No signs of neuroinflammation in women with chronic fatigue syndrome or Q fever fatigue syndrome using the TSPO ligand [11C]-PK11195, 2021

jaybee00

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https://europepmc.org/article/ppr/ppr306486
Background:

The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study we investigated neuroinflammation in female CFS and QFS patients compared with healthy women, using Positron Emission Tomography (PET) with the TSPO ligand [ 11 C]-PK11195. Methods The study population consisted of CFS patients (n = 9), QFS patients (n = 10), and healthy controls (n = 9). All subjects were women, matched for age (± 5 years) and neighbourhood, between 18 and 59 years of age, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last six months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview (MINI). All subjects underwent a [ 11 C]-PK11195 PET scan and the [ 11 C]-PK11195 binding potential (BP ND ) was calculated. Results No statistically significant differences in BP ND were found for CFS patients or QFS patients when compared to healthy controls. BP ND of [ 11 C]-PK11195 positively correlated with symptom severity scores in QFS patients, but a negative correlation was found in CFS patients. Conclusions In contrast to what was previously reported for CFS, we found no significant difference in BP ND of [ 11 C]-PK11195 when comparing CFS or QFS patients to healthy neighbourhood controls. In this small series we were unable to find signs of neuroinflammation in patients with CFS and QFS. Trial registration EudraCT number: 2014-004448-37
 

Judee

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How does a PET scan differ from a SPEC scan? I think I have heard that for ME/CFS a SPEC scan is the recommendation. Don't ask me where or why.

I just think it was because whatever it is that shows in our brains only shows up on SPEC. ???
 

Hip

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This new 2021 paper is in sharp contrast to the original Japanese 2014 study which also used [11C]PK11195 to detect microglial activation in ME/CFS patients, and found that microglia were indeed activated.

[11C]PK11195 binds to activated microglia in the brain, and is then detected via a PET scan.

I understand [11C]PK11195 is old technology these days, as better and more sensitive markers of microglial activation have been developed such as [18F]DPA-714. There is a new Japanese study underway using this, but I have not seen any results published yet.



Note that this new 2021 study involves Professor Jos W.M. Van der Meer, who is considered to be the Dutch Simon Wessely.

Professor Van der Meer has always been strongly opposed any biomedical explanation of ME/CFS. He does not believe ME/CFS is a real biological disease, but considers it an "all in the mind" condition.

I'd like to see the ME/CFS patient selection criteria they used in this 2021 study, and would like to know how sick the patients were that they recruited. If these were very mild patients, as opposed to moderate or severe patients, then that might explain why no microglial activation and brain inflammation were found.
 

Pyrrhus

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Here is a link to the full text of this pre-print: (it hasn't been peer-reviewed)
https://assets.researchsquare.com/files/rs-348289/v1/3fa863c2-ddb4-4767-b6e8-02e0bb7c8616.pdf

Due to the fact that the authors are prominent BioPsychoSocial (BPS) proponents, this pre-print has been received with some skepticism in the ME community. In particular, Dr. Mark Vink dissected this non-peer-reviewed pre-print in a Twitter thread.

Dr. Mark Vink notes that:
  1. The "CFS" patients were not tested for PEM or neurological symptoms.
  2. The "CFS" patients were not considered "post-infectious".
  3. The authors appear to have used outdated Fukuda diagnostic criteria, not currently accepted criteria.
  4. A previous study by these authors was debunked in a re-analysis.
 

livinglighter

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What will it seriously take for such groups of researchers to stop trying to contradict biophysical ME findings?

Did other poorly conditions such as MS, AIDS, etc. Have the same battle?

I’m hanging on to hope when I read positive findings but then these said groups of people are busy reinforcing psychosomatic beliefs.

How does the Fukuda and Oxford criteria get banned plain and straight? Or is this something that just has to be accepted will happens until a large enough study reveals something favourable?
 
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Pyrrhus

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Did other poorly conditions such as MS, AIDS, etc. Have the same battle?
Yes, there was a prominent U.C. Berkeley epidemiologist who spent years publishing about how HIV doesn't cause AIDS. He argued that AIDS was caused by drug use and destructive behaviors in the gay community. He even advised foreign governments on the development of their national AIDS strategy.
 

bensmith

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Sorry guys I’m just really frustrated, it’s like two steps forward two steps back.

Thanks @Pyrrhus for providing Mark Vink’s follow up.

Thanks @Ben for clarifying about the other illnesses.

I am learning the key thing here is to focus on what doctors can currently do for you.
trust me i get it. I’m having a bad day today and just so sick of being ill. Just the way of this crappy life. Hopefully we get help some day.
 

Pyrrhus

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Here's an interesting excerpt from the discussion section:

Although the set-up of this study was similar to that of Nakatomi et al., using the same TSPO ligand
([11C]-PK11195) (5), a number of important differences can be discerned.

First of all, for reasons of homogeneity, our study only included women. Around 75% of CFS patients are female and, although the percentage of women in QFS is lower (52%) (11, 31), we felt that we should avoid a gender effect in a study with such a small sample size. Nakatomi et al. included 30–40% males without presenting separate data for men and women (31).
[...]
A second difference between our study and that of Nakatomi et al. is that we distinguished CFS patients, with often heterogenic aetiologies (31), from post-infectious fatigue syndrome patients, i.e., QFS patients.
[...]
When using small numbers of included patients, as is the case in both studies, subtle differences like these might contribute to the different outcomes that are seen.

This brings us to a final difference, i.e., the method used for determining the binding of [11C]-PK11195. We
used pharmacokinetic binding with an arterial input function whereas Nakatomi et al. used the
cerebellum as a reference region in reference tissue modelling.
We feel that the latter is methodologically
less sound as no brain region is devoid of TSPO, meaning that the cerebellum is not an objective
reference region, and the cerebellum may actually be involved in the disease process. Whether binding of
the [11C]-PK11195 ligand is considered enhanced, normal or even lowered, may be explained by this
difference in methodology.
(spacing and emphasis added)

I think the last point is particularly important.

Yes, the authors are correct that Nakatomi et al.'s choice of the cerebellum as a reference region is indeed problematic, as I and others have previously pointed out. Here is what they say about their arterial input function:

The two-tissue compartment model was used to obtain the non-displaceable binding potential (BPnd) of
[11C]-PK11195, using the metabolite-corrected plasma curve as the input function. The delay and the blood volume were individually fitted. It was assumed that the distribution volume of the nondisplaceable compartment (K1/k2) and the dissociation rate (k4) from the specific binding site was equal for all regions. A coupled fitting was performed for cortical regions that calculated a common K1/k2 and k4, which were then used to calculate an individual K1 and k3 for all regions. The BPnd was defined as k3/k4.
Is a two-tissue compartment model sufficient to model distribution from the blood (first compartment), through the first part of the blood-brain-barrier into the Cerebrospinal Fluid (CSF) (second compartment), and then through the final part of the blood-brain-barrier into the brain parenchyma (third compartment)?

Can we assume that there is no miscalculation due to activated macrophages in the blood that could bind the TSPO ligand?
 
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mitoMAN

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I dont think neuroinflammation is a huge problem for mild-moderate patients. But defintely for severe - very severe patients. I have gone myself from mild to severe within a long 17 years. And my neurological symptoms changed SO MUCH!
Depending on selection of patients, the study will either be positive or negative.

1.
https://pubmed.ncbi.nlm.nih.gov/24665088/
Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study

@Pyrrhus made a good comparison of both studies posted by you and this one.

2.
https://pubmed.ncbi.nlm.nih.gov/29348371/
[Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]
Neuroinflammation
was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms

Article about it by Healthrising
https://www.healthrising.org/blog/2...mation-found-chronic-fatigue-syndrome-me-cfs/

3. Article by OMF -
MEA Summary Review: Study suggests brain inflammation in ME/CFS | 15 January 2019

https://www.omf.ngo/wp-content/uplo...unger-How-Brain-Inflammation-Causes-MECFS.pdf
Jarred Younger, PhD | How Brain Inflammation Causes ME/CFS

Article about it:
https://meassociation.org.uk/2019/0...brain-inflammation-in-me-cfs-15-january-2019/
Study:
https://link.springer.com/article/10.1007/s11682-018-0029-4

Good Video of Dr. Younger explaining:


4. First Mouse Model of Chronic Fatigue Syndrome
https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_html/-char/en
Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine


5. A neuro-inflammatory model to explain the onset, symptoms, and flare-ups of ME/CFS
https://ccisupport.org.nz/research/a-neuro-inflammatory-model/



A view Summaries:

https://me-pedia.org/wiki/Neuroinflammation

New #12
https://forums.phoenixrising.me/thr...le-olt1177-emapunil.82585/reply?quote=2333469
 

Pyrrhus

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Possibly relevant:
https://sci-hub.se/https://doi.org/10.1021/jm8011678
4.3. Immunomodulation. The presence of TSPO in a wide range of immunomodulatory cells such as microglia, blood monocytes, lymphocytes, and leukocytes implies TSPO involvement in immune response; however, the mechanism through which this occurs is largely unknown. Macrophages express high numbers of TSPO binding sites, and in mouse studies, TSPO ligands, specifically benzodiazepines, inhibit the capacity of macrophages to produce ROS and inflammatory cytokines such as IL-1, TNFR, and IL-6. Furthermore, TSPO is involved in the regulation of phagocyte oxidative metabolism, a process that is normally required for inducing effective elimination of foreign antigens.
 
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anni66

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From paper

The Japanese study included 30 to 40% males but did not report results separately. Inflammation is more prevalent in male mice models

Illness duration was longer than japanese study so inflammation may have been related to viral activity?

Did they control for stage in menstrual cycle ?