Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation (2018) Albrecht et al.

Cheshire

Cheshire

Senior Member (Voting Rights)
Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal.

Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables.

Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p’s ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p’s < 0.03). SUVR was not significantly associated with any other clinical variable.

Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
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https://www.sciencedirect.com/science/article/pii/S0889159118302423?via=ihub

And an article on the Karolinska Institute website:
https://ki.se/en/news/people-with-fibromyalgia-have-inflammation-of-the-brain
 
I found the following passage interesting with respect to a potential two (or multi)- hit model of onset (MIA = maternal immune activation) :

We propose that an immune challenge during prenatal development causes changes in microglial function in adulthood that shares common features with changes in microglial function in neurodegenerative diseases such as Alzheimer’s disease. Early-life events such as MIA might contribute to the neurogenic reserve by setting the basis on how an individual might withstand secondary challenges later in life.86

Lahiri et al.28 propose a 'Latent Early-life Associated Regulation' model, positing latent changes in the expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life.28

Our data provide evidence for this hypothesis on the level of microglia functionality.
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httpsw.nature.com/articles/tp201780://ww

While this relates to a mouse model of schizophrenia (and subsequent treatment with minocycline) , pre-natal priming of microglia could set up a situation where a later environmental insult (e.g. physical in fibromyalgia or viral in ME/CFS) appears to be the initial trigger rather than one of many possible triggers that tip already primed microglia into a chronic activated state?
 
Marco said:
pre-natal priming of microglia could set up a situation where a later environmental insult (e.g. physical in fibromyalgia or viral in ME/CFS) appears to be the initial trigger rather than one of many possible triggers that tip already primed microglia into a chronic activated state?
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It's an interesting idea but it doesn't seem relevant to my family's experience of ME. (That's not to say that it's not relevant to others.)

I did not suffer from any immune challenge that I am aware of during either of my pregnancies, and yet both of my children later developed what appears to be ME at the same time.
 
Merged thread

Source: EurekAlert

Date: September 27, 2018

URL:
https://www.eurekalert.org/pub_releases/2018-09/mgh-rtf092718.php

Research teams find widespread inflammation in the brains of fibromyalgia patients
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PET imaging studies at Mass. General Hospital, Karolinska Institutet reveal elevated glial activation, correlation with fatigue levels

A study by Massachusetts General Hospital (MGH) researchers - collaborating with a team at the Karolinska Institutet in Sweden - has documented for the first time widespread inflammation in the brains of patients with the poorly understood condition called fibromyalgia. Their report has been published online in the journal Brain, Behavior and Immunity.

'We don't have good treatment options for fibromyalgia, so identifying a potential treatment target could lead to the development of innovative, more effective therapies,' says Marco Loggia, PhD, of the MGH-based Martinos Center for Biomedical Imaging, co-senior author of the report.

'And finding objective neurochemical changes in the brains of patients with fibromyalgia should help reduce the persistent stigma that many patients face, often being told their symptoms are imaginary and there's nothing really wrong with them.'

Characterized by symptoms including chronic widespread pain, sleep problems, fatigue, and problems with thinking and memory, fibromyalgia affects around 4 million adults in the U.S., according to the Centers for Disease Control and Prevention. Previous research from the Karolinska group led by Eva Kosek, MD, PhD, co-senior author of the current study, suggested a potential role for neuroinflammation in the condition - including elevated levels of inflammatory proteins in the cerebrospinal fluid - but no previous study has directly visualized neuroinflammation in fibromyalgia patients.

A 2015 study by Loggia's team used combined MR/PET scanning to document neuroinflammation - specifically activation of glial cells - in the brains of patients with chronic back pain. Hypothesizing that similar glial activation might be found in fibromyalgia patients as well, his team used the same PET radiopharmaceutical, which binds to the translocator protein (TSPO) that is overexpressed by activated glial cells, in their study enrolling 20 fibromyalgia patients and 14 control volunteers.

More at
https://www.eurekalert.org/pub_releases/2018-09/mgh-rtf092718.php
 
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@Simon M @JaimeS @Andy @adambeyoncelowe @Inara
@Perrier


August 24, 2018 : One more target (TSPO Gene) identified previously by Machine Learning :


Screen Shot 2018-10-10 at 17.02.20.png



So far, Machine Learning was able to identify before any other Researcher these potential targets :

-Pyruvate Dehydrogenase (Fluge et. al)
-Phospholipid Metabolism dysregulation (Hanson et. al, Naviaux et. al)
- Fas Ligand (FASLG - Michael Sakora)
-Possibly impaired Liver function (Hanson et. al)


@Graham i would like to argue that there is a "Matrix" involved in ME/CFS Research as you suggested. It's the Selfish Gene at play.
 
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Merged thread

https://www.sciencedirect.com/science/article/pii/S0889159118302423?via=ihub#b0175

Very interesting article about neuroinflamation in FM, using PET-MRI with a tracer for glial activation.
I think it has lots of interesting information regarding LDN, Duloxetine and how to asses brain inflamation.
It also refers to the work of Jared Younger and Dr Nakatomi, from Japan.
There is Glial activity dected in the Cingulated Cortex in this FM study and in the Nakatomi study; and in this sudy this activity is associated with the severity of fatigue.
 
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leokitten said:
May I ask those who’ve been following FM research, is the evidence base for neuroinflammation in FM and stronger than in ME?
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I would argue against using the term neuroinflammation. It is a buzz word with too little precision. The 2018 study suggested some microglial activation. That does not amount to inflammation. I am not ware of anything much being reported since but I don't search on fibromyalgia.
 
Jonathan Edwards said:
I would argue against using the term neuroinflammation. It is a buzz word with too little precision. The 2018 study suggested some microglial activation. That does not amount to inflammation. I am not ware of anything much being reported since but I don't search on fibromyalgia.
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Ok, just wondering in relation to the recent Younger DXM trial not showing significant efficacy and whether the FM evidence base on microglial activation was stronger than in ME. They chose DXM because it inhibits microglia so wondered if it was a surprise that it didn’t work.

I personally have trialed multiple drugs that supposedly inhibit microglial activation and, like most others with ME, got no benefit from them. Even if we see microglial activation I think the research community doesn’t yet know what to make of it.
 
leokitten said:
Ok, just wondering in relation to the recent Younger DXM trial not showing significant efficacy and whether the FM evidence base on microglial activation was stronger than in ME. They chose DXM because it inhibits microglia so wondered if it was a surprise that it didn’t work.

I personally have trialed multiple drugs that supposedly inhibit microglial activation and, like most others with ME, got no benefit from them. Even if we see microglial activation I think the research community doesn’t yet know what to make of it.
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The other thing as @Jonathan Edwards the (Japenese) study, which found evidence of microglia activation, hasn't been replicated. Also, they used an old (not very specific) binding agent in that study; it was supposed to be replicated with one of the newer (more specific) binding agents but I don't recall a published second study.
 
FMMM1 said:
The other thing as @Jonathan Edwards the (Japenese) study, which found evidence of microglia activation, hasn't been replicated. Also, they used an old (not very specific) binding agent in that study; it was supposed to be replicated with one of the newer (more specific) binding agents but I don't recall a published second study.
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Hopefully this study will get published soon. They did a talk at a conference last year. I believe it does replicate some of what Nakatomi et al. found and I believe they used a 2nd gen radiotracer [11C]DPA-713 (Nakatomi used a 1st gen)

https://www.s4me.info/threads/tspo-pet-mri-reveals-increased-neuroinflammation-in-basal-ganglia-in-chronic-fatigue-syndrome-patients.16206/
 
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