The ME Association End of Week Research Round-up | 14 February 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.

This information will be included in the monthly update to the central Research Index which is made freely available as a download at the end of every month.

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

  • Last week’s round-up featured a critical review by Dr Keith Geraghty of psychological treatment protocols and early treatment data for medically unexplained symptoms, including ME/CFS, under the UK Government initiative ‘Improving Access to Psychological Therapies’ (IAPT).

ME/CFS Research Published 8th – 14th February 2020

This week, 9 new research studies have been published. Some highlights include:

  • Dr Elisa Oltra’s team from the University of Valencia, Spain published the results of their study, funded by the MEA Ramsay Research Fund, using samples from the UK ME Biobank. They were looking at miRNA’s (which control gene expression) in Peripheral blood mononuclear cells (PBMC’s) (types of immune cells) and Extracellular Vesicles (EV) (small parcels that carry information and ‘cargo’ between cells) from people with severe ME/CFS and healthy controls. They found that people with ME/CFS have higher numbers but smaller sizes of EV’s compared to controls. They found 27 miRNA’s to be either over- or under- expressed in ME/CFS compared to controls. Further studies are needed to assess the viability of these results as diagnostic biomarkers. We wrote a summary review of this study, which you can download for free.
  • Researchers from the Netherlands have found reduced cerebral blood flow (blood flow to the brain) in ME/CFS patients during a head-up tilt test, compared to healthy controls. This reduction in cerebral blood flow was present in ME/CFS patients with or without the presence of orthostatic intolerance, although it was worse in those with symptoms of orthostatic intolerance and POTS. The researchers concluded “This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.”
  • A research team from Germany have discovered a potential subset of ME/CFS patients who have elevated levels of autoantibodies against β2 adrenergic receptors (AdR). β2 adrenergic receptors bind adrenaline, a hormone and neurotransmitter, and have wide-spread effects on various areas of the body, including circulation and heart rate, muscle contraction, eye sight, digestion and blood sugar regulation. The researchers found that IgGs (immunoglobulin G- a type of antibody) from healthy controls could stimulate the β2 receptor cells, whereas IgGs from the ME/CFS subset had no effect. The authors conclude “The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.” However, this study was only carried out on 10 patients, 5 of whom had raised levels of the autoantibodies, and so further larger studies are needed in order to confirm the significance of these results.
  • Australian researchers have identified three cellular biomarkers that, in combination, can identify ME/CFS patient samples from controls with very high specificity. The three biomarkers are that Lymphocytes (type of immune cells) from ME/CFS patients die faster in culture medium (in the lab) than those from healthy controls and exhibit abnormalities in mitochondrial respiratory function, as well as abnormalities in signalling activity by the cellular stress-sensing kinase (enzyme) TORC1. These differences were correlated with disease severity. The authors conclude, “We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample.” Replication is needed in larger numbers and against other diseases in order to confirm the diagnostic value of these biomarkers.

ME/CFS Research references and abstracts

1. Almenar-Perez E et al. (2020)
Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Scientific Reports 10 (1): 2064.

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystemic disease of unknown etiology, affecting thousands of individuals worldwide. Its diagnosis still relies on ruling out medical problems leading to unexplained fatigue due to a complete lack of disease-specific biomarkers.

Our group and others have explored the potential value of microRNA profiles (miRNomes) as diagnostic tools for this disease. However, heterogeneity of participants, low numbers, the variety of samples assayed, and other pre-analytical variables, have hampered the identification of  disease-associated miRNomes.

In this study, our team has evaluated, for the first time, ME/CFS miRNomes in peripheral blood mononuclear cells (PBMCs) and extracellular vesicles (EVs) from severely ill patients recruited at the monographic UK ME biobank to assess, using standard operating procedures (SOPs), blood fractions with optimal diagnostic power for a rapid translation of a miR-based diagnostic method into the clinic.

Our results show that routine creatine kinase (CK) blood values, plasma EVs physical characteristics (including counts, size and zeta-potential), and a limited number of differentially expressed PBMC and EV miRNAs appear significantly associated with severe ME/CFS (p < 0.05). Gene enrichment analysis points to epigenetic and neuroimmune dysregulated pathways, in agreement with previous reports. Population validation by a cost-effective approach limited to these few potentially discriminating variables is granted.

2. Campen CM et al. (2020)
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography.
Clinical Neurophysiology Practise [Epub ahead or print].

Abstract
Objective: The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.

Methods: 429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.

Results: End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P<.0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P<.0005).

Conclusions: During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.

Significance: This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.

3. Cossington J et al. (2020)
Potential benefits of a ketogenic diet to improve response and recovery from physical exertion in people with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A feasibility study.
International Journal of Sport, Exercise and Health Research 3 (2): 33-39.

Abstract
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) affects approximately 250,000 people in the UK. The condition varies in severity causing long-term physical and cognitive fatigue which is not alleviated by rest. Whilst the pathology is not understood, recent evidence suggests metabolic abnormalities may be associated with the manifestation of symptoms, particularly involving the metabolism of glucose and energy production. The use of ketone bodies as an alternative energy substrate may be beneficial to people with ME/CFS, in order to by-pass the glycolytic pathway, enhance energy production and reduce fatiguing outcomes.

Study Design and Methods: Using a pragmatic collective case study with repeated measures methodology we investigated the feasibility of following a ketogenic diet and potential effects of the high fat, low carbohydrate diet on response to physical activity in people with ME/CFS (n=3) and healthy controls (n=3) using a submaximal exercise stress test both with and without dietary intervention. Exercise tolerance (mins), rate of oxygen consumption (VO2) to workload (75W), respiratory exchange ratio (RER), rate of perceived effort (RPE) and lactate response were measured throughout and descriptive statistics performed.

Results: We found that the ketogenic diet was followed, with compliance higher in the pwME/CFS. Variations in response following the ketogenic diet was observed across individuals in minutes performed, VO2, HR, RER, and RPE post diet but the KD only limited exercise capacity in the control individuals. Individuals responded differently to the KD but group trends have been reported as means and standard deviation. The KD resulted in a decrease in RER at submax in the controls with a mean change of 0.07 from baseline (0.86 ± 0.1) to post intervention (0.79 ± 0.1) compared to a mean change of 0.02 in the ME/CFS from baseline (1.03 ± 0.1) to post intervention (1.01 ± 0.1). A decrease in VO2 (L/min) at submax showed a mean change of 0.06 (L/min) in the pwME/CFS at baseline (1.34 ± 0.1) to post intervention (1.27 ± 0.2) compared to a mean change of 0.07 (L/min) in the controls at baseline (1.40 ± 0.3) to post intervention (1.33 ± 0.2). HR (bpm) at submax decreased in all individuals, with a mean change of 4 (bpm), with pwME/CFS at baseline (139 ± 8.2) to post intervention (135 ± 14) and control individuals at baseline (107 ± 7.8) to intervention (103 ± 3.2). RPE at submax decreased in the pwME/CFS from baseline (6 ± 1.0) to post intervention (5 ± 2.1) whereas the controls increased from baseline (2 ± 1.0) to post intervention (3 ± 1.5).

Conclusion: Our observations suggest individualised but metabolic flexibility in healthy individuals is achievable via dietary manipulation showing the ability to switch from glucose to fats under controlled conditions. The different response in substrate utilisation in individuals with ME/CFS suggests that potential metabolic abnormalities may be present in ME/CFS. Further investigation is now warranted in order to assess whether the KD is beneficial for people with ME/CFS.

4. Friedberg F (2020)
Legitimizing myalgic encephalomyelitis/chronic fatigue syndrome: indications of change over a decade.
Fatigue: Biomedicine, Health and Behaviour [Epub ahead of print].

Abstract
This commentary identifies recent scientific and clinical milestones that appear to have increased legitimization of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These milestones include government-funded reports recognizing the seriousness of ME/CFS, new initiatives for biomedical research sponsored by the US National Institutes of Health, official endorsement of the ME/CFS name, publication of practitioner primers, and the launch of a new peer-review fatigue journal. These positive developments are tempered by ongoing illness challenges including patient stigma, absence of diagnostic markers, a lack of established treatments, and a dearth of researchers and knowledgeable, interested clinicians.

5. Hartwig J et al. (2020)
IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS.
Brain, Behaviour and Immunity [Epub ahead of print].

Abstract
Background: There is emerging evidence of a network of natural autoantibodies against GPCR which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients.

Methods: We comparatively analyzed the effects of polyclonal IgG on β2 AdR signaling and immune cell function in vitro. 16 IgG fractions were isolated from serum of 5 ME/CFS patients with elevated (CFS AABhigh) and 5 with normal levels (CFS AABnorm) of β2 AdR autoantibodies, and from 6 healthy controls (HC). The effect of each IgG on β-arrestin recruitment and cAMP production in β2 AdR and M3/4R reporter cell lines was studied. Further effect of each IgG on human monocyte cytokine production and on T cell proliferation in vitro was analyzed. In addition, studies on cytokine production in β2 AdR wild type and knockout mice splenocytes incubated with IgG fractions were performed.

Results: We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AABhigh had no effect. The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice. In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes. Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28. IgG fractions from CFS AABhigh patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AABnorm had an intermediate effect. We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.

Conclusions: We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.

6. Hornig M (2020)
Can the light of immunometabolism cut through “brain fog”?
Journal of Clinical Investigation [Epub ahead of print].

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease with heterogeneous constitutional and neurological complaints. Infection-like symptoms often herald disease onset, but no pathogen or immune defect has been conclusively linked.

In this issue of the JCI, Mandarano et al. illuminate bioenergetic derangements of ME/CFS T cell subsets. CD4+ and CD8+ T cells had impaired resting glycolysis. CD8+ cells additionally showed activation-related metabolic remodeling deficits and decreased mitochondrial membrane potential; a subset had increased resting mitochondrial mass. Immune senescence and exhaustion paradigms offer only partial explanations. Hence, unique mechanisms of disrupted immunometabolism may underlie the complex neuroimmune dysfunction of ME/CFS.

7. Li M et al. (2020)
Associations of occupational stress, workplace violence and organizational support on chronic fatigue symptoms among nurses.
Journal of Advanced Nursing [Epub ahead of print].

Abstract
Background: Chronic fatigue syndrome is an agnogenic disease worldwide. Nurses are at a high risk of chronic fatigue syndrome. However, no research has been done to examine the associations of workplace violence, organizational support and occupational stress with chronic fatigue syndrome among Chinese nurses. This study aimed to examine effects of these factors on chronic fatigue syndrome in this occupational group.

Methods: The study was conducted in Liaoning province from December 2017 to January 2018. Self‐administered questionnaires were distributed to 1200 nurses, including Effort‐Reward‐Imbalance, Workplace Violence Scale, Survey of Perceived Organizational Support, together with age, gender, marital status, education levels, physical activities, job rank, monthly income and weekly working hours. Complete responses were obtained from 1080 (90%) participants. Chronic fatigue syndrome was diagnosed by doctors according to the Centers for Disease Control and Prevention criteria. Multivariable logistic regression was performed to examine these independent risk factors.

Results: The prevalence of chronic fatigue syndrome was 6.76%. The results of logistic regression analysis showed that nurses who experienced serious higher levels of overcommitment, workplace violence and less organizational support were more likely to be classified as chronic fatigue syndrome.

Conclusion: There was a high prevelence of chronic fatigue syndrome. Lower workplace violence, more organizational support and lower overcommitment could be effective resources for reducing chronic fatigue syndrome.

8. Lidbury BA and Fisher PR (2020)
Biomedical Insights that Inform the Diagnosis of ME/CFS.
Diagnostics 10 (2): 92.

Abstract
It is well known that myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), whether considered as separate diseases or as the one chronic syndrome, continue to generate debate. Discussions on language, definitions and theoretical parameters continue, but whatever your position, one can now agree that ME and/or CFS (referred to hereafter as ME/CFS) is a disease with a physiological basis, rooted in biochemical and molecular dysfunction in the cells of sick individuals, and not attitudes that can be alleviated by psychological therapies. As a result, biomedical imperatives must now become the focus of research enquiry in order to find clinically translatable answers as soon as possible.

This book is intended as a landmark volume to mark this shift in thinking and to consolidate recent fundamental discoveries and biomedical insights as pathways towards tangible diagnostics, and eventual ME/CFS treatments. Australian researchers, with their collaborators locally and abroad, have been at the forefront of discovery in the biomedical realm, and this book draws together fundamental and applied insights that have emerged from scientific and clinical enquiry.

9. Missailidis D et al. (2020)
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
International Journal of Molecular Science 21 (3).

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS.

Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity.

This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.

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