2015 – Page 11 – American ME and CFS Society

Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

Abstract:

BACKGROUND: The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue.

Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.

DISCUSSION: Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation.

This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.

SUMMARY: It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.

Source: Morris G, Berk M, Walder K, Maes M. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. BMC Med. 2015 Feb 6;13:28. doi: 10.1186/s12916-014-0259-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320458/ (Full article)

Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome

Abstract:

BACKGROUND: Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.

METHODS: Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.

RESULTS: In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16 h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16 h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.

CONCLUSION: EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

Source: Brown AE, Jones DE, Walker M, Newton JL. Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. PLoS One. 2015 Apr 2;10(4):e0122982. doi: 10.1371/journal.pone.0122982. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383615/ (Full article)

Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

OBJECTIVES: Previous research has provided evidence for dysregulation in peripheral cytokines in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To date only one study has examined cytokines in cerebrospinal fluid (CSF) samples of CFS/ME patients. The purpose of this pilot study was to examine the role of cytokines in CSF of CFS/ME patients.

METHODS: CSF was collected from 18 CFS/ME patients and 5 healthy controls. The CSF samples were examined for the expression of 27 cytokines (interleukin- (IL-) 1β, IL-1ra, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF) using the Bio-Plex Human Cytokine 27-plex Assay.

RESULTS: Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls.

CONCLUSIONS: This preliminary investigation suggests that perturbations in inflammatory cytokines in the CSF of CFS/ME patients may contribute to the neurological discrepancies observed in CFS/ME.

Source: Peterson D, Brenu EW, Gottschalk G, Ramos S, Nguyen T, Staines D, Marshall-Gradisnik S. Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediators Inflamm. 2015;2015:929720. doi: 10.1155/2015/929720. Epub 2015 Mar 5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365360/ (Full article)

Fibromyalgia and chronic fatigue syndrome: management issues

Abstract:

Fibromyalgia and chronic fatigue syndrome represent two of the most commonly encountered functional somatic syndromes in clinical practice. Both have been contentious diagnoses in the past, and this diagnostic dispute has resulted in a therapeutic nihilism that has been of great detriment to their management and to alleviation of the intense suffering and disability that they have caused their innumerable sufferers.

A new age has dawned in terms of a better understanding of these syndromes’ physiology and improved approaches to their management. Here, the diagnosis and management of these closely related disorders are discussed, with particular reference to the recent empirical evidence that has come to light as a consequence of neurophysiological insights and robustly designed randomised clinical trials.

Much work remains to be done in this vein, but we are better placed to facilitate recovery from these disorders than we have been previously. Whilst remission should always be a goal, complete symptom resolution is not the norm, but ‘moderate’ improvements are certainly attainable with appropriate management.

Source: Bourke J. Fibromyalgia and chronic fatigue syndrome: management issues. Adv Psychosom Med. 2015;34:78-91. doi: 10.1159/000369087. Epub 2015 Mar 3. https://www.ncbi.nlm.nih.gov/pubmed/25832515

Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues

Abstract:

There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined.

Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM.

Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems’ abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.

Source: Romano GF, Tomassi S, Russell A, Mondelli V, Pariante CM. Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues. Adv Psychosom Med. 2015;34:61-77. doi: 10.1159/000369085. Epub 2015 Mar 30. https://www.ncbi.nlm.nih.gov/pubmed/25832514

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay.

Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling.

Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

Source: Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31. https://www.ncbi.nlm.nih.gov/pubmed/25824300

Immunomodulating and antioxidant effects of polysaccharide conjugates from the fruits of Ziziphus Jujube on Chronic Fatigue Syndrome rats

Abstract:

To detect the treatment effect of the fruits of Ziziphus Jujube in Chronic Fatigue Syndrome (CFS). Jujube polysaccharide conjugates (JPC) were isolated from the fruits of Z. Jujube. General physicochemical properties of JPC were analyzed.

A four-week rats CFS model was established and JPC were orally administrated, the behavior experiments were conducted after CFS. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of malondialdehyde (MDA) in serum were elevated and T lymphocyte proliferation, CD4(+)/CD8(+) ratio and natural killer (NK) cells activity were analyzed.

JPC markedly improved behaviors of CFS rats, also decreased MDA levels in serum, and elevated T lymphocyte proliferation, CD4(+)/CD8(+) ratio and natural killer (NK) cells activities. This suggests that JPC can improve the immune system and antioxidant activity of CFS rats and might be regarded as a biological response modifier.

Source: Chi A, Kang C, Zhang Y, Tang L, Guo H, Li H, Zhang K. Immunomodulating and antioxidant effects of polysaccharide conjugates from the fruits of Ziziphus Jujube on Chronic Fatigue Syndrome rats. Carbohydr Polym. 2015 May 20;122:189-96. doi: 10.1016/j.carbpol.2014.12.082. Epub 2015 Jan 14. https://www.ncbi.nlm.nih.gov/pubmed/25817658

Chronic fatigue syndrome: Features of a population of patients from northern Italy

Abstract:

In this study we analyzed the clinical features of a population of Italian patients with chronic fatigue syndrome (CFS) diagnosed according to the CDC-1994 criteria. The aim was to investigate CFS patients and their relatives, in order to search for events related to the onset of the disease and to identify correlations with other diseases. The analysis was carried out by examining medical records belonging to 82 patients suffering from the syndrome. The documentation was collected between 2008 and 2011 and provided by the non-profit Italian organization AMCFS (Associazione Malati di CFS). The influence of gender on the age of onset and association with potential risk factors were investigated in patients and in their relatives. From the results a significant correlation between the age of onset and autoimmunity was observed.

Source: Capelli E, Lorusso L, Ghitti M, Venturini L, Cusa C, Ricevuti G. Chronic fatigue syndrome: Features of a population of patients from northern Italy. Int J Immunopathol Pharmacol. 2015 Mar;28(1):53-9. Doi: 10.1177/0394632015572074. https://www.ncbi.nlm.nih.gov/pubmed/25816406

Chronic fatigue syndrome and fibromyalgia in Canada: prevalence and associations with six health status indicators

Abstract:

INTRODUCTION: Few studies have considered the factors independently associated with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) or considered the impact of these conditions on health status using population-based data.

METHODS: We used data from the nationally representative 2010 Canadian Community Health Survey (n = 59 101) to describe self-reported health professional-diagnosed CFS and/or FM, and their associations with 6 health status indicators.

RESULTS: In 2010, diagnosed CFS and FM are reported by 1.4% (95% confidence interval [CI]: 1.3%-1.6%) and 1.5% (1.4%-1.7%), respectively, of the Canadian household population aged 12 years and over, with comorbid CFS and FM affecting 0.3% (0.3%-0.4%) of that population. Prevalent CFS and/or FM were more common among women, adults aged 40 years and over, those with lowest income, and those with certain risk factors for chronic disease (i.e. obesity, physical inactivity and smoking). After controlling for differences between the groups, people with CFS and/or FM reported poorer health status than those with neither condition on 5 indicators of health status, but not on the measure of fair/poor mental health. Having both CFS and FM and having multiple comorbid conditions was associated with poorer health status.

CONCLUSION: Co-occurrence of CFS and FM and having other chronic conditions were strongly related to poorer health status and accounted for much of the differences in health status. Understanding factors contributing to improved quality of life in people with CFS and/or FM, particularly in those with both conditions and other comorbidities, may be an important area for future research.

Source: Rusu C, Gee ME, Lagacé C, Parlor M. Chronic fatigue syndrome and fibromyalgia in Canada: prevalence and associations with six health status indicators. Health Promot Chronic Dis Prev Can. 2015 Mar;35(1):3-11. [Article in English, French; Abstract available in French from the publisher] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939456/ (Full article)

The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach?

Abstract:

Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and typically affecting a variety of bodily systems including the immune system.

Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system.

Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients. Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration. This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.

Source: Gambuzza ME, Salmeri FM, Soraci L, Soraci G, Sofo V, Marino S, Bramanti P. The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach? CNS Neurol Disord Drug Targets. 2015;14(7):903-14. https://www.ncbi.nlm.nih.gov/pubmed/25808894