Welcome to the 87th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

Authors: Haffke M, Freitag H, Rudolf G, Seifert M, Doehner W, Scherbakov N, … Sotzny F (Charité - Universitätsmedizin Berlin , Germany).
Publication: Journal of Translational Medicine
Link: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03346-2

 
Approximately 10-30% of COVID-19 patients report ongoing symptoms at six months post mild-moderate infection, with fatigue, exertion intolerance and post exertional malaise, some of the most commonly reported symptoms of post-COVID syndrome (PCS). A subset of these patients fulfils the diagnostic criteria for ME/CFS. COVID-19 is known to infect endothelial cells, and the authors sought to investigate endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
 
Participants for the peripheral arterial tonometry (PAT) study included 30 PCS patients with persistent fatigue and exertion intolerance, 14 of whom fulfilled the Canadian Consensus Criteria for ME/CFS, and 15 age and sex matched healthy controls (HC) with no known history of COVID-19 infection. Peripheral endothelial function was assessed using reactive hyperaemia peripheral arterial tonometry (RH-PAT). Multiple endothelial biomarkers were identified in the PAT study and were subsequently validated by a second group of participants, which included 56 PCS patients (26 of whom met the diagnostic criteria for ME/CFS), 50 HC and 20 post-COVID healthy controls (PCHC).  
 
The authors found that 10 PCS participants (including 5 with ME/CFS) showed ED. ED was not found in any of the HCs. A paradoxical positive correlation of the reactive hyperaemia index (RHI) with age, blood pressure and BMI was found in PCS but not ME/CFS patients. Elevated Endothelin-1 concentration was seen in ME/CFS and PCS patients compared to HCs. Angiopoietin-2 was lower in PCS patients and PCHC compared to HCs.
 
The authors conclude that a subset of PCS patients shows evidence of endothelial dysfunction, reflected in a diminished RHI and altered endothelial biomarkers. The authors propose that the elevated ET-1 levels seen in PCS patients indicate that endothelial hypoperfusion plays a role in PCS and may provide an avenue for therapeutic intervention. Different biomarker profiles may suggest multiple pathomechanisms among patient subgroups.

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The Role of Kynurenine Pathway and NAD⁺ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Authors: Dehhaghi M, Panahi HKS, Kavyani B, Heng B, Tan V, Braidy N, Guillemin GJ (Macquarie University, Australia)
Publication: Aging and Disease
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116917/
 
The metabolism of tryptophan is involved in the production of energy, the transcription of DNA to RNA, DNA repair, apoptosis, and the production of serotonin. The kynurenine pathway (KP) breaks tryptophan into either neuroprotective or neurotoxic metabolites, depending on the regulation of enzymes and catabolites. This review seeks to elucidate the ways the metabolites of tryptophan can influence symptoms of ME/CFS, and how, in turn, the hallmarks of ME/CFS can alter the specific path taken within the kynurenine pathway, leading to abnormal metabolism, and thus increasing ME/CFS symptoms.
 
Only a small portion of tryptophan is broken down into serotonin, with 90% turned into kynurenine and then to further metabolites. Inflammation and immune activation increase the kynurenine pathway, with increases in tryptophan metabolism reducing the serotonin pathway and increasing the kynurenine and kynurenine metabolite production.
The authors suggest an overactive immune system causes the breakdown of neurotransmitters, an increase in cytokines causing further inflammation, and the downregulation of serotonin; that could be associated with ME/CFS symptoms, such as headaches, sleep difficulties, fatigue, and mood dysregulation. Inflammation activates microglia in large portions of the brains of ME/CFS patients, with these important sites of tryptophan metabolism into neurotoxic products causing a suppression of astrocytes, thus a reduction in serotonin, leading to depression, mood disorders and sleep problems. Altered tryptophan metabolism leads to oxidative and nitrosative stress that further leads to cellular dysfunction and triggers a further immune response. Reduced gut microflora diversity in ME/CFS results in abnormal ratios of genera, resulting in altered levels of catabolites, which also cause alteration to the KP and tryptophan metabolites.
 
The authors suggest that through understanding the kynurenine pathway, a diagnostic marker (such as elevated IDO1) could be found. They also suggest that the kynurenine pathway could provide therapeutic opportunities, such as supplementation of CoQ₁₀ and tryptophan metabolites nicotinamide riboside and nicotinamide mononucleotide, although clinical studies are needed to support this.

Figure: Kynurenine pathway and NAD+ salvage pathway

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Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

Authors: Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, … Chatterjee A (University of Otago, New Zealand)
Publication: Frontiers in Neurology
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174654/pdf/fneur-13-877772.pdf
 
In this paper, the authors attempt to provide a mechanism to explain how the central nervous system’s (CNS) inflammatory/immunological and stress responses could become dysfunctional, following an initial infection or stress event, which could result in chronic relapse and recovery cycles associated with ME/CFS and more recently, Long-COVID.
 
The authors hypothesise that abnormal signaling and transportation of molecules between the peripheral system and the CNS occur through neurovascular pathways such as the inflammatory reflex, gateway reflex, or a disrupted blood-brain barrier (BBB). They suggest that the atypical functioning of these mechanisms triggers neuroinflammation which, if the initial stressor is not resolved, causes the common symptoms associated with ME/CFS and Long-COVID; namely, pain, fatigue, brain fog, unrefreshing sleep and post-exertional malaise.
 
The authors propose that the partial recovery/relapse cycles seen in ME/CFS are due to chronic neuroinflammation which is sustained by systemic stress responses due to increased serotonin levels and dysfunction of the hypothalamus pituitary adrenal (HPA) axis. The HPA axis is one of the most important mediators of the body’s response to stress and if impaired could mean ME/CFS patients’ protective response against the body’s inflammatory/immune reactions would be diminished. Further, serotonin has many roles throughout the CNS, modulating other systems in response to stress. Serotonin in excess leads to many abnormal symptoms such as dysfunctional muscle contraction, migraines, sleep disruption, and cognitive dysfunction. The authors propose that it is through these two mechanisms (HPA axis dysfunction and elevated serotonin) that the illnesses of ME/CFS and Long COVID are sustained.


Figure: Mechanisms proposed to facilitate the onset of ME/CFS and its progression to a chronic sustained illness with relapse/partial recovery phases. 

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Queensland researchers find overlap in pathology of long COVID and chronic fatigue syndrome

Authors: Sheehan H
Publication: ABC News
Link: https://www.abc.net.au/news/2022-08-11/long-covid-and-chronic-fatigue-syndrome-pathology-overlap/101318522
 
Researchers at Griffith University report that the calcium ion dysfunction which they have identified in ME/CFS is also present in Long COVID patients. This research study has since been published https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00528-y.
 
The Australian Medical Association Queensland President, Dr Maria Boulton, welcomed the announcement, though indicated that the results would need to be independently verified. She acknowledged that medical research isn’t as well funded in Australia as in the US and UK and called on the Queensland government to fund more research into Long COVID “because it is essential that we stay ahead of the curve”.

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