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Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda) 2025; 40:0. [PMID: 39960432 DOI: 10.1152/physiol.00056.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/27/2024] [Accepted: 02/11/2025] [Indexed: 04/26/2025] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder of unclear etiology that affects many individuals worldwide. One of its hallmark symptoms is prolonged fatigue following exertion, a feature also observed in long COVID, suggesting an underlying dysfunction in energy production in both conditions. Here, mitochondrial dysfunction and its potential pathogenetic role in these disorders are reviewed.
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Affiliation(s)
- Abu Mohammad Syed
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, United States
| | - Alexander K Karius
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, United States
| | - Jin Ma
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, United States
| | - Ping-Yuan Wang
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, United States
| | - Paul M Hwang
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, United States
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2
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Todhunter-Brown A, Campbell P, Broderick C, Cowie J, Davis B, Fenton C, Markham S, Sellers C, Thomson K. Recent research in myalgic encephalomyelitis/chronic fatigue syndrome: an evidence map. Health Technol Assess 2025:1-78. [PMID: 40162526 PMCID: PMC11973615 DOI: 10.3310/btbd8846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Background Myalgic encephalomyelitis/chronic fatigue syndrome is a chronic condition, classified by the World Health Organization as a nervous system disease, impacting around 17 million people worldwide. Presentation involves persistent fatigue and postexertional malaise (a worsening of symptoms after minimal exertion) and a wide range of other symptoms. Case definitions have historically varied; postexertional malaise is a core diagnostic criterion in current definitions. In 2022, a James Lind Alliance Priority Setting Partnership established research priorities relating to myalgic encephalomyelitis/chronic fatigue syndrome. Objective(s) We created a map of myalgic encephalomyelitis/chronic fatigue syndrome evidence (2018-23), showing the volume and key characteristics of recent research in this field. We considered diagnostic criteria and how current research maps against the James Lind Alliance Priority Setting Partnership research priorities. Methods Using a predefined protocol, we conducted a comprehensive search of Cochrane, MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature. We included all English-language research studies published between January 2018 and May 2023. Two reviewers independently applied inclusion criteria with consensus involving additional reviewers. Studies including people diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome using any criteria (including self-report), of any age and in any setting were eligible. Studies with < 10 myalgic encephalomyelitis/chronic fatigue syndrome participants were excluded. Data extraction, coding of topics (involving stakeholder consultation) and methodological quality assessment of systematic reviews (using A MeaSurement Tool to Assess systematic Reviews 2) was conducted independently by two reviewers, with disagreements resolved by a third reviewer. Studies were presented in an evidence map. Results Of the 11,278 identified studies, 742 met the selection criteria, but only 639 provided sufficient data for inclusion in the evidence map. These reported data from approximately 610,000 people with myalgic encephalomyelitis/chronic fatigue syndrome. There were 81 systematic reviews, 72 experimental studies, 423 observational studies and 63 studies with other designs. Most studies (94%) were from high-income countries. Reporting of participant details was poor; 16% did not report gender, 74% did not report ethnicity and 81% did not report the severity of myalgic encephalomyelitis/chronic fatigue syndrome. Forty-four per cent of studies used multiple diagnostic criteria, 16% did not specify criteria, 24% used a single criterion not requiring postexertional malaise and 10% used a single criterion requiring postexertional malaise. Most (89%) systematic reviews had a low methodological quality. Five main topics (37 subtopics) were included in the evidence map. Of the 639 studies; 53% addressed the topic 'what is the cause?'; 38% 'what is the problem?'; 26% 'what can we do about it?'; 15% 'diagnosis and assessment'; and 13% other topics, including 'living with myalgic encephalomyelitis/chronic fatigue syndrome'. Discussion Studies have been presented in an interactive evidence map according to topic, study design, diagnostic criteria and age. This evidence map should inform decisions about future myalgic encephalomyelitis/chronic fatigue syndrome research. Limitations An evidence map does not summarise what the evidence says. Our evidence map only includes studies published in 2018 or later and in English language. Inconsistent reporting and use of diagnostic criteria limit the interpretation of evidence. We assessed the methodological quality of systematic reviews, but not of primary studies. Conclusions We have produced an interactive evidence map, summarising myalgic encephalomyelitis/chronic fatigue syndrome research from 2018 to 2023. This evidence map can inform strategic plans for future research. We found some, often limited, evidence addressing every James Lind Alliance Priority Setting Partnership priority; high-quality systematic reviews should inform future studies. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme as award number NIHR159926.
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Affiliation(s)
| | | | | | - Julie Cowie
- NESSIE, Glasgow Caledonian University, Glasgow, UK
| | | | - Candida Fenton
- NESSIE, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Sarah Markham
- NESSIE Patient and public involvement member, UK
- Department of Biostatistics and Health Informatics, King's College London, London, UK
| | - Ceri Sellers
- NESSIE, Glasgow Caledonian University, Glasgow, UK
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Bar-Tana J. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS. J Transl Med 2025; 23:297. [PMID: 40059164 PMCID: PMC11892318 DOI: 10.1186/s12967-025-06220-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 02/10/2025] [Indexed: 05/13/2025] Open
Abstract
Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined. In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. 'mTORC1 Syndrome' (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.
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Affiliation(s)
- Jacob Bar-Tana
- Hebrew University Medical School, 91120, Jerusalem, Israel.
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Bansal AS, Seton KA, Brooks JCW, Carding SR. Cognitive Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Aetiology and Potential Treatments. Int J Mol Sci 2025; 26:1896. [PMID: 40076522 PMCID: PMC11899462 DOI: 10.3390/ijms26051896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/07/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Systemic infection and inflammation impair mental function through a combination of altered attention and cognition. Here, we comprehensively review the relevant literature and report personal clinical observations to discuss the relationship between infection, peripheral inflammation, and cerebral and cognitive dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction in ME/CFS could result from low-grade persistent inflammation associated with raised pro-inflammatory cytokines. This may be caused by both infectious and non-infectious stimuli and lead to altered regional cerebral blood flow accompanied by disturbed neuronal function. Immune dysregulation that manifests as a subtle immunodeficiency or the autoimmunity targeting of one or more neuronal receptors may also be a contributing factor. Efforts to reduce low-grade systemic inflammation and viral reactivation and to improve mitochondrial energy generation in ME/CFS have the potential to improve cognitive dysfunction in this highly disabling condition.
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Affiliation(s)
| | - Katharine A. Seton
- Food, Microbiome and Health Research Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK;
| | | | - Simon R. Carding
- Food, Microbiome and Health Research Programme, Quadram Institute Bioscience, Norwich NR4 7UQ, UK;
- Norwich Medical School, University East Anglia, Norwich NR4 7TJ, UK
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Baraniuk JN. Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics-Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2025; 26:1282. [PMID: 39941050 PMCID: PMC11818353 DOI: 10.3390/ijms26031282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort ("fatigue") that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.
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Affiliation(s)
- James N Baraniuk
- Department of Medicine and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20007, USA
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Taylor TL, Dodds F, Tharpe M, Zumbro EL, Hankes M, Jones R, Rumble D, Antoine L, Allen-Watts K, Sims A, Chandra R, Goodin BR, Younger J, Buford TW. The potential impact of exercise on affect and neuroinflammation in older adults living with fibromyalgia: a scoping review. Front Hum Neurosci 2025; 18:1463935. [PMID: 39834401 PMCID: PMC11743465 DOI: 10.3389/fnhum.2024.1463935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Fibromyalgia (FM) is a widespread chronic pain condition with prevalence increasing in older adults. Older adults living with FM experience longer pain symptom durations that can negatively impact their quality of life. Affect and neuroinflammation are potential factors that can exacerbate pain symptoms. Exercise is a recommended intervention to manage pain symptoms; however, adherence limitations persist. Drawing on the Biopsychosocial Framework of Chronic Pain, this scoping review explores how exercise impacts factors related to neuroinflammation and affect, and how these factors contribute to exercise adherence in older adults living with FM. Methods We conducted a scoping search of articles related to exercise and older adults living with FM published before 2024. The extracted study characteristics include publication type, study design, affect outcomes, neuroinflammation outcomes, exercise type, exercise adherence, and sample demographic information. Results We have provided an overview of the relationship between affect and neuroinflammation in studies including older adults living with FM and highlight the impact of exercise on affect and neuroinflammation in older adults living with FM. A conceptual framework is provided illustrating the reciprocal relationship between exercise, affective changes, neuroinflammation, and exercise adherence. Discussion Our results suggest that exercise may improve affect, while limited evidence suggests that aerobic and resistance exercise improve neuroinflammation. Finally, implications for importance and future directions in the context of potential biological factors impacted are provided.
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Affiliation(s)
- Taylor L. Taylor
- Department of Family and Community Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Fitzgerald Dodds
- Department of Physical Therapy, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL, United States
| | - McKenna Tharpe
- Department of Physical Therapy, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Emily L. Zumbro
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Michael Hankes
- Department of Physical Therapy, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Raymond Jones
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Deanna Rumble
- Department of Psychology and Counseling, University of Central Arkansas, Conway, AR, United States
| | - Lisa Antoine
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kristen Allen-Watts
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrew Sims
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
| | - Reshu Chandra
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Burel R. Goodin
- Department of Anesthesiology, Washington University Pain Center, Washington University, St. Louis, MO, United States
| | - Jarred Younger
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Thomas W. Buford
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Veterans Affairs, Birmingham/Atlanta Geriatric Research, Education, and Clinical Center (GRECC), Birmingham, AL, United States
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Thapaliya K, Inderyas M, Barnden L. Review of Neuroimaging Methods in ME/CFS. Methods Mol Biol 2025; 2920:257-277. [PMID: 40372688 DOI: 10.1007/978-1-0716-4498-0_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
The brain is the most complex organ in the human body, and is involved in memory, speech, and movement, as well as regulating the functions of many other organs within the body. Various imaging techniques have detected subtle brain changes in vivo in ME/CFS. This chapter explores different neuroimaging studies used to investigate structural, functional, neurochemical, and tissue microstructural alterations in ME/CFS. These include magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT).
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Affiliation(s)
- Kiran Thapaliya
- National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia.
| | - Maira Inderyas
- National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia
| | - Leighton Barnden
- National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia
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Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Martens MAG, Cowen PJ. Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla. Nutrients 2024; 16:3308. [PMID: 39408275 PMCID: PMC11478479 DOI: 10.3390/nu16193308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/25/2024] [Accepted: 09/28/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic medical condition with no specific pharmacological treatment. Creatine, a nutrient essential for maintaining energy homeostasis in the cells, is a candidate for interventions in ME/CFS. METHODS Fourteen participants with ME/CFS received supplementation with 16 g creatine monohydrate for 6 weeks. Before starting creatine and on the last day of treatment, participants underwent brain magnetic resonance spectroscopy (MRS) scanning of the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), followed by symptom, cognition, and hand-grip strength assessments. RESULTS Eleven participants completed the study. Creatine treatment increased creatine concentration in both the pgACC and DLPFC (p = 0.004 and 0.012, respectively), decreased fatigue and reaction time (RT) on congruent and incongruent trials of the Stroop test (p = 0.036 and 0.014, respectively), and increased hand-grip strength (p = 0.0004). There was a positive correlation between increases in pgACC creatine and changes in RT on Stroop congruent and incongruent trials (p = 0.048 and p = 0.022, respectively). Creatine was well tolerated, and none of the participants stopped treatment. CONCLUSION Creatine supplementation over six weeks in ME/CFS patients increased brain creatine and improved fatigue and some aspects of cognition. Despite its methodological limitations, this study encourages placebo-controlled investigations of creatine treatment in ME/CFS.
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Affiliation(s)
- Beata R. Godlewska
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK; (A.L.S.); (A.L.S.); (M.A.G.M.); (P.J.C.)
- Oxford Health NHS Foundation Trust, Oxford OX4 4XN, UK
| | - Amy L. Sylvester
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK; (A.L.S.); (A.L.S.); (M.A.G.M.); (P.J.C.)
- Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Uzay E. Emir
- Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford OX1 2JD, UK; (U.E.E.); (W.T.C.)
- Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Ann L. Sharpley
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK; (A.L.S.); (A.L.S.); (M.A.G.M.); (P.J.C.)
| | - William T. Clarke
- Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford OX1 2JD, UK; (U.E.E.); (W.T.C.)
| | - Marieke A. G. Martens
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK; (A.L.S.); (A.L.S.); (M.A.G.M.); (P.J.C.)
- Oxford Health NHS Foundation Trust, Oxford OX4 4XN, UK
- Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford OX1 2JD, UK; (U.E.E.); (W.T.C.)
| | - Philip J. Cowen
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK; (A.L.S.); (A.L.S.); (M.A.G.M.); (P.J.C.)
- Oxford Health NHS Foundation Trust, Oxford OX4 4XN, UK
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Kaur R, Greeley B, Ciok A, Mehta K, Tsai M, Robertson H, Debelic K, Zhang LX, Nelson T, Boulter T, Siu W, Nacul L, Song X. A Multimodal Magnetic Resonance Imaging Study on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Feasibility and Clinical Correlation. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1370. [PMID: 39202651 PMCID: PMC11356663 DOI: 10.3390/medicina60081370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/15/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024]
Abstract
Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a neurological disorder characterized by post-exertional malaise. Despite its clinical relevance, the disease mechanisms of ME/CFS are not fully understood. The previous studies targeting brain function or metabolites have been inconclusive in understanding ME/CFS complexity. We combined single-voxel magnetic resonance spectroscopy (SV-MRS) and functional magnetic resonance imaging (fMRI). Our objectives were to examine the feasibility of the multimodal MRI protocol, identify possible differences between ME/CFS and healthy controls (HCs), and relate MRI findings with clinical symptoms. Methods: We enrolled 18 female ME/CFS participants (mean age: 39.7 ± 12.0 years) and five HCs (mean age: 45.6 ± 14.5 years). SV-MRS spectra were acquired from three voxels of interest: the anterior cingulate gyrus (ACC), brainstem (BS), and left dorsolateral prefrontal cortex (L-DLPFC). Whole-brain fMRI used n-back task testing working memory and executive function. The feasibility was assessed as protocol completion rate and time. Group differences in brain metabolites and fMRI activation between ME/CFS and HCs were compared and correlated with behavioral and symptom severity measurements. Results: The completion rate was 100% regardless of participant group without causing immediate fatigue. ME/CFS appeared to show a higher N-Acetylaspartate in L-DLPFC compared to HCs (OR = 8.49, p = 0.040), correlating with poorer fatigue, pain, and sleep quality scores (p's = 0.001-0.015). An increase in brain activation involving the frontal lobe and the brainstem was observed in ME/CFS compared to HCs (Z > 3.4, p's < 0.010). Conclusions: The study demonstrates the feasibility of combining MRS and fMRI to capture neurochemical and neurophysiological features of ME/CFS in female participants. Further research with larger cohorts of more representative sampling and follow-ups is needed to validate these apparent differences between ME/CFS and HCs.
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Affiliation(s)
- Raminder Kaur
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
- Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
| | - Brian Greeley
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
| | - Alexander Ciok
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
- Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
| | - Kashish Mehta
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
- Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
| | - Melody Tsai
- Women’s Health Research Institute, Vancouver, BC V6H 3N1, Canada
- Complex Chronic Diseases Program, BC Women’s Hospital, Vancouver, BC V6H 3N1, Canada;
| | | | - Kati Debelic
- ME/FM Society of BC, Vancouver, BC V6J 5M4, Canada
| | - Lan Xin Zhang
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
| | - Todd Nelson
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
- Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
| | - Travis Boulter
- Complex Chronic Diseases Program, BC Women’s Hospital, Vancouver, BC V6H 3N1, Canada;
- ME/FM Society of BC, Vancouver, BC V6J 5M4, Canada
| | - William Siu
- Medical Imaging, Royal Columbian Hospital, New Westminster, BC V3L 3W7, Canada;
| | - Luis Nacul
- Women’s Health Research Institute, Vancouver, BC V6H 3N1, Canada
- Complex Chronic Diseases Program, BC Women’s Hospital, Vancouver, BC V6H 3N1, Canada;
- Department of Family Practice, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Xiaowei Song
- Research and Evaluation, Fraser Health Authority, Surrey, BC V3T 0H1, Canada; (R.K.); (B.G.); (A.C.); (K.M.); (T.N.)
- Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
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10
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Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol 2024; 15:1386607. [PMID: 38887284 PMCID: PMC11180809 DOI: 10.3389/fimmu.2024.1386607] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 04/11/2024] [Indexed: 06/20/2024] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available. Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease's multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances. This comprehensive model not only advances our understanding of ME/CFS's pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease's complexity and the multifaceted approach required for its study and management.
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Affiliation(s)
- Hayley E. Arron
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
| | - Benjamin D. Marsh
- MRCPCH Consultant Paediatric Neurodisability, Exeter, Devon, United Kingdom
| | - Douglas B. Kell
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Lyngby, Denmark
| | - M. Asad Khan
- Directorate of Respiratory Medicine, Manchester University Hospitals, Wythenshawe Hospital, Manchester, United Kingdom
| | - Beate R. Jaeger
- Long COVID department, Clinic St Georg, Bad Aibling, Germany
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
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11
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Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW. Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies. Trends Mol Med 2024; 30:443-458. [PMID: 38443223 DOI: 10.1016/j.molmed.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/29/2024] [Accepted: 02/13/2024] [Indexed: 03/07/2024]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed 'long COVID' (LC). Both ME/CFS and LC share many clinical similarities. Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.
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Affiliation(s)
- Sarah J Annesley
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, VIC, Australia.
| | - Daniel Missailidis
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, VIC, Australia
| | - Benjamin Heng
- Macquarie Medical School, Faculty of Medicine, Human and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Elisha K Josev
- Neurodisability & Rehabilitation, Clinical Sciences, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC, Australia; Mercy Hospital for Women, Heidelberg, VIC, Australia
| | - Christopher W Armstrong
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia
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12
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Plank JR, Morgan CA, Smith AK, Sundram F, Hoeh NR, Muthukumaraswamy S, Lin JC. Detection of Neuroinflammation Induced by Typhoid Vaccine Using Quantitative Magnetization Transfer MR: A Randomized Crossover Study. J Magn Reson Imaging 2024; 59:1683-1694. [PMID: 37540052 DOI: 10.1002/jmri.28938] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND The role of neuroinflammation in psychiatric disorders is not well-elucidated. A noninvasive technique sensitive to low-level neuroinflammation may improve understanding of the pathophysiology of these conditions. PURPOSE To test the ability of quantitative magnetization transfer (QMT) MR at 3 T for detection of low-level neuroinflammation induced by typhoid vaccine within a clinically reasonable scan time. STUDY TYPE Randomized, crossover, placebo-controlled. SUBJECTS Twenty healthy volunteers (10 males; median age 34 years). FIELD STRENGTH/SEQUENCE Magnetization prepared rapid gradient-echo and MT-weighted 3D fast low-angle shot sequences at 3 T. ASSESSMENT Participants were randomized to either vaccine or placebo first with imaging, then after a washout period received the converse with a second set of imaging. MT imaging, scan time, and blood-based inflammatory marker concentrations were assessed pre- and post-vaccine and placebo. Mood was assessed hourly using the Profile of Mood States questionnaire. QMT parameter maps, including the exchange rate from bound to free pool (kba) were generated using a two-pool model and then segmented into tissue type. STATISTICAL TESTS Voxel-wise permutation-based analysis examined inflammatory-related alterations of QMT parameters. The threshold-free cluster enhancement method with family-wise error was used to correct voxel-wise results for multiple comparisons. Region of interest averages were fed into mixed models and Bonferroni corrected. Spearman correlations assessed the relationship between mood scores and QMT parameters. Results were considered significant if corrected P < 0.05. RESULTS Scan time for the MT-weighted acquisition was approximately 11 minutes. Blood-based analysis showed higher IL-6 concentrations post-vaccine compared to post-placebo. Voxel-wise analysis found three clusters indicating an inflammatory-mediated increase in kba in cerebellar white matter. Cerebellar kba for white matter was negatively associated with vigor post-vaccine but not post-placebo. DATA CONCLUSION This study suggested that QMT at 3 T may show some sensitivity to low-level neuroinflammation. Further studies are needed to assess the viability of QMT for use in inflammatory-based disorders. EVIDENCE LEVEL 1 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Julia R Plank
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Catherine A Morgan
- Centre for Advanced MRI, Auckland UniServices Limited, Auckland, New Zealand
- School of Psychology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Alex K Smith
- Wellcome Centre for Integrative Neuroimaging (WIN), Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Frederick Sundram
- Department of Psychological Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Nicholas R Hoeh
- Department of Psychological Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Suresh Muthukumaraswamy
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Joanne C Lin
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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13
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Szaflarski JP, Szaflarski M. Traumatic Brain Injury Outcomes After Recreational Cannabis Use. Neuropsychiatr Dis Treat 2024; 20:809-821. [PMID: 38586307 PMCID: PMC10999198 DOI: 10.2147/ndt.s453616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/23/2024] [Indexed: 04/09/2024] Open
Abstract
Purpose Basic science data indicate potential neuroprotective effects of cannabinoids in traumatic brain injury (TBI). We aimed to evaluate the effects of pre-TBI recreational cannabis use on TBI outcomes. Patients and Methods We used i2b2 (a scalable informatics framework; www.i2b2.org) to identify all patients presenting with acute TBI between 1/1/2014 and 12/31/2016, then conducted a double-abstraction medical chart review to compile basic demographic, urine drug screen (UDS), Glasgow Coma Scale (GCS), and available outcomes data (mortality, modified Rankin Scale (mRS), duration of stay, disposition (home, skilled nursing facility, inpatient rehabilitation, other)) at discharge and at specific time points thereafter. We conducted multivariable nested ordinal and logistic regression analyses to estimate associations between cannabis use, other UDS results, demographic factors, and selected outcomes. Results i2b2 identified 6396 patients who acutely presented to our emergency room with TBI. Of those, 3729 received UDS, with 22.2% of them testing positive for cannabis. Mortality was similar in patients who tested positive vs negative for cannabis (3.9% vs 4.8%; p = 0.3) despite more severe GCS on admission in the cannabis positive group (p = 0.045). Several discharge outcome measures favored the cannabis positive group who had a higher rate of discharge home vs other care settings (p < 0.001), lower discharge mRS (p < 0.001), and shorter duration of hospital stay (p < 0.001) than the UDS negative group. Multivariable analyses confirmed mostly independent associations between positive cannabis screen and these post-TBI short- and long-term outcomes. Conclusion This study adds evidence about the potentially neuroprotective effects of recreational cannabis for short- and long-term post-TBI outcomes. These results need to be confirmed via prospective data collections.
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Affiliation(s)
- Jerzy P Szaflarski
- Department of Neurology, University of Alabama at Birmingham (UAB), Heersink School of Medicine, Birmingham, AL, USA
| | - Magdalena Szaflarski
- Department of Sociology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
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14
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Saito S, Shahbaz S, Luo X, Osman M, Redmond D, Cohen Tervaert JW, Li L, Elahi S. Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome. Front Immunol 2024; 15:1341843. [PMID: 38304426 PMCID: PMC10830702 DOI: 10.3389/fimmu.2024.1341843] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/04/2024] [Indexed: 02/03/2024] Open
Abstract
Introduction A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed. Methods We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC). Results Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores. Conclusion Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.
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Affiliation(s)
- Suguru Saito
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
| | - Shima Shahbaz
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
| | - Xian Luo
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, Canada
| | - Mohammed Osman
- Department of Medicine, Division of Rheumatology, Edmonton, AB, Canada
| | - Desiree Redmond
- Department of Medicine, Division of Rheumatology, Edmonton, AB, Canada
| | | | - Liang Li
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, Canada
- Department of Chemistry, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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15
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Kitagawa M, Abiko K, Sheriff S, Maudsley AA, Li X, Sawamura D, Ahn S, Tha KK. Brain Temperature as an Indicator of Cognitive Function in Traumatic Brain Injury Patients. Metabolites 2023; 14:17. [PMID: 38248820 PMCID: PMC10818445 DOI: 10.3390/metabo14010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/27/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
Whether brain temperature noninvasively extracted by magnetic resonance imaging has a role in identifying brain changes in the later phases of mild to moderate traumatic brain injury (TBI) is not known. This prospective study aimed to evaluate if TBI patients in subacute and chronic phases had altered brain temperature measured by whole-brain magnetic resonance spectroscopic imaging (WB-MRSI) and if the measurable brain temperature had any relationship with cognitive function scores. WB-MRSI was performed on eight TBI patients and fifteen age- and sex-matched control subjects. Brain temperature (T) was extracted from the brain's major metabolites and compared between the two groups. The T of the patients was tested for correlation with cognitive function test scores. The results showed significantly lower brain temperature in the TBI patients (p < 0.05). Brain temperature derived from N-acetylaspartate (TNAA) strongly correlated with the 2 s paced auditory serial addition test (PASAT-2s) score (p < 0.05). The observation of lower brain temperature in TBI patients may be due to decreased metabolic activity resulting from glucose and oxygen depletion. The correlation of brain temperature with PASAT-2s may imply that noninvasive brain temperature may become a noninvasive index reflecting cognitive performance.
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Affiliation(s)
- Maho Kitagawa
- Laboratory for Biomarker Imaging Science, Graduate School of Biomedical Science and Engineering, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-8638, Japan; (M.K.); (X.L.)
| | - Kagari Abiko
- Department of Rehabilitation, Hokkaido University Hospital, Sapporo 060-8648, Japan;
- Department of Rehabilitation, Sapporo Azabu Neurosurgical Hospital, Sapporo 065-0022, Japan
| | - Sulaiman Sheriff
- Department of Radiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (S.S.); (A.A.M.)
| | - Andrew A. Maudsley
- Department of Radiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (S.S.); (A.A.M.)
| | - Xinnan Li
- Laboratory for Biomarker Imaging Science, Graduate School of Biomedical Science and Engineering, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-8638, Japan; (M.K.); (X.L.)
| | - Daisuke Sawamura
- Department of Rehabilitation Science, Hokkaido University Faculty of Health Sciences, Sapporo 060-0812, Japan;
| | - Sinyeob Ahn
- Siemens Healthineers, San Francisco, CA 94553, USA;
| | - Khin Khin Tha
- Laboratory for Biomarker Imaging Science, Graduate School of Biomedical Science and Engineering, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-8638, Japan; (M.K.); (X.L.)
- Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-8638, Japan
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16
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Miwa K, Inoue Y. Repetitive transcranial magnetic stimulation ameliorates symptoms in patients with myalgic encephalomyelitis (chronic fatigue syndrome). IBRO Neurosci Rep 2023; 15:335-341. [PMID: 38025661 PMCID: PMC10661112 DOI: 10.1016/j.ibneur.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Background Central nervous system dysfunction has been postulated to cause debilitating symptoms in patients with myalgic encephalomyelitis (ME) (originally called "chronic fatigue syndrome"). Repetitive transcranial magnetic stimulation (rTMS) is a newly developed neuromodulatory procedure and has been suggested to facilitate the cortical neural activity. Methods This study enrolled 30 patients with ME (7 men and 23 women) with a mean age of 39 ± 12 years, who received rTMS treatment of both the left dorsolateral prefrontal cortex and the left primary motor area in the brain. The performance status score (0-9) for restricting activities of daily living, orthostatic intolerance (OI) during a 10-min standing test, neurologic disequilibrium diagnosed as unstable standing with their feet together and eyes closed, neuropathic pain or fibromyalgia, and muscle weakness were compared before and after treatment. Results After therapy, favorable effects were observed with a decrease in performance status score or index for restriction of activities of daily living of ≥ 2 points in 20 patients (67%). OI with the inability to complete the 10-min standing test was resolved in 10 (83%) out of 12 patients, and disequilibrium was resolved in 15 (88%) out of 17 patients. Neuropathic pain or fibromyalgia was attenuated in seven (70%) out of 10 patients. Muscle weakness with grip power of < 10 kg was resolved in two (50%) out of four patients. No untoward effects were encountered in all the study patients. Conclusion The treatment with rTMS is effective in alleviating various symptoms, especially OI and disequilibrium, and in improving the activities of daily living in patients with ME.
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Affiliation(s)
| | - Yukichi Inoue
- Department of Neurology, Toyama Prefectural Rehabilitation Hospital & Support Center for Children with Disabilities, Toyama, Japan
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17
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Allan-Blitz LT, Akbari O, Kojima N, Saavedra E, Chellamuthu P, Denny N, MacMullan MA, Hess V, Shacreaw M, Brobeck M, Turner F, Slepnev VI, Ibrayeva A, Klausner JD. Unique immune and inflammatory cytokine profiles may define long COVID syndrome. Clin Exp Med 2023; 23:2925-2930. [PMID: 37061998 PMCID: PMC10105906 DOI: 10.1007/s10238-023-01065-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 04/02/2023] [Indexed: 04/17/2023]
Abstract
PURPOSE Long COVID is estimated to occur in 5-10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood. METHODS We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection. RESULTS Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID. CONCLUSION Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.
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Affiliation(s)
- Lao-Tzu Allan-Blitz
- Division of Global Health Equity: Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 USA
| | - Omid Akbari
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
| | - Noah Kojima
- Department of Medicine, University of California Los Angeles, Los Angeles, CA USA
| | | | | | | | | | | | | | | | | | | | - Albina Ibrayeva
- Department of Medicine, University of California Los Angeles, Los Angeles, CA USA
| | - Jeffrey D. Klausner
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
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18
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Xu J, Lodge T, Kingdon C, Strong JWL, Maclennan J, Lacerda E, Kujawski S, Zalewski P, Huang WE, Morten KJ. Developing a Blood Cell-Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302146. [PMID: 37653608 PMCID: PMC10602530 DOI: 10.1002/advs.202302146] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/12/2023] [Indexed: 09/02/2023]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients' lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self-report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, a single-cell Raman platform and artificial intelligence are utilized to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. These results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the development of new therapeutics are identified. This study presents a promising approach for aiding in the diagnosis and management of ME/CFS and can be extended to other unexplained chronic diseases such as long COVID and post-treatment Lyme disease syndrome, which share many of the same symptoms as ME/CFS.
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Affiliation(s)
- Jiabao Xu
- Department of Engineering ScienceUniversity of OxfordParks RoadOxfordOX1 3PJUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG12 8LTUK
| | - Tiffany Lodge
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordThe Women CentreJohn Radcliffe HospitalHeadley Way, HeadingtonOxfordOX3 9DUUK
| | - Caroline Kingdon
- Faculty of Infectious DiseasesLondon School of Hygiene and Tropical MedicineKeppel StLondonWC1E 7HTUK
| | - James W. L. Strong
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordThe Women CentreJohn Radcliffe HospitalHeadley Way, HeadingtonOxfordOX3 9DUUK
| | - John Maclennan
- Soft Cell Biological ResearchAttwood Innovation Center453 S 600 ESt. GeorgeUT84770USA
| | - Eliana Lacerda
- Faculty of Infectious DiseasesLondon School of Hygiene and Tropical MedicineKeppel StLondonWC1E 7HTUK
| | - Slawomir Kujawski
- Department of Exercise Physiology and Functional AnatomyCollegium Medicum in BydgoszczNicolaus Copernicus University in TorunSwietojanska 20Bydgoszcz85‐077Poland
| | - Pawel Zalewski
- Department of Exercise Physiology and Functional AnatomyCollegium Medicum in BydgoszczNicolaus Copernicus University in TorunSwietojanska 20Bydgoszcz85‐077Poland
- Department of Experimental and Clinical PhysiologyWarsaw Medical UniversityStefana Banacha 2aWarszawa02‐097Poland
| | - Wei E. Huang
- Department of Engineering ScienceUniversity of OxfordParks RoadOxfordOX1 3PJUK
| | - Karl J. Morten
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordThe Women CentreJohn Radcliffe HospitalHeadley Way, HeadingtonOxfordOX3 9DUUK
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19
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Chaves-Filho AM, Braniff O, Angelova A, Deng Y, Tremblay MÈ. Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome. Brain Res Bull 2023; 201:110702. [PMID: 37423295 DOI: 10.1016/j.brainresbull.2023.110702] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/13/2023] [Accepted: 07/06/2023] [Indexed: 07/11/2023]
Abstract
After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties ("brain fog"), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions. Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.
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Affiliation(s)
| | - Olivia Braniff
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Angelina Angelova
- Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, F-91400 Orsay, France
| | - Yuru Deng
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada; Department of Molecular Medicine, Université Laval, Québec City, Québec, Canada; Neurology and Neurosurgery Department, McGill University, Montréal, Québec, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Advanced Materials and Related Technology (CAMTEC) and Institute on Aging and Lifelong Health (IALH), University of Victoria, Victoria, British Columbia, Canada.
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20
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Uhde M, Indart AC, Green PH, Yolken RH, Cook DB, Shukla SK, Vernon SD, Alaedini A. Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome. Brain Behav Immun Health 2023; 30:100627. [PMID: 37396339 PMCID: PMC10308215 DOI: 10.1016/j.bbih.2023.100627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 07/04/2023] Open
Abstract
The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
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Affiliation(s)
- Melanie Uhde
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Alyssa C. Indart
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
| | - Peter H.R. Green
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
- Celiac Disease Center, Columbia University, New York, NY, USA
| | - Robert H. Yolken
- The Stanley Laboratory of Developmental Neurovirology, Johns Hopkins University, Baltimore, MD, USA
| | - Dane B. Cook
- Department of Kinesiology, University of Wisconsin - Madison, Madison, WI, USA
| | - Sanjay K. Shukla
- Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, WI, USA
| | | | - Armin Alaedini
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA
- Institute of Human Nutrition, Columbia University, New York, NY, USA
- Celiac Disease Center, Columbia University, New York, NY, USA
- Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA
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21
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Allan-Blitz LT, Goodrich J, Hu H, Akbari O, Klausner JD. Altered Tumor Necrosis Factor Response in Neurologic Postacute SARS-CoV-2 Syndrome. J Interferon Cytokine Res 2023; 43:307-313. [PMID: 37384921 PMCID: PMC10354723 DOI: 10.1089/jir.2023.0051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 04/27/2023] [Indexed: 07/01/2023] Open
Abstract
Neurologic manifestations of postacute sequelae after SARS-CoV-2 infection (neuro-PASC) are common; however, the underlying drivers of those symptoms remain poorly understood. Prior work has postulated that immune dysregulation leads to ongoing neuroinflammation. We aimed to identify the cytokines involved in that immune dysregulation by comparing 37 plasma cytokine profiles among 20 case patients with neuro-PASC to 20 age- and gender-matched controls. Neuro-PASC cases were defined as individuals with self-reported persistent headache, general malaise, and anosmia or ageusia at least 28 days post-SARS-CoV-2 infection. As a sensitivity analysis, we repeated the main analysis among only participants of Hispanic heritage. In total, 40 specimens were tested. Participants were an average of 43.5 years old (interquartile range 30-52), 20 (50.0%) of whom identified as women. Levels of tumor necrosis factor alpha (TNFα) were 0.76 times lower [95% confidence interval (CI) 0.62-0.94] among cases of neuro-PASC compared with controls, as were levels of C-C motif chemokine 19 (CCL19) (0.67; 95% CI 0.50-0.91), C-C motif chemokine 2 (CCL2) (0.72; 95% CI 0.55-0.95), chemokine interferon-gamma inducible protein 10 (CXCL10) (0.63; 95% CI 0.42-0.96), and chemokine interferon-gamma inducible protein 9 (CXCL9) (0.62; 95% CI 0.38-0.99). Restricting analysis of TNF and CCL19 to participants who identified as Hispanic did not alter results. We noted a reduction in TNFα and down-stream chemokines among patients with neuro-PASC, suggesting an overall immune attenuation.
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Affiliation(s)
- Lao-Tzu Allan-Blitz
- Division of Global Health Equity, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Jesse Goodrich
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Howard Hu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Omid Akbari
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Jeffrey D. Klausner
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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22
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Mueller C, Jordan I, Jones C, Lawson P, Younger JW. Abnormal immune system response in the brain of women with Fibromyalgia after experimental endotoxin challenge. Brain Behav Immun Health 2023; 30:100624. [PMID: 37114015 PMCID: PMC10126845 DOI: 10.1016/j.bbih.2023.100624] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/13/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Background The pathophysiology of fibromyalgia (FM) is thought to include an overactive immune system, leading to central nervous system sensitization, allodynia, and hyperalgesia. We aimed to test this theory using an experimental immune system activation procedure and neuroimaging with magnetic resonance spectroscopic imaging (MRSI). Methods Twelve women with FM and 13 healthy women (healthy controls; HC) received 0.3 or 0.4 ng/kg endotoxin and underwent MRSI before and after the infusion. Changes in brain levels of choline (CHO), myo-inositol (MI), N-Acetylaspartate (NAA), and MRSI-derived brain temperature were compared between groups and dosage levels using mixed analyses of variance. Results Significant group-by-time interactions in brain temperature were found in the right thalamus. Post-hoc testing revealed that brain temperature increased by 0.55 °C in the right thalamus in FM (t(10) = -3.483, p = 0.006), but not in HCs (p > 0.05). Dose-by-time interactions revealed brain temperature increases in the right insula after 0.4 ng/kg (t(12) = -4.074, p = 0.002), but not after 0.3 ng/kg (p > 0.05). Dose-by-time interactions revealed decreased CHO in the right Rolandic operculum after 0.4 ng/kg endotoxin (t(13) = 3.242, p = 0.006) but not 0.3 ng/kg. In the left paracentral lobule, CHO decreased after 0.3 ng/kg (t(9) = 2.574, p = 0.030) but not 0.4 ng/kg. Dose-by-time interactions affected MI in several brain regions. MI increased after 0.3 ng/kg in the right Rolandic operculum (t(10) = -2.374, p = 0.039), left supplementary motor area (t(9) = -2.303, p = 0.047), and left occipital lobe (t(10) = -3.757, p = 0.004), with no changes after 0.4 ng/kg (p > 0.05). Group-by time interactions revealed decreased NAA in the left Rolandic operculum in FM (t(13) = 2.664, p = 0.019), but not in HCs (p > 0.05). A dose-by-time interaction showed decreased NAA in the left paracentral lobule after 0.3 ng/kg (t(9) = 3.071, p = 0.013) but not after 0.4 ng/kg (p > 0.05). In the combined sample, there was a main effect of time whereby NAA decreased in the left anterior cingulate (F[1,21] = 4.458, p = 0.047) and right parietal lobe (F[1,21] = 5.457, p = 0.029). Conclusion We found temperature increases and NAA decreases in FM that were not seen in HCs, suggesting that FM patients may have abnormal immune responses in the brain. The 0.3 and 0.4 ng/kg had differential effects on brain temperature and metabolites, with neither dose effecting a stronger response overall. There is insufficient evidence provided by the study to determine whether FM involves abnormal central responses to low-level immune challenges.
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Affiliation(s)
- Christina Mueller
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Indonesia Jordan
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chloe Jones
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Prentiss Lawson
- Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jarred W. Younger
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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23
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Komaroff AL, Lipkin WI. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front Med (Lausanne) 2023; 10:1187163. [PMID: 37342500 PMCID: PMC10278546 DOI: 10.3389/fmed.2023.1187163] [Citation(s) in RCA: 130] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
Some patients remain unwell for months after "recovering" from acute COVID-19. They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function and that can leave some people housebound and disabled. The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as to persisting illnesses that can follow a wide variety of other infectious agents and following major traumatic injury. Together, these illnesses are projected to cost the U.S. trillions of dollars. In this review, we first compare the symptoms of ME/CFS and Long COVID, noting the considerable similarities and the few differences. We then compare in extensive detail the underlying pathophysiology of these two conditions, focusing on abnormalities of the central and autonomic nervous system, lungs, heart, vasculature, immune system, gut microbiome, energy metabolism and redox balance. This comparison highlights how strong the evidence is for each abnormality, in each illness, and helps to set priorities for future investigation. The review provides a current road map to the extensive literature on the underlying biology of both illnesses.
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Affiliation(s)
- Anthony L. Komaroff
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - W. Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, United States
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24
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Cocchetto A, Seymour C, Mothersill C. A Proposed New Model to Explain the Role of Low Dose Non-DNA Targeted Radiation Exposure in Chronic Fatigue and Immune Dysfunction Syndrome. Int J Mol Sci 2023; 24:ijms24076022. [PMID: 37046994 PMCID: PMC10094351 DOI: 10.3390/ijms24076022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/14/2023] [Accepted: 03/18/2023] [Indexed: 04/14/2023] Open
Abstract
Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is considered to be a multidimensional illness whose etiology is unknown. However, reports from Chernobyl, as well as those from the United States, have revealed an association between radiation exposure and the development of CFIDS. As such, we present an expanded model using a systems biology approach to explain the etiology of CFIDS as it relates to this cohort of patients. This paper proposes an integrated model with ionizing radiation as a suggested trigger for CFIDS mediated through UVA induction and biophoton generation inside the body resulting from radiation-induced bystander effects (RIBE). Evidence in support of this approach has been organized into a systems view linking CFIDS illness markers with the initiating events, in this case, low-dose radiation exposure. This results in the formation of reactive oxygen species (ROS) as well as important immunologic and other downstream effects. Furthermore, the model implicates melanoma and subsequent hematopoietic dysregulation in this underlying process. Through the identification of this association with melanoma, clinical medicine, including dermatology, hematology, and oncology, can now begin to apply its expansive knowledge base to provide new treatment options for an illness that has had few effective treatments.
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Affiliation(s)
- Alan Cocchetto
- National CFIDS Foundation Inc., Hull, MA 02045-1602, USA
| | - Colin Seymour
- Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Carmel Mothersill
- Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada
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25
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Tate WP, Walker MOM, Peppercorn K, Blair ALH, Edgar CD. Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID. Int J Mol Sci 2023; 24:ijms24065124. [PMID: 36982194 PMCID: PMC10048882 DOI: 10.3390/ijms24065124] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/28/2023] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.
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Affiliation(s)
- Warren P Tate
- Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Max O M Walker
- Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Katie Peppercorn
- Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Anna L H Blair
- Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Christina D Edgar
- Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, Dunedin 9054, New Zealand
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27
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Rizvi AA, Kathuria A, Al Mahmeed W, Al-Rasadi K, Al-Alawi K, Banach M, Banerjee Y, Ceriello A, Cesur M, Cosentino F, Galia M, Goh SY, Janez A, Kalra S, Kempler P, Lessan N, Lotufo P, Papanas N, Santos RD, Stoian AP, Toth PP, Viswanathan V, Rizzo M. Post-COVID syndrome, inflammation, and diabetes. J Diabetes Complications 2022; 36:108336. [PMID: 36228563 PMCID: PMC9534783 DOI: 10.1016/j.jdiacomp.2022.108336] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/30/2022] [Accepted: 10/02/2022] [Indexed: 01/08/2023]
Abstract
The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease. Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called "Long COVID" or "Post-COVID Syndrome". It is thought that a chronic, low-grade inflammatory and immunologic state persists during this phase, which may last for weeks or months. Although numerous insights have been gained into COVID-related hyperglycemia and diabetes, its prediction, course, and management remain to be fully elucidated.
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Affiliation(s)
- Ali A Rizvi
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL, USA.
| | - Amita Kathuria
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL, USA
| | - Wael Al Mahmeed
- Heart and Vascular Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates
| | | | - Kamila Al-Alawi
- Department of Training and Studies, Royal Hospital, Ministry of Health, Muscat, Oman
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Yajnavalka Banerjee
- Department of Biochemistry, Mohamed Bin Rashid University, Dubai, United Arab Emirates
| | | | - Mustafa Cesur
- Clinic of Endocrinology, Ankara Güven Hospital, Ankara, Turkey
| | - Francesco Cosentino
- Unit of Cardiology, Karolinska Institute and Karolinska University Hospital, University of Stockholm, Sweden
| | - Massimo Galia
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bind), University of Palermo, Italy
| | - Su-Yen Goh
- Department of Endocrinology, Singapore General Hospital, Singapore
| | - Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Slovenia
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital & BRIDE, Karnal, India
| | - Peter Kempler
- Department of Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Nader Lessan
- The Research Institute, Imperial College London Diabetes Centre, Abu Dhabi, United Arab Emirates
| | - Paulo Lotufo
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, Brazil
| | - Nikolaos Papanas
- Diabetes Center, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
| | - Raul D Santos
- Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Anca P Stoian
- Faculty of Medicine, Diabetes, Nutrition and Metabolic Diseases, Carol Davila University, Bucharest, Romania
| | - Peter P Toth
- Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Italy
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28
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Kim N, Kim J, Yang BR, Hahm BJ. Associations of unspecified pain, idiopathic pain and COVID-19 in South Korea: a nationwide cohort study. Korean J Pain 2022; 35:458-467. [PMID: 36175345 PMCID: PMC9530679 DOI: 10.3344/kjp.2022.35.4.458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/18/2022] [Accepted: 06/30/2022] [Indexed: 12/02/2022] Open
Abstract
Background Few studies have investigated unspecified or idiopathic pain associated with COIVD-19. This study aimed to provide the incidence rates of unspecified pain and idiopathic pain in patients with COVID-19 for 90 days after COVID-19 diagnosis. Methods A propensity score matched cohort was used, including all patients with COVID-19 in South Korea, and analyzed their electronic medical records. The control group consisted of those who had not had tests for COVID-19 at all. Unspecified pain diagnoses consisted of diagnoses related to pain included in the ICD-10 Chapter XVIII. Idiopathic pain disorders included fibromyalgia, temporomandibular joint disorders, headaches, chronic prostatitis, complex regional pain syndrome, atypical facial pain, irritable bowel syndrome, and interstitial cystitis. Results After matching, the number of participants in each group was 7,911. For most unspecified pain, the incidences were higher in the COVID-19 group (11.7%; 95% confidence interval [CI], 11.0–12.5) than in the control group (6.5%; 95% CI, 6.0–7.1). For idiopathic pain, only the headaches had a significantly higher incidence in the COVID-19 group (6.6%; 95% CI, 6.1–7.2) than in the control group (3.7%; 95% CI, 3.3–4.1). However, using a different control group that included only patients who visited a hospital at least once for any reasons, the incidences of most unspecified and idiopathic pain were higher in the control group than in the COVID-19 group. Conclusions Patients with COVID-19 might be at a higher risk of experiencing unspecified pain in the acute phase or after recovery compared with individuals who had not had tests for COVID-19.
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Affiliation(s)
- Namwoo Kim
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea.,Department of Clinical Medical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Jeewuan Kim
- Department of Statistics and Data Science, Yonsei University, Seoul, Korea
| | - Bo Ram Yang
- College of Pharmacy, Chungnam National University, Daejeon, Korea
| | - Bong-Jin Hahm
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea.,Department of Psychiatry and Behavioral Sciences, Seoul National University College of Medicine, Seoul, Korea
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29
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Plank JR, Glover SC, Moloney BD, Hoeh NR, Sundram F, Sumner RL, Muthukumaraswamy S, Lin JC. A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder. Trials 2022; 23:822. [PMID: 36175917 PMCID: PMC9524133 DOI: 10.1186/s13063-022-06738-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 09/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD. METHODS/DESIGN This double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD. Eligible participants with MDD (n = 48) will be stratified into the high and low inflammatory groups according to the levels of high-sensitivity C-reactive protein (hs-CRP) and then randomized to receive LDN or placebo for an initial 12 weeks, followed by a further 12 weeks during which all participants will receive LDN. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, and 24 weeks, to assess the effectiveness of the anti-depressant response. The secondary outcomes include the use of MRI techniques including quantitative magnetization transfer (qMT), echo-planar spectroscopic imaging (EPSI), and diffusion-weighted imaging (DWI) to help to elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. Electroencephalography, blood samples, cognitive tasks, and additional questionnaires will also be used to determine if there is a specific profile of symptoms in individuals with inflammatory MDD. Healthy participants (n = 24) will be recruited for baseline outcome measures only, to enable comparison with patients with MDD. DISCUSSION This trial contributes to the literature on inflammation in MDD, including the understanding of the pathophysiology and efficacy of anti-inflammatory treatments. The investigation of inflammatory mechanisms in MDD is an important first step in the development of biomarkers to classify patient sub-groups, increase the accuracy of diagnosis, and tailor the approach to patients in clinical practice. This study may provide evidence of the benefit of LDN for the groups in whom conventional anti-depressants are ineffective and lead the way for translation into clinical practice. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN12622000881730 . Registered on 21 June 2022.
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Affiliation(s)
- Julia R Plank
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand
| | - Stephanie C Glover
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand
| | - Ben D Moloney
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand
| | - Nicholas R Hoeh
- Department of Psychological Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 22-30 Park Avenue, Grafton, Auckland, 1023, New Zealand
| | - Frederick Sundram
- Department of Psychological Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 22-30 Park Avenue, Grafton, Auckland, 1023, New Zealand
| | - Rachael L Sumner
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand
| | - Suresh Muthukumaraswamy
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand
| | - Joanne C Lin
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand.
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30
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Nikitina AY, Chimagomedova AS, Levin OS. Neurological Complications of COVID-19 in the Elderly. NEUROSCIENCE AND BEHAVIORAL PHYSIOLOGY 2022; 52:625-634. [PMID: 36119647 PMCID: PMC9468529 DOI: 10.1007/s11055-022-01287-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 11/24/2022]
Abstract
SARS-CoV-2 virus is a β-coronavirus and produces a severe viral pneumonia which can be complicated by acute respiratory distress syndrome and multiorgan failure. As knowledge of the new coronavirus infection (COVID-19) increases, it has become known that SARS-CoV-2 has pronounced neurotropism, producing a wide spectrum of neurological complications. This article addresses the characteristics of the neurological complications of COVID-19 in elderly people.
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Affiliation(s)
- A. Yu. Nikitina
- Russian Medical Academy of Continuing Professional Education, Russian Ministry of Health, Moscow, Russia
| | - A. Sh. Chimagomedova
- Russian Medical Academy of Continuing Professional Education, Russian Ministry of Health, Moscow, Russia
| | - O. S. Levin
- Russian Medical Academy of Continuing Professional Education, Russian Ministry of Health, Moscow, Russia
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31
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Filippi M, Krähenmann R, Fissler P. The Link Between Energy-Related Sensations and Metabolism: Implications for Treating Fatigue. Front Psychol 2022; 13:920556. [PMID: 35800955 PMCID: PMC9255916 DOI: 10.3389/fpsyg.2022.920556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Energy-related sensations include sensation of energy and fatigue as well as subjective energizability and fatigability. First, we introduce interdisciplinary useful definitions of all constructs and review findings regarding the question of whether sensations of fatigue and energy are two separate constructs or two ends of a single dimension. Second, we describe different components of the bodily energy metabolism system (e.g., mitochondria; autonomic nervous system). Third, we review the link between sensation of fatigue and different components of energy metabolism. Finally, we present an overview of different treatments shown to affect both energy-related sensations and metabolism before outlining future research perspectives.
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Affiliation(s)
- Marco Filippi
- Psychiatric Services Thurgau, Münsterlingen, Switzerland
- University Hospital for Psychiatry and Psychotherapy, Paracelsus Medical University, Salzburg, Austria
| | - Rainer Krähenmann
- Psychiatric Services Thurgau, Münsterlingen, Switzerland
- University Hospital for Psychiatry and Psychotherapy, Paracelsus Medical University, Salzburg, Austria
- Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zürich, Switzerland
- *Correspondence: Rainer Krähenmann,
| | - Patrick Fissler
- Psychiatric Services Thurgau, Münsterlingen, Switzerland
- University Hospital for Psychiatry and Psychotherapy, Paracelsus Medical University, Salzburg, Austria
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Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol 2022; 13:877772. [PMID: 35693009 PMCID: PMC9174654 DOI: 10.3389/fneur.2022.877772] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/19/2022] [Indexed: 12/16/2022] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, "brain fog" affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.
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Affiliation(s)
- Warren Tate
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Max Walker
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Eiren Sweetman
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
| | - Amber Helliwell
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Katie Peppercorn
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Christina Edgar
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Anna Blair
- Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia
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Brain temperature as an indicator of neuroinflammation induced by typhoid vaccine: Assessment using whole-brain magnetic resonance spectroscopy in a randomised crossover study. Neuroimage Clin 2022; 35:103053. [PMID: 35617872 PMCID: PMC9136180 DOI: 10.1016/j.nicl.2022.103053] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 11/23/2022]
Abstract
MRSI-derived whole-brain temperature did not detect low-level neuroinflammation. Regional brain temperature was a more sensitive measure of neuroinflammation. MRSI/EPSI might be a useful measure of neuroinflammation in psychiatric disorders. Prior studies indicate a pathogenic role of neuroinflammation in psychiatric disorders; however, there are no accepted methods that can reliably measure low-level neuroinflammation non-invasively in these individuals. Magnetic resonance spectroscopic imaging (MRSI) is a versatile, non-invasive neuroimaging technique that demonstrates sensitivity to brain inflammation. MRSI in conjunction with echo-planar spectroscopic imaging (EPSI) measures brain metabolites to derive whole-brain and regional brain temperatures, which may increase in neuroinflammation. The validity of MRSI/EPSI for measurement of low level neuroinflammation was tested using a safe experimental model of human brain inflammation – intramuscular administration of typhoid vaccine. Twenty healthy volunteers participated in a double-blind, placebo-controlled crossover study including MRSI/EPSI scans before and 3 h after vaccine/placebo administration. Body temperature and mood, assessed using the Profile of Mood States, were measured every hour up to four hours post-treatment administration. A mixed model analysis of variance was used to test for treatment effects. A significant proportion of brain regions (44/47) increased in temperature post-vaccine compared to post-placebo (p < 0.0001). For temperature change in the brain as a whole, there was no significant treatment effect. Significant associations were seen between mood scores assessed at 4 h and whole brain and regional temperatures post-treatment. Findings indicate that regional brain temperature may be a more sensitive measure of low-level neuroinflammation than whole-brain temperature. Future work where these measurement techniques are applied to populations with psychiatric disorders would be of clinical interest.
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Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front Cell Neurosci 2022; 16:888232. [PMID: 35614970 PMCID: PMC9124899 DOI: 10.3389/fncel.2022.888232] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/13/2022] [Indexed: 12/20/2022] Open
Abstract
Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features - post exertional malaise and decreased cerebral blood flow - are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
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Affiliation(s)
- Herbert Renz-Polster
- Division of General Medicine, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medicine Mannheim, Heidelberg University, Mannheim, Germany
| | - Marie-Eve Tremblay
- Axe Neurosciences, Centre de recherche du CHU de Québec, Université Laval, Quebec, QC, Canada
- Département de Médecine Moléculaire, Université Laval, Quebec, QC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Center for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Dorothee Bienzle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Joachim E. Fischer
- Division of General Medicine, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medicine Mannheim, Heidelberg University, Mannheim, Germany
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Sharma P, Bharti S, Garg I. Post COVID fatigue: Can we really ignore it? Indian J Tuberc 2022; 69:238-241. [PMID: 35379408 PMCID: PMC8220285 DOI: 10.1016/j.ijtb.2021.06.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/09/2021] [Indexed: 01/09/2023]
Abstract
Long-COVID, also referred to as post-acute COVID-19, chronic COVID-19, post-COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), generally refers to symptoms that develop during or after acute COVID-19 illness, continue for ≥12 weeks, and are not explained by an alternative diagnosis. It is not yet known whether "long-COVID" represents a new syndrome unique to COVID-19 or overlaps with recovery from similar illnesses. It's difficult for physicians to predict when symptoms will improve as it varies differently in different people. Patient's recovery depends on various factors including age, associated comorbidities, severity of COVID-19 infection. Some symptoms, like fatigue, might continue even while others improve or go away. This review addresses the pathogenesis, presentation of post covid fatigue, its severity and its management.
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Affiliation(s)
- Priya Sharma
- AIIMS PATNA, EDAR, DNB TB and Respiratory Diseases, Kalpana Chawla Govt Medical College, Karnal, Haryana, 132001, India,Corresponding author
| | - Sumit Bharti
- IDCCM Fellow at Max Mohali, MD Respiratory Diseases, Kalpana Chawla Govt Medical College, Karnal, Haryana, 132001, India
| | - Isha Garg
- Kalpana Chawla Govt Medical College, Karnal, Haryana, 132001, India
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Lin JC, Mueller C, Campbell KA, Thannickal HH, Daredia AF, Sheriff S, Maudsley AA, Brunner RC, Younger JW. Investigating whole-brain metabolite abnormalities in the chronic stages of moderate or severe traumatic brain injury. PM R 2022; 14:472-485. [PMID: 33930238 PMCID: PMC9212770 DOI: 10.1002/pmrj.12623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Evidence suggests that neurometabolic abnormalities can persist after traumatic brain injury (TBI) and drive clinical symptoms such as fatigue and cognitive disruption. Magnetic resonance spectroscopy has been used to investigate metabolite abnormalities following TBI, but few studies have obtained data beyond the subacute stage or over large brain regions. OBJECTIVE To measure whole-brain metabolites in chronic stages of TBI. DESIGN Observational study. SETTING University. PARTICIPANTS Eleven men with a moderate or severe TBI more than 12 months prior and 10 age-matched healthy controls completed whole-brain spectroscopic imaging. MAIN MEASURES Ratios of N-acetylaspartate (NAA), choline (CHO), and myo-inositol (MI) to creatine (CR) were measured in whole-brain gray and white matter as well as 64 brain regions of interest. Arterial spin labeling (ASL) data were also collected to investigate whether metabolite abnormalities were accompanied by differences in cerebral perfusion. RESULTS There were no differences in metabolite ratios within whole-brain gray and white matter regions of interest (ROIs). Linear regression showed lower NAA/CR in the white matter of the left occipital lobe but higher NAA/CR in the gray matter of the left parietal lobe. Metabolite abnormalities were observed in several brain regions in the TBI group including the corpus callosum, putamen, and posterior cingulate. However, none of the findings survived correction for multiple comparison. There were no differences in cerebral blood flow between patients and controls. CONCLUSION Higher MI/CR may indicate ongoing gliosis, and it has been suggested that low CHO/CR at chronic time points may indicate cell death or lack of healthy turnover and repair. However, with the small sample size of this study, we caution against the over interpretation of our results. None of the findings within ROIs survived correction for multiple comparison. Thus, they may be considered possible avenues for future research in this area.
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Affiliation(s)
- Joanne C. Lin
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Christina Mueller
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kelsey A. Campbell
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Altamish F. Daredia
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sulaiman Sheriff
- Department of Radiology, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Andrew A. Maudsley
- Department of Radiology, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Robert C. Brunner
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jarred W. Younger
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Stanculescu D, Bergquist J. Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne) 2022; 9:818728. [PMID: 35345768 PMCID: PMC8957276 DOI: 10.3389/fmed.2022.818728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/11/2022] [Indexed: 12/15/2022] Open
Abstract
We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS. Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS. New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions.
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Affiliation(s)
| | - Jonas Bergquist
- Division of Analytical Chemistry and Neurochemistry, Department of Chemistry - Biomedical Center, Uppsala University, Uppsala, Sweden.,The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden
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Low Tissue Creatine: A Therapeutic Target in Clinical Nutrition. Nutrients 2022; 14:nu14061230. [PMID: 35334887 PMCID: PMC8955088 DOI: 10.3390/nu14061230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 11/25/2022] Open
Abstract
Low tissue creatine characterizes many conditions, including neurodegenerative, cardiopulmonary, and metabolic diseases, with a magnitude of creatine shortfall often corresponds well to a disorder’s severity. A non-invasive monitoring of tissue metabolism with magnetic resonance spectroscopy (MRS) might be a feasible tool to evaluate suboptimal levels of creatine for both predictive, diagnostic, and therapeutic purposes. This mini review paper summarizes disorders with deficient creatine levels and provides arguments for assessing and employing tissue creatine as a relevant target in clinical nutrition.
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Bansal R, Gubbi S, Koch CA. COVID-19 and chronic fatigue syndrome: An endocrine perspective. J Clin Transl Endocrinol 2022; 27:100284. [PMID: 34877261 PMCID: PMC8641402 DOI: 10.1016/j.jcte.2021.100284] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/13/2021] [Accepted: 11/27/2021] [Indexed: 12/15/2022] Open
Abstract
Patients recovering from COVID-19 may have persistent debilitating symptoms requiring long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help. Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the hypothalamo-pituitary-adrenal (HPA) axis, adrenal and thyroid function. We here review the literature and potential pathophysiological mechanisms involved in and related to post COVID-19 symptoms with an emphasis on endocrine function.
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Affiliation(s)
- Rashika Bansal
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Sriram Gubbi
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christian A. Koch
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA, United States
- Dept of Medicine/Endocrinology, The University of Tennessee Health Science Center, Memphis, TN, United States
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O'Boyle S, Nacul L, Nacul FE, Mudie K, Kingdon CC, Cliff JM, Clark TG, Dockrell HM, Lacerda EM. A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne) 2022; 8:688159. [PMID: 35155455 PMCID: PMC8835111 DOI: 10.3389/fmed.2021.688159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 12/27/2021] [Indexed: 01/04/2023] Open
Abstract
We propose a framework for the treatment, rehabilitation, and research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using a natural history of disease approach to outline the distinct disease stages, with an emphasis on cases following infection to provide insights into prevention. Moving away from the method of subtyping patients based on the various phenotypic presentations and instead reframing along the lines of disease progression could help with defining the distinct stages of disease, each of which would benefit from large prospective cohort studies to accurately describe the pathological mechanisms taking place therein. With a better understanding of these mechanisms, management and research can be tailored specifically for each disease stage. Pre-disease and early disease stages call for management strategies that may decrease the risk of long-term morbidity, by focusing on avoidance of further insults, adequate rest to enable recovery, and pacing of activities. Later disease stages require a more holistic and tailored management approach, with treatment-as this becomes available-targeting the alleviation of symptoms and multi-systemic dysfunction. More stringent and standardised use of case definitions in research is critical to improve generalisability of results and to create the strong evidence-based policies for management that are currently lacking in ME/CFS.
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Affiliation(s)
- Shennae O'Boyle
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- UK Health Security Agency, London, United Kingdom
| | - Luis Nacul
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- B.C. Women's Hospital and Health Centre, Vancouver, BC, Canada
| | - Flavio E. Nacul
- Pro-cardiaco Hospital and Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Kathleen Mudie
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Caroline C. Kingdon
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Jacqueline M. Cliff
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Taane G. Clark
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Hazel M. Dockrell
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Eliana M. Lacerda
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Chronic fatigue syndrome and cognitive deficit are associated with acute-phase neuropsychiatric manifestations of COVID-19: A 9-month follow-up study. Neurol Sci 2022; 43:2231-2239. [PMID: 35059902 PMCID: PMC8776380 DOI: 10.1007/s10072-021-05786-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/24/2021] [Indexed: 12/28/2022]
Abstract
The preva
lence of long-COVID symptoms is rising but it is not still possible to predict which patients will present them, and which types of symptoms they will present. We followed up 95 patients with confirmed COVID-19 for 9 months to identify and characterize long-COVID symptoms. Easy fatigability was the most common symptom (51.04%), followed by anxiety (38.54%), dyspnea (38.54%), and new-onset headache (38.54%). There was no association between COVID-19 severity in the acute phase and the number of long-COVID symptoms (F(1,93) = 0.75, p = 0.45), and cognitive function (MoCA) scores (F(1,90) = 0.073, p = 0.787) at follow-up. Being female (F(1,92) = − 2.27, p = 0.02), having a higher number of symptoms (F(1,93) = 2.76, p = 0.0068), and experiencing constitutional neuropsychiatric symptoms (F(1,93) = 2.529, p = 0.01) in the acute phase were associated with having chronic fatigue syndrome at follow-up. Moreover, constitutional neuropsychiatric symptoms in the acute phase were associated with a lower MoCA score (F(1,93) = 10.84, p = 0.001) at follow-up. Specific clinical presentations such as constitutional neuropsychiatric symptoms in the acute phase might be predictors of debilitating long-COVID symptoms such as chronic fatigue syndrome and cognitive deficits.
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Godlewska BR, Williams S, Emir UE, Chen C, Sharpley AL, Goncalves AJ, Andersson MI, Clarke W, Angus B, Cowen PJ. Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla. Psychopharmacology (Berl) 2022; 239:163-171. [PMID: 34609538 PMCID: PMC8770374 DOI: 10.1007/s00213-021-05986-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/13/2021] [Indexed: 12/05/2022]
Abstract
RATIONALE Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction. METHODS We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference. RESULTS Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants. CONCLUSIONS The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.
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Affiliation(s)
- Beata R. Godlewska
- grid.4991.50000 0004 1936 8948Psychopharmacology Research Unit, Department of Psychiatry, University of Oxford, Oxford, UK
| | - Stephen Williams
- grid.5379.80000000121662407Division of Informatics, Imaging and Data Science, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Uzay E. Emir
- grid.4991.50000 0004 1936 8948Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK ,grid.169077.e0000 0004 1937 2197School of Health Sciences, Purdue University, West Lafayette, IN USA
| | - Chi Chen
- grid.4991.50000 0004 1936 8948Psychopharmacology Research Unit, Department of Psychiatry, University of Oxford, Oxford, UK
| | - Ann L. Sharpley
- grid.4991.50000 0004 1936 8948Psychopharmacology Research Unit, Department of Psychiatry, University of Oxford, Oxford, UK
| | - Ana Jorge Goncalves
- grid.5379.80000000121662407Wolfson Molecular Imaging Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Monique I. Andersson
- grid.4991.50000 0004 1936 8948Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - William Clarke
- grid.4991.50000 0004 1936 8948Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK
| | - Brian Angus
- grid.4991.50000 0004 1936 8948Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Philip J. Cowen
- grid.4991.50000 0004 1936 8948Psychopharmacology Research Unit, Department of Psychiatry, University of Oxford, Oxford, UK ,grid.416938.10000 0004 0641 5119Neurosciences Building, Warneford Hospital, Oxford, OX3 7JX UK
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Raijmakers R, Roerink M, Keijmel S, Joosten L, Netea M, van der Meer J, Knoop H, Klein H, Bleeker-Rovers C, Doorduin J. No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [ 11C]-PK11195. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2022; 9:9/1/e1113. [PMID: 34815320 PMCID: PMC8611501 DOI: 10.1212/nxi.0000000000001113] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 09/15/2021] [Indexed: 12/20/2022]
Abstract
Background and Objectives The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide ([11C]-PK11195). Methods The study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [11C]-PK11195 PET scan, and the [11C]-PK11195 binding potential (BPND) was calculated. Results No statistically significant differences in BPND were found for patients with CFS or patients with QFS compared with HSs. BPND of [11C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS. Discussion In contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS. Trial Registration Information EudraCT number 2014-004448-37.
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Affiliation(s)
- Ruud Raijmakers
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands.
| | - Megan Roerink
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Stephan Keijmel
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Leo Joosten
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Mihai Netea
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Jos van der Meer
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Hans Knoop
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Hans Klein
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Chantal Bleeker-Rovers
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
| | - Janine Doorduin
- From the Radboud Expertise Center for Q Fever (R.R., S.K., L.J., M.N., J.M., C.B.-R.), Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center; Department of Internal Medicine (R.R., M.R., S.K., L.J., M.N., J.M., C.B.-R.), Radboud University Medical Center, Nijmegen; Department of Medical Psychology (H. Knoop), Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam; Department of Psychiatry (H. Klein), University of Groningen, University Medical Center Groningen; and Department of Nuclear Medicine and Molecular Imaging (J.D.), University of Groningen, University Medical Center Groningen, the Netherlands
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44
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van Campen C(LMC, Rowe PC, Visser FC. Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. MEDICINA (KAUNAS, LITHUANIA) 2021; 58:medicina58010028. [PMID: 35056336 PMCID: PMC8778312 DOI: 10.3390/medicina58010028] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022]
Abstract
Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.
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Affiliation(s)
| | - Peter C. Rowe
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
| | - Frans C. Visser
- Stichting CardioZorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands;
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45
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Nelson T, Zhang LX, Guo H, Nacul L, Song X. Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings. Front Neurol 2021; 12:769511. [PMID: 34975729 PMCID: PMC8718708 DOI: 10.3389/fneur.2021.769511] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/29/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body. Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria. Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients. Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.
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Affiliation(s)
- Todd Nelson
- Evaluation and Research, Surrey Memorial Hospital, Fraser Health, Surrey, BC, Canada
- Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Lan-Xin Zhang
- Evaluation and Research, Surrey Memorial Hospital, Fraser Health, Surrey, BC, Canada
- Department of Human Biology, Physiology, University of Toronto, Toronto, ON, Canada
| | - Hui Guo
- Evaluation and Research, Surrey Memorial Hospital, Fraser Health, Surrey, BC, Canada
- Department of Diagnostic Imaging, Tianjin Medical University General Hospital, Tianjin, China
| | - Luis Nacul
- Complex Chronic Diseases Program, BC Women's Hospital and Health Centre, Vancouver, BC, Canada
- Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Xiaowei Song
- Evaluation and Research, Surrey Memorial Hospital, Fraser Health, Surrey, BC, Canada
- Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
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46
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Stanculescu D, Sepúlveda N, Lim CL, Bergquist J. Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Neurol 2021; 12:789784. [PMID: 34966354 PMCID: PMC8710546 DOI: 10.3389/fneur.2021.789784] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/11/2021] [Indexed: 01/01/2023] Open
Abstract
We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS. Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences - and despite heat stroke being an acute condition - the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.
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Affiliation(s)
| | - Nuno Sepúlveda
- CEAUL—Centro de Estatística e Aplicações da Universidade de Lisboa, Lisbon, Portugal
- Department of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
| | - Chin Leong Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Jonas Bergquist
- Analytical Chemistry and Neurochemistry, Department of Chemistry—BMC, Uppsala University, Uppsala, Sweden
- The ME/CFS Collaborative Research Center at Uppsala University, Uppsala, Sweden
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47
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Nikitina AJ, Levin OS. [Chronic fatigue syndrome against the background of the COVID-19 pandemic]. Zh Nevrol Psikhiatr Im S S Korsakova 2021; 121:92-98. [PMID: 34870921 DOI: 10.17116/jnevro202112110292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The more we learn about the new coronavirus infection, the more we understand that we will feel the echoes of the pandemic for many years, and those who have successfully endured the acute phase of COVID-19 may face the consequences of the infection. One of the most frequent manifestations will be the development of chronic fatigue syndrome (CFS) after COVID-19. This article discusses the possible causes of the development of CFS, as well as possible ways of its treatment and prevention.
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Affiliation(s)
- A J Nikitina
- Russian Medical Academy of continuous Professional Education, Moscow, Russia
| | - O S Levin
- Russian Medical Academy of continuous Professional Education, Moscow, Russia
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48
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Nikitina AJ, Chimagomedova AS, Levin OS. [Neurological complications of COVID-19 in elderly people]. Zh Nevrol Psikhiatr Im S S Korsakova 2021; 121:5-15. [PMID: 34870908 DOI: 10.17116/jnevro20211211025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Virus SARS-CoV2 (beta-coronavirus) can induce severe pneumonia with acute respiratory distress syndrome, respiratory failure and multiorgan dysfunction. As more we learned about Covid-19, we understand that SARS-CoV-2 have neuroinvasive properties and can cause different neurological complications. In this article we discusses about the features of neurological sequences of Covid-19 in elderly people.
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Affiliation(s)
- A J Nikitina
- Russian Medical Academy of continuous Professional Education, Moscow, Russia
| | - A Sh Chimagomedova
- Russian Medical Academy of continuous Professional Education, Moscow, Russia
| | - O S Levin
- Russian Medical Academy of continuous Professional Education, Moscow, Russia
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49
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Li X, Julin P, Li TQ. Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Tomography 2021; 7:675-687. [PMID: 34842817 PMCID: PMC8628916 DOI: 10.3390/tomography7040056] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/13/2021] [Accepted: 10/18/2021] [Indexed: 11/17/2022] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS. In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor. In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.
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Affiliation(s)
- Xia Li
- Institute of Information Engineering, China Jiliang University, 258 Xueyuan Street, Xiasha Higher Education Zone, Hangzhou 310018, China;
| | - Per Julin
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, S-17177 Stockholm, Sweden;
| | - Tie-Qiang Li
- Institute of Information Engineering, China Jiliang University, 258 Xueyuan Street, Xiasha Higher Education Zone, Hangzhou 310018, China;
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, S-17177 Stockholm, Sweden
- Department of Medical Radiation and Nuclear Medicine, C2-76, Karolinska University Hospital, Huddinge, S-14186 Stockholm, Sweden
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50
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Kujawski S, Słomko J, Newton JL, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S, Zalewski P. Network Analysis of Symptoms Co-Occurrence in Chronic Fatigue Syndrome. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182010736. [PMID: 34682478 PMCID: PMC8535251 DOI: 10.3390/ijerph182010736] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/08/2021] [Accepted: 10/10/2021] [Indexed: 11/16/2022]
Abstract
Chronic fatigue syndrome (CFS) is a heterogenous disorder of multiple disabling symptoms with complex manifestations. Network analysis is a statistical and interrogative methodology to investigate the prevalence of symptoms (nodes) and their inter-dependent (inter-nodal) relationships. In the present study, we explored the co-occurrence of symptoms in a cohort of Polish CFS patients using network analysis. A total of 110 patients with CFS were examined (75 females). The mean age of the total sample was 37.93 (8.5) years old while the mean duration of symptoms in years was 4.4 (4). Post-exertional malaise (PEM) was present in 75.45% of patients, unrefreshing sleep was noted in 89.09% and impaired memory or concentration was observed in 87.27% of patients. The least prevalent symptom was tender cervical or axillary lymph nodes, noted in 34.55% of the total sample. Three of the most densely connected nodes were the total number of symptoms, sore throat and PEM. PEM was positively related with impairment in memory or concentration. Both PEM and impairment in memory or concentration presence are related to more severe fatigue measured by CFQ and FIS. PEM presence was positively related with the presence of multi-joint pain and negatively with tender lymph nodes and muscle pain. Sore throat was related with objective and subjective autonomic nervous system impairment. This study helps define symptom presentation of CFS with the pathophysiology of specific systems and links with multidisciplinary contemporary molecular pathology, including comparative MRI.
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Affiliation(s)
- Sławomir Kujawski
- Department of Exercise Physiology and Functional Anatomy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (J.S.); (P.Z.)
- Correspondence:
| | - Joanna Słomko
- Department of Exercise Physiology and Functional Anatomy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (J.S.); (P.Z.)
| | - Julia L. Newton
- Population Health Sciences Institute, The Medical School, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK;
| | - Natalie Eaton-Fitch
- National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute of Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia; (N.E.-F.); (D.R.S.); (S.M.-G.)
- Consortium Health International for Myalgic Encephalomyelitis, Menzies Health Institute Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia
| | - Donald R. Staines
- National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute of Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia; (N.E.-F.); (D.R.S.); (S.M.-G.)
- Consortium Health International for Myalgic Encephalomyelitis, Menzies Health Institute Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia
| | - Sonya Marshall-Gradisnik
- National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute of Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia; (N.E.-F.); (D.R.S.); (S.M.-G.)
- Consortium Health International for Myalgic Encephalomyelitis, Menzies Health Institute Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia
| | - Paweł Zalewski
- Department of Exercise Physiology and Functional Anatomy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (J.S.); (P.Z.)
- National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute of Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia; (N.E.-F.); (D.R.S.); (S.M.-G.)
- Consortium Health International for Myalgic Encephalomyelitis, Menzies Health Institute Queensland, Griffith University, Gold Coast, Brisbane, QLD 4222, Australia
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