The ME Association End of Week Research Round-up | 17 January 2020


Charlotte Stephens, Research Correspondent, ME Association.

This is a new feature that we will be doing at the end of every week as a result of your feedback.

We will post a list of abstracts from research studies published on ME/CFS and will include simple summaries of those studies we feel are worth additional comment.

The studies will then be added to the central Research Index at the end of each month when we will make the updated version freely available. We will also continue to produce more detailed summaries of especially interesting and important new research.

N.B. In the last week only one research study was published, so we are able to cover it in more depth. Other studies from 1st January are listed at the bottom of this blog.

ME/CFS Research Published 11th – 17th January 2020

Germain A et al. (2020)
Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids.
Metabolites 10 (1): 34.

Abstract
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems.

We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways.

Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms.

Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.

Disturbances in the metabolism of many of these molecules can be linked to many of the symptoms of ME/CFS.

Simple Summary

  • The researchers looked at levels of different metabolites (substances produced during various metabolic reactions carried out in the body) in the blood of 26 females with ME/CFS and compared that to the levels in 26 healthy female controls.
  • They highlighted the ones that were significantly different (either higher or lower levels) in the ME/CFS patients compared to controls.
  • Metabolites found to be different included reduced levels of Acyl Cholines, Dipeptides and Steroids (androgenic, progestin and corticosteroids) and increased levels of Sphingolipids and Ceramides.
  • They then looked at the pathways in the body that these metabolites are involved in to get an idea of how these differing levels might be affecting the body and how they might relate to the symptoms of ME/CFS.
  • Disturbances in the metabolism of many of these molecules can be linked to many of the symptoms of ME/CFS.
  • Larger studies are needed to confirm these findings and validate their meanings.

Conclusions

“We are reporting on the largest number of metabolites in the ME/CFS field to date… However, we have not unequivocally identified a plasma biomarker or set of biomarkers with abundances drastically different between controls and ME/CFS patients…”

“Nevertheless, the metabolites emphasized as a result of our analysis, most specifically acylcholines and steroids, should be considered in light of the metabolic impact even modest changes can have along with the complexity of sources that drain metabolites into the circulatory system.”

Further information (more detail on the specific compounds found):

  • Acyl Cholines are part of the fatty acid metabolism pathway. Several of these were found to be more than twice as low in patients compared to controls. Lowered levels of these could explain a disruption in blood pressure regulation, resulting in dizziness, light-headedness, blurred vision, and orthostatic intolerance. They are also linked to gut problems (leaky gut syndrome, irritable bowel syndrome and altered gut microbiome). They are also involved in nervous system regulation and cognitive function.
  • Dipeptides are small proteins. One found to be lowered is involved in brain metabolism and another is involved in B6 metabolism. However, our understanding of variations in plasma dipeptide levels is still limited.
  • Steroids are involved in a wide range of functions in the body, including the stress response, regulating salt and water balance, immune response, inflammation regulation, protein metabolism and hormone regulation. Steroids are involved in the hypothalamic-pituitary- adrenal axis (HPA), which has often been suggested to be involved in ME/CFS. The HPA axis regulates so many functions of our bodies, including energy usage, temperature, immune system, digestion and mood. Therefore, the reduced levels of steroids could be linked to a majority of the symptoms and systems affected in ME/CFS patients.
  • Sphingolipids are found in brain tissue and they have a severe impact on neural tissue when out of balance.

ME/CFS Research Published 1st – 10th January 2020

1. Araja D et al. (2020)
PSY44 Economic burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (me/cfs) to patients: comparative study.
Value in Health 22 (3): s909.

Abstract
N/A

2. Bolton MJ et al. (2020)
Low-dose naltrexone as a treatment for chronic fatigue syndrome.
BMJ Case Reports 13 (1).

Abstract
Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn’s disease, fibromyalgia and Gulf War Illness.

Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances.

This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg.

Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available.

3. Do-Young Kim et al. (2020)
Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
Journal of Translational Medicine 18: 7.

Abstract
Background: Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.

Methods: RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.

Results: Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%).

Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.

Conclusions: This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.

4. Escorihuela RM et al. (2020)
Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis.
Journal of Translational Medicine 18: 4.

Abstract
Background: Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.

Methods: In this case–control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.

Results: CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.

Conclusions: Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.

5. He Q et al. (2020)
Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine.
Biological and Pharmaceutical Bulletin 43 (1): 110-115.

Abstract
Background: The diagnosis of chronic fatigue syndrome (CFS) is mainly symptom-based, and the etiology is still unclear. Here, we evaluated the pathological changes in the brain of a mouse model of CFS and studied the effects of Kampo medicine.

Methods: A mouse model of CFS was established through six repeated injections of Brucella abortus (BA) every two weeks for a period of 12 weeks. Neuroinflammation was measured by estimating interleukin (IL)-1β, IL-6, and interferon-gamma (IFN-γ), and oxidative stress by nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) 6 weeks after the last injection. Hippocampal neurogenesis was evaluated through Ki-67, doublecortin (DCX), and 5-bromodeoxyuridine (BrdU) assays. The effects of Kampo medicines (Hochuekkito (TJ-41) and Hachimijiogan (TJ-7)) on neuroinflammation during CFS were studied.

Results: The wheel-running activity of mice was decreased by about 50% compared to baseline at 6 weeks after the last BA injection. The levels of IL-1β, IL-6, 3-NT, and 4-HNE were increased in both the cortex and the hippocampus of CFS mice at 6 weeks after the last BA injection. Hippocampal neurogenesis was unchanged in CFS mice. Treatment with TJ-41 and TJ-7 reduced the expressions of IL-1β, IL-6, and IFN-γ in the hippocampus but not in the cortex.

Conclusions: The results of the present study indicate that neuroinflammation and oxidative stress play important roles in the pathogenesis of CFS. The data further suggest that treatment with TJ-41 and TJ-7 could help reduce the inflammation associated with CFS in the hippocampus, but failed to improve the symptoms in CFS mice.

6. Jonsjo MA et al. (2020)
The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) – associations with symptoms.
Psychoneuroendocrinology 113.

Abstract
Background: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.

Methods: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0–10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.

Results and conclusions: Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1.

Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

7. Lee JS et al. (2020)
An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome.
Biomolecules 10 (1). Link:

Abstract
Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required.

We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model.

Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity. In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions.

Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.

8. Parslow RM et al. (2020)
Development of a conceptual framework to underpin a health-related quality of life outcome measure in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): prioritisation through card ranking.
Quality of Life Research.

Abstract
Purpose: Chronic fatigue syndrome (CFS)/myalgic encephalopathy (ME) is relatively common in children and is disabling at an important time in their development. This study aimed to develop a conceptual framework of paediatric CFS/ME using the patient-perspective to ensure that the content of a new outcome measure includes the outcomes most important to young people.

Methods: We developed a child-centred interactive card ranking exercise that included health-related quality of life (HRQoL) outcomes identified from a previous review of the literature as well as qualitative work. Adolescents and their parents selected and ranked the outcomes most important to them and discussed each outcome in further detail. Adolescents were purposively sampled from a single specialist paediatric CFS/ME service in England. Interviews were audio recorded and transcribed verbatim, and thematic framework analysis was used to develop the final conceptual framework.

Results: We interviewed 43 participants in which there are 21 adolescents, 12–17 years of age with mild–moderate CFS/ME and their parents (20 mothers and 2 fathers). ‘Symptoms’, ‘tiredness’, ‘payback and crashing’ and ‘activities and hobbies’ were ranked most important to improve by both children and parents. Children ranked ‘school’ higher than parents and parents ranked ‘mood’ higher than children. A youth- specific CFS/ME conceptual framework of HRQoL was produced that included 4 outcome domains and 11 subdomains: sleep, tiredness, problems concentrating, individual symptoms, fluctuation and payback, daily and general activities, participation in school, leisure and social life, mood, anxiety and self-esteem.

Conclusions: An interactive card ranking exercise worked well for adolescents aged 12–17 to elicit the most important outcomes to them and explore each domain in further detail. We developed a final conceptual framework of HRQoL that forms the basis of a new paediatric patient-reported outcome measure (PROM) in CFS/ME.

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