MEA Research Roundup

ME/CFS Research Published 12 – 18 July 2022 

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.

Audio Commentary by Dr Katrina Pears

ME/CFS Research Published 12 – 18 July 2022 

It’s been another busy week for research, with a huge range of topics. There have been seven new ME/CFS studies and sixteen studies on Long Covid this week. 

We have highlighted two very different studies below: 

Paper four (4) is a clinical trial conducted in China comparing the use of CBT verus Qigong exercise (specifically Prolong Life with Nine Turn Method (PLWNT)). Qigong is simple poses and breathing patterns to promote a healthy flow and reduce stagnation of qi (energy), it is similar to tai chi however, not a series of movements.  

The study protocol used to investigate was strong and a lot of detail is given in the paper, with 90 participants who were randomly assigned to the treatment groups, however, there was no control group. Both groups went through a rather intense programme for 12 weeks, with each group receiving an hour of face-to-face class every week and practiced at home for 30 minutes for 6 days a week. The primary outcome measured was fatigue and secondary outcomes measured were sleep, anxiety, depression and changes in the neuropeptide Y (NPY) in the blood. 

Unsurprisingly, neither of these treatments were seen to cure ME/CFS. No difference was found between the symptoms measured for either treatment received, however, the qigong exercises scored slightly better. Despite no real difference being seen between the treatments, the authors strongly recommend qigong for rehabilitation. This is surprising to me, as the evidence provided in this study does not provide a strong case for this. 

I have previously tried some qigong exercises as part of my tai chi classes a few years ago. Initially, I found these very hard work, especially on my arms. However, I did see my muscle strength increase, which was not measured in this study or any effects of post-exertional malaise (PEM), which seems to be commonly missed in these high intensity treatment programmes. 

Paper five (5) is a metabolomic study which means it is a large-scale comprehensive measurement of low-weight small molecules and metabolites within a biological specimen. These types of studies are high output with a large amount of data being collected, and a heavy reliance on statistical tests to find differences. This study analysed plasma from 106 ME/CFS patients and 91 healthy controls.  

The study revealed some important differences in a range of different metabolites particularly decreased phospholipids, which point to peroxisomal dysfunction in ME/CFS patients, which is the dysfunction of small membrane-enclosed organelles that contain enzymes involved in metabolic reactions, including in energy metabolism. Furthermore, these findings are consistent with previous studies, showing the dysregulation of peroxisomal metabolism and the tricarboxylic acid (TCA) cycle (Armstrong et al., 2015; Yamano et al., 2016; Hoel et al., 2021).  

This study adds good evidence to the growing field of support on the pathogenesis of ME/CFS being related to dysregulation of peroxisomal metabolism and the tricarboxylic acid (TCA) cycle. There is hope that this could lead to a biomarker being found. This study has many strengths, especially in the sample sized used, however, the authors explicitly express the need to verify their results independently on another cohort, which I hope is picked up by another research group. 

Despite the huge complexity of these studies, with a huge understanding of biosynthesis needed, I personally think studies like this using metabolomics are the way forward to finding answers to the many unknown questions in ME/CFS. 

You may also be interested in reading paper six (6) on orthostatic stress in Long Covid and ME/CFS and paper seven (7) on the recruitment for the decodeME study. 

ME/CFS Research References and Abstracts  

1. No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) 

Ueland, M., Hajdarevic, R., Mella, O. et al.  

Transl Psychiatry 12, 277 (2022). 

Abstract 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown.  

An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants.  

We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10−8).  

As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls).  

We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510.  

No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts.  

However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus. 

2. Animal Models for Neuroinflammation and Potential Treatment Methods 

Tamura Y, Yamato M, Kataoka Y.  

Front Neurol. 2022 Jun 27;13:890217. 

Abstract 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology and without effective treatment options.  

The onset of ME/CFS is often associated with neuroinflammation following bacterial or viral infection.  

A positron emission tomography imaging study revealed that the degree of neuroinflammation was correlated with the severity of several symptoms in patients with ME/CFS. 

In animal studies, lipopolysaccharide- and polyinosinic-polycytidylic acid-induced models are thought to mimic the pathological features of ME/CFS and provoke neuroinflammation, characterized by increased levels of proinflammatory cytokines and activation of microglia.  

In this review, we described the anti-inflammatory effects of three compounds on neuroinflammatory responses utilizing animal models.  

The findings of the included studies suggest that anti-inflammatory substances may be used as effective therapies to ameliorate disease symptoms in patients with ME/CFS. 

3. Olmesartan alleviates symptoms of chronic fatigue syndrome in mice 

Sadique Saqulain, Rahul Kumar Sharma, Ajay Singh Kushwah, Manish Kumar 

ResearchSquare [Preprint] 

Abstract 

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a lifestyle-related ailment that affects physical and mental abilities.  

The etiology is largely unidentified but there are certain multifactorial mechanisms responsible such as mitochondrial aerobic pathways aberrations, hypothalamic-pituitary-adrenal (HPA) axis deregulation, immune hyperactivation, free radicals, pathogen infections, and central neurohumoral alterations.  

Olmesartan is an antihypertensive drug that acts on the angiotensin 1 (AT1 ) receptor. The present research evaluated the efficiency of Olmesartanagainst CFS.  

CFS was induced by lipopolysaccharide (LPS, 1mg/kg, i.p.) once on day 1 trailed by a forced swim (10 minutes) continued for 21 consecutive times once each day. Olmesartan (1and 3mg/kg, p.o.) and dexamethasone (standard drug, 0.5mg/kg, i.p.) were given from the 1 st to 21 st day.  

Immobility time was noted in the forced swim test (FST). Elevated plus maze, raised zero maze, and open field tests were employed to assess animal behavior. Plasma glucose and cortisol, lipid peroxidation, and GSH levels were determined in the whole brain. LPS and repeated forced swim sessions instigated symptoms of CFS such as memory deficit and depression and anxiety-like symptoms.  

Findings suggested that Olmesartan shortened the immobility period of mice against CFS in FST. Olmesartan reduced memory deficits, increased ambulation, and exerted an anxiolytic effect. Olmesartan treatment reduced blood cortisol levels, brain TBARS, and enhanced brain GSHin the CFS mouse model.  

Hence, Olmesartan may prove to be an effective treatment for CFS and related behavioral discrepancies. 

4. The Qigong of Prolong Life With Nine Turn Method Relieve Fatigue, Sleep, Anxiety and Depression in Patients With Chronic Fatigue Syndrome: A Randomized Controlled Clinical Study 

Xie F, You Y, Guan C, Xu J and Yao F 

Front. Med., 9:828414 

Abstract 

Background: Chronic fatigue syndrome (CFS) is a complex disease of unknown etiology and mechanism. The purpose of this study was to investigate the effect of Prolong Life with Nine Turn Method (PLWNT) Qigong exercise on CFS focusing on fatigue, sleep quality, depression, and anxiety. 

Methods: A total of 90 participants diagnosed with CFS were randomly assigned into two parallel groups: PLWNT and cognitive behavioral therapy (CBT). The participants in the PLWNT or CBT group participated in qigong exercise or cognitive behavior education program, respectively, once a week in-person and were supervised online during the remaining 6 days at home, over 12 consecutive weeks. The primary outcome was fatigue (Multi-dimensional Fatigue Inventory 20 [MFI-20]), and secondary outcomes were sleep quality (Pittsburgh Sleep Quality Index [PSQI]), anxiety, depression (Hospital Anxiety and Depression Scale [HADS]), and changes in the Neuropeptide Y (NPY) of peripheral blood. 

Results: The within-group comparisons of the PLWNT and CBT groups revealed significant improvement in both groups in MFI-20, PSQI, and HADS scores (P < 0.05). No significant difference were found between the PLWNT and CBT groups, even though the effective rate of the PLWNT group was 62.22%, which is slightly than 50.00% of the CBT group. The fatigue scores in the PLWNT group were positively correlated with sleep degree (r = 0.315) and anxiety degree (r = 0.333), only anxiety degree (r = 0.332) was found to be positively correlated with fatigue in the CBT group. The analysis of peripheral blood showed that NPY decreased after PLWNT intervention but increased significantly in the CBT. 

Conclusion: The PLWNT qigong exercise has potential to be an effective rehabilitation method for CFS symptoms including fatigue, sleep disturbance, anxiety, and depression. Future studies should expand study sample size for in-depth investigation to determine the optimal frequency and intensity of PLWNT qigong intervention in CFS patients. 

5. Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI. 

International Journal of Molecular Sciences. 2022; 23(14):7906. 

Abstract 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems.  

People with ME/CFS often report a prodrome consistent with infections.  

Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls.  

Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013).  

Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873.  

Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle.  

These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease. 

6. Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Vernon SD, Funk S, Bateman L, Stoddard GJ, Hammer S, Sullivan K, Bell J, Abbaszadeh S, Lipkin WI, Komaroff AL.   

Front Med (Lausanne). 2022 Jun 23;9:917019. 

Abstract 

Background: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing. 

Methods: We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app. 

Participants: People with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT. 

Results: The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01). 

Conclusions: A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS. 

7. DecodeME: community recruitment for a large genetics study of myalgic encephalomyelitis / chronic fatigue syndrome 

Devereux-Cooke, A., Leary, S., McGrath, S.J. et al.  

BMC Neurol 22, 269 (2022). 

Abstract 

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy. 

Methods: Here we describe DecodeME, an ongoing study co-produced by people with lived experience of ME/CFS and scientists. Together we designed the study and obtained funding and are now recruiting up to 25,000 people in the UK with a clinical diagnosis of ME/CFS.  

Those eligible for the study are at least 16 years old, pass international study criteria, and lack any alternative diagnoses that can result in chronic fatigue. These will include 5,000 people whose ME/CFS diagnosis was a consequence of SARS-CoV-2 infection.  

Questionnaires are completed online or on paper. Participants’ saliva DNA samples are acquired by post, which improves participation by more severely-affected individuals.  

Digital marketing and social media approaches resulted in 29,000 people with ME/CFS in the UK pre-registering their interest in participating.  

We will perform a genome-wide association study, comparing participants’ genotypes with those from UK Biobank as controls. This should generate hypotheses regarding the genes, mechanisms and cell types contributing to ME/CFS disease aetiology. 

Discussion: The DecodeME study has been reviewed and given a favourable opinion by the North West – Liverpool Central Research Ethics Committee (21/NW/0169). Relevant documents will be available online (www.decodeme.org.uk). Genetic data will be disseminated as associated variants and genomic intervals, and as summary statistics. Results will be reported on the DecodeME website and via open access publications. 

Long-COVID Research References  

  1. Local anesthetics as a therapeutic tool for post COVID-19 patients: A case report 
  1. Orbito-Frontal Cortex Hypometabolism in Children With Post-COVID Condition (Long COVID): A Preliminary Experience 
  1. Long-COVID in immunocompromised children 
  1. Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes? 
  1. Conceptualizing a Traditional Chinese Medicine and Pathology of Arousal Diagnostic and Pathophysiological Framework for Postacute Sequelae of COVID-19 
  1. The Role of Acupuncture for Long COVID: Mechanisms and Models 
  1. Improvement in Long-COVID Symptoms Using Acupuncture: A Case Study 
  1. Long COVID and its Management 
  1. Spectrum of neurological manifestations among acute COVID-19 and long COVID-19 – A retrospective observational study 
  1. Postural balance and its association with functionality and quality of life in non-hospitalized patients with post-acute COVID-19 syndrome 
  1. Neurological manifestations of post-COVID-19 syndrome S1-guideline of the German society of neurology 
  1. Orbito-Frontal Cortex Hypometabolism in Children With Post-COVID Condition (Long COVID): A Preliminary Experience 
  1. The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study 
  1. Physical and psychological reconditioning in long COVID syndrome: Results of an out-of-hospital exercise and psychological – based rehabilitation program 
  1. Management of Long COVID-The CoviMouv' Pilot Study: Importance of Adapted Physical Activity for Prolonged Symptoms Following SARS-CoV2 Infection 
  1. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome 

Dr Katrina Pears
Research Correspondent

Dr Katrina Pears - MEA Research Correspondent
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