Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al

Evidence of widespread metabolite abnormalities in Myalgicencephalomyelitis/chronic fatigue syndrome: assessmentwith whole-brain magnetic resonance spectroscopy is a 2019 research study of neuroinflammation in ME/CFS.

Authors

Christina Mueller (MS), Joanne Lin, Sulaiman Sheriff, Andrew Maudsley, under the direction of Dr. Jarred Younger of the Neuroinflammation, Pain and Fatigue Laboratory at University of Alabama at Birmingham and with University of Miami Miller School of Medicine radiology experts.

Funding

This study was funded through Solve ME/CFS Initiatives' Ramsay Award Program and the National Institutes of Health (NIH) [grant number EB016064].

Abstract and Conclusion

Abstract

Previous neuroimaging studies have detected markers of neuroinflammation in patients wit h Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). choline (CHO), myoinositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), an d compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.

Conclusion

This study is the first to investigate whole-brain MRS markers of neuroinflammation in ME/CFS. We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed brain areas, suggesting ME/CFS is driven by diffuse pathophysiological processes affecting the whole brain, rather than regionally limited, which is consistent with the heterogeneity of its clinical symptoms. Our findings add support to the hypothesis that ME/CFS is the result of chronic, low-level neuroinflammation. While the whole-brain results are preliminary, we note that they largely agree with past publications that use MRS in ME/CFS. These results should be replicated in future studies with larger samples to further establish the profile of pathophysiological abnormalities in the brains of ME/CFS patients. Ultimately, the development of sensitive MRI markers of ME/CFS could supplement clinical tests to help guide treatment decisions.

Overview

The following information is provided by Solve ME/CFS Initiative.

What you need to know:

• Dr. Jarred Younger and his co-authors completed a neuroimaging study of a female cohort of 15 individuals with ME/CFS (who met a modified Fukuda case definition) and 15 age-matched healthy controls using magnetic resonance spectroscopy (MRS).
• MRS, a type of MRI scan, provides a non-invasive method for evaluating the types and quantities of chemicals in the brain using 3D images and can give a readout of metabolic changes.
• The researchers found that “metabolite and temperature abnormalities were distributed across large portions of the brain” in ME/CFS participants, as compared to controls.
  • The most significant finding was elevation of choline in the anterior cingulate (ACC) area of the brain on the left side. Increases in choline are associated with immune cell activation and the authors note that previous research indicates a critical role for the ACC region in cytokine-induced fatigue.
  • Lactate (a byproduct of glycolysis in an oxygen-limited environment) was found to be increased in a number of brain areas, consistent with brain inflammation and an energy deficit at the cellular level.
  • Higher average temperatures were observed in five brain areas; the researchers included assessments that showed this finding wasn’t attributable to differences in blood flow or whole-body temperature. Inflammation requires more metabolic expenditures and three of the five areas also measured increased lactate, suggesting increased metabolism that could be related to neuroinflammation.                                   
• The authors acknowledge a few limitations of the study, including the small sample size, but these preliminary results support a hypothesis of neuroinflammation in ME/CFS and provide a benchmark for replication using larger study groups. 

Talks and interviews

• 2018, ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study

• Images from talk: "ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study"
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  Choline results: (L) ME/CFS patient (R) Healthy control patient. Image discussed @16:21

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  Lactate results: (L) ME/CFS patient (R) Healthy control patient. Image discussed @20:02

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  Thermometry results: (L) ME/CFS patient (R) Healthy control patient. Image discussed @26:00

See also

• Brain inflammation
• Jarred Younger
• Neuroinflammation
• Solve ME/CFS Initiative
• Neurology of ME/CFS
• List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis

Learn more

• 2019, Brain Imaging and Behavior publication from Dr. Jarred Younger’s SMCI Ramsay pilot study supports involvement of neuroinflammation in ME/CFS

metabolite A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.

National Institutes of Health (NIH) - A set of biomedical research institutes operated by the U.S. government, under the auspices of the Department of Health and Human Services.

metabolite A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.

creatine (CR) - A natural substance that turns into creatine phosphate in the body, which helps make ATP. ATP provides the energy for muscles Often taken as a supplement to improve sports performance. (Learn more: www.webmd.com)

metabolite A chemical compound produced by, or involved in, metabolism. The term is often used to refer to the degradation products of drugs in the body.

cerebellum A part of the brain at the back of the skull in vertebrates, beneath the occipital lobe of the cerebrum. Its name reflects the fact that it looks like a smaller version of the cerebrum. Its main known functions are the coordination of unconscious muscle movements and the maintenance of body positional equilibrium.

cerebral 1. of or relating to the brain or the intellect 2. of, relating to, affecting, or being the cerebrum.