Mechanisms of ME/CFS & Long Covid with predominant fatigue: a magnetic resonance spectroscopy study of the brain & muscle at 7 Tesla, 2025, Godlewska

https://academic.oup.com/ijnp/article/28/Supplement_1/i60/8009437
https://academic.oup.com/ijnp/article-pdf/28/Supplement_1/i60/61854477/pyae059.104.pdf

Journal Article
MECHANISMS OF MYALGIC ENCEPHALITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) AND LONG COVID WITH PREDOMINANT FATIGUE: A MAGNETIC RESONANCE SPECTROSCOPY STUDY OF THE BRAIN AND MUSCLE AT 7 TESLA

*Beata Godlewska1, Uzay E Emir2,4, Ann L Sharpley1, Stephen Williams3, Ana Jorge Gonçalves5, Betty Raman6, Ladislav Valkovič6,7, Philip J Cowen1

1Department of Psychiatry, University of Oxford, Oxford, UK, 2Wellcome Centre for Integrative Neuroimaging, University of Oxford, UK, 3Division of Informatics, Imaging and Data Science; Faculty of Medicine, Biology and Health; University of Manchester, UK, 4School of Health Sciences, Purdue University, USA, 5Wolfson Molecular Imaging Centre, Faculty of Biology, Medicine and Health, University of Manchester, UK, 6Oxford Centre for Clinical MR Research (OCMR), RDM Cardiovascular Medicine, University of Oxford, UK, 7Department of Imaging Methods, Institute of Measurement Science, Slovak Academy of Sciences, SVK

International Journal of Neuropsychopharmacology, Volume 28, Issue Supplement_1, February 2025, Pages i60–i61, https://doi.org/10.1093/ijnp/pyae059.104
Published:

12 February 2025

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Abstract

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating condition, which core symptoms are fatigue not caused by exertion and not alleviated by rest, post- exertional malaise, decline in functioning, and cognitive symptoms, often described as 'brain fog’ (1). Similar symptoms are also present in 'long-COVID’, a sequela of the acute infection with the SARS-CoV- 2 virus (2). While underlying pathogenetic processes are still largely unknown impaired mitochondrial function and energy metabolism in both conditions, and clotting problems in long-COVID, have been suggested.

Aims & Objectives
the aim was to investigate differences in the biochemistry of the brain and muscle between patients with ME/CFS, long-COVID and healthy volunteers (HV), using the state-of-art ultra- high-field proton magnetic resonance spectroscopy (H1-MRS) at 7 Tesla (7T). In particular, we aimed to assess metabolites involved in energy processing (creatine and lactate). Additionally, we aimed to explore the relationship between MRS findings with the cognitive function. Method: 24 CFS/ME patients, 25 long-COVID patients with predominant fatigue, and 24 healthy volunteers underwent H1-MRS scanning of the brain and calf muscle at 7 Tesla. Voxels were positioned in the pregenual and dorsal ACC (pgACC and dACC, respectively). Participants completed the Stroop Color and Word Test, testing ability to inhibit cognitive interference, related to the ACC function. Other cognitive functions tested included verbal memory and learning, working memory, verbal fluency and executive function.

Results
Compared to HV, participants with ME/CFS had increased levels of lactate in both pgACC (ME/CFS 1.52 mM, HV 1.22; p=0.003) and dACC (ME/CFS 1.45 mM, HV 1.40 mM; p=0.005), while participants with long-COVID had decreased concentrations of total choline in dACC as compared to healthy individuals (long-COVID 2.25 mM, HV 2.77 mM; p=0.0002). In the ME/CFS group, we observed a negative correlation between verbal fluency and both pgACC and dACC lactate concentrations (pgACCr=-0.614, p=0.01; dACC r=-0,623, p=0.008), while in the long-COVID group we observed a correlation between total choline concentrations and executive function (r=-0.592, p=0.005). There were no significant between-group differences in terms of muscle metabolites.

Discussion & Conclusions
In ME/CFS, increased levels of lactate suggest dysfunction in energy metabolism, with lactate accumulation suggesting ill mitochondrial health and a shift towards anaerobic metabolism (3). Low levels of total choline in long-COVID patients are interesting in the context of the recently reported association between blood clots and 'brain fog’ in long COVID (4), and reports of neuroprotective effects of choline in animal models, preventing disseminated intravascular coagulation (5). Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations with fatigue and brain fog, may differ. This has implications for future research, suggesting that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood, and that different treatments may be needed despite similarity of symptoms.

References
1) Prins, J.B., van der Meer, J.W., Bleijenberg, G. (2006) 'Chronic fatigue syndrome.’ Lancet, 367, pp.346–355.

2) Kelly, J.D., Curteis, T., Rawal, A., et al. (2023) 'SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis.’ Eur Respir Rev, 32, pp.220254.

3) Brooks, G.A. (2018) 'The Science and Translation of Lactate Shuttle Theory.’ Cell Metab, 27, pp.757- 785.

4) Taquet, M., Skorniewska, Z., Hampshire, A., et al. (2023) 'Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization.’ Nat Med, 29, pp.2498-2508

5)Blusztajn, J.K., Slack, B.E. and Mellott, T.J. (2017) 'Neuroprotective actions of dietary choline.’ Nutrients, 9, p.815.

Short Communications (Oral Abstracts)

 

Were the ME/CFS patients pre-pandemic? And did they check them for covid-antigens?

Could different illness durations explain the differences?

 

Another study finding high brain lactate in ME/CFS using brain imaging. Most of the previous studies are from Dikoma Shungu's lab, so good to see another group studying this.

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study (Shungu et al, 2009, NMR in Biomedicine)

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder (Shungu et al, 2010, NMR in Biomedicine)

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology (Shungu et al, 2012, NMR in Biomedicine)

Multimodal and Simultaneous Assessments of Brain and Spinal Fluid Abnormalities in Chronic Fatigue Syndrome and the Effects of Psychiatric Comorbidity (Shungu et al, 2017, Journal of the Neurological Sciences)

Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia (Shungu et al, 2017, Fatigue: Biomedicine, Health & Behavior)

Evidence of widespread metabolite abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Assessment with whole-brain Magnetic Resonance Spectroscopy. (Younger et al, 2019, Brain Imaging and Behavior)

Not yet published study found elevated MRS-measured lactate in gulf war illness (though not significant by my calculation).

 

I'm not convinced that it's not just a difference between healthy, active people and inactive people who feel lousy all day. They need some inactive non-ME/LC subjects, and maybe some subjects fighting viral infections.

 

It could be that both viral infections and ME involve higher lactate levels in the brain. So I am not sure what that would rule out other than suggesting that perhaps they involve some of the same features.

24/25 subjects and controls seems pretty decent for this kind of study. Interesting that lactate levels seem to negatively correlate with some of the test scores.

 

This study is interesting. 15 people with gulf war illness did two exercise tests separated by 24 hours. They did an n-back cognitive test before the first exercise then again immediately after the second exercise test.

The group of participants where cognitive score decreased after exercise had significantly higher brain lactate before exercise than the opposite group. (After exercise, they had similar levels.)

Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness (Baraniuk et al, 2013, American Journal of Translational Research)

 

My first reaction to lactate in the brain was: Bad news. No medical knowledge, that shows.
A quick search showed that lactate in the brain has many functions. Fuel and protection among them..
What caught my eye was; lactate as protection of the BBB.

Question: Could a high fever disrupt the Blood Brain Barrier?