @Sasha, and @Andy. Thank you!

 

[Ravn]

The counter argument is that our problems with energy production in isolated blood cells shows a strong peripheral mechanism, mediated by blood. This does not run counter to the idea of central inflammation, but rather shows that central inflammation is not by itself a complete argument. For this to be causal then you would need a blood transmitted factor being produced that is shutting down metabolism. Presuming of course that the blood finding is correct.

Yes, JY clearly stated that the neuroinflammation he found wasn't the 'start' of ME, he doesn't know what causes said neuroinflammation in the first place.

There's another take on neuroinflammation discussed in this thread:
https://www.s4me.info/threads/a-com...ry-paradigm-for-me-cfs-2018-mackay-tate.7187/
That paper also posits neuroinflammation as central to ME and proposes that there must be an as yet unidentified 'endogenous' factor involved in triggering/perpetuating the inflammation. Could this be the mysterious 'factor in the blood'?

 

[adambeyoncelowe]

Yes, JY clearly stated that the neuroinflammation he found wasn't the 'start' of ME, he doesn't know what causes said neuroinflammation in the first place.

There's another take on neuroinflammation discussed in this thread:
https://www.s4me.info/threads/a-com...ry-paradigm-for-me-cfs-2018-mackay-tate.7187/
That paper also posits neuroinflammation as central to ME and proposes that there must be an as yet unidentified 'endogenous' factor involved in triggering/perpetuating the inflammation. Could this be the mysterious 'factor in the blood'?

The Ron Davis 'sticky blood' paper suggests microvascular problems impede the flow of blood in susceptible individuals and that this causes problems.

Les Simpson had a similar theory before Ron did, and Byron Hyde thinks microvascular problems are key to the problem too (though he focuses on their effects on the brain).

Similarly, both the London Revised and Ramsay criteria required circulatory impairment (though most symptoms in that category are found in others in CCC and ICC; usually they're under autonomic symptoms).

It's possible that two or more things have an interplay. For instance, it could be that a metabolic trap or a dauer state is causing blood to thicken, and thus starving muscles and brain of oxygen. But it could also, theoretically, be due to chronic dehydration and electrolyte depletion, themselves caused by ongoing bladder or GI problems.

In these theories, it's not clear whether the microvascular problems pose a risk in the first place, or whether they develop as a result of some change in homoeostasis.

Then you have to wonder how/if calcium channel problems might fit into the mix, or dorsal root ganglionitis, or the findings of the two-day CPET.

Anyway, these are all just theories. We might not know until we see some replication of some or all of these elements.

 

[Inara]

Does somebody know if Fractalkine was studied in ME?

Edit: Found it. Sorry.
Edit2: Jarred Younger looked at fractalkine?

 

[Fungi]

I've remembered another model for PEM: translocation of gut bacteria into the blood stream due to leaky gut-type issues. I can't remember where I read that one, though?

This is interesting. What if pesticides/growth hormones/antibiotics used on animals and food are crossing into the blood through a leaky gut. Or what if, when the body is busy fighting a virus some chemicals sneak in through the back door e.g. the gut. Just like a hacker bombards a company's email to keep the server busy, the server is unable to maintain a secure firewall. A hacker takes advantage of this to breach the security and get into areas of the network where they shouldn't be to wreak havoc on the network and cause the system to crash.

 

[alex3619]

Crossing of bacteria through the gut into the body is, even now, not well supported. Crossing of bacterial products, such as the superantigen lipopolysaccharides, are well supported. These are large molecules, so crossing of smaller molecules is very likely.

 

[Amw66]

The counter argument is that our problems with energy production in isolated blood cells shows a strong peripheral mechanism, mediated by blood. This does not run counter to the idea of central inflammation, but rather shows that central inflammation is not by itself a complete argument. For this to be causal then you would need a blood transmitted factor being produced that is shutting down metabolism. Presuming of course that the blood finding is correct.

The mysterious " something in the serum" ?