Tag: biomarker

Dysregulation of extracellular vesicle protein cargo in female ME/CFS cases and sedentary controls in response to maximal exercise

Abstract:

In healthy individuals, physical exercise improves cardiovascular health and muscle stre ngth, alleviates fatigue, and reduces risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance. We hypothesized that altered extracellular vesicle (EV) signaling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post-exertional malaise).

EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age- and BMI-matched female sedentary controls at three time points: before, 15 minutes, and 24 hours after a maximal cardiopulmonary exercise test. EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag-based (TMT) proteomics.

The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS. Differentially abundant proteins in ME/CFS patients vs. controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system, and brain signaling.

Source: Ludovic Giloteaux, Katherine A. Glass, Arnaud Germain, Sheng Zhang, Maureen R. Hanson. Dysregulation of extracellular vesicle protein cargo in female ME/CFS cases and sedentary controls in response to maximal exercise. bioRxiv 2023.08.28.555033; doi: https://doi.org/10.1101/2023.08.28.555033 https://www.biorxiv.org/content/10.1101/2023.08.28.555033v1.full (Full text)

Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery

Abstract:

Background: There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions.

Methods: A pilot multicentre, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS, and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-beta-LGB), zonulin-1 (ZO-1), LPS, sCD14, and IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the ROC curve analysis.

Results: FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-beta-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1beta negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS, and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001).

Conclusions: Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.

Source: Franz Martin, Manuel Blanco Suárez2 Paola Zambrano, Óscar Cáceres Calle, Miriam Almirall, Jose Alegre-Martín, Beatriz Lobo, Ana María Gonzalez-Castro, Javier Santos, Joan Carles Domingo, Joanna Jurek, Jesús Castro-Marrero. Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery. Front. Immunol., Sec. Mucosal Immunity, Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1253121 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1253121/abstract

Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome

Abstract:

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated.

We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud’s symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients.

All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR.

SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity.

Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes.

Source: van Eeden C, Redmond D, Mohazab N, Larché MJ, Mason AL, Cohen Tervaert JW, Osman MS. Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(15):12057. https://doi.org/10.3390/ijms241512057 https://www.mdpi.com/1422-0067/24/15/12057 (Full text)

System and methods to determine ME/CFS & Long Covid disease severity using wearable sensor & survey data

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with high probability of misdiagnosis and significant unmet medical needs that affects as many as 2.5 million people in the U.S. and causes enormous burden for patients, their caregivers, the healthcare system and society. Between 84 to 91 percent of ME/CFS patients are not yet diagnosed [6, 19], and at least one-quarter of ME/CFS patients are house- or bedbound at some point in their lives [12, 13]. The impact of ME/CFS to the U.S. economy, is about $17 to $24 billion in medical bills and lost income from lost household and labor force productivity per year [7, 13].

Current widely used diagnosis methods of ME/CFS and other diseases with similar clinical symptoms like Long COVID [6, 21] are highly dependent on patients’ self reporting [4, 5] and standardized survey, which are not optimal for medical diagnosis. In a joint study with The Bateman Horne Center (BHC)1, we designed and developed a system prototype that was able to stably collect terabytes of inertial measurement unit (IMU) time-series data, and analyzed multiple candidate parameters derived from them that could be used as reliable biomarkers for ME/CFS and other diseases with similar clinical symptoms.

Utilizing our system prototype, MetaProcessor, we conducted grouped t-tests on data collected from the EndoPAT study group (55 recruited, 51 participated, 30 ME/CFS, 15 Long COVID, 6 healthy control) to evaluate the predictive power of Upright Position Time (UpTime), Hours of Upright Activity (HUA), and Steps/Day. Through statistical analysis, we were able to assert the following for ME/CFS versus healthy control:

1. UpTime yielded a low p-value of 0.00004, indicating a significant difference between the groups and demonstrating its potential as a reliable measure for differentiating ME/CFS from healthy control populations.

2. HUA had a p-value of less than 0.00004, suggesting it could also serve as a useful measure for distinguishing ME/CFS from healthy control groups.

3. Steps/Day, x-axis and y-axis, had p-values of 0.01059 and 0.08665, respectively, indicating that step count may be relevant for differentiating ME/CFS individuals from healthy controls, but step count alone may not be sufficient to reliably distinguish between these groups.

In a linear regression analysis, we found a moderately positive correlation between UpTime and HUA with r 2 = 0.68. Overall, we can confidently conclude that UpTime is a superior overall predictor due to its objective nature and the lowest p-values observed across all groups.

Source: System and methods to determine ME/CFS & Long Covid disease severity using wearable sensor & survey data. Sun, Y. Thesis, Bachelor of Science, The University of Utah. https://ccs.neu.edu/~ysun/publications/system-and-methods-to-determine-mecfs-and-longcovid-disease-severity-using-wearable-sensor-and-survey-data.pdf (Full text)

Bioimpedance spectroscopy characterization of osmotic stress processes in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME-CFS) blood samples

Abstract:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/ CFS) is a disabling, chronic, multi-system and complex disease. Currently, there are no specific laboratory tests to directly [diagnose ME/CFS](https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html). In this work we study the use of impedance spectroscopy as a potential technique for the diagnosis of this disease. A specific device for the electrical characterization of peripheral blood mononuclear cells was designed and implemented.

Impedance spectroscopy measurements in the range from 1 Hz to 500 MHz were made after osmotic stress of the samples with sodium chloride solution 1M. The evolution in time after the osmotic stress at two specific frequencies (1.36 kHz and 154 kHz) was analysed. The device showed its sensitivity to the presence of cells and the evolution of the osmotic process. Higher values of impedance were measured for 1.36 kHz in ME/CFS patients compared to control samples. Results help to further understand the relation of bioimpedance measurements with ME/CFS samples physical properties and osmotic processes.

Source: Alberto Olmo Fernández, Sara Martínez Rodríguez, Daniel Martín Fernández, et al. Bioimpedance spectroscopy characterization of osmotic stress processes in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME-CFS) blood samples. Authorea. July 11, 2023.
DOI: 10.22541/au.168909663.38868952/v1 https://www.authorea.com/doi/full/10.22541/au.168909663.38868952/v1 (Full text)

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multifactorial disease that causes increasing morbidity worldwide, and many individuals with ME/CFS symptoms remain undiagnosed due to the lack of diagnostic biomarkers. Its etiology is still unknown, but increasing evidence supports a role of herpesviruses (including HHV-6A and HHV-6B) as potential triggers.
Interestingly, the infection by these viruses has been reported to impact the expression of microRNAs (miRNAs), short non-coding RNA sequences which have been suggested to be epigenetic factors modulating ME/CFS pathogenic mechanisms. Notably, the presence of circulating miRNAs in plasma has raised the possibility to use them as valuable biomarkers for distinguishing ME/CFS patients from healthy controls.
Thus, this study aimed at determining the role of eight miRNAs, which were selected for their previous association with ME/CFS, as potential circulating biomarkers of the disease. Their presence was quantitatively evaluated in plasma from 40 ME/CFS patients and 20 healthy controls by specific Taqman assays, and the results showed that six out of the eight of the selected miRNAs were differently expressed in patients compared to controls; more specifically, five miRNAs were significantly upregulated (miR-127-3p, miR-142-5p, miR-143-3p, miR-150-5p, and miR-448), and one was downmodulated (miR-140-5p). MiRNA levels directly correlated with disease severity, whereas no significant correlations were observed with the plasma levels of seven pro-inflammatory cytokines or with the presence/load of HHV-6A/6B genome, as judged by specific PCR amplification.
The results may open the way for further validation of miRNAs as new potential biomarkers in ME/CFS and increase the knowledge of the complex pathways involved in the ME/CFS development.
Source: Soffritti I, Gravelsina S, D’Accolti M, Bini F, Mazziga E, Vilmane A, Rasa-Dzelzkaleja S, Nora-Krukle Z, Krumina A, Murovska M, et al. Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(13):10582. https://doi.org/10.3390/ijms241310582 https://www.mdpi.com/1422-0067/24/13/10582 (Full text)

Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specific test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufficient knowledge about the disease. Prior studies have shown that patients with ME/CFS/SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the differences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.

Methods: This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the difference in serum acylcarnitine levels between the two groups.

Results: The electronic search identified 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had significantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high.

Conclusion: The patient group had significantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.

Source: Jinushi R, Masuda S, Tanisaka Y, Nishiguchi S, Shionoya K, Sato R, Sugimoto K, Shin T, Shiomi R, Fujita A, Mizuide M, Ryozawa S. Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis. J Transl Med. 2023 Jun 19;21(1):398. doi: 10.1186/s12967-023-04226-z. PMID: 37337273; PMCID: PMC10280864. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10280864/ (Full text)

A Unique Circular RNA Expression Pattern in the Peripheral Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers. In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson’s disease and Alzheimer’s disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted. In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally.

In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease. Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups. A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS.

Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes. Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.

Source: Yuning Cheng, Si-Mei Xu, Konii Takenaka, Grace Lindner, Ashton Curry-Hyde, Michael Janitz. A Unique Circular RNA Expression Pattern in the Peripheral Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Gene. Available online 15 June 2023, 147568. https://doi.org/10.1016/j.gene.2023.147568 https://www.sciencedirect.com/science/article/abs/pii/S0378111923004092

Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background and purpose: Free-water-corrected diffusion tensor imaging (FW-DTI), a new analysis method for diffusion MRI, can indicate neuroinflammation and degeneration. There is increasing evidence of autoimmune etiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We used FW-DTI and conventional DTI to investigate microstructural brain changes related to autoantibody titers in patients with ME/CFS.

Methods: We prospectively examined 58 consecutive right-handed ME/CFS patients who underwent both brain MRI including FW-DTI and a blood analysis of autoantibody titers against β1 adrenergic receptor (β1 AdR-Ab), β2 AdR-Ab, M3 acetylcholine receptor (M3 AchR-Ab), and M4 AchR-Ab. We investigated the correlations between these four autoantibody titers and three FW-DTI indices-free water (FW), FW-corrected fractional anisotropy (FAt), and FW-corrected mean diffusivity-as well as two conventional DTI indices-fractional anisotropy (FA) and mean diffusivity. The patients’ age and gender were considered as nuisance covariates. We also evaluated the correlations between the FW-DTI indices and the performance status and disease duration.

Results: Significant negative correlations between the serum levels of several autoantibody titers and DTI indices were identified, mainly in the right frontal operculum. The disease duration showed significant negative correlations with both FAt and FA in the right frontal operculum. The changes in the FW-corrected DTI indices were observed over a wider extent compared to the conventional DTI indices.

Conclusions: These results demonstrate the value of using DTI to assess the microstructure of ME/CFS. The abnormalities of right frontal operculum may be a diagnostic marker for ME/CFS.

Source: Kimura Y, Sato W, Maikusa N, Ota M, Shigemoto Y, Chiba E, Arizono E, Maki H, Shin I, Amano K, Matsuda H, Yamamura T, Sato N. Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome. J Neuroimaging. 2023 May 27. doi: 10.1111/jon.13128. Epub ahead of print. PMID: 37243973. https://pubmed.ncbi.nlm.nih.gov/37243973/

Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case criteria following exclusion of any other potential medical conditions. While there are some studies that report potential biomarkers for ME/CFS, their efficacy has not been validated. The aim of this systematic review is to collate and appraise literature pertaining to a potential biomarker(s) which may effectively differentiate ME/CFS patients from healthy controls.

Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane review guidelines. PubMed, Embase and Scopus were systematically searched for articles containing “biomarker” and “ME/CFS” keywords in the abstract or title and if they included the following criteria: (1) were observational studies published between December 1994 and April 2022; (2) involved adult human participants; (3) full text is available in English (4) original research; (5) diagnosis of ME/CFS patients made according to the Fukuda criteria (1994), Canadian Consensus Criteria (2003), International Consensus Criteria (2011) or Institute of Medicine Criteria (2015); (6) study investigated potential biomarkers of ME/CFS compared to healthy controls. Quality and Bias were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.

Results: A total of 101 publications were included in this systematic review. Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%), endovascular/circulatory (17.82%), neurological (7.92%), ion channel (8.91%) and physical dysfunction biomarkers (8.91%). Most of the potential biomarkers reported were blood-based (79.2%). Use of lymphocytes as a model to investigate ME/CFS pathology was prominent among immune-based biomarkers. Most biomarkers had secondary (43.56%) or tertiary (54.47%) selectivity, which is the ability for the biomarker to identify a disease-causing agent, and a moderate (59.40%) to complex (39.60%) ease-of-detection, including the requirement of specialised equipment.

Conclusions: All potential ME/CFS biomarkers differed in efficiency, quality, and translatability as a diagnostic marker. Reproducibility of findings between the included publications were limited, however, several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness. The heterogeneity shown across many of the included studies highlights the need for multidisciplinary research and uniform protocols in ME/CFS biomarker research.

Source: Maksoud R, Magawa C, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review. BMC Med. 2023 May 24;21(1):189. doi: 10.1186/s12916-023-02893-9. PMID: 37226227; PMCID: PMC10206551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206551/ (Full text)