Tag: Vernon

RESTORE ME: a RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Background: The energy metabolite oxaloacetate is significantly lower in the blood plasma of ME/CFS subjects. A previous open-label trial with oxaloacetate supplementation demonstrated a significant reduction in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-related fatigue.

Methods: In this follow-up trial, 82 ME/CFS subjects were enrolled in a 3-month randomized, double-blinded, controlled study, receiving either 2,000 mg of oxaloacetate or control per day. The primary endpoints were safety and reduction in fatigue from baseline. Secondary and exploratory endpoints included functional capacity and general health status.

Results: Anhydrous enol-oxaloacetate (oxaloacetate) was well tolerated at the tested doses. Oxaloacetate significantly reduced fatigue by more than 25% from baseline, while the control group showed a non-significant reduction of approximately 10%. Intergroup analysis showed a significant decrease in fatigue levels in the oxaloacetate group (p = 0.0039) with no notable change in the control group. A greater proportion of subjects in the oxaloacetate group achieved a reduction in fatigue greater than 25% compared to the control group (p < 0.05). Additionally, 40.5% of the oxaloacetate group were classified as “enhanced responders,” with an average fatigue reduction of 63%. Both physical and mental fatigue improved with oxaloacetate supplementation.

Conclusion: Oxaloacetate is well tolerated and effectively helps reduce fatigue in ME/CFS patients.

Clinical trial registration: https://clinicaltrials.gov/study/NCT05273372.

Source: Alan B. Cash, Suzanne D. Vernon, Candace Rond, Saeed Abbaszadeh, Jen Bell, Brayden Yellman, Lucinda Bateman, David Kaufman. RESTORE ME: a RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front. Neurol., 26 November 2024. Sec. Experimental Therapeutics. Volume 15 – 2024 | https://doi.org/10.3389/fneur.2024.1483876 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1483876/full (Full text)

BioMapAI: Artificial Intelligence Multi-Omics Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Abstract:

Chronic diseases like ME/CFS and long COVID exhibit high heterogeneity with multifactorial etiology and progression, complicating diagnosis and treatment. To address this, we developed BioMapAI, an explainable Deep Learning framework using the richest longitudinal multi-‘omics dataset for ME/CFS to date.

This dataset includes gut metagenomics, plasma metabolome, immune profiling, blood labs, and clinical symptoms. By connecting multi-‘omics to asymptom matrix, BioMapAI identified both disease- and symptom-specific biomarkers, reconstructed symptoms, and achieved state-of-the-art precision in disease classification. We also created the first connectivity map of these ‘omics in both healthy and disease states and revealed how microbiome-immune-metabolome crosstalk shifted from healthy to ME/CFS.

Thus, we proposed several innovative mechanistic hypotheses for ME/CFS: Disrupted microbial functions – SCFA (butyrate), BCAA (amino acid), tryptophan, benzoate – lost connection with plasma lipids and bile acids, and activated inflammatory and mucosal immune cells (MAIT, γδT cells) with INFγ and GzA secretion. These abnormal dynamics are linked to key disease symptoms, including gastrointestinal issues, fatigue, and sleep problems.

Source: Xiong R, Fleming E, Caldwell R, Vernon SD, Kozhaya L, Gunter C, Bateman L, Unutmaz D, Oh J. BioMapAI: Artificial Intelligence Multi-Omics Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. bioRxiv [Preprint]. 2024 Jun 28:2024.06.24.600378. doi: 10.1101/2024.06.24.600378. PMID: 38979186; PMCID: PMC11230215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11230215/ (Full text available as PDF file)

What Long COVID investigators can learn from four decades of ME/CFS research

Abstract:

Four decades of research in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have yielded lessons that may be instructive for those devising criteria to better comprehend Post-Acute Sequelae of SARS CoV-2 Infection (PASC) and Long COVID.

For instance, substantial effort has been devoted to defining classification systems, operationalizing methods, and developing instruments with adequate reliability and validity in the ME/CFS field.

The current article provides guidelines for developing a case definition for Long COVID and discusses the significance of psychometric issues and criterion variance, including how to specify symptoms, develop thresholds, subtypes, and exclusionary conditions. ME/CFS research could enhance our knowledge of Long COVID pathophysiology, early diagnosis, prognosis, and the identification of effective treatments.

Source: Leonard A. Jason, Benjamin H. Natelson, Hector Bonilla, Zaki A. Sherif, Suzanne D. Vernon, Monica Verduzco Gutierrez, Lisa O’Brien, Emily Taylor. What Long COVID investigators can learn from four decades of ME/CFS research. Brain Behavior and Immunity Integrative, Volume 4, 2023, 100022. https://www.sciencedirect.com/science/article/pii/S2949834123000211 (Full text)

Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes

Introduction: Cognitive impairment is experienced by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of COVID-19 (PASC). Patients report difficulty remembering, concentrating, and making decisions. Our objective was to determine whether orthostatic hemodynamic changes were causally linked to cognitive impairment in these diseases.

Methods: This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject’s total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment.

Results: Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls). Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge. Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge. Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively. Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (−1.5, p = 0.04). Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age.

Discussion: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.

Source: Day Heather, Yellman Brayden, Hammer Sarah, Rond Candace, Bell Jennifer, Abbaszadeh Saeed, Stoddard Greg, Unutmaz Derya, Bateman Lucinda, Vernon Suzanne D. Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes. Frontiers in Neuroscience, VOLUME=17, 2023. DOI=10.3389/fnins.2023.1203514. ISSN=1662-453X. https://www.frontiersin.org/articles/10.3389/fnins.2023.1203514 (Full text)

Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

  • Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
  • Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
  • Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
  • Enhanced IL-10 regulatory response may drive the observed immunosuppression.
  • Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.

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 cohorts of ME/CFS and control study participants, 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. 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.

Source: Melanie Uhde, Alyssa C. Indart, Peter H.R. Green, Robert H. Yolken, Dane B. Cook, Sanjay K. Shukla, Suzanne D. Vernon, Armin Alaedini.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome. Brain, Behavior, & Immunity – Health, 2023, 100627. ISSN 2666-3546, https://doi.org/10.1016/j.bbih.2023.100627.
https://www.sciencedirect.com/science/article/pii/S2666354623000418 (Full text)

Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.

Methods: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.

Results: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.

Conclusion: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.

Source: Vernon SD, Hartle M, Sullivan K, Bell J, Abbaszadeh S, Unutmaz D, Bateman L. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work. 2023 Mar 7. doi: 10.3233/WOR-220581. Epub ahead of print. PMID: 36911963. https://content.iospress.com/articles/work/wor220581 (Full text)

Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients

Highlights

  • Multi-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS.
  • Reduced gut microbial diversity and increased plasma sphingomyelins in ME/CFS.
  • Short-term patients had more severe gut microbial dysbiosis with decreased butyrate.
  • Long-term patients had more significant metabolic and clinical aberrations

Summary

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disorder manifesting as severe fatigue and post-exertional malaise. The etiology of ME/CFS remains elusive.

Here, we present a deep metagenomic analysis of stool combined with plasma metabolomics and clinical phenotyping of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) compared with healthy controls (n = 79).

First, we describe microbial and metabolomic dysbiosis in ME/CFS patients. Short-term patients showed significant microbial dysbiosis, while long-term patients had largely resolved microbial dysbiosis but had metabolic and clinical aberrations.

Second, we identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts. These revealed potential functional mechanisms underlying disease onset and duration, including reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate.

In addition to the insights derived, our data represent an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Source: Ruoyun Xiong, Courtney Gunter, Elizabeth Fleming, Suzanne D. Vernon, Lucinda Bateman, Derya Unutmaz, Julia Oh. Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patients. Cell Host & Microbe 31, 273–287. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(23)00021-5 (Full text)

Improvement of Long COVID symptoms over one year

Abstract:

Importance: Early and accurate diagnosis and treatment of Long COVID, clinically known as post-acute sequelae of COVID-19 (PASC), may mitigate progression to chronic diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our objective was to determine the utility of the DePaul Symptom Questionnaire (DSQ) to assess the frequency and severity of common symptoms of ME/CFS, to diagnose and monitor symptoms in patients with PASC.

Methods: This prospective, observational cohort study enrolled 185 people that included 34 patients with PASC that had positive COVID-19 test and persistent symptoms of >3 months and 151 patients diagnosed with ME/CFS. PASC patients were followed over 1 year and responded to the DSQ at baseline and 12 months. ME/CFS patients responded to the DSQ at baseline and 1 year later. Changes in symptoms over time were analyzed using a fixed-effects model to compute difference-in-differences estimates between baseline and 1-year follow-up assessments.

Participants: Patients were defined as having PASC if they had a previous positive COVID-19 test, were experiencing symptoms of fatigue, post-exertional malaise, or other unwellness for at least 3 months, were not hospitalized for COVID-19, had no documented major medical or psychiatric diseases prior to COVID-19, and had no other active and untreated disease processes that could explain their symptoms. PASC patients were recruited in 2021. ME/CFS patients were recruited in 2017.

Results: At baseline, patients with PASC had similar symptom severity and frequency as patients with ME/CFS and satisfied ME/CFS diagnostic criteria. ME/CFS patients experienced significantly more severe unrefreshing sleep and flu-like symptoms. Five symptoms improved significantly over the course of 1 year for PASC patients including fatigue, post-exertional malaise, brain fog, irritable bowel symptoms and feeling unsteady. In contrast, there were no significant symptom improvements for ME/CFS patients.

Conclusion and relevance: There were considerable similarities between patients with PASC and ME/CFS at baseline. However, symptoms improved for PASC patients over the course of a year but not for ME/CFS patients. PASC patients with significant symptom improvement no longer met ME/CFS clinical diagnostic criteria. These findings indicate that the DSQ can be used to reliably assess and monitor PASC symptoms.

Source: Oliveira CR, Jason LA, Unutmaz D, Bateman L, Vernon SD. Improvement of Long COVID symptoms over one year. Front Med (Lausanne). 2023 Jan 9;9:1065620. doi: 10.3389/fmed.2022.1065620. PMID: 36698810; PMCID: PMC9868805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868805/ (Full text)

Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.

Methods: We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app.

Participants: People with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT.

Results: The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01).

Conclusions: A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.

Source: Vernon SD, Funk S, Bateman L, Stoddard GJ, Hammer S, Sullivan K, Bell J, Abbaszadeh S, Lipkin WI, Komaroff AL. Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne). 2022 Jun 23;9:917019. doi: 10.3389/fmed.2022.917019. PMID: 35847821; PMCID: PMC9285104. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285104/ (Full text)

Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.

Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).

Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.

One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

Source: Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI. Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv [Preprint]. 2022 Jan 11:2021.06.14.21258895. doi: 10.1101/2021.06.14.21258895. PMID: 35043127; PMCID: PMC8764736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764736/ (Full text)