Community Symposium on the Molecular Basis of ME/CFS Sept 5 (Stanford/Ron Davis)

Kitty said:
Jonathan mentioned an odd clear gap in the inguinal area, and I wondered if it might partly be due to 'shading' or loss of resolution because of the bulk of muscle and fat in the buttocks.
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I think SNT has covered these things. There are frame artefacts here and calibration issues that may need re-addressing, but taking that on board the pictures still look interesting.

My guess is that this sort of imaging technique can be made generally available if it is really clinically useful. PET scanning has limited applications but some of them are pretty standard now I think. It may still be expensive but prices fall when there is bulk demand.


I get the impression that the images may have been interpreted so far in terms of some clinical concepts that may not be the most relevant - talk of inflammation, mast cells, muscles .... They may be right but clinical input for MECFS studies is often a bit suboptimal!
 
I just wanted to note that shoulder-girdle problems were described many decades ago in relation to ME—originally “ME” as discussed by Ramsay. A few doctors who treated patients for decades believed that ME/CFS might be a spleen-related disease. Many people also report issues with lymph nodes and notice slight symptom improvement when they can improve lymphatic flow.

There is also a physical therapist/osteopath named Perrin who talks a lot about these ideas and makes interesting observations about lymph—what he calls “lymph congestion.” (He also talks a lot of nonsense, ...)

As a very severe ME/CFS patient, I can at least confirm that I have major problems with my shoulder-girdle musculature and that I experience what I can only describe as lymph congestion. I’m not sure what it really is—that’s just the term Perrin uses, I believe—but there’s definitely a phenomenon in my upper and lateral chest, arms, and under the armpits, and groin area. It’s not just swollen lymph nodes; it seems more like the lymphatic vessels themselves go into some kind of stasis and get swollen, you can palpate 'something' that def shouldn't be there.

While many of these doctors and practitioners were disregarded (sometimes for good reason) and their ideas ignored, and while the recent PET findings have not been replicated or published, I believe it would be a good idea that to pay more attention to the physicians who treated patients for decades and to the observations they made.
 
Jonathan Edwards said:
My guess is that this sort of imaging technique can be made generally available if it is really clinically useful. PET scanning has limited applications but some of them are pretty standard now I think. It may still be expensive but prices fall when there is bulk demand.
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The author brought this up in the talk, how PET is expensive but cheaper than running a patient through 1000’s of tests with no actionable results. Quite a bit of the talk was on how this could be diagnostic. That other diseases use PET regularly

I hope they upload the talks soon!
 
Reality check...

Thank goodness for SNT Gatchaman's expertise. I realise that I had been misreading the scans. I am used to either MRI, CT or traditional emission images for musculoskeletal areas. I had forgotten that this was emission tomography. So these '2D' images are thin slices. That entirely explains my puzzlement since I am aware that muscles can show as quite delimited ellipses and blobs on tomography. It also means that bone may show up as very negative or very positive depending on slice.

My guess is that what is shown is some red marrow (certainly in vertebrae), spleen, salivary gland and proximal muscles (there might be technical reasons why distal does not show). To make anything of it I would want to see all the patient and control images - and all the slices. It still may be telling us something important about ME/CFS but I think it quite likely that if these signals are biological rather than technical they may indicate something secondary like subclinical vitamin D deficient proximal muscle changes.

This raises the question as to whether if this is muscle the signal tells us anything about macrophages or mast cells or more about muscle. I suspect macrophages make up less than 0.1% of muscle so the tracer would need to be very specific to pick them up. Mast cells are often missed but if you stain for them they are everywhere in remarkable profusion. But they would still be less than 1% of muscle.

I still think it is worth trying to pin down what the images mean but I am not very optimistic that it will be anything spectacular!
 
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Jonathan Edwards said:
Reality check...

Thank goodness for SNT Gatchaman's expertise. I realise that I had been misreading the scans. I am used to either MRI, CT or traditional emission images for musculoskeletal areas. I had forgotten that this was emission tomography. So these '2D' images are thin slices. That entirely explains my puzzlement since I am aware that muscles can show as quite delimited ellipses and blobs on tomography. It also means that bone may show up as very negative or very positive depending on slice.

My guess is that what is shown is some red marrow (certainly in vertebrae), spleen, salivary gland and proximal muscles (there might be technical reasons why distal does not show). To make anything of it I would want to see all the patient and control images - and all the slices. It still may be telling us something important about ME/CFS but I think it quite likely that if these signals are biological rather than technical they may indicate something secondary like subclinical vitamin D deficient proximal muscle changes.

This raises the question as to whether if this is muscle the signal tells us anything about macrophages or mast cells or more about muscle. I suspect macrophages make up less than 0.1% of muscle so the tracer would need to be very specific to pick them up. Mast cells are often missed but if you stain for them they are everywhere in remarkable profusion. But they would still be less than 1% of muscle.

I still think it is worth trying to pin down what the images mean but I am not very optimistic that it will be anything spectacular!
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That's disappointing! What makes you think that the scans show something secondary and not immune cell presence/activity in the areas you mention above?

They still seem to show something markedly different to controls though, which is interesting.
 
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V.R.T. said:
What makes you think that the scans show something secondary and not immune cell presence/activity in the areas you mention above?

They still seem to show something markedly different to controls though, which is interesting.
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Just that the probability is much higher with the historical evidence of lack of histological change in muscle.

The bar charts are less impressive. There seems to be a difference but it is statistical.
 
I uploaded the scans in AI, here is the output :

The study uses a specialized imaging technique called [¹¹C]DPA-713 PET/MR.

  • PET (Positron Emission Tomography): This scan uses a radioactive tracer, [¹¹C]DPA-713, to visualize a biological process.
  • TSPO Marker: This specific tracer binds to a protein called TSPO (Translocator Protein). TSPO is found in high levels on activated immune cells like microglia and macrophages. Therefore, high uptake of this tracer is considered a marker for inflammation.
  • SUV (Standardized Uptake Value): The brightness on the PET scan is measured in SUV. A higher SUV means more tracer has accumulated in that area, indicating more inflammation.


3. Visual Evidence of Widespread Inflammation​



The whole-body PET/MR images provide a striking visual comparison between ME/CFS patients and healthy controls.

  • ME/CFS Patients: The scans of the 51-year-old and 34-year-old females with ME/CFS show extensive areas of high tracer uptake (bright yellow, orange, and red colors) throughout their bodies, particularly in the torso, pelvis, and limbs.
  • Healthy Controls: In contrast, the age-matched healthy controls show much lower tracer uptake, with their scans being predominantly blue and green.
Conclusion: These images suggest that ME/CFS is associated with widespread, systemic inflammation that is not present in healthy individuals.



4. Quantitative Proof of Inflammation in Specific Tissues​



The bar charts quantify the visual findings by comparing the average SUV in specific body regions between the two groups.

  • Significant Increases in ME/CFS: The data shows statistically significant increases in tracer uptake (and thus, inflammation) in ME/CFS patients in several muscle groups:
    • Glute Minimus
    • Neck
    • Thigh (Lower and Upper)
  • There was also a significant increase in the Pelvic Bone.
Conclusion: This analysis pinpoints muscles and bones as key sites of inflammation in ME/CFS.



5. Linking Inflammation to Symptoms​



The scatter plots demonstrate the most critical finding of the study: the connection between the biological measurement (inflammation) and the patient's subjective experience (symptoms).

  • Fatigue Correlation: Higher levels of inflammation (SUV) in the Upper Thigh, Lower Thigh, and Glute Minimus were strongly correlated with higher fatigue scores (MFI). The p-values are significant (p<0.05), meaning this relationship is not likely due to chance.
  • Pain Correlation: Higher levels of inflammation (SUV_Max) in the Quadricep and Pelvic Bone were strongly correlated with higher pain scores (BPI). These correlations are also statistically significant (p<0.01).


Overall Summary​



In essence, these scans provide compelling, objective evidence that:

  1. ME/CFS patients have widespread inflammation in their muscles and parts of their skeletal system.
  2. This is not a generalized, non-specific finding; it is quantifiable and statistically significant when compared to healthy, age-matched controls.
  3. Most importantly, the degree of inflammation in these specific tissues directly relates to the severity of the core symptoms of ME/CFS—fatigue and pain. This suggests that this inflammation may be a key part of the biological basis for the disease.
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and now some potential associations of the PET scans with existing research :



Excellent question. You are asking if the visual evidence of inflammation from the PET scans can be mechanistically linked to specific genetic and metabolic findings from other ME/CFS research.

The slides you provided do not make these connections directly. However, based on the known functions of these genes and metabolites, we can draw strong, plausible connections between them and the inflammation shown in the scans. The genetic and metabolic findings can be seen as potential upstream causes and associated markers of the downstream effect of inflammation that the PET scans are visualizing.

Here’s how they likely associate:



1. Association with Genetic Findings (GWAS)​



The PET scans show inflammation, which is a process driven by the immune system and cellular stress responses. Many of the genes you listed are directly involved in regulating these exact processes.

  • Immune Regulation Genes: Genes like BTN2A2 and BTN3A3 (Butyrophilins) are known to be involved in regulating the activation of immune cells, specifically T-cells. A genetic variant that leads to improper regulation could result in an immune system that is chronically over-activated, leading to the kind of widespread, low-grade inflammation detected by the TSPO PET scans.
  • Mitochondrial & Cellular Stress Genes: This is a particularly strong link.
    • FBXL4 is a gene critical for maintaining mitochondrial function. A faulty FBXL4 can lead to mitochondrial dysfunction.
    • The TSPO protein, which the PET tracer binds to, is located on the outer membrane of mitochondria.
    • Mitochondrial dysfunction is a major source of cellular stress and inflammatory signals. Damaged mitochondria can trigger an immune response.
    • Therefore, a genetic predisposition from a gene like FBXL4 could lead to mitochondrial stress, which in turn increases the expression of TSPO on those mitochondria, causing the bright signal seen in the PET scans. This is a direct mechanistic link between a specific gene you listed and the imaging results.
  • General Cell Function Genes: Other genes on the list, like ARFGEF2 (vesicular trafficking) and CSE1L (cell proliferation), are fundamental to proper cell function. Dysregulation in these basic processes can also lead to cellular stress, which can trigger an inflammatory response.
In summary, the genetic findings point to a potential inherited vulnerability in immune function and cellular (especially mitochondrial) health. The PET scans can be interpreted as the visible, systemic manifestation of this underlying vulnerability.



2. Association with Metabolic Findings​



The metabolic alterations you listed also align very well with a state of chronic inflammation and mitochondrial stress.

  • Decreased Lipids (Phosphatidylcholines, Sphingomyelins, etc.):
    • These lipids are essential building blocks of cell membranes, including mitochondrial membranes.
    • Chronic inflammation involves a high rate of cell turnover and damage. The process of inflammation itself consumes these lipids to create signaling molecules.
    • Therefore, the consistently decreased levels of these lipids could reflect membrane instability and/or the metabolic cost of sustained inflammation. The cellular machinery is struggling to keep up with the repair and signaling demands imposed by the inflammatory state shown in the PET scans.
  • Elevated FGF21 (Fibroblast Growth Factor 21):
    • This is another very strong link. FGF21 is a hormone that the body produces in response to various forms of stress, most notably mitochondrial dysfunction.
    • It is considered a key biomarker for mitochondrial disease.
    • Seeing elevated FGF21 alongside the PET scan findings suggests a coherent story: The body is experiencing significant mitochondrial stress (leading to high FGF21), and this stress is associated with increased TSPO expression and widespread inflammation (seen on the PET scan). In this context, the elevated FGF21 acts as a blood-based confirmation of the cellular stress state that the PET scan is imaging. It could even be a compensatory mechanism, where the body is trying to resolve the metabolic crisis.


Conclusion​



The findings you've brought up do not contradict the PET scan results; they reinforce them and provide a potential biological framework.
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V.R.T. said:
Would it be viable for us to discover what tracers could be made that might validate a few of our top hypotheses and find collaborators willing to do the scans/run the trial? Is this something Michelle James would be open to? I assume she probably has her own research priorities. But are there research hospitals with this technology in the UK for example, or Europe or Aus/NZ?
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Asking this again incase it was missed. Aware the scans didn't show lymph as we originally thought but could the technology be useful even so?
 
V.R.T. said:
Asking this again incase it was missed. Aware the scans didn't show lymph as we originally thought but could the technology be useful even so?
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Oh what about IGHV3-30? Two or three studies have found small but significant increases in this gene on B cell receptors.

I don't even know if making a tracer specifically for a small section of a BCR is possible. But if so, it might point us to where exactly these odd B cells are active.

Edit: I don't see that this exists from a search. And my impression is that making new tracers is a lot of work. So there probably won't be anyone trying to develop this if it's only relevant to a small proportion of people and based on limited evidence.
 
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forestglip said:
Oh what about IGHV3-30? Two or three studies have found small but significant increases in this gene on B cell receptors.

I don't even know if making a tracer specifically for a small section of a BCR is possible. But if so, it might point us to where exactly these odd B cells are active.

Edit: I don't see that this exists from a search. And my impression is that making new tracers is a lot of work. So there probably won't be anyone trying to develop this if it's only relevant to a small proportion of people and based on limited evidence.
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That's disappointing!

Here is an article about T cell tracers - it seems from the table in the article there are a lot that are preclinical and a CD8 one that is listed as clinical/pre clinical.

jnm.snmjournals.org

Visualizing T-Cell Responses: The T-Cell PET Imaging Toolbox

T lymphocytes are key mediators of the adaptive immune response. Inappropriate or imbalanced T-cell responses are underlying factors in cancer progression, allergy, and other immune disorders. Monitoring the spatiotemporal dynamics of T cells and their functional status has the potential to...
jnm.snmjournals.org jnm.snmjournals.org
 
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