frontiers in Neurology: Neuroinflammation and cytokines in ME/CFS: A critical review of research methods - Michael VanElzakker et al - 2018

[Kalliope]

Review article is provisionally accepted and full text will be published soon

Neuroinflammation and cytokines in ME/CFS: A critical review of research methods

We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies. We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.

 

[Sly Saint]

I know this is from a few years ago but has it been completely ruled out?:

 

[Forbin]

I know this is from a few years ago but has it been completely ruled out?

I think this (the Columbia study in the video above) was more about showing a trend in a large group of patients (~300) vs controls, rather than producing "a consistent and replicable diagnostic cytokine profile" for individual patients.

 

[Kalliope]

Merged thread - full paper now published

Neuroinflammation and Cytokines in ME/CFS: A Critical Review of Research Methods

Conclusion
The above review focused on neuroinflammation and the methods used to measure it. We argued for the importance of anchoring methodological details in known biological mechanisms and existing research literature.

The ME/CFS research field has been stuck in a somewhat defensive posture, with a focus on demonstrating “this is a real condition” by showing significant biological differences between patients and controls. We believe this has led to a situation in which too much is made of the specifics reported by descriptive studies (such as the average “cytokine profile” present in cases vs. controls at the moment of assay) and not enough emphasis has been placed on potential mechanisms driving symptoms. The field is ready to move past proving “this is a real condition” and to start elucidating the specific relationship of ME/CFS symptoms to neuroinflammation.

Moving past a defensive posture and toward understanding pathophysiology requires careful focus on research methods. In designing a study, a goal of ME/CFS researchers should be to determine if a significant result can actually inform disease mechanisms, or if it is simply a reportable difference between patients and controls. For example, a PET study of TSPO binding may find differences between patients and controls when using a cerebellum reference, and this holds some value for the “this is a real condition” argument. But because of the difficulty in interpretation, such a study is less valuable for discerning actual pathophysiology.

In consideration of neuroinflammation-related mechanisms and research methods, the following recommendations emerge:

• The relationship of ME/CFS to neuroinflammation is a fundamental question that needs to be directly addressed from multiple research angles.

• The existing neuroinflammation basic science literature should serve as a guide for choosing ROIs in ME/CFS brain scan studies.

• ME/CFS causes changes to patients' lives that could accidentally be explaining some study results (i.e., sedentary lifestyle or diet can affect cytokines). This makes careful selection of control groups particularly important.

• Cytokines seem attractive because they are easy to collect and measure, but are a very noisy variable and the specific findings of any given study should not be overinterpreted.

• Some methodological details are so fundamental (e.g., brainstem registration, or selection of a “baseline” reference brain region or metabolite, or choosing between blood serum and cerebrospinal fluid) that they can be completely responsible for a study's results or lack thereof.

 

[Andy]

We are pleased and proud to announce that our two research fellows, Sydney A. Brumfield and Paula S. Lara Mejia, have written and released their first professional science articles about myalgic encephalomyelitis in conjunction with their mentor Michael B. VanElzakker. The article, Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods, was published in Frontiers on January 10.

VanElzakker, Brumfield and Mejia’s article is a critical review of cytokine and neuroinflammation literature in ME research. The article’s main premise is that neuroimaging has not always been employed appropriately in order to spot issues within the brainstem where, they feel, abnormalities are most likely to be found.

https://www.meaction.net/2019/01/14/neuroinflammation-and-cytokines-research-fellows/

 

[Peter]

Interesting points. One thing is the important science, and focus on measuring the right things, if even possible. Guess the main point also could be transferable to other parts of ME research. But my knowledge of this is limited.

But do think that the main point, the rhetorics of «this is a real disease» is problematic and to defensive. We are way beyond having to make this point over and over again. Media often highlight this point, but maybe we all, patients, scientists and others should avoid this language and/or focus. Quite often, in my opinion to often, you hear the real disease language from different scientists. Says a lot about the situation and lack of knowledge among media and people not involved, but science is luckily way ahead of such statements. So wish we could bury the language of "this is a real disease" once and for all.

 

[rvallee]

Interesting points. One thing is the important science, and focus on measuring the right things, if even possible. Guess the main point also could be transferable to other parts of ME research. But my knowledge of this is limited.

But do think that the main point, the rhetorics of «this is a real disease» is problematic and to defensive. We are way beyond having to make this point over and over again. Media often highlight this point, but maybe we all, patients, scientists and others should avoid this language and/or focus. Quite often, in my opinion to often, you hear the real disease language from different scientists. Says a lot about the situation and lack of knowledge among media and people not involved, but science is luckily way ahead of such statements. So wish we could bury the language of "this is a real disease" once and for all.

There are still people actively working their ass off to erase this disease and blur it all into the psychosomatic BS. As long as the majority opinion within medicine is that it's not, it will unfortunately have to be repeated.

We're still very much in the "change comes one funeral at a time" phase of things, far too many people have signed their name to assertions that it is a fake disease and there is no need to do anything who are still in positions of influence. With our liberation will come a lot of careers crashing down and a lot of awkward questions that lead to embarrassing, and incriminating, answers.

That's the main reason why there is still so much resistance. It's not about science, it's about careers and covering asses from serious accountability. Institutions hate embarrassment and most of the medical institutions deserve major embarrassment over this. Medicine is just not supposed to operate on a "I just don't believe it despite the evidence" basis. That it did for decades and through the desperate pleas of millions is an extremely bad look, especially as this failure keeps happening over and over again.

 

[Hoopoe]

@Jonathan Edwards I believe you pointed out the apparent contradiction between studies showing neuroinflammation and studies showing hypoperfusion (hypometabolism?).

The metabolism of the radioligand
Multiple studies have now shown that people with ME have different overall metabolism from that of healthy controls — from processing of sugars versus fats versus proteins, to overall metabolic rate. If these preliminary findings are correct, then the radioligand might be metabolized more slowly in people with ME, leading to an accumulation of the radioligand over time. This problem would be complicated by the poor penetrance of first-gen radioligands: more and more radioligand would be taken up very slowly by people with ME, but perhaps would not be broken down at the same rate. This would make it appear as though people with ME had more neuroinflammation than healthy controls, but in fact could be a sign of slowed metabolism, instead.

Second-gen radioligands wouldn’t completely eliminate this issue, but they would make it less of a problem by entering the brain in greater profusion in both groups. The chance of buildup over time in people with ME would still be present, but the proportional difference would not be as dramatic. Finally, using A-line sampling to determine how much radioligand is “left” in the blood at intervals could eliminate the problem almost entirely.

https://www.meaction.net/2019/01/14/neuroinflammation-and-cytokines-research-fellows/

Yarred Younger said something similar. His findings could also be due to altered metabolism rather than neuroinflammation.

 

[obeat]

Anecdote N=1. I have been on candesartan for hypertension for 4 months. Angiotensin receptor blockers are being studied for reducing neuroinflammation. I have had a complete cessation of migraines and some improvement in cognitive function ( maybe due to fewer migraines??)
BUT no reduction in fatigue. However being migraine free is a wonderful bonus.