The ME Association End of Week Research Round-up and Index Update

July 31, 2020

Charlotte Stephens, Research Correspondent, ME Association.

We show below brief summaries of the research studies about ME/CFS that have been published in the last week, followed by the abstracts from those studies.

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research.

This extensive library of research is updated at the end of every month, and is correct to the end of July 2020. It is a free resource available to anyone.

The Index provides an A-Z of published research studies and 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 in a particular area that you might be interested in, 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 lay explanations of the more important and interesting work that has been published to date.

ME/CFS Research Published 24 July – 30 July 2020

This week, 4 new research studies have been published. Highlights include: 

  • Researchers from Sweden found increased levels of antibodies to adrenergic and muscarinic receptors (located on sympathetic nerves and regulate the release of the neurotransmitter/ stress hormone, noradrenaline) in ME/CFS patients compared to controls.
    This is in agreement with previous findings from other research groups and suggests there is an autoimmune component to ME/CFS.
  • A Physician from Cologne, Germany, has written a review article proposing that the progression from mild to severe ‘chronic fatigue' could be in part due to vitamin D3 deficiency, along with mineral deficiencies and that addressing these should be considered in order to stop the progression of ‘chronic fatigue' to a more severe form.

ME/CFS Research references and abstracts

1. Bynke A et al. (2020)
Autoantibodies to Beta-Adrenergic and Muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME) patients – a validation study in plasma and cerebrospinal fluid from two Swedish cohorts.
Brain, Behavior & Immunity [Epub ahead of print].

Myalgic encephalomyelitis (ME) also known as ME/CFS (Chronic Fatigue Syndrome) or ME/SEID (Systemic Exertion Intolerance Disorder), is a disabling and often long-lasting disease that can drastically impair quality of life and physical/social functioning of the patients.

Underlying pathological mechanisms are to a large extent unknown, but the presence of autoantibodies, cytokine pattern deviations and the presentation of cognitive and autonomic nervous system related symptoms provide evidence for ME being an immunological disorder with elements of autoimmunity.

Increased levels of autoantibodies binding to adrenergic and muscarinic receptors in ME-patients have been reported. It is hypothesized that these autoantibodies have pathological significance and contribute to the ME-specific symptoms, however, these observations need to be validated.

This study was designed to investigate potential differences in adrenergic and muscarinic receptor autoantibody levels in plasma and cerebrospinal fluid (CSF) samples between ME patients and gender and age-matched healthy controls, and to correlate the autoantibody levels to disease severity.

We collected bodyfluids and health-related questionnaires from two Swedish ME cohorts, plasma and CSF from one of the cohorts (n=24), only plasma from the second cohort (n=24) together with plasma samples (n=24) and CSF (n=6) from healthy controls. All samples were analyzed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1-5 acetylcholine receptors using an ELISA technique. The questionnaires were used as measures of disease severity.

Significant increases in autoantibody levels in ME patients compared to controls were found for M3 and M4 -receptors in both cohorts and β1, β2, M3 and M4- receptors in one cohort. No significant correlations were found between autoantibody levels and disease severity. No significant levels of autoantibodies were detected in the CSF samples.

These findings support previous findings that there exists a general pattern of increased antibody levels to adrenergic and muscarinic receptors within the ME patient group.

However, the role of increased adrenergic and muscarinic receptor autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate the clinical significance of these findings.

2. Hock A. (2020)
A Proposal for Explaining Progression from Light/Moderate to Severe Chronic Fatigue.
ES Journal of Nutritional Health 1 (2).

Background: Chronic mild to moderate fatigue is also called chronic idiopathic fatigue. Physicians at best consider about psychotherapy for treatment. But most physicians do not view this condition as a real disease.

In contrast, debilitating chronic severe disease has been termed chronic fatigue syndrome (CFS), or if more severe, myalgic encephalopathy (CFS/ME).

Meanwhile published metabolic aberrations in CFS/ME suggest estimating these diseases no longer as mere psychiatric diseases. The metabolic results inspire to further exploration of cell stress response mechanisms, which are summarized in this paper.

Interestingly, cell stress responses were tightly linked to vitamin D3 – mediated effects, such as homeostatic regulation of metabolism, energy and redox balance, as well as defense against pathogens and toxins.

Specific personality traits, prevalence of indoor activities, latitude and climate predispose to vitamin D3 deficiency, which is supposed to represent a missing link for a comprehensive model of disease progression from mild chronic fatigue to most severe forms.

By diagnosing vitamin D deficiency in early stages of chronic fatigue, the progression to severe and debilitating chronic fatigue may be prevented. In more severe stages of chronic fatigue, such as CFS/ME, resistance against mere vitamin D replenishment seems to be the rule. Some causal mechanisms for this resistance and potential treatment options are shown.

Conclusion: Scientific insight to the biomolecular mechanisms of cell homeostasis helps to understand and treat all clinically manifestations associated with different stages of chronic fatigue.

3. Holden S et al. (2020)
A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease.
Journal of Translational Medicine 18 (1): 290.

Background: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest.

The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate.

The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls.

Methods: Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.

Results: Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes.

Conclusion: Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies.

Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.

4. Lim E and Son C (2020)
Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Journal of Translational Medicine 18 (1): 289.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown causes.

From the perspectives on the etiology and pathophysiology, ME/CFS has been labeled differently, which influenced changes in case definitions and terminologies. This review sought to feature aspects of the history, developments, and differential symptoms in the case definitions.

Methods: A search was conducted through PubMed published to February 2020 using the following search keywords: case definition AND chronic fatigue syndrome [MeSH Terms]. All reference lists of the included studies were checked. Of the included studies, the number of citations and the visibility in the literatures of the definitions were considered for comparisons of the criteria.

Results: Since the first ‘ME' case definition was developed in 1986, 25 case definitions/diagnostic criteria were created based on three conceptual factors (etiology, pathophysiology, and exclusionary disorders).

These factors can be categorized into four categories (ME, ME/CFS, CFS, and SEID) and broadly characterized according to primary disorder (ME-viral, CFS-unknown, ME/CFS-inflammatory, SEID-multisystemic), compulsory symptoms (ME and ME/CFS-neuroinflammatory, CFS and SEID-fatigue and/or malaise), and required conditions (ME-infective agent, ME/CFS, CFS, SEID-symptoms associated with fatigue, e.g., duration of illness).

ME and ME/CFS widely cover all symptom categories, while CFS mainly covers neurologic and neurocognitive symptoms. Fatigue, cognitive impairment, PEM, sleep disorder, and orthostatic intolerance were the overlapping symptoms of the 4 categories, which were included as SEID criteria.

Conclusions: This study comprehensively described the journey of the development of case definitions and compared the symptom criteria. This review provides broader insights and explanations to understand the complexity of ME/CFS for clinicians and researchers.

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