Though science may speed along a bit fast to ‘catch’ on audio, you can also listen to me read this article on #MEAction’s Soundcloud here.
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.
We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying the brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects.
They also argue that, due to several different factors, it is unlikely that a true “cytokine profile” will ever be discovered in people with ME — or in any other group of individuals.
What’s the issue with neuroimaging in ME?
VanElzakker et al. discuss three potential issues that must be addressed in order to move forward in neuroinflammation research in ME:
• How would a measured component of neuroinflammation lead to [the] symptoms [seen in people with ME]?
• How do we accurately measure that component of neuroinflammation?
• What can and cannot be concluded from the chosen method?
Today we’ll talk just about their observations on PET, or positron emission tomography.
PET scans are a type of imaging used to examine metabolic processes, in this case those in the central nervous system. PET scans are often viewed as having more potential for discovery than scans that solely allow the clinician to view static morphology. However, they are also more expensive and therefore more of a challenge to fund at a rate that will allow the researcher to reach statistical significance with what he or she finds.
The brainstem is key
The authors then argue that traditional neuroimaging was not intended to study the brainstem, where issues in people with ME may lie.
When performing neuroimaging, software lines up the anatomy of each participant’s brain to that of others. Unfortunately, most neuroimaging is focused on the parts of the brain responsible for ‘higher’ cognitive processes, rather than autonomic function (control of breathing and heart rate, e.g.), arousal, pain, and neuroimmune functions, which are all associated with the brainstem. These are arguably some of the most important things to study in people with ME.
The brainstem is made up of many small areas responsible for very different things, and small imaging errors can lead to significant interpretative issues. The authors note the problems must be remarkable to show up anyway, as they did in Nakatomi’s 2014 imaging study. Software to ensure that brainstem aligned with brainstem person to person would likely be revealing.
The brainstem also pulses with every heartbeat, and is therefore very prone to movement-related imaging errors. By measuring heartrate in conjunction with the scan, it is possible to compensate for this issue as Barnden et al. did in their 2016 study. The authors note that Barnden’s studies and also Costa’s, which focused specifically on the brainstem and used more appropriate imaging techniques, did find abnormalities such as brain stem hypoperfusion.
Using the right marker for neuroinflammation
Radioligands are radioactive substances that bind to particular tissues and receptors, lighting them up on scans like PET. Some radioligands are a single, radioactive isotope — like the iodine used to image your thyroid — and others are proteins geared to bind to very particular receptors.
Nakatomi et al. (2014) used a radioligand specifically keyed to neuroinflammation, but VanElzakker et al. point out that the ligand used was not very specific — that is, it may have bound to other things in the body. Also, it may have some trouble getting into the brain in the first place, making imaging challenging.
Second-generation ligands now exist that are more specific and have higher penetrance.
Brains may not be perfectly healthy in one spot and notably inflamed in another
The authors note that, in order to determine neuroinflammation, most studies compare one part of the patient’s brain to another part of the same patient’s brain: the cerebellum is typically used as the reference/control. However, there is no reason why there shouldn’t be a generalized increase in neuroinflammation in people with ME, with some parts of the brain more affected than others. This decreases the chances of spotting the neuroinflammatory ‘signal’.
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.
Binding of the radioligand can be influenced by the patient’s genetic code
There are SNPs that can affect how well a radioligand binds to receptors; the patient should be tested for these variants before a scan.
That’s it for today, folks, but I hope to cover their observations on the MRI process soon. We are very proud of Paulita and Sydney’s progress and of all their hard work!