Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study, 6/2023, Mueller, et al

Jared Younger's group. The journal is "PAIN". The text is behind a paywall.

Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study.

Mueller, Christinaa,*; Fang, Yu-Hua D.b; Jones, Chloec; McConathy, Jonathan E.d; Raman, Fabiod; Lapi, Suzanne E.d; Younger, Jarred W.c

This observational study aimed to determine whether individuals with fibromyalgia (FM) exhibit higher levels of neuroinflammation than healthy controls (HCs), as measured with positron emission tomography using [18F]DPA-714, a second-generation radioligand for the translocator protein (TSPO). Fifteen women with FM and 10 HCs underwent neuroimaging. Distribution volume (VT) was calculated for in 28 regions of interest (ROIs) using Logan graphical analysis and compared between groups using multiple linear regressions. Group (FM vs HC) was the main predictor of interest and TSPO binding status (high- vs mixed-affinity) was added as a covariate. The FM group had higher VT in the right postcentral gyrus (b = 0.477, P = 0.033), right occipital gray matter (GM; b = 0.438, P= 0.039), and the right temporal GM (b = 0.466, P = 0.042). The FM group also had lower VT than HCs in the left isthmus of the cingulate gyrus (b = −0.553, P = 0.014). In the subgroup of high-affinity binders, the FM group had higher VT in the bilateral precuneus, postcentral gyrus, parietal GM, occipital GM, and supramarginal gyrus. Group differences in the right parietal GM were associated with decreased quality of life, higher pain severity and interference, and cognitive problems. In support of our hypothesis, we found increased radioligand binding (VT) in the FM group compared with HCs in several brain regions regardless of participants' TSPO binding status. The ROIs overlapped with prior reports of increased TSPO binding in FM. Overall, increasing evidence supports the hypothesis that FM involves microglia-mediated neuroinflammation in the brain.

https://journals.lww.com/pain/Abstract/9900/Evidence_of_neuroinflammation_in_fibromyalgia.335.aspx

 

no paywall here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502894/

Younger briefly discusses the study here:

https://www.youtube.com/watch?v=GS8rgE9HKSU

 

Wow, this paper has been gathering dust in this corner of S4ME. So, Younger's lab is coming up with similar study with ME/CFS with 20 patients. My guess would be that it'll show similar results as FMS study. If the methodology is correct, i.e. the protein binding means activated microglial cells, then it is a conclusive proof of neuroinflammation, I would think. Assuming the study gets replicated, of course.

The key sentence in the video: there is no drug to calm down microglia yet. Which means no treatment even if the hypothesis turned out to be true. I've read somewhere though, dopamine downregulates activated microglia. (It was a Chinese paper and I can't find it in PubMed anymore for some reason).

 

What is causing the microglaia to be activated?

 

That's the million dollar question if this is actually happening. As far as I am aware a few possibilities are: reduced cerebral blood flow, some issue with the glial cells becoming sensitized themselves, an excess metabolite, signaling from other parts of the body through things like the Vegas nerve. I'm sure there are other possibilities too.

 

Maybe because nobody could work out what it means?
I tried to understand it but it is couched in so much jargon that I could not work out even what they were measuring. They seem to have found increased 'distribution volume' in some places but less in another with p values that look marginal. The pictures show a few small blobs, the meaning of which is completely obscure to me and does not look at all like inflammatory foci.

In ME studies looking at microglial activation labels have not given a consistent answer. The first Nakatomi study looked potentially interesting but the pictures didn't look to me very convincing and it was not replicated.

Neuroinflammation is a pretty unhelpful term, as has been pointed out at major scientific meetings by people who thought they were studying it. Microglial activation can occur secondary to all sorts of brain changes and is best simply discussed as microglial activation I think.

 

Thanks for chiming in and clarifying; attempting to read it gave me a headache, LOL! They appeared to have used different tracer from Nakatomi study though, so I was thinking maybe it's something new. ME/CFS study of the same is a bit bigger and being funded by NIH, I think. I hope that it'll be a bit more conclusive and garner a replication attempt.

 

There have been some reports of cells like monocytes becoming sensitive and activated after COVID. Since microglia are of the similar class, maybe they are getting sensitive through the same mechanism. Assuming the reports of monocytes getting sensitive are correct.
Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity - PubMed (nih.gov)

 

That study is underwhelming. They found some shifts in gene expression in circulating monocyte including it seems more CD16 (the main marker of 'non-classical' state). This sort of 'activation' of monocytes in the absence of something straightforward such as raised CRP or ESR is pretty hard to interpret since monocytes do not do much until they have emigrated into tissues. The changes are most likely to be due to shifts in maturation relating to antigen clearance by antibody and complement engagement. Antibody does not get into brain much and CD16+ macrophages are largely absent from brain. Brain is also largely closed off from inflammatory cells and mediators of other sorts.

The Nakatomi study showed diffuse symmetrical signal largely in mid brain, which does not make a lot of sense in terms of inflammation other than perhaps as a response to some midbrain degenerative process. The Younger study shows strange isolated hot spots (I think) in just one or two sites on a brain slice. That doesn't make a lot of sene in inflammation terms either except perhaps as a response to micro infarcts.

I worry that these studies are done by people who do not have a broad understanding of the relevant clinical and radiological backgrounds and that, like the NIH 'deep phenotypic' study a few odd readings are being clutched at as the only straws in otherwise negative findings.