Category: Biomarker

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

Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects

Abstract:

Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) have similar profiles of pain, fatigue, cognitive dysfunction and exertional exhaustion. Post-exertional malaise suggests exercise alters central nervous system functions. Lumbar punctures were performed in GWI, CFS and control subjects after (i) overnight rest (nonexercise) or (ii) submaximal bicycle exercise. Exercise induced postural tachycardia in one third of GWI subjects (Stress Test Activated Reversible Tachycardia, START). The remainder were Stress Test Originated Phantom Perception (STOPP) subjects. MicroRNAs (miRNA) in cerebrospinal fluid were amplified by quantitative PCR. Levels were equivalent between nonexercise GWI (n = 22), CFS (n = 43) and control (n = 22) groups. After exercise, START (n = 22) had significantly lower miR-22-3p than control (n = 15) and STOPP (n = 42), but higher miR-9-3p than STOPP. All post-exercise groups had significantly reduced miR-328 and miR-608 compared to nonexercise groups; these may be markers of exercise effects on the brain. Six miRNAs were significantly elevated and 12 diminished in post-exercise START, STOPP and control compared to nonexercise groups. CFS had 12 diminished miRNAs after exercise. Despite symptom overlap of CFS, GWI and other illnesses in their differential diagnosis, exercise-induced miRNA patterns in cerebrospinal fluid indicated distinct mechanisms for post-exertional malaise in CFS and START and STOPP phenotypes of GWI.

Source: James N. Baraniuk & Narayan Shivapurkar. Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects. Scientific Reports 7, Article number: 15338 (2017) doi:10.1038/s41598-017-15383-9    https://www.nature.com/articles/s41598-017-15383-9 (Full article)

Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study

Abstract:

PURPOSE: To compare physiological responses of chronic fatigue syndrome (CFS/ME), multiple sclerosis (MS) and healthy controls (HC) following a 24-h repeated exercise test.

METHODS: Ten CFS, seven MS and 17 age- and gender-matched healthy controls (10, CFS HC; and seven, MS HC) were recruited. Each participant completed a maximal incremental cycle exercise test on day 1 and again 24 h later. Heart rate (HR), blood pressure (BP), rating of perceived exertion (RPE), oxygen consumption (V˙O2), carbon dioxide production and workload (WL) were recorded. Data analysis investigated these responses at anaerobic threshold (AT) and peak work rate (PWR).

RESULTS: On day 2, both CFS and MS had significantly reduced max workload compared to HC. On day 2, significant differences were apparent in WL between CFS and CFS HC (93 ± 37 W, 132 ± 42 W, P<0·042). CFS workload decreased on day 2, alongside a decrease in HR but with an increase in V˙O2 (ml  kg  min-1 ). This was in comparison with an increase in WL, HR and V˙O2 for CFS HC. MS demonstrated a decreased WL compared to MS HC on both days of the study (D1 81 ± 30 W, 116 ±30 W; D2 84 ± 29 W, 118 ± 36 W); however, patients with MS were able to achieve a higher WL on day 2 alongside MS HC.

CONCLUSION: These results suggest that exercise exhibits a different physiological response in MS and CFS/ME, demonstrating repeated cardiovascular exercise testing as a valid measure for differentiating between fatigue conditions.

© 2017 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

Source: Hodges LD, Nielsen T, Baken D. Clin Physiol Funct Imaging. Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study. 2017 Aug 7. doi: 10.1111/cpf.12460. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28782878

Researchers identify biomarkers associated with chronic fatigue syndrome severity

Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signaling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.

The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.

You can read the rest of this article here: http://med.stanford.edu/news/all-news/2017/07/researchers-id-biomarkers-associated-with-chronic-fatigue-syndrome.html

The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a common and severe disease with a considerable social and economic impact. So far, the etiology is not known, and neither a diagnostic marker nor licensed treatments are available yet. The EUROMENE network of European researchers and clinicians aims to promote cooperation and advance research on ME/CFS. To improve diagnosis and facilitate the analysis of clinical trials surrogate markers are urgently needed. As a first step for developing such biomarkers for clinical use a database of active biomarker research in Europe was established called the ME/CFS EUROMENE Biomarker Landscape project and the results are presented in this review. Further we suggest strategies to improve biomarker development and encourage researchers to take these into consideration for designing and reporting biomarker studies.

Source: Carmen Scheibenbogen, Helma Freitag, Julià Blanco, Enrica Capelli, Eliana Lacerda, Jerome Authier, Mira Meeus, Jesus Castro Marrero, Zaiga Nora-Krukle, Elisa Oltra, Elin Bolle Strand, Evelina Shikova, Slobodan Sekulic and Modra Murovska. The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE. Journal of Translational Medicine201715:162. https://doi.org/10.1186/s12967-017-1263-z https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1263-z (Full article)

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome

 

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

Results: Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS.

Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

Conclusions: Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.

 

Source: Dorottya Nagy-Szakal, Brent L. Williams, Nischay Mishra, Xiaoyu Che, Bohyun Lee, Lucinda Bateman, Nancy G. Klimas, Anthony L. Komaroff, Susan Levine, Jose G. Montoya, Daniel L. Peterson, Devi Ramanan, Komal Jain, Meredith L. Eddy, Mady Hornig and W. Ian Lipkin. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome20175:44. DOI: 10.1186/s40168-017-0261-y https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-017-0261-y#MOESM1 (Full article)