Tag: Peterson

Cognitive assessment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a cognitive substudy of the multi-site clinical assessment of ME/CFS (MCAM)

Abstract:

Introduction: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience cognitive problems with attention, information processing speed, working memory, learning efficiency, and executive function. Commonly, patients report worsening of cognitive symptoms over time after physical and/or cognitive challenges. To determine, monitor, and manage longitudinal decrements in cognitive function after such exposures, it is important to be able to screen for cognitive dysfunction and changes over time in clinic and also remotely at home. The primary objectives of this paper were: (1) to determine whether a brief computerized cognitive screening battery will detect differences in cognitive function between ME/CFS and Healthy Controls (HC), (2) to monitor the impact of a full-day study visit on cognitive function over time, and (3) to evaluate the impact of exercise testing on cognitive dysfunction.

Methods: This cognitive sub-study was conducted between 2013 and 2019 across seven U.S. ME/CFS clinics as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study. The analysis included 426 participants (261 ME/CFS and 165 HC), who completed cognitive assessments including a computerized CogState Brief Screening Battery (CBSB) administered across five timepoints (T0-T4) at the start of and following a full day in-clinic visit that included exercise testing for a subset of participants (182 ME/CFS and 160 HC). Exercise testing consisted of ramped cycle ergometry to volitional exhaustion. The primary outcomes are performance accuracy and latency (performance speed) on the computerized CBSB administered online in clinic (T0 and T1) and at home (T2-T4).

Results: No difference was found in performance accuracy between ME/CFS and HCs whereas information processing speed was significantly slower for ME/CFS at most timepoints with Cohen’s d effect sizes ranging from 0.3-0.5 (p < 0.01). The cognitive decline over time on all CBSB tasks was similar for patients with ME/CFS independent of whether exercise testing was included in the clinic visit.

Conclusion: The challenges of a clinic visit (including cognitive testing) can lead to further cognitive deficits. A single short session of intense exercise does not further reduce speed of performance on any CBSB tasks.

Source: Lange G, Lin JS, Chen Y, Fall EA, Peterson DL, Bateman L, Lapp C, Podell RN, Natelson BH, Kogelnik AM, Klimas NG, Unger ER. Cognitive assessment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a cognitive substudy of the multi-site clinical assessment of ME/CFS (MCAM). Front Neurosci. 2024 Nov 1;18:1460157. doi: 10.3389/fnins.2024.1460157. PMID: 39554847; PMCID: PMC11565701. https://pmc.ncbi.nlm.nih.gov/articles/PMC11565701/ (Full text)

Chronic Overlapping Pain Conditions in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a sample from the Multi-site Clinical Assessment of ME/CFS (MCAM) study

Abstract:

Background: Chronic overlapping pain conditions (COPCs), pain-related conditions that frequently occur together, may occur in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and could impact illness severity. This study aimed to identify comorbid COPCs in patients with ME/CFS and evaluate their impact on illness severity.

Methods: We used data from 923 participants in the Multi-Site Clinical Assessment of ME/CFS study, conducted in seven U.S. specialty clinics between 2012 and 2020, who completed the baseline assessment (595 ME/CFS and 328 healthy controls (HC)). COPCs included chronic low back pain (cLBP), chronic migraine/headache (cMHA), fibromyalgia (FM), interstitial cystitis/irritable bladder (IC/IB), irritable bowel syndrome (IBS), temporomandibular disorder (TMD). Illness severity was assessed through questionnaires measuring symptoms and functioning. Multivariate analysis of variance and analysis of covariance models were used for analyses. Log-binomial regression analyses were used to compute prevalence of COPCs and prevalence ratios (PR) between groups with 95% confidence intervals. Both unadjusted and adjusted results with age and sex are presented.

Results: 76% of participants with ME/CFS had at least one COPCs compared to 17.4% of HC. Among ME/CFS participants, cMHA was most prevalent (48.1%), followed by FM (45.0%), cLBP (33.1%), and IBS (31.6%). All individual COPCs, except TMD, were significantly more frequent in females than males. The unadjusted PR (ME/CFS compared to HC) was highest for FM [147.74 (95% confidence interval (CI) = 20.83-1047.75], followed by cLBP [39.45 (12.73-122.27)], and IC/IB [13.78 (1.88-101.24)]. The significance and order did not change after age and sex adjustment. The COPC comorbidities of cLBP and FM each had a significant impact on most health measures, particularly in pain attributes (Cohen’s d effect size 0.8 or larger). While the impact of COPC comorbidities on non-pain attributes and quality of life measures was less pronounced than that on pain, statistically significant differences between ME/CFS participants with and without COPCs were still evident.

Conclusions: More than 75% of ME/CFS participants had one or more COPCs. Multiple COPCs further exacerbated illness severity, especially among females with ME/CFS. Assessment and management of COPCs may help improve the health and quality of life for patients with ME/CFS.

Source: Fall EA, Chen Y, Lin JS, Issa A, Brimmer DJ, Bateman L, Lapp CW, Podell RN, Natelson BH, Kogelnik AM, Klimas NG, Peterson DL, Unger ER; MCAM Study Group. Chronic Overlapping Pain Conditions in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a sample from the Multi-site Clinical Assessment of ME/CFS (MCAM) study. BMC Neurol. 2024 Oct 18;24(1):399. doi: 10.1186/s12883-024-03872-0. PMID: 39425035; PMCID: PMC11488184. https://pmc.ncbi.nlm.nih.gov/articles/PMC11488184/ (Full text)

Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway

Abstract:

Background: Tetrahydrobiopterin (BH4) and its oxidized derivative dihydrobiopterin (BH2) were found to be strongly elevated in ME/CFS patients with orthostatic intolerance (ME + OI).

Objective: However, the molecular mechanism of biopterin biogenesis is poorly understood in ME + OI subjects. Here, we report that the activation of the non-oxidative pentose phosphate pathway (PPP) plays a critical role in the biogenesis of biopterins (BH4 and BH2) in ME + OI subjects.

Research design and results: Microarray-based gene screening followed by real-time PCR-based validation, ELISA assay, and finally enzyme kinetic studies of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TALDO1), and transketolase (TK) enzymes revealed that the augmentation of anaerobic PPP is critical in the regulations of biopterins. To further investigate, we devised a novel cell culture strategy to induce non-oxidative PPP by treating human microglial cells with ribose-5-phosphate (R5P) under a hypoxic condition of 85%N2/10%CO2/5%O2 followed by the analysis of biopterin metabolism via ELISA, immunoblot, and dual immunocytochemical analyses. Moreover, the siRNA knocking down of the taldo1 gene strongly inhibited the bioavailability of phosphoribosyl pyrophosphate (PRPP), reduced the expressions of purine biosynthetic enzymes, attenuated GTP cyclohydrolase 1 (GTPCH1), and suppressed subsequent production of BH4 and its metabolic conversion to BH2 in R5P-treated and hypoxia-induced C20 human microglia cells. These results confirmed that the activation of non-oxidative PPP is indeed required for the upregulation of both BH4 and BH2 via the purine biosynthetic pathway. To test the functional role of ME + OI plasma-derived biopterins, exogenously added plasma samples of ME + OI plasma with high BH4 upregulated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in human microglial cells indicating that the non-oxidative PPP-induced-biopterins could stimulate inflammatory response in ME + OI patients.

Conclusion: Taken together, our current research highlights that the induction of non-oxidative PPP regulates the biogenesis of biopterins contributing to ME/CFS pathogenesis.

Source: Bulbule S, Gottschalk CG, Drosen ME, Peterson D, Arnold LA, Roy A. Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway. J Cent Nerv Syst Dis. 2024 Aug 19;16:11795735241271675. doi: 10.1177/11795735241271675. PMID: 39161795; PMCID: PMC11331476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331476/ (Full text)

Augmentation of Anaerobic Pentose Phosphate Pathway Dysregulates Tetrahydrobiopterin Metabolism in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) Patients with Orthostatic Intolerance: A Pilot Study

Abstract:

Tetrahydrobiopterin (BH4), an essential cofactor of amino acid metabolism, was found to be strongly elevated in ME/CFS patients with Orthostatic intolerance (ME + OI). However, the molecular mechanism of BH4 upregulation is poorly understood in ME + OI patients. Here, we report that the activation of the non-oxidative pentose phosphate pathway (PPP) plays a critical role in the biosynthesis of BH4 in ME + OI patients.

Microarray-based gene screening followed by real-time PCR-based validation, ELISA assay, and finally enzyme kinetic studies of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TALDO1), and transketolase (TK) enzymes revealed that the augmentation of anaerobic PPP is critical in the pathogenesis of ME + OI. Along with the upregulated anaerobic PPP enzymes, we observed that biopterin metabolites such as BH4 and dihydrobiopterin (BH2) are strongly upregulated suggesting the disruption of biopterin homeostasis in ME + OI patients.

To explore the molecular role of anaerobic PPP in biopterin metabolism, we devised a novel cell culture strategy to induce non-oxidative PPP by treating human microglial cells with ribose-5-phosphate (R5P) under a hypoxic condition of 85%N2/10%CO2/5%O2 followed by the analysis of BH4 and BH2 upregulation via ELISA, immunoblot and dual immunocytochemical analyses.

These results confirmed that the activation of non-oxidative PPP is indeed required for the upregulation of both BH4 and BH2. Moreover, the siRNA knocking down of the taldo1 gene strongly inhibited the expression of GTP cyclohydrolase 1 (GTPCH1) and subsequent production of BH4 and its metabolic conversion to BH2 in R5P-treated and hypoxia-induced C20 human microglia cells. To test the functional role of ME + OI plasma-derived biopterins, exogenously added plasma samples of ME + OI plasma with high BH4 upregulated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in human microglial cells indicating that the non-oxidative PPP-induced-biopterins could stimulate inflammatory response in ME + OI patients.

Source: Sarojini Bulbule, Carl Gunnar Gottschalk, Molly E Drosen et al. Augmentation of Anaerobic Pentose Phosphate Pathway Dysregulates Tetrahydrobiopterin Metabolism in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) Patients with Orthostatic Intolerance: A Pilot Study, 11 December 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3716093/v1] https://www.researchsquare.com/article/rs-3716093/v1 (Full text)

Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Common Data Element item content analysis

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem chronic disease estimated to affect 836,000-2.5 million individuals in the United States. Persons with ME/CFS have a substantial reduction in their ability to engage in pre-illness levels of activity. Multiple symptoms include profound fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, orthostatic intolerance, pain, and other symptoms persisting for more than 6 months. Diagnosis is challenging due to fluctuating and complex symptoms. ME/CFS Common Data Elements (CDEs) were identified in the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element Repository. This study reviewed ME/CFS CDEs item content.

Methods: Inclusion criteria for CDEs (measures recommended for ME/CFS) analysis: 1) assesses symptoms; 2) developed for adults; 3) appropriate for patient reported outcome measure (PROM); 4) does not use visual or pictographic responses. Team members independently reviewed CDEs item content using the World Health Organization International Classification of Functioning, Disability and Health (ICF) framework to link meaningful concepts.

Results: 119 ME/CFS CDEs (measures) were reviewed and 38 met inclusion criteria, yielding 944 items linked to 1503 ICF meaningful concepts. Most concepts linked to ICF Body Functions component (b-codes; n = 1107, 73.65%) as follows: Fatiguability (n = 220, 14.64%), Energy Level (n = 166, 11.04%), Sleep Functions (n = 137, 9.12%), Emotional Functions (n = 131, 8.72%) and Pain (n = 120, 7.98%). Activities and Participation concepts (d codes) accounted for a smaller percentage of codes (n = 385, 25.62%). Most d codes were linked to the Mobility category (n = 69, 4.59%) and few items linked to Environmental Factors (e codes; n = 11, 0.73%).

Discussion: Relatively few items assess the impact of ME/CFS symptoms on Activities and Participation. Findings support development of ME/CFS-specific PROMs, including items that assess activity limitations and participation restrictions. Development of psychometrically-sound, symptom-based item banks administered as computerized adaptive tests can provide robust assessments to assist primary care providers in the diagnosis and care of patients with ME/CFS.

Source: Slavin MD, Bailey HM, Hickey EJ, Vasudevan A, Ledingham A, Tannenbaum L, Bateman L, Kaufman DL, Peterson DL, Ruhoy IS, Systrom DM, Felsenstein D, Kazis LE. Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Common Data Element item content analysis. PLoS One. 2023 Sep 12;18(9):e0291364. doi: 10.1371/journal.pone.0291364. PMID: 37698999. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0291364 (Full text)

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect 0.4%-2.5% of the global population. Most cases are unexplained; however, some patients describe an antecedent viral infection or response to antiviral medications.

We report here a multicenter study for the presence of viral nucleic acid in blood, feces, and saliva of patients with ME/CFS using polymerase chain reaction and high-throughput sequencing.

We found no consistent group-specific differences other than a lower prevalence of anelloviruses in cases compared to healthy controls. Our findings suggest that future investigations into viral infections in ME/CFS should focus on adaptive immune responses rather than surveillance for viral gene products.

Source: Briese T, Tokarz R, Bateman L, Che X, Guo C, Jain K, Kapoor V, Levine S, Hornig M, Oleynik A, Quan PL, Wong WH, Williams BL, Vernon SD, Klimas NG, Peterson DL, Montoya JG, Ian Lipkin W. A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome. J Med Virol. 2023 Aug;95(8):e28993. doi: 10.1002/jmv.28993. PMID: 37526404. https://pubmed.ncbi.nlm.nih.gov/37526404/ 

Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted.

Methods: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture.

Results: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4-44.3%) and 33.6% (IQR 22.9-43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions.

Conclusion: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

Source: Querec TD, Lin JS, Chen Y, Helton B, Kogelnik AM, Klimas NG, Peterson DL, Bateman L, Lapp C, Podell RN, Natelson BH, Unger ER; MCAM Study Group. Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study. J Transl Med. 2023 Apr 3;21(1):242. doi: 10.1186/s12967-023-03958-2. PMID: 37013608. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03958-2 (Full text)

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation.

We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells.

We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.

Source: Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2023 Jan 19;24(3):2010. doi: 10.3390/ijms24032010. PMID: 36768336; PMCID: PMC9916395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916395/ (Full text)

Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

Abstract:

Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization’s economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair.

While a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID. Interestingly, Long-haul COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness, depression, and chronic inflammation.

In our current hypothesis-driven review article, we attempt to discuss the molecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan, Epstein-Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Source: Gottschalk CG, Peterson D, Armstrong J, Knox K, Roy A. Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases. Infect Agent Cancer. 2023 Feb 7;18(1):7. doi: 10.1186/s13027-023-00485-z. PMID: 36750846; PMCID: PMC9902840. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902840/ (Full text)

Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)

Abstract:

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy.

A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells.

Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.

Source: Gottschalk G, Peterson D, Knox K, Maynard M, Whelan RJ, Roy A. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2022 Apr 26:103731. doi: 10.1016/j.mcn.2022.103731. Epub ahead of print. PMID: 35487443. https://www.sciencedirect.com/science/article/abs/pii/S1044743122000379?via%3Dihub (Full text)