Functional Status and Well-Being in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Compared with People with Multiple Sclerosis and Healthy Controls

Abstract Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS. Methods GDF15 was measured in serum from patients with ME/CFS (n = 150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n = 150) and a cohort of patients with multiple sclerosis (n = 50). Results Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~ 7 months (IQR 6.7–8.8) apart, 720 pg/ml (95% CI 625–816) vs 670 pg/ml (95% CI 598–796), P = 0.5. GDF15 levels were 491 pg/ml in controls (95% CI 429–553), 546 pg/ml (95% CI 478–614) in MS patients, 560 pg/ml (95% CI 502–617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI 531–674) in severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS. Conclusions Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.

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Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study

Biomolecules ◽

10.3390/biom11070961 ◽

2021 ◽

Vol 11 (7) ◽

pp. 961

Author(s):

Paula Fernandez-Guerra ◽

Ana C. Gonzalez-Ebsen ◽

Susanne E. Boonen ◽

Julie Courraud ◽

Niels Gregersen ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Complex Disease ◽

Mononuclear Cells ◽

Coupling Efficiency ◽

Well Being ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Flux Analysis ◽

Proteomic Profiling ◽

Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction. Here, we evaluated patients' symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls. We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being. This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels. Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

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Comparison of the finger plethysmography derived stroke volumes by Nexfin CO Trek and suprasternal aortic Doppler derived stroke volume measurements in adults with myalgic encephalomyelitis/chronic fatigue syndrome and in healthy controls

Technology and Health Care ◽

10.3233/thc-202669 ◽

2021 ◽

pp. 1-14

Author(s):

C. (Linda) M.C. van Campen ◽

Freek W.A. Verheugt ◽

Peter C. Rowe ◽

Frans C. Visser

Keyword(s):

Chronic Fatigue Syndrome ◽

Stroke Volume ◽

Chronic Fatigue ◽

Calibration Procedure ◽

Myalgic Encephalomyelitis ◽

Tilt Test ◽

Healthy Controls ◽

Tilt Testing ◽

Fatigue Syndrome ◽

Finger Plethysmography

BACKGROUND: Finger plethysmography derived stroke volumes are frequently measured during tilt table testing. There are two algorithms to determine stroke volumes: Modelflow and NexfinCO Trek. Most tilt studies used Modelflow, while there are differences between the two algorithms. OBJECTIVE: To compare stroke volume indices by Nexfin CO Trek (SVINexfinCOTrek) with suprasternal Doppler derived SVI (SVIDoppler) in healthy controls (HC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during tilt testing. These patients may have a large SVI decrease during the tilt enabling a large range of SVI to be studied. METHODS: One hundred and fifty-four patients and 39 HC with a normal tilt test were included. Supine and end-tilt SVIDoppler and SVINexfinCOTrek were compared using the Bland-Altman analysis. Also, the effect of calibrating supine SVINexfinCOTrek to SVIDoppler was studied RESULTS: Supine and end-tilt SVINexfinCOTrek were significantly higher than SVIDoppler: both P< 0.005. Bias, limits of agreement, and percent error (PE) were high with PE’s between 37 and 43%. The calibration procedure resulted in an acceptable variance with a PE of 29%. CONCLUSIONS: SVINexfinCOTrek overestimates stroke volumes compared to SVIDoppler, leading to high PE’s. Calibration reduced variance to an acceptable level, allowing SVINexfinCOTrek to be used for assessment of SVI changes during tilt testing

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Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis

Journal of Translational Medicine ◽

10.1186/s12967-019-02184-z ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 2

Author(s):

Rosa María Escorihuela ◽

Lluís Capdevila ◽

Juan Ramos Castro ◽

María Cleofé Zaragozà ◽

Sara Maurel ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Chronic Fatigue Syndrome ◽

Frequency Domain ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Potential Biomarker ◽

Fatigue Severity

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.

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Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Insights in Biomedicine ◽

10.21767/2572-5610.10027 ◽

2017 ◽

Vol 02 (02) ◽

Cited By ~ 5

Author(s):

Leonard A Jason

Keyword(s):

Multiple Sclerosis ◽

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Fatigue Syndrome

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Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study

Diagnostics ◽

10.3390/diagnostics9020041 ◽

2019 ◽

Vol 9 (2) ◽

pp. 41 ◽

Cited By ~ 6

Author(s):

Nacul ◽

de Barros ◽

Kingdon ◽

Cliff ◽

Clark ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Cross Sectional Study ◽

Myalgic Encephalomyelitis ◽

Activity Levels ◽

Healthy Controls ◽

Sectional Study ◽

Cross Sectional ◽

Fatigue Syndrome ◽

Laboratory Test Results

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity. We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L). The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02–0.15) compared to controls, and OR = 0.16 (95% CI = 0.07–0.40), compared to mild cases). This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.

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Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21031142 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1142

Author(s):

Daniel Missailidis ◽

Oana Sanislav ◽

Claire Y. Allan ◽

Sarah J. Annesley ◽

Paul R. Fisher

Keyword(s):

Chronic Fatigue Syndrome ◽

Sensitivity And Specificity ◽

Respiratory Function ◽

Death Rate ◽

Frozen Storage ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Healthy Controls ◽

Fatigue Syndrome ◽

Mitochondrial Respiratory

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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A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis

Journal of Immunology Research ◽

10.1155/2016/9064529 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Ekua W. Brenu ◽

Simon Broadley ◽

Thao Nguyen ◽

Samantha Johnston ◽

Sandra Ramos ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Chronic Fatigue Syndrome ◽

Cd8 T Cells ◽

Preliminary Investigation ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Effector Memory ◽

Fatigue Syndrome ◽

The Status

Background. CD8+ T cells have putative roles in the regulation of adaptive immune responses during infection. The purpose of this paper is to compare the status of CD8+ T cells in Multiple Sclerosis (MS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).Methods. This preliminary investigation comprised 23 CFS/ME patients, 11 untreated MS patients, and 30 nonfatigued controls. Whole blood samples were collected from participants, stained with monoclonal antibodies, and analysed on the flow cytometer. Using the following CD markers, CD27 and CD45RA (CD45 exon isoform 4), CD8+ T cells were divided into naïve, central memory (CM), effector memory CD45RA− (EM), and effector memory CD45RA+ (EMRA) cells.Results. Surface expressions of BTLA, CD127, and CD49/CD29 were increased on subsets of CD8+ T cells from MS patients. In the CFS/ME patients CD127 was significantly decreased on all subsets of CD8+ T cells in comparison to the nonfatigued controls. PSGL-1 was significantly reduced in the CFS/ME patients in comparison to the nonfatigued controls.Conclusions. The results suggest significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients. These deficits reported may contribute to the pathogenesis of these diseases. However, larger sample size is warranted to confirm and support these encouraging preliminary findings.

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