Biomarker – Page 10 – American ME and CFS Society

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

Abstract:

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.

Source: Nacul, L.; de Barros, B.; Kingdon, C.C.; Cliff, J.M.; Clark, T.G.; Mudie, K.; Dockrell, H.M.; Lacerda, E.M. Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study. Diagnostics 2019, 9, 41. https://www.mdpi.com/2075-4418/9/2/41 (Full article available as PDF file)

Artificial intelligence based discovery of the association between depression and chronic fatigue syndrome

Abstract:

BACKGROUND: Both of the modern medicine and the traditional Chinese medicine classify depressive disorder (DD) and chronic fatigue syndrome (CFS) to one type of disease. Unveiling the association between depressive and the fatigue diseases provides a great opportunity to bridge the modern medicine with the traditional Chinese medicine.

METHODS: In this work, 295 general participants were recruited to complete Zung Self-Rating Depression Scales and Chalder Fatigue Scales, and meanwhile, to donate plasma and urine samples for 1H NMR-metabolic profiling. Artificial intelligence methods was used to analysis the underlying association between DD and CFS. Principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to analyze the metabolic profiles with respect to gender and age. Variable importance in projection and t-test were employed in conjunction with the PLS-DA models to identify the metabolite biomarkers. Considering the asymmetry and complexity of the data, convolutional neural networks (CNN) model, an artificial intelligence method, was built to analyze the data characteristics between each groups.

RESULTS: The results showed the gender- and age-related differences for the candidate biomarkers of the DD and the CFS diseases, and indicated the same and different biomarkers of the two diseases. PCA analysis for the data characteristics reflected that DD and CFS was separated completely in plasma metabolite. However, DD and CFS was merged into one group.

LIMITATION: Lack of transcriptomic analysis limits the understanding of the association of the DD and the CFS diseases on gene level.

CONCLUSION: The unmasked candidate biomarkers provide reliable evidence to explore the commonality and differences of the depressive and the fatigue diseases, and thereby, bridge over the traditional Chinese medicine with the modern medicine.

Source: Zhang F, Wu C, Jia C, Gao K, Wang J, Zhao H, Wang W, Chen J. Artificial intelligence based discovery of the association between depression and chronic fatigue syndrome. J Affect Disord. 2019 Mar 8;250:380-390. doi: 10.1016/j.jad.2019.03.011. [Epub ahead of print]

Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

BACKGROUND: There are no known objective biomarkers to assist with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A small number of studies have shown that ME/CFS patients exhibit an earlier onset of ventilatory threshold (VT) on the second of two cardiopulmonary exercise tests (CPET) performed on consecutive days. However, cut-off values which could be used to differentiate between ME/CFS patients have not been established.

METHODS: 16 ME/CFS patients and 10 healthy controls underwent CPET on a cycle-ergometer on 2-consecutive days. Heart rate (HR), ventilation, ratings of perceived exertion (RPE) and work rate (WR) were assessed on both days.

RESULTS: WR at VT decreased from day 1 to day 2 and by a greater magnitude in ME/CFS patients (p < 0.01 group × time interaction). No interaction effects were found for any other parameters. ROC curve analysis of the percentage change in WR at VT revealed decreases of - 6.3% to - 9.8% provided optimal sensitivity and specificity respectively for distinguishing between patients with ME/CFS and controls.

CONCLUSION: The decrease in WR at VT of 6.3-9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS.

Source: Nelson MJ, Buckley JD, Thomson RL, Clark D, Kwiatek R, Davison K. Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Transl Med. 2019 Mar 14;17(1):80. doi: 10.1186/s12967-019-1836-0. (Full study)

Multidimensional Comparison of Cancer-Related Fatigue and Chronic Fatigue Syndrome: The Role of Psychophysiological Markers

Abstract:

OBJECTIVE: The present study compared cancer-related fatigue (CRF) and chronic fatigue syndrome (CFS) using multidimensional measurements with the aim of better understanding characteristics and exploring markers of two similar fatigue syndromes.

METHODS: Twenty-five patients with CRF and twenty patients with CFS completed questionnaires, including the Fatigue Severity Scale (FSS), Hospital Anxiety Depression Scale (HADS), Perceived Stress Scale (PSS), and Pittsburgh Sleep Quality Index (PSQI). Additionally, levels of high sensitivity C-reactive protein (hs-CRP), heart rate variability (HRV), and electroencephalography (EEG) were obtained. Neurocognitive functioning was also evaluated.

RESULTS: Both groups showed comparable levels of psychological variables, including fatigue. Compared to CFS subjects, CRF patients had significantly higher hs-CRP levels and a reduced HRV-index. The within-group analyses revealed that the FSS score of the CRF group was significantly related to scores on the HADS-anxiety, HADS-depression, and PSQI scales. In the CFS group, FSS scores were significantly associated with scores on the PSS and the absolute delta, theta, and alpha powers in frontal EEG.

CONCLUSION: Findings indicate that different pathophysiological mechanisms underlie CFS and CRF. Inflammatory marker and HRV may be potential biomarkers for distinguishing two fatigue syndromes and frontal EEG parameters may be quantitative biomarkers for CFS.

Source: Park HY, Jeon HJ, Bang YR, Yoon IY. Multidimensional Comparison of Cancer-Related Fatigue and Chronic Fatigue Syndrome: The Role of Psychophysiological Markers. Psychiatry Investig. 2019 Jan 7. doi: 10.30773/pi.2018.10.26. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30605994

Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery.

In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS.

We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.

Source: Arnaud Germain, David Ruppert , Susan M. Levine and Maureen R. Hanson. Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites 2018, 8(4), 90; doi:10.3390/metabo8040090 https://www.mdpi.com/2218-1989/8/4/90/htm (Full article)

Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

Methods: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

Results: Correlations between the covariates ranged between [− 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10−7, 1 × 10−5, and 3 × 10−3, respectively.

Conclusions: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.

Source: Kenny L. De Meirleir, Tatjana Mijatovic, Krishnamurthy Subramanian, Karen A. Schlauch and Vincent C. Lombardi. Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis. Journal of Translational Medicine201816:322
https://doi.org/10.1186/s12967-018-1696-z Received: 1 September 2018, Accepted: 14 November 2018, Published: 21 November 2018 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1696-z (Full article)

Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide, with the capacity to persist for several years. ME/CFS is characterized by disabling fatigue of at least 6 months, accompanied serious fatigue and musculoskeletal pain, in addition to impaired short-term memory or concentration, and unrefreshing sleep or extended post-exertional. While the etiology of the disease is still debated, evidence suggest oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes. The shape of erythrocytes change from biconcave discoid to an ellipsoid due shear flow in microcapillaries that provides a larger specific surface area-to-volume ratio for optimal microvascular perfusion and tissue oxygenation establishing the importance not only of total hematocrit but also of the capacity for large deformations in physiology. Clinically, ME/CFS patients show normal arterial oxygen saturation but nothing much is known about microvascular perfusion. In this work, we tested the hypothesis that the erythrocyte deformability in ME/CFS is adversely affected, using a combination of biophysical and biochemical techniques.

We tested the deformability of RBCs using a high-throughput microfluidic device which mimics blood flow through microcapillaries. We perfused RBCs (suspension in plasma) from ME/CFS patients and from age and sex matched healthy controls (n=9 pairs of donors) through a high-throughput microfluidic platform of 5µm width and 3-5 µm height. We recorded the movement of the cells at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by the cells to completely enter the test channels), average transit velocity (velocity of the cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that RBCs from ME/CFS patients had higher entry time (~12%, p<0.0001), lower average transit velocity (~17%, p<0.0001) and lower elongation index (~14%, p<0.0001) as compared to RBCs from healthy controls. Taken together, this data shows that RBCs from ME/CFS patients have reduced deformability. To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates.

To understand the basis for differences in deformability, we investigated the changes in the fluidity of the membrane using a lateral diffusion assay using pyrenedecanoic acid (PDA), and observed that RBCs from ME/CFS patients have lower membrane fluidity (~30%, p<0.01). Apart from the fluidity, Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the RBC plasma membrane (~18%, p<0.0001). Higher levels of reactive oxygen species (ROS) in RBCs from ME/CFS patients (~30%, p<0.008) were also observed, as compared to healthy controls. Using scanning electron microscopy (SEM), we also observed changes in RBC morphology between ME/CFS patients and healthy controls (presence of different morphological subclasses like biconcave disc, leptocyte, acanthocyte and burr cells; area and aspect ratio; levels of RBC aggregation). Despite these changes in RBC physiology, the hemoglobin levels remained comparable between healthy donors and ME/CFS patients. Finally, preliminary studies show that RBCs from recovering ME/CFS patients do not show such differences in cellular physiology, suggesting a connection between RBC deformability and disease severity.

Taken together, our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress, and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease.

Source: Saha, A. K., Schmidt, B. R., Wilhelmy, J., Nguyen, V., Do, J., Suja, V. C., Nemat-Gorgani, M., Ramasubramanian, A. K., & Davis, R. W. (2018).Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome. Blood, 132(Suppl 1), 4874. Accessed November 28, 2018. https://doi.org/10.1182/blood-2018-99-117260.

Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

A random-sequence peptide microarray can interrogate serum antibodies in a broad, unbiased fashion to generate disease-specific immunosignatures. This approach has been applied to cancer detection, diagnosis of infections, and interrogation of vaccine response. We hypothesized that there is an immunosignature specific to ME/CFS and that this could aid in the diagnosis.

We studied two subject groups meeting the Canadian Consensus Definition of ME/CFS. ME/CFS (n = 25) and matched control (n = 25) sera were obtained from a Canadian study. ME/CFS (n = 25) sera were obtained from phase 1/2 Norwegian trials (NCT01156909). Sera from six healthy controls from the USA were included in the analysis. Canadian cases and controls were tested for a disease immunosignature.

By combining results from unsupervised and supervised analyses, a candidate immunosignature with 654 peptides was able to differentiate ME/CFS from controls. The immunosignature was tested and further refined using the Norwegian and USA samples. This resulted in a 256-peptide immunosignature with the ability to separate ME/CFS cases from controls in the international data sets.

We were able to identify a 256-peptide signature that separates ME/CFS samples from healthy controls, suggesting that the hit-and-run hypothesis of immune dysfunction merits further investigation. By extending testing of both our signature and one previously reported in the literature to larger cohorts, and further interrogating the specific peptides we and others have identified, we may deepen our understanding of the origins of ME/CFS and work towards a clinically meaningful diagnostic biomarker.

Source: Günther, O.P., Gardy, J.L., Stafford, P. et al. Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Mol Neurobiol (2018). https://doi.org/10.1007/s12035-018-1354-8 https://link.springer.com/article/10.1007%2Fs12035-018-1354-8 (Full article)

Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Maximal CPET is used to evaluate the coordinated metabolic, muscular, respiratory and cardiac contributions to energy production in patients with ME/CFS. In this patient population, CPET also elicits a robust post-exertional symptom flare (termed, post-exertional malaise); a cardinal symptom of the disease. CPET measures are highly reliable and reproducible in both healthy and diseased populations. However, evidence to date indicates that ME/CFS patients are uniquely unable to reproduce CPET measures during a second test, despite giving maximal effort during both tests, due to the effects of PEM on energy production.

Methodology: To document and assess functional impairment due to the effects of post-exertional malaise in ME/CFS, a 2-day CPET procedure (2-day CPET) has been used to first measure baseline functional capacity (CPET1) and provoke post-exertional malaise, then assess changes in CPET variables 24 h later with a second CPET to assess the effects of post-exertional malaise on functional capacity. The second CPET measures changes in energy production and physiological function, objectively documenting the effects of post-exertional malaise. Use of CPET as a standardized stressor to induce post-exertional malaise and quantify impairment associated with post-exertional malaise has been employed to examine ME/CFS pathology in several studies. This article discusses the results of those studies, as well as the standardized techniques and procedures for use of the 2-day CPET in ME/CFS patients, and potentially other fatiguing illnesses.

Conclusions: Basic concepts of CPET are summarized, and special considerations for performing CPET on ME/CFS patients are detailed to ensure a valid outcome. The 2-day CPET methodology is outlined, and the utility of the procedure is discussed for assessment of functional capacity and exertion intolerance in ME/CFS.

Source: Staci Stevens, Chris Snell, Jared Stevens, Betsy Keller and J. Mark VanNess. Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Pediatr., 04 September 2018 | https://doi.org/10.3389/fped.2018.00242 https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full (Full article)

A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy

Abstract:

Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME), is a debilitating disorder characterized by physical and mental exhaustion. Mitochondrial and energetic dysfunction has been investigated in CFS patients due to a hallmark relationship with fatigue, however, no consistent conclusion has yet been achieved.

Single-cell Raman spectra (SCRS) are label-free biochemical profiles, indicating phenotypic fingerprints of single cells. In this study, we applied a new approach using single-cell Raman microspectroscopy (SCRM) to examine 0 cells that lack mitochondrial DNA (mtDNA), and peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls.

The experimental results show that Raman bands associated with phenylalanine in 0 cells and CFS patient PBMCs were significantly higher than wild type model and healthy controls. Remarkably, an increase in intensities of Raman phenylalanine bands were also observed in CFS patients. As similar changes were observed in the 0 cell model with a known deficiency in the mitochondrial respiratory chain as well as in CFS patients, our results suggest that the increase in cellular phenylalanine may relate to mitochondrial/energetic dysfunction in both systems.

Interestingly, phenylalanine can be used as a potential biomarker for diagnosis of CFS by SCRM. A machine learning classification model achieved an accuracy rate of 98% correctly assigning Raman spectra to either the CFS group or the control group. SCRM combined with machine learning algorithm therefore has the potential to become a diagnostic tool for CFS.

Source: Jiabao Xu, Michelle Potter, Cara Tomas, Jo Elson, Karl Morten, Joanna Poulton, Ning Wang, Hanqing Jin, Zhaoxu Hou and Wei Huang. A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy. Analyst, 22 Aug 2018. http://pubs.rsc.org/en/Content/ArticleLanding/2018/AN/C8AN01437J#!divAbstract