Research Roundup: ME/CFS Research Published 20-26 November 2021

December 2, 2021


The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

It’s definitely been a busier week with a lot more variety of papers, with eight new research studies on ME/CFS and twelve studies on Long Covid this week.  

We have highlighted two papers on ME/CFS from the selection below:  

Paper one (1) analysed blood samples from 40 ME/CFS patients and 40 healthy controls, particularly focusing on: 

  • Cytokines (small proteins involved in the immune systems and blood cells),  
  • Fatty Acid Binding Protein 2 (FAPB-2) (involved in fatty acid transport), 
  • Tryptophan (an essential amino acid, involved in nutrient balancing and growth),  
  • some of its metabolites via serotonin (key hormone that stabilizes our mood, feelings of well-being, and happiness) and kynurenine (metabolite of the amino acid tryptophan used in the production of niacin (a B vitamin)). 

The study found that ME/CFS patients have higher levels in a range of compounds compared to controls, including serotonin and kynurenine. The authors conducted statistical analysis to find correlations between compounds and metabolic processes, which for some of the compounds studied suggested: 

inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease”. 

Interestingly as well, differences were found in the duration of the disease, which further shows that ME/CFS changes over time. However, a much more detailed study separating patients on duration of illness is needed. 

These results may help in producing biomarkers, but also the authors hope that targeted treatments could be investigated further.  It is also worth looking at the list of limitations of the study listed by the authors in the full text, such as, supplement intake was not looked at before blood samples were taken. 

Paper four (4) is a preprint therefore has not been peer-reviewed yet, however this study compares the effect on the brain of exercise in ME/CFS and Gulf War Illness (GWI) patients.  

This study looked at re-analysing MRI data from 36 ME/CFS patients, 78 GWI Patients and 31 controls. The study found differences between ME/CFS and GWI patients using cognitive tests before and after exercise, where different parts of the brain showed different amounts of activation. The study also looked at the effect of post-exertional malaise (PEM) using follow up tests on different days.  

The findings from this study and the oppositive effects of exercise on brain activity on ME/CFS and PEM shows the two diseases have different mechanisms and pathophysiology. The study also showed the parts of the brain with contribute to PEM (Midbrain and isthmus nuclei). This study also shows that there is a need to further investigate the effects of PEM on brain dysfunction.  

You also might be interested in reading paper seven (7) and in the Long Covid reference section papers four (4), ten (10) and twelve (12). 

ME/CFS Research References and Abstracts  

1. Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Simonato M, Dall’Acqua S, Zilli C, Sut S, Tenconi R, Gallo N, Sfriso P, Sartori L, Cavallin F, Fiocco U, Cogo P, Agostinis P, Aldovini A, Bruttomesso D, Marcolongo R, Comai S, Baritussio A.  
Biomedicines. 2021; 9(11):1724. 

Abstract 

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease.  

Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine.  

ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls.  

Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively.  

No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease.  

Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection.  

Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism.  

Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.  

2. Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients 

Du Preez S, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S.  
Int J Environ Res Public Health 18(22):11879.  

Abstract 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder.  

Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS.  

TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown.  

This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls.  

The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted. 

3. An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Wirth, K.J., Scheibenbogen, C. & Paul, F.  
J Transl Med19, 471 (2021). 

Abstract 

There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). 

 In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms.  

We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia. 

4. Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM) 

Baraniuk, J.N.; Amar, A.; Pepermintwala, H.; Washington, S.D.  
Preprints2021, 2021110420  

Abstract 

Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Gulf War Ill-ness (GWI) and control subjects had fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020).  

Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction.  

Methods: Activated midbrain nuclei were inferred by re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network.  

Results: Before exercise, control and GWI had greater activation during cognition than ME/CFS in left pedunculotegmental nucleus. Postexercise ME/CFS had greater activation than GWI for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI indicating reciprocal patterns of activation. Controls had no changes.  

Conclusions: Exercise caused opposite effects with increased activation in ME/CFS but decreased activation in GWI indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI. 

5. You + ME Registry: A Research Platform to Facilitate Clinical and Therapeutic Discoveries in ME/CFS and Related Diseases 

Ramiller, A.; Mudie, K.; Seibert, E.; Whittaker, S.  

Paragraph locked by Katrina Pears

Preprints2021, 2021110478 

Abstract 

ME/CFS (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome) is a chronic, complex, heterogeneous disease that affects millions and lacks both diagnostics and treatments.  

Big data, or the collection of vast quantities of data that can be mined for information, has transformed the understanding of many complex illnesses like cancer (1,2) and multiple sclerosis (3,4), by dissecting heterogeneity, identifying subtypes, and enabling the development of personalized treatments. It is possible that big data can reveal the same for ME/CFS.  

Solve M.E. developed and launched the You + ME Registry to collect longitudinal health data from people with ME/CFS, people with Long COVID (LC) and control volunteers using rigorous protocols designed to harmonize with other groups collecting data from similar groups of people.  

The Registry is an invaluable resource because it integrates with a symptom tracking app, as well as a biorepository, to provide a robust and rich dataset that is available to qualified researchers. Accordingly, it facilitates collaboration that may ultimately uncover causes and help accelerate the development of therapies. 

6. Hidden from Sight: Why the complexity of ME/CFS needs to be recognised by policy makers 

Űstűnkaya T and Machin R 
People, Place and Policy (2021): 15/2, pp. 91-99 

Abstract 

An estimated 260,000 people in the UK are living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); this neurological condition has been described as ‘a serious, chronic, complex, and multisystem disease that frequently and dramatically limits the activities of affected patients’ (Institute of Medicine, 2015).  Despite this, there remains a lack of clarity about the diagnosis and treatment of ME/CFS.  

The authors of this paper refer to ME/CFS but recognise that other terms (for example systemic exertion intolerance disease, chronic fatigue immunity deficiency syndrome, and post-viral fatigue syndrome) are used to describe this neurological condition, and for some people these are preferred names.  

This paper adopts the definition of ME/CFS as a neurological condition of unknown origin as defined by the World Health Organisation and accepted by the UK Department of Health (WHO, n.d.). 

7. Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome 

O.A., Maksoud, R., Beeraka, N.M., Madhunapantula, S.V., Sinelnikov, M.,Nikolenko,  V.N.,  Neganova,  M.E.,  Klochkov,  S.G.,  Amjad  Kamal,  M.,  Marshall-Gradisnik,  S.,  Staines,  D.R. 
Journal of Advanced Research (2021), 

Abstract 

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems.  

Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors.  

Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition.  

Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 

Aims of Review: In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology. 

Key Scientific Concepts of Review: The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS.  

Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population.  

There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea.  

Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition. 

8. Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) 

Li X, Julin P, Li TQ.  
Tomography. 2021 Nov 1;7(4):675-687. 

Abstract 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS.  

In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner.  

Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor.  

In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area.  

For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis. 

Long Covid Research References   

  1. The role of polyspecific T-cell exhaustion in severe outcomes for COVID-19 patients having latent pathogen infections such as Toxoplasma gondii 
  1. Persistent symptoms following SARS-CoV-2 infection among children and young people: a meta-analysis of controlled and uncontrolled studies 
  1. Understanding and tracking the impact of long COVID in the United Kingdom 
  1. Do vaccines protect against long COVID? What the data say 
  1. Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form 
  1. Long-Term Evolution of Malnutrition and Loss of Muscle Strength after COVID-19: A Major and Neglected Component of Long COVID-19 
  1. Post-acute COVID-19 syndrome (PACS): a new tsunami requiring a universal case definition 
  1. Understanding and tracking the impact of long COVID in the United Kingdom 
  1. Post-Acute Sequelae of COVID-19 and Cardiovascular Autonomic Dysfunction: What Do We Know? 
  1. Mast cell activation is associated with post-acute COVID-19 syndrome 
  1. Characterizing Long COVID: Deep Phenotype of a Complex Condition 
  1. Endothelial dysfunction in COVID-19: A potential predictor of long-COVID?

Dr Katrina Pears
MEA Research Correspondent

  

  

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