Category: Biomarker

A Glimpse into Dr. Ron Davis’ Talk in London

From Open Medicine Foundation.
June 1, 2018

Dear Friends,

I prepared this statement for Ashley Haugen to read yesterday at the Western Massachusetts  Department of Public Health screening of Unrest. This is new information from the Severely ill Patient Study (SIPS) that I also presented in London:

“We have made considerable progress in analyzing the data from the severely ill patient study. This has taken some time because we have only had one bioinformatic scientist analyzing the massive amount of data.

We have found that there are a considerable number of mutations that are more common in ME/CFS patients than in healthy controls. This would suggest that these mutations make a patient more susceptible to having ME/CFS. It could also indicate that some of the mutations are responsible for the severity of the patients we studied. We also see a large number of metabolomic changes that have been previously seen in less severe patients. These metabolomic differences between healthy controls and our severely ill patients are often much bigger than in studies with less severe patients. A more detailed analysis of this data may aid us in developing treatments.

One area we are currently studying using the genetic and metabolomic data is the possibility there may be one or more metabolic traps. This is a metabolic state that a patient can develop, possibly caused by physical stress such as infection. Once a patient is in this state they cannot easily get out by rest.

We are conducting system biology and pathway analysis that shows that a metabolic trap is possible, and that some of the observed mutations make it more likely. If this is the case we should be able to push the patients out of this state by a specific metabolic intervention. We are very hopeful that this could be a one time treatment, take only a few days, and be relatively inexpensive.”

Sending greetings from London,

Ronald W. Davis, PhD
Director, OMF ME/CFS Scientific Advisory Board
Director, Stanford Genome Technology Center

Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients

Abstract:

Chronic fatigue syndrome (CFS) is a disorder associated with fatigue, pain, and structural/functional abnormalities seen during magnetic resonance brain imaging (MRI). Therefore, we evaluated the performance of structural MRI (sMRI) abnormalities in the classification of CFS patients versus healthy controls and compared it to machine learning (ML) classification based upon self-report (SR). Participants included 18 CFS patients and 15 healthy controls (HC). All subjects underwent T1-weighted sMRI and provided visual analogue-scale ratings of fatigue, pain intensity, anxiety, depression, anger, and sleep quality. sMRI data were segmented using FreeSurfer and 61 regions based on functional and structural abnormalities previously reported in patients with CFS. Classification was performed in RapidMiner using a linear support vector machine and bootstrap optimism correction.

We compared ML classifiers based on (1) 61 a priori sMRI regional estimates and (2) SR ratings. The sMRI model achieved 79.58% classification accuracy. The SR (accuracy = 95.95%) outperformed both sMRI models. Estimates from multiple brain areas related to cognition, emotion, and memory contributed strongly to group classification. This is the first ML-based group classification of CFS. Our findings suggest that sMRI abnormalities are useful for discriminating CFS patients from HC, but SR ratings remain most effective in classification tasks.

Source: Sevel LS, Boissoneault J, Letzen JE, Robinson ME, Staud R. Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients. Exp Brain Res. 2018 May 30. doi: 10.1007/s00221-018-5301-8. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29846797

Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study

Abstract:

Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME) is an acquired, complex and multisystem condition of unknown etiology, no established diagnostic lab tests and no universally FDA-approved drugs for treatment. CFS/ME is characterised by unexplicable disabling fatigue and is often also associated with numerous core symptoms. A growing body of evidence suggests that extracellular vesicles (EVs) play a role in cell-to-cell communication, and are involved in both physiological and pathological processes. To date, no data on EV biology in CFS/ME are as yet available.

The aim of this study was to isolate and characterise blood-derived EVs in CFS/ME. Blood samples were collected from 10 Spanish CFS/ME patients and 5 matched healthy controls (HCs), and EVs were isolated from the serum using a polymer-based method. Their protein cargo, size distribution and concentration were measured by Western blot and nanoparticle tracking analysis. Furthermore, EVs were detected using a lateral flow immunoassay based on biomarkers CD9 and CD63.

We found that the amount of EV-enriched fraction was significantly higher in CFS/ME subjects than in HCs (p = 0.007) and that EVs were significantly smaller in CFS/ME patients (p = 0.014). Circulating EVs could be an emerging tool for biomedical research in CFS/ME. These findings provide preliminary evidence that blood-derived EVs may distinguish CFS/ME patients from HCs. This will allow offer new opportunities and also may open a new door to identifying novel potential biomarkers and therapeutic approaches for the condition.

Source: Castro-Marrero J, Serrano-Pertierra E, Oliveira-Rodríguez M, Zaragozá MC, Martínez-Martínez A, Blanco-López MDC, Alegre J. Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study. J Extracell Vesicles. 2018 Mar 22;7(1):1453730. doi: 10.1080/20013078.2018.1453730. eCollection 2018. https://www.ncbi.nlm.nih.gov/pubmed/29696075

Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review

Abstract:

Chronic fatigue syndrome (CFS), commonly known as myalgic encephalomyelitis (ME), is a debilitating disease of unknown etiology. CFS/ME is a heterogeneous disease associated with a myriad of symptoms but with severe, prolonged fatigue as the core symptom associated with the disease. There are currently no known biomarkers for the disease, largely due to the lack of knowledge surrounding the eitopathogenesis of CFS/ME. Numerous studies have been conducted in an attempt to identify potential biomarkers for the disease.

This mini-review offers a brief summary of current research into the identification of metabolic abnormalities in CFS/ME which may represent potential biomarkers for the disease. The progress of research into key areas including immune dysregulation, mitochondrial dysfunction, 5′-adenosine monophosphate-activated protein kinase activation, skeletal muscle cell acidosis, and metabolomics are presented here. Studies outlined in this mini-review show many potential causes for the pathogenesis of CFS/ME and identify many potential metabolic biomarkers for the disease from the aforementioned research areas.

The future of CFS/ME research should focus on building on the potential biomarkers for the disease using multi-disciplinary techniques at multiple research sites in order to produce robust data sets. Whether the metabolic changes identified in this mini-review occur as a cause or a consequence of the disease must also be established.

Source: Cara Tomas; Julia Newton. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochemical Society Transactions Apr 17, 2018; DOI: https://doi.org/10.1042/BST20170503. http://www.biochemsoctrans.org/content/early/2018/04/16/BST20170503

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment.

METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed.

RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines.

CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.

Source: Richardson AM, Lewis DP, Kita B, Ludlow H, Groome NP, Hedger MP, de Kretser DM, Lidbury BA. Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection. J Transl Med. 2018 Apr 12;16(1):97. doi: 10.1186/s12967-018-1473-z. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1473-z (Full article)

Ophthalmic correlates of Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disorder. With the exception of disabling fatigue, there are few definitive clinical features of the condition. As a consequence, patients often have difficulty gaining an appropriate diagnosis. As such, identifying distinct clinical feature of ME/CFS is an important issue. One under researched area of ME/CFS associated symptoms concerns problems related to vision.

People with ME/CFS consistently report a range of symptoms related to the quality of their vision including pain in the eyes, hypersensitivity to light, difficulty focusing on images, slow eye movements, and difficulty tracking object movement. However, there has been little attempt to verify patients’ self-reports using objective methods. The purpose of the experiments presented in this thesis was to determine the effects of ME/CFS on: (i) performance on a range of tests of visual sensitivity and (ii) the morphology of the retina.

Compared to controls, the ME/CFS group exhibited reduced accommodation, larger pupil diameters, reduced colour discrimination and poorer contrast sensitivity towards lower spatial frequencies. Thinning in the photoreceptor layers of the retina (the Outer Segment & the Outer Nuclear layer) was also apparent. These findings support the claims of people with ME/CFS that they experience problems related to their vision and its function. They also represent a potential marker of ME/CFS that may aid in its diagnosis.

Source: Ahmed, Nadia Sultana. Ophthalmic Correlates of Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Thesis, Univeristy of Leicester, 15-Feb-2018

Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often suffer from gastrointestinal symptoms and many are diagnosed with irritable bowel syndrome (IBS). Previous studies, including from our laboratory, have demonstrated that the ME/CFS gut bacterial composition is altered and less diverse when compared to healthy individuals. Patients have increased biomarkers of inflammation and leaky gut syndrome. To further investigate dysbiosis in the ME/CFS gut microbiome, we sought to characterize the eukaryotes present in the gut of 49 individuals with ME/CFS and 39 healthy controls. Using 18S rRNA sequencing, we have identified eukaryotes in stool samples of 17 healthy individuals and 17 ME/CFS patients. Our analysis demonstrates a small, nonsignificant decrease in eukaryotic diversity in ME/CFS patients compared to healthy individuals. In addition, ME/CFS patients show a nonsignificant increase in the ratio of fungal phyla Basidiomycota to Ascomycota, which is consistent with ongoing inflammation in ME/CFS. We did not identify specific eukaryotic taxa that are associated with ME/CFS disease status.

Source: Alexandra H. Mandarano, Ludovic Giloteaux, Betsy A. Keller, Susan M. Levine, Maureen R. Hanson. Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. Peer J. January 22, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784577/https://peerj.com/articles/4282/ (Full article)

New Diagnostic Biomarkers for Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without symptoms of infection or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. The pathogenesis of CFS is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of CFS and diagnostic uncertainty. We performed comprehensive metabolomic analyses of blood samples obtained from patients with CFS and healthy controls to establish an objective diagnosis of CFS. Here, we review previous findings concerning the immune, endocrine, and metabolic system in animal models for CFS and the patients, and present our results which may contribute to the development of a diagnostic biomarker for CFS.

Source: Yamano E, Kataoka Y. New Diagnostic Biomarkers for Chronic Fatigue Syndrome. Brain Nerve. 2018 Jan;70(1):27-34. doi: 10.11477/mf.1416200946. [Article in Japanese]  https://www.ncbi.nlm.nih.gov/pubmed/29348372

Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Background: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) frequently have overlapping symptoms, leading to the suggestion that the same disease processes may underpin the two disorders – the unitary hypothesis. However, studies investigating the two disorders have reported substantial clinical and/or biological differences them, suggesting distinct pathophysiological underpinnings.

Purpose: The purpose of this study was to further add to the body of evidence favoring different disease processes in CFS and FM by comparing ventricular cerebrospinal fluid lactate levels among patients with CFS alone, FM alone, overlapping CFS and FM symptoms, and healthy control subjects.

Methods: Ventricular lactate was assessed in vivo with proton magnetic resonance spectroscopic imaging (1H MRSI) with the results normed across the 2 studies in which the data were collected.

Results: Mean CSF lactate levels in CFS, FM and CFS+FM did not differ among the three groups, but were all significantly higher than the mean values for control subjects.

Conclusion: While patients with CFS, FM and comorbid CFS and FM can be differentiated from healthy subjects based on measures of CFS lactate, this neuroimaging outcome measure is not a viable biomarker for differentiating CFS from FM or from patients in whom symptoms of the two disorders overlap.

Source: Natelson BH, Vu D, Coplan JD, Mao X, Blate M, Kang G, Soto E, Kapusuz T, Shungu DC. Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia. Fatigue. 2017;5(1):15-20. doi: 10.1080/21641846.2017.1280114. Epub 2017 Feb 20.  https://www.ncbi.nlm.nih.gov/pubmed/29308330 

 

Decreased connectivity and increased BOLD complexity in the default mode network in individuals with chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome / myalgic encephalomyelitis (CFS) is a debilitating disease with unknown pathophysiology and no diagnostic test. This study investigated the default mode network (DMN) in order to understand the pathophysiology of CFS and to identify potential biomarkers.

Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798s, we evaluated the default mode network using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps and complexity of activity. General linear model (GLM) univariate analysis was used for inter group comparison to account for age and gender differences. Hierarchical regression analysis was used to test whether fMRI measures could be used to explain variances of health scores.

BOLD signals in the posterior cingulate cortex (PCC), the driving hub in the DMN, were more complex in CFS in both resting state and task (P < 0.05). The FCs between medial prefrontal cortex (mPFC) and both inferior parietal lobules (IPLs) were weaker (P < 0.05) during resting state, while during task mPFC – left IPL and mPFC – PCC were weaker (P < 0.05). The DFCs between the DMN hubs were more complex in CFS (P < 0.05) during task. Each of these differences accounted for 7 – 11% variability of health scores. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potential used as a diagnostic biomarker for CFS.

Source: Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Decreased connectivity and increased BOLD complexity in the default mode network in individuals with chronic fatigue syndrome. Brain Connect. 2017 Nov 20. doi: 10.1089/brain.2017.0549. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29152994