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Second study confirms neuroinflammation in ME subcortical brain

Pyrrhus

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Many of you will remember the landmark Japanese study from 2014 that used PET tracers to detect and image neuroinflammation in the brains of ME patients. Previously, no one had the technology to detect and image neuroinflammation in ME, as standard MRI's are totally unable to detect or image neuroinflammation at all. They found that the neuroinflammation in ME patients were largely based in the subcortical region of the brain, including the brainstem at the top of the spinal cord.
https://pubmed.ncbi.nlm.nih.gov/24665088/

At the time, I asked Tony Komaroff if this means that the term "encephalomyelitis" can now be considered accurate, and he answered "Yes, if these results are independently confirmed."

Now it looks like these results may have been (partially) replicated. A doctoral student in the James lab at Stanford will be presenting a talk, a typical prelude to a publication, showing how she detected and imaged neuroinflammation in a specific part of the subcortical brain in ME patients. Specifically, she looked at a part of the subcortical brain called the basal ganglia. Although the Japanese study didn't highlight neuroinflammation in the basal ganglia, the Japanese study did highlight significant neuroinflammation surrounding the basal ganglia, especially in the thalamus and amygdala.

From the Japanese 2014 paper:
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. ... We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. ... Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. ... Region-of-interest analysis revealed that 11C- (R)-PK11195 BPND values in CFS/ME patients were significantly higher than those in healthy controls in the cingulate, hippocampus, thalamus, midbrain, and pons and tended to be higher in the amygdala (Table 2).

And here is the tweet about the work from the doctoral student in the James lab at Stanford:

We will have to wait for the new publication before we can make a more thorough comparison of the two studies.

Thread and blog on the 2014 paper:
https://forums.phoenixrising.me/threads/neuroinflammation-in-patients-with-cfs-me-pet-study.29219/
https://forums.phoenixrising.me/thr...uroinflammation-encephalitis-in-me-cfs.29941/

Other related threads:
https://forums.phoenixrising.me/threads/neuroinflammation-may-cause-mental-sluggishness.78409/
https://forums.phoenixrising.me/thr...flammation-july-18th-2020-by-amy-proal.80788/
https://forums.phoenixrising.me/thr...-a-critical-review-of-research-methods.76890/

Neuroinflammation in fibromyalgia and post-treatment Lyme:
https://forums.phoenixrising.me/thr...mmation-in-post-treatment-lyme-disease.75319/
https://forums.phoenixrising.me/thr...in-the-brains-of-fibromyalgia-patients.61667/
 
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Diwi9

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@Pyrrhus - Thank you for sharing this!

During my onset, on a number of occasions I felt like my head had concrete in it. I even experienced derealization at times. As I have improved from those early days, cognitive dysfunction (namely processing speed and working memory) and sensory issues (especially sound and vision) remain troubling. I am thankful that the brain is being examined, because even if my physical fatigue, stamina, and pain cannot be dealt with, I'd like to have my full brain function so that I could work from home one day.
 

Cinders66

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It sounds like a very small study?

I think that i saw cort say the Japanese themselves are publishing a replication paper soon.

it’s frustrating because it doesn’t seem to be that some studies are not showing inflammation it’s just that hardly any neuroinflammaction studies have/are being done which is pretty sucky when you consider the name M. Encephalomyelitis. I speak as someone who’s just woken up feeling like my brains been over zapped in a microwave.
 

percyval577

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it’s frustrating because it doesn’t seem to be that some studies are not showing inflammation it’s just that hardly any neuroinflammaction studies have/are being done which is pretty sucky when you consider the name M. Encephalomyelitis
Yes, but inflammation may not equal inflammation. The early findings that have coined the name couldn´t get refound in most of the cases, but this doesn´t mean that they are meaningless.

The japanese PET study, here now replicated for the basal ganglia, found TSPO elevated, if I remember rightly, a molecule which is known to be elevated in inflammation. But there might be other tasks for it, not only in typical inflammation or so.

The other findings from neuro imaging have been indeed partly inconsistent, so far. But the findings may only have investigated effects up- or downstream, and might therefore vary.

So all in all, not bad news here. I think, it´s even good and important news.
 
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percyval577

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I just had a short glance at the review Li et al 2015 PMC4567528/ doi: 10.1016/j.phrs.2015.03.022

Perspective: Evolving understanding of translocator protein 18 kD (TSPO)

page six says
Beyond its potential role as a transporter, TSPO could also act as a receptor or sensor, in line with its function in Rhodobacter where RsTSPO is part of a regulatory process that facilitates the switch between photosynthesis and respiration in response to changes in light and oxygen conditions. The role of RsTSPO in this signaling path appears to involve porphyrin transport and regulation of photosynthetic genes [21,22]; however, given the location of TSPO in the outer membrane of mitochondria in higher organisms, it is hard to visualize a similar stress response mechanism. In plants and cyanobacteria, it has been shown that the knockout of a TSPO homolog is significantly less sensitive to salt stress [56]. In contrast, when Arabidopsis is challenged with oxidative stress by porphyrin-induced cytotoxicity, TSPO overexpression protects against chlorosis [32, 57]. The role of TSPO in these stress responses remains to be determined. The elevated expression level of TSPO under various stressful conditions, such as oxidative stress, salt stress and inflammation in bacteria, plants and animals, suggests an evolutionarily conserved stress sensing or stress combating role for TSPO. Considering the ability of TSPO to bind and potentially transport porphyrin compounds, high levels of TSPO could provide a mechanism for alleviating oxidative stress, through favoring the removal [21,58] or degradation of porphyrin [27].
I think this is very hot. It´s possibly a switch on and off for different energy porductions, which could be crusial in the basal ganglia, say for encoding a forward firing vs a lateral firing. And it possibly reacts to salt stress, which would be in line with the Davis finding in white blood cells.

I think a malfunction of the basal ganglia are understandable with a lot of symptoms, including downstream and/or side effects say in blood cells or the gut from which mechanism ever.

To me it makes perfectly sense. Hope it will hold the water.
 

MonkeyMan

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It would be wonderful if this means we are getting closer to a definite bio-marker. My brain so often feels swollen.
Yes - mine too. The only thing that gives me mental clarity - medical marijuana - has a nasty effect on me for many weeks after I use it: my brain feels like a piece of concrete and I suffer from increased mental fogginess.

Any other medical marijuana users out there who have the same experience?
 

Countrygirl

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When I had a brain scan in 2008, one of the brain abnormalities mentioned was that the right half of the basal ganglia was obliterated. In another scan in 2018, most of the left half was also destroyed, leaving very little of the BG remaining. Could this be explained by the above findings?
 

Pyrrhus

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When I had a brain scan in 2008, one of the brain abnormalities mentioned was that the right half of the basal ganglia was obliterated. In another scan in 2018, most of the left half was also destroyed, leaving very little of the BG remaining. Could this be explained by the above findings?
So sorry to hear about those findings, Countrygirl. That sounds a bit scary.

The studies mentioned above only imply that there is neuroinflammation in the basal ganglia. It does not address what is causing this neuroinflammation. It could be a viral infection, an autoimmune process, clogged lenticulo-striate arteries, or something else entirely.

Best wishes.
 
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pattismith

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Yes, but inflammation may not equal inflammation. The early findings that have coined the name couldn´t get refound in most of the cases, but this doesn´t mean that they are meaningless.

The japanese PET study, here now replicated for the basal ganglia, found TSPO elevated, if I remember rightly, a molecule which is known to be elevated in inflammation. But there might be other tasks for it, not only in typical inflammation or so.

The other findings from neuro imaging have been indeed partly inconsistent, so far. But the findings may only have investigated effects up- or downstream, and might therefore vary.

So all in all, not bad news here. I think, it´s even good and important news.
In-vivo imaging of neuroinflammation in veterans with Gulf War illness

ZeynabAlshelha1Daniel S.Albrechta1CourtneyBerganaOluwaseunAkejubDaniel J.ClauwcLisaConboydRobert R.EdwardseMinhaeKimaYvonne C.LeefEkaterinaProtsenkoaVitalyNapadowaeKimberlySullivangMarco L.Loggiaa


Highlights


Gulf war illness (GWI) is a chronic condition characterised by musculoskeletal pain, cognitive problems and fatigue.

Levels of translocator protein (TSPO), a marker of neuroinflammation, are increased in the brain of veterans with GWI.

These results support a role for neuroinflammation in GWI.

Abstract
Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue.

The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role.

Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes.

However, neuroinflammation has not previously been directly observed in veterans with GWI.

To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes.


Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13).

Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices.

There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines.

Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.
 

Pyrrhus

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Yes, but inflammation may not equal inflammation.
Thanks, percyval, for raising this very important issue. There is a lot of confusion between Neuroinflammation and Classical (Greco-Roman) Inflammation. I will try to explain the difference.

Neuroinflammation is a term that came into usage in the research community around 2004. It is used to describe immune activation of the resident immune cells in the central nervous system (CNS).[1][2] This contrasts with classical Greco-Roman inflammation, which was originally defined as swelling, redness, heat, and pain, but has come to mean infiltration of tissues by blood-borne immune cells.

Unlike classical inflammation, neuroinflammation does NOT imply infiltration of tissues by blood-borne immune cells, it only implies immune activation of the resident immune cells in the CNS. As such, the term “neuroinflammation” must not be confused with the term “encephalitis", which has traditionally implied classical inflammation. (Although "traditional" usage can change over time.) Because of this distinction, the relatively recent term “neuroinflammation” has generated considerable confusion in the scientific community.[3]

The immune cells in the CNS that are activated in neuroinflammation are the tissue-resident macrophages of the CNS, which, for purely historical reasons, are also called microglia.[1][4] Like other macrophages, they fight infections and repair tissue damage.[5] In the case of minor infections or minor tissue damage, these tissue-resident macrophages can often resolve the situation on their own. Only in more serious situations, the tissue-resident macrophages will secrete cytokines to attract help from blood-borne immune cells, which is then where classical inflammation comes into play.

References
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431634/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC483051/
[3] https://pubmed.ncbi.nlm.nih.gov/21889505/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719181/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025335/
 
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Pyrrhus

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The Japanese PET study, here now replicated for the basal ganglia, found TSPO elevated, if I remember rightly, a molecule which is known to be elevated in inflammation. But there might be other tasks for it, not only in typical inflammation or so.
Thanks for raising this other important point.

In order to detect neuroinflammation, you need to detect an immune-activated tissue-resident macrophage. Under the microscope, this is easy to do. An inactive tissue-resident macrophage just looks like a blob sitting around, while an immune-activated tissue-resident macrophage looks like a spiky blob running around looking for something to do.

But that's in vitro. In vivo, it's a bit more complicated. To detect an immune-activated tissue-resident macrophage in a living brain, you have to find a biomarker that is expressed by an immune-activated tissue-resident macrophage but that is NOT expressed by an inactive tissue-resident macrophage. This is where the translocator (TSPO) protein comes into play. (This protein used to be called the peripheral benzodiazepine receptor, or just PBR).

TSPO is expressed by a tissue-resident macrophage when it becomes immune-activated. Therefore, if we can image the regions where TSPO is expressed, we can get a good idea of where the neuroinflammation is. In general, this approach has proved itself quite useful over the last decade or so.

But TSPO is also expressed by another type of brain cell, called an astrocyte. And there is a baseline low-level of TSPO expression throughout the brain, providing a slight background signal. In order to image areas of the brain that have much higher-than-baseline levels of TSPO, we need to subtract out this background signal.

Traditionally, this is done by subtracting out the signal found in the cerebellum, which assumes that there is no neuroinflammation in the cerebellum. This may not be a good assumption in the case of ME/CFS, where patients routinely fail the Romberg test, raising the question of how to more reliably subtract out the background signal. The standard use of the cerebellar signal as a proxy for background TSPO expression may need to be reconsidered in the case of ME/CFS.

So, in the future, we may one day find a more sensitive and specific biomarker for neuroinflammation, better than TSPO. Ideally, this would be one that is wholly unique to immune-activated tissue-resident macrophages, with no need to subtract any background signal.
 

Marylib

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@Pyrrhus At the time, I asked Tony Komaroff if this means that the term "encephalomyelitis" can now be considered accurate, and he answered "Yes, if these results are independently confirmed."

I was at that conference and I remember your asking that question after Tony's summary. At the time, I was trying to help some people transcribe that summary. Thanks for keeping an eye on this line of research, and for your detailed explanations. It will be interesting to read the new paper once it's published.
 

Pyrrhus

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I was at that conference and I remember your asking that question after Tony's summary. At the time, I was trying to help some people transcribe that summary. Thanks for keeping an eye on this line of research, and for your detailed explanations. It will be interesting to read the new paper once it's published.
And I remember Nancy Klimas (or someone near her) let out an audible gasp when she heard his response!

It's sad, though, that it's taken six years to get a partial replication. Some of us behind the scenes were pushing to have it replicated in 2015. Some researchers showed real interest, but life always gets in the way, and the funding and expertise just didn't seem to be there at the time...
 
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pattismith

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So, in the future, we may one day find a more sensitive and specific biomarker for neuroinflammation, better than TSPO. Ideally, this would be one that is wholly unique to immune-activated tissue-resident macrophages, with no need to subtract any background signal.
some articles I read propose P2X7 as a new marker for neuroinflammation.
However, it may be more useful in acute neuroinfammation than in chronic one, as shown in Parkinson.

(I can find many new papers linking neuroinflammation to P2X7 upregulation in neurodegenerative diseases)
 
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I have a genetic change at P2RY2. Because it plays a role at muscle contraction and neurotransmitssion. maybe it is a reason, why I have sometimes problems with my muscles, who knows...

I found this info in the net:

P2Y receptor signaling is mediated through coupling to G proteins, mainly Gq/11, with P2Y12, P2Y13 and P2Y14 signaling through Gi/o. Activation of P2Y receptors initiates a wide range of signaling cascades including PLCbeta, PLD, PLA2, AC and MAPK/MEK kinase. P2Y receptors are found in most human tissues. They have diverse physiological roles including regulation of platelet aggregation, muscle contraction, neurotransmission, and epithelial cell communication and migration.
http://www.genecards.org/cgi-bin/carddisp.pl?gene=P2RY2&keywords=P2RY2
 

MonkeyMan

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No, I would not describe experiencing-that. Can you clarify- What is mental clarity followed by fogginess?
Sure! If I use medical marijuana I become extraordinarily (100%) clear-headed for the whole day, and even extending into the next. But then after that, I pay the price: poor sleep, night after night, along with a heavy, swollen feeling in my head. And all the mental clarity I enjoyed is replaced with brain fog. It's terribly frustrating.
 
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It's terribly frustrating.
Odd. Its a remarkable anti-inflammatory. Everything thats swelling and throbbing- is less so after using some of that. Everything hurting, hurts less. Nauseated- less. My doctor even wrote me an Rx after hearing about the bowel shut down I experienced from their anti nausea pill.

Its not. a provider of mental clarity for me- yet there is a form of increased clarity because of this less inflamed condition and it seems: more energy is available- that ATP are firing to some degree when they weren't before.
 

Mary

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@Pyrrhus - I don't know if it was your explanation or my brain is working better today, but your two posts above re inflammation and TSPO (this one and this one) were amazingly easy to follow and comprehend. Ordinarily I would get about two sentences in and then go to the end, trying to just get the heart of the matter. But I read each one through in its entirety with no difficulty, so thank you!