Discussion - Does ME involve brain inflammation?

In that case if we can't show this is the case we should abandon the theory that neuroinflammation is the cause of depression.
I can't see this happening...

 

When it comes to the effects of low-grade inflammation in the brain and how this might cause the mental health conditions it has been linked to (which include major depression, bipolar, OCD, schizophrenia and the cognitive symptoms of ME/CFS), the answer might lie in the way the neuroinflammation affects neurotransmitters, particularly glutamate.

Activated microglia are known to secrete a large amount of glutamate via their glutamate transporters. Ref: here.

And glutamate released from activated microglia down-regulates astrocyte glutamate transporters (whose function is to remove glutamate from the brain's extracellular spaces): this leads to the 'collusion' hypothesis for even further increases in extracellular glutamate in neuroinflammation. Ref: here.

One Japanese study determined that chronic microglial activation occurs in ME/CFS.

Chronic microglial activation has been shown to be caused by persistent coxsackievirus B infections of the central nervous system (which are found in ME/CFS). Coxsackievirus B can chronically infect astrocytes. Also, HHV-6 has the ability infect astrocyte cells and dysregulate their glutamate clearance mechanisms.

Other diseases or conditions which involve chronic microglial activation include: hepatitis C virus infection, Lyme neuroborreliosis, systemic lupus erythematosus, schizophrenia and bipolar disorder.

Rönnbäck and Hansson hypothesized that one of the reasons IL-1β, TNF-α and IL-6 cause mental fatigue and cognitive dysfunction is because these cytokines impede the clearance of glutamate performed by astrocyte cells, leading to raised levels of extracellular glutamate in the brain, which they hypothesize may affect neurotransmission.



So although low-grade neuroinflammation may not do much in terms of observable physical effects on the brain, it may nevertheless still modify neurotransmitters in a way that creates mental or cognitive symptoms.

 

I am on a good Cfs stage where
I am mostly in remission must of the time and what I can tell is when I feel inflamed. Cannot tell you what it is, but I even get bumps in the head. Ussually on the top left or right. One time I had it on the forehead pretty obvious. Some plp tell me my face swells when I am inflamed. I also have the inflammatory citokines through the roof so I can tell ( I cannot sleep, titunus gets very pronounce....

 

The Baraniuk paper is very interesting but this is not a typical inflammatory protein pattern. I think Komaroff tends to grossly oversimplify the analysis. It looks from the Baraniuk study as if there is some cellular change either in brain or meninges but I do not think we can call this 'encephalitis' or even usefully 'neuroinflammation'.

The other paper found an unusual pattern of proteins but the methodology is strange and when looking at so many variables it is always hard to know if it is not just a chance finding. I don't remember the proteins in the two studies coming up the same - which is what would be meaningful.

 

I wonder how many people actually think depression is due to neuroinflammation and on what grounds? What gets published in reviews in the literature is most drivel these days - all marketing for grant applications. But if neuroinflammation causes both depression and ME then presumably ME is just depression? This is the sort of level of analysis that is making medical science a joke these days

 

I think it starts at the meninges and that changes the signaling.

It is not classic inflammation.

 

Microglials can also be activated by mast cells.

 

Perhaps a little off topic, Admin please move if you like.

How many of us, have a “ME/CFS” diagnosis from GP/clinic, but have not seen a consultant or had any sort of scans done?

I am in the U.K. Saw a Consultant in 2001 when they ruled out M.S. (only by hands on tests) and diagnosed me with PVFS which I gradually recovered from, eventually to about 90-95% capacity.

Repeated infections led to Sepsis 2013 (via resistant antibiotic) led to relapse and ME(/CFS) diagnosis. Would put myself at 35-40% capacity?

2013 onwards. No Consultant, no scans, a few blood tests.

 

that's me since 2001

 

I think there is a general trend in psychiatry to think that mental illness has to start in the brain, whether it's psychosocial or neuroinflammation. It's much more likely that at least some part of depression/anxiety comes from low grade inflammation in the gut, which affects the brain, but as far as I can tell there's very little good research into that.

 

Inflammation in the gut may also be part of the picture, as inflammation in the peripheral organs such as the gut are known to trigger nerve signals sent to the brain (via the vagus nerve) which instruct the brain to ramp up its own internal state immune activation. So in this way, peripheral inflammation can ramp up brain inflammation. A nice paper on this is here:

From inflammation to sickness and depression: when the immune system subjugates the brain

If you already have a low-level persistent infection in the brain (which post-mortem studies found in ME/CFS), then you will have some low-grade neuroinflammation to start with; but if there is also a low-level persistent infection in the gut (which studies have also shown to exist ME/CFS), then conceivably there may be an additive effect, in which the gut inflammation further exacerbates the existing brain inflammation.

One additional factor that might be involved is immune priming, which is where a previous exposure to a pathogen and its antigens sensitizes ("primes") the immune system, such that on any subsequent exposures, the immune response will kick in fast and strong even when that pathogen is present at very low levels. So in this way, even a low-level infection may produce a substantial immune response.

 

This is what seems to make the most sense to myself and how I experience symptoms.

Do you think it's possible that for whatever reason the immune system gets primed against commensal bacteria in the gut and looses tolerance?
I think I have seen some studies on immune reaction to microbiome in ME/CFS, but I don't remember where or how significant their findings were.

 

I don't know, I have not seen much about immune priming and the gut microbiome, but it's interesting that immune priming involves the up-regulation of Toll-like receptors (TLR, see this post), so that is part of the immune sensitization.

Then given that TLR4 is triggered by LPS from Gram-negative bacteria, TLR2 by many pathogen antigens, and TLR3 by viral dsRNA, its possible that the conditions in an enterovirus-infected gut with additional bacterial dysbiosis could be triggering an exaggerated immune response, because of a sensitized primed immune state.

 

This is what irritates me on ME research, we shouldn’t be spending years discussing hypotheticals, we can either use the tools out there to assess things or not. I saw the lancet are hosting a conference on effects of inflammation and immunity on the brain & mind conditions. Ofcourse ME isn’t featured (going back to the other thread on whether the medical profession regard our illness has a serious biological basis, they don’t because we know we won’t be included in such things) but MS and Alzheimer’s and depression , narcolepsy schizophrenia etc is. Interestingly Hugh Parry, formerly of the CMRC, is presenting on manipulating microglial in degenerative neurological conditions, so this is clearly an area he’s big on yet the CMRC, obsessing on genetics, has done nothing to further PET scan ME research endeavour in the U.K. so we haven’t had the 2014 Japanese stuff replicated, yet. But on the bright side, once we have proven microglial activation in ME we might be able to apply the stuff they’re working on.

http://www.thelancetsummit.com/resources/updateable/pdf/24555_LNEU2018_Program_website_04.06.pdf

 

I understand that the Japanese are planning a replication study, using a more sensitive marker of microglial activation. The original Japanese study used PK11195 which binds to activated microglia and then is detected in a brain scan. But I've read PK11195 is old hat theses days, as better activated microglial binders are available.

But whether low-grade neuroinflammation accounts for none, some or all of the cognitive and mental symptoms of ME/CFS is an unanswered question.

 

I saw a diagram showing FOXO has something to do with blood vessel formation