Tag: Marshall-Gradisnik

Altered brain connectivity in Long Covid during cognitive exertion: a pilot study

Abstract:

Introduction: Debilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection.

Methods: Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to-ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores.

Results: Two ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI.

Discussion: Multiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep-wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov.

Source: Barnden L, Thapaliya K, Eaton-Fitch N, Barth M, Marshall-Gradisnik S. Altered brain connectivity in Long Covid during cognitive exertion: a pilot study. Front Neurosci. 2023 Jun 22;17:1182607. doi: 10.3389/fnins.2023.1182607. PMID: 37425014; PMCID: PMC10323677. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323677/ (Full text)

A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls.

Methods: Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17.

Results: Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult.

Conclusions: There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.

Source: Taccori A, Maksoud R, Eaton-Fitch N, Patel M, Marshall-Gradisnik S. A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med. 2023 Jul 5;21(1):440. doi: 10.1186/s12967-023-04295-0. PMID: 37408028; PMCID: PMC10320942. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320942/ (Full text)

Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case criteria following exclusion of any other potential medical conditions. While there are some studies that report potential biomarkers for ME/CFS, their efficacy has not been validated. The aim of this systematic review is to collate and appraise literature pertaining to a potential biomarker(s) which may effectively differentiate ME/CFS patients from healthy controls.

Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane review guidelines. PubMed, Embase and Scopus were systematically searched for articles containing “biomarker” and “ME/CFS” keywords in the abstract or title and if they included the following criteria: (1) were observational studies published between December 1994 and April 2022; (2) involved adult human participants; (3) full text is available in English (4) original research; (5) diagnosis of ME/CFS patients made according to the Fukuda criteria (1994), Canadian Consensus Criteria (2003), International Consensus Criteria (2011) or Institute of Medicine Criteria (2015); (6) study investigated potential biomarkers of ME/CFS compared to healthy controls. Quality and Bias were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.

Results: A total of 101 publications were included in this systematic review. Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%), endovascular/circulatory (17.82%), neurological (7.92%), ion channel (8.91%) and physical dysfunction biomarkers (8.91%). Most of the potential biomarkers reported were blood-based (79.2%). Use of lymphocytes as a model to investigate ME/CFS pathology was prominent among immune-based biomarkers. Most biomarkers had secondary (43.56%) or tertiary (54.47%) selectivity, which is the ability for the biomarker to identify a disease-causing agent, and a moderate (59.40%) to complex (39.60%) ease-of-detection, including the requirement of specialised equipment.

Conclusions: All potential ME/CFS biomarkers differed in efficiency, quality, and translatability as a diagnostic marker. Reproducibility of findings between the included publications were limited, however, several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness. The heterogeneity shown across many of the included studies highlights the need for multidisciplinary research and uniform protocols in ME/CFS biomarker research.

Source: Maksoud R, Magawa C, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review. BMC Med. 2023 May 24;21(1):189. doi: 10.1186/s12916-023-02893-9. PMID: 37226227; PMCID: PMC10206551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206551/ (Full text)

Symptom presentation and quality of life are comparable in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and post COVID-19 condition

Abstract:
Background and Οbjective: Considerable overlap exists in the clinical presentation of Post COVID-19 Condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The current study aimed to compare symptoms and patient-reported Quality of Life (QoL) among people with Post COVID-19 Condition and ME/CFS in Australia. Methods: QoL data was collected from n=61 ME/CFS patients, n=31 Post COVID-19 Condition patients, and n=54 Healthy Controls (HCs) via validated instruments. The ME/CFS and Post COVID-19 Condition participants also provided self-reported severity and frequency of symptoms derived from the Canadian and International Consensus Criteria for ME/CFS and the World Health Organization case definition for Post COVID-19 Condition. Study variables were compared with Chi-square, Fisher’s exact, Fisher-Freeman-Halton, Mann-Whitney U, and Kruskal-Wallis H tests using Statistical Package for the Social Sciences version 29. Symptom clusters among the two illness cohorts were identified with hierarchical cluster analysis.
Results: ME/CFS was associated with a higher prevalence of short-term memory loss (p=0.039), muscle weakness (p<0.001), lymphadenopathy (p=0.013), and nausea (p=0.003). People with ME/CFS also reported more severe light-headedness (p=0.011) and more frequent unrefreshed sleep (p=0.011), but less frequent heart palpitations (p=0.040). Symptom prevalence, severity, and frequency were otherwise comparable. Few differences existed in the QoL of the two illness cohorts, both of which returned significantly impaired QoL scores when compared with HCs (p<0.001). Cluster analysis of symptom prevalence revealed four clusters: 1) Low gastrointestinal, low neurosensory; 2) Moderate gastrointestinal, low orthostatic and memory loss; 3) Moderate gastrointestinal, high orthostatic and memory loss; and 4) High gastrointestinal, high pain, which did not differ in sociodemographic information, illness status, or diagnostic criteria met.
Conclusions: Post COVID-19 Condition and ME/CFS are remarkably similar in presentation and, like ME/CFS, Post COVID-19 Condition has a profound and negative impact on patient QoL. Gastrointestinal symptoms may have a role in determining ME/CFS and Post COVID-19 Condition subtypes.
Source: Weigel B, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. Symptom presentation and quality of life are comparable in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and post COVID-19 condition. Population Medicine. 2023;5(Supplement):A372. doi:10.18332/popmed/165669.  http://www.populationmedicine.eu/Symptom-presentation-and-quality-of-life-are-comparable-in-Myalgic-Encephalomyelitis,165669,0,2.html

Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID (WHO Delphi consensus), and 10 healthy control (HC) subjects on 3D, T1-weighted MRI images acquired using sub-millimeter isotropic resolution using an ultra-high field strength of 7 Tesla.

Group comparisons with HC detected significantly larger volumes in ME/CFS for pons (p = 0.004) and whole brainstem (p = 0.01), and in long COVID for pons (p = 0.003), superior cerebellar peduncle (p = 0.009), and whole brainstem (p = 0.005). No significant differences were found between ME/CFS and long COVID volumes. In ME/CFS, we detected positive correlations between the pons and whole brainstem volumes with “pain” and negative correlations between the midbrain and whole brainstem volumes with “breathing difficulty.”

In long COVID patients a strong negative relationship was detected between midbrain volume and “breathing difficulty.” Our study demonstrated an abnormal brainstem volume in both ME/CFS and long COVID consistent with the overlapping symptoms.

Source: Thapaliya K, Marshall-Gradisnik S, Barth M, Eaton-Fitch N, Barnden L. Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients. Frontiers in Neuroscience, 2023 March 2; 17:1125208. https://www.frontiersin.org/articles/10.3389/fnins.2023.1125208/full (Full text)

Connectivity between Salience and Default Mode Networks and subcortical nodes distinguishes between two classes of ME/CFS

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with unknown pathophysiology. Functional MRI (fMRI) studies in ME/CFS have reported disparate connectivities for the brain salience (SA) and default mode (DMN) networks.

In this study, we acquired resting state and task fMRI with an advanced scanner for improved subject numbers: 24 healthy controls (HC) and 42 ME/CFS patients, 18 meeting International Consensus Criteria (ICC) and 24 meeting Fukuda criteria. We evaluated mean FC between SA and DMN network hub, and subcortical regions known to be involved in ME/CFS. We tested the hypothesis that ME/CFS connectivity differed from HC and the ICC and Fukuda classes are distinguished by different connectivities with HC for different pairs of SA, DMN or subcortical hubs.

During resting state fMRI only two connections differed from HC, both for Fukuda ME/CFS and both with an SA hub. During task fMRI 10 ME/CFS connections differed from HC, 5 for ICC and 5 for Fukuda. None were common to both classes. Eight of the 10 different connections involved an SA hub, six of 10 were weaker in ME/CFS, 4 stronger.

SA connections to the hippocampus and brainstem reticular activation system (RAS) differed from and were stronger than HC. The SA mediates the relative activity of the DMN and executive networks and imbalance will have functional consequences. The RAS and hippocampus modulate cortical activation. Different regulatory connections are consistent with the impaired cognitive performance and sleep-wake cycle of ME/CFS. Different neuropathology is involved in ICC and Fukuda classes.

Source: Su J, Thapaliya K, Eaton-Fitch N, Marshall-Gradisnik SM, Barnden LR. Connectivity between Salience and Default Mode Networks and subcortical nodes distinguishes between two classes of ME/CFS. Brain Connect. 2022 Nov 9. doi: 10.1089/brain.2022.0049. Epub ahead of print. PMID: 36352819. https://pubmed.ncbi.nlm.nih.gov/36352819/

Understanding myalgic encephalomyelitis

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition characterized by post-exertional neuroimmune exhaustion (PENE) accompanied by neurological, immunological, gastrointestinal (GI), and mitochondrial disturbances (1). The global prevalence of ME/CFS is ∼1%, affecting 17 million to 24 million people (2). ME/CFS is heterogeneous not only in symptom presentation but also illness trajectories, which can be worsening, plateauing, improving, or relapsing-remitting. Approximately 25% of patients with ME/CFS are considered severe and are bound to their homes. Although the etiology of ME/CFS is elusive, a large proportion of patients (∼60%) report post-infectious onset, such as after Epstein-Barr virus infection (3). The recent emergence of a chronic post-infectious condition, called Long Covid, overlaps considerably with ME/CFS in immunological, mitochondrial, and neurological dysfunctions (4). These similarities have resulted in increased interest and acceptance of ME/CFS as a disease and may stimulate research, the development of a diagnostic test, and pharmacotherapeutic interventions in ME/CFS that may be applied to Long Covid.

Read the rest of this article HERE.

Source: Sonya Marshall-Gradisnik and Natalie Eaton-Fitch. Understanding myalgic encephalomyelitis. SCIENCE, 8 Sep 2022, Vol 377, Issue 6611, pp. 1150-1151, DOI: 10.1126/science.abo126 https://www.science.org/doi/10.1126/science.abo1261 (Full text)

Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic condition associated with post-infectious onset, impaired natural killer (NK) cell cytotoxicity and impaired ion channel function, namely Transient Receptor Potential Melastatin 3 (TRPM3). Long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has resulted in neurocognitive, immunological, gastrointestinal, and cardiovascular manifestations recently recognised as post coronavirus disease 2019 (COVID-19) condition. The symptomatology of ME/CFS overlaps significantly with post COVID-19; therefore, this research aimed to investigate TRPM3 ion channel function in post COVID-19 condition patients.

Methods: Whole-cell patch-clamp technique was used to measure TRPM3 ion channel activity in isolated NK cells of N = 5 ME/CFS patients, N = 5 post COVID-19 patients, and N = 5 healthy controls (HC). The TRPM3 agonist, pregnenolone sulfate (PregS) was used to activate TRPM3 function, while ononetin was used as a TRPM3 antagonist.

Results: As reported in previous research, PregS-induced TRPM3 currents were significantly reduced in ME/CFS patients compared with HC (p = 0.0048). PregS-induced TRPM3 amplitude was significantly reduced in post COVID-19 condition compared with HC (p = 0.0039). Importantly, no significant difference was reported in ME/CFS patients compared with post COVID-19 condition as PregS-induced TRPM3 currents of post COVID-19 condition patients were similar of ME/CFS patients currents (p > 0.9999). Isolated NK cells from post COVID-19 condition and ME/CFS patients were resistant to ononetin and differed significantly with HC (p < 0.0001).

Conclusion: The results of this investigation suggest that post COVID-19 condition patients may have impaired TRPM3 ion channel function and provide further evidence regarding the similarities between post COVID-19 condition and ME/CFS. Impaired TRPM3 channel activity in post COVID-19 condition patients suggest impaired ion mobilisation which may consequently impede cell function resulting in chronic post-infectious symptoms. Further investigation into TRPM3 function may elucidate the pathomechanism, provide a diagnostic and therapeutic target for post COVID-19 condition patients and commonalities with ME/CFS patients.

Source: Sasso EM, Muraki K, Eaton-Fitch N, Smith P, Lesslar OL, Deed G, Marshall-Gradisnik S. Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients. Mol Med. 2022 Aug 19;28(1):98. doi: 10.1186/s10020-022-00528-y. PMID: 35986236.  https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00528-y (Full text)

Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome

There remains ambiguity surrounding the role of dietary supplementation and nutrient intake on the health status of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients, yet supplement use and dietary modification appear to be common among people with the condition. This pilot cross-sectional study aimed to investigate if supplement use or nutrient intake was associated with self-reported health-related quality of life (HRQoL) scores among Australians with ME/CFS.

The eligibility criteria for this study included being a resident of Australia, being aged between 18 and 65 years, and having received a formal diagnosis of ME/CFS from a physician. Participants completed a series of self-administered questionnaires querying sociodemographic information, symptom presentation, HRQoL, routine supplement use, and nutrient intake. The 36-item Short-Form Health Survey version 2 (SF-36) was employed to assess participants’ HRQoL. Daily nutrient intake was estimated from participants’ responses to the Dietary Questionnaire for Epidemiological Studies (Cancer Council Victoria, Australia). Multiple linear regression analysis was performed for each of the eight SF-36 domains. Age, gender, body mass index, employment, education were controlled variables in each model, with supplement and nutrient variables entered in a stepwise manner.

Twenty-four Australians with ME/CFS, 54.2% of which met the International Consensus Criteria case definition for ME/CFS, participated in the study. Three of the eight regression models were statistically significant, being the ‘role limitations due to physical health problems’ (adjusted R 2 = 0.733, P < 0.001), ‘bodily pain’ (adjusted R 2 = 0.544, P = 0.004), and ‘general health perceptions’ (adjusted R 2 = 0.743, P < 0.001) SF-36 domains. Positive associations were observed between HRQoL and the routine use of vitamin C (ß = 0.300, P = 0.042) and herbal supplements (ß = 0.618, P < 0.001), as well as daily saturated fat (ß = 0.860, P < 0.001), total folate (ß = 0.710, P < 0.001), and calcium intake (ß = 0.897, P = 0.003). However, the routine use of evening primrose oil supplements (ß = -0.385, P = 0.006) and daily intakes of alpha-linolenic acid (ß = −0.543, P = 0.001), long chain omega-3 fatty acids (ß = −0.431, P = 0.017), and iodine (ß = −0.602, P = 0.034) were negatively associated with HRQoL scores. None of the supplements or nutrients studied had consistent associations with HRQoL across the three significant regression models.

The findings of this pilot study suggest that there may be links between dietary supplementation and nutrient intake with HRQoL among people with ME/CFS. Future studies should investigate supplement use, daily nutrient intake, and their relationships with HRQoL and symptom presentation among people with ME/CFS longitudinally and compared with healthy controls to further elucidate the role of supplements and nutrient intake in the management of ME/CFS.

Read the full study HERE.

Source: Weigel, B., Eaton-Fitch, N., Passmore, R., Cabanas, H., Staines, D., & Marshall-Gradisnik, S. (2022). Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the Nutrition Society, 81(OCE3), E80. doi:10.1017/S0029665122001057 https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/dietary-supplements-daily-nutrient-intake-and-healthrelated-quality-of-life-among-people-with-myalgic-encephalomyelitischronic-fatigue-syndrome/F837EC4FE783FFAEB44F66F7748C11F6 (Full text)

Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) patients suffer from neurocognitive impairment. In this study, we investigated cortical volumetric and thickness changes in ME/CFS patients and healthy controls (HC). We estimated mean surface-based cortical volume and thickness from 18 ME/CFS patients who met International Consensus Criteria (ICC) and 26 HC using FreeSurfer. Vertex-wise analysis showed significant reductions in the caudal middle frontal gyrus (p = 0.0016) and precuneus (p = 0.013) thickness in ME/CFS patients compared with HC.

Region based analysis of sub-cortical volumes found that amygdala volume (p = 0.002) was significantly higher in ME/CFS patients compared with HC. We also performed interaction-with-group regressions with clinical measures to test for cortical volume and thickness correlations in ME/CFS with opposite slopes to HC (abnormal). ME/CFS cortical volume and thickness regressions with fatigue, heart-rate variability, heart rate, sleep disturbance score, respiratory rate, and cognitive performance were abnormal. Our study demonstrated different cortical volume and thickness in ME/CFS patients and showed abnormal cortical volume and thickness regressions with key symptoms of ME/CFS patients.

Source: Thapaliya Kiran, Marshall-Gradisnik Sonya, Staines Donald, Su Jiasheng, Barnden Leighton. Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Frontiers in Neuroscience, Vol 16, 2022. DOI=10.3389/fnins.2022.848730 https://www.frontiersin.org/articles/10.3389/fnins.2022.848730/full   (Full text)