Tag: Gulf War Illness

Post-Exertional Malaise in Veterans with Gulf War Illness

Abstract:

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO).

Sixty-seven Veterans (n=39 GWI; n=28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hours post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA).

Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α=0.05). Data were analyzed for the full sample of Veterans with GWI (n=39) compared to CO (n=28) and a subsample of Veterans (n=18) who endorsed “feeling unwell after physical exercise or exertion” (“PEM endorsers”) during screening.

Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to “PEM endorsers” resulted in significant interactions for Pain- and GWI-related PEM models.

These results indicate that not all GVs with GWI experience PEM 24 hr after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.

Source: Lindheimer JB, Stegner AJ, Wylie GR, Klein-Adams JC, Almassi NE, Ninneman JV, Van Riper SM, Dougherty RJ, Falvo MJ, Cook DB. Post-exertional malaise in veterans with gulf war illness. Int J Psychophysiol. 2020 Jan;147:202-212. doi: 10.1016/j.ijpsycho.2019.11.008. Epub 2019 Nov 28. PMID: 31786249; PMCID: PMC6957714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957714/ (Full text)

Novel characterization of endogenous transient receptor potential melastatin 3 ion channels from Gulf War Illness participants

Abstract:

Gulf War Illness (GWI) is a chronic condition characterized by multisystem symptoms that still affect up to one-third of veterans who engaged in combat in the Gulf War three decades ago. The aetiology of GWI is mainly explained by exposure to multiple toxic agents, vaccines, and medications. As there is a significant overlap in symptoms between GWI and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), the objective of this study was to investigate a biomarker widely reported in Natural Killer (NK) cells from ME/CFS patients, the Transient Receptor Potential Melastatin 3 (TRPM3) ion channel.

NK cells from 6 healthy controls (HC) and 6 GWI participants were isolated, and TRPM3 function was assessed through whole-cell patch-clamp. As demonstrated by prior studies, NK cells from HC expressed typical TRPM3 function after pharmacomodulation.

In contrast, this pilot investigation demonstrates a dysfunctional TRPM3 in NK cells from GWI participants through application of a TRPM3 agonist and confirmed by a TRPM3 antagonist. There was a significant reduction in TRPM3 function from GWI than results measured in HC. This study provides an unprecedented research field to investigate the involvement of TRP ion channels in the pathomechanism and potential medical interventions to improve GWI quality of life.

Source: Marshall-Gradisnik S, Martini Sasso E, Eaton-Fitch N, Smith P, Baraniuk JN, Muraki K. Novel characterization of endogenous transient receptor potential melastatin 3 ion channels from Gulf War Illness participants. PLoS One. 2024 Jun 25;19(6):e0305704. doi: 10.1371/journal.pone.0305704. PMID: 38917121; PMCID: PMC11198784. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11198784/ (Full text)

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Abstract:

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood.

These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration.

Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

Source: Cohen J, Mathew A, Dourvetakis KD, Sanchez-Guerrero E, Pangeni RP, Gurusamy N, Aenlle KK, Ravindran G, Twahir A, Isler D, Sosa-Garcia SR, Llizo A, Bested AC, Theoharides TC, Klimas NG, Kempuraj D. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells. 2024 Mar 14;13(6):511. doi: 10.3390/cells13060511. PMID: 38534355; PMCID: PMC10969521. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10969521/ (Full text)

Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: To examine ocular symptoms and signs of veterans with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnosis, ME/CFS symptoms, and controls.

Methods: This was a prospective, cross-sectional study of 124 South Florida veterans in active duty during the Gulf War era. Participants were recruited at an ophthalmology clinic at the Miami Veterans Affairs Hospital and evaluated for a diagnosis of ME/CFS, or symptoms of ME/CFS (intermediate fatigue, IF) using the Canadian Consensus criteria. Ocular symptoms were assessed via standardised questionnaires and signs via comprehensive slit lamp examination. Inflammatory blood markers were analysed and compared across groups.

Results: Mean age was 55.1 ± 4.7 years, 88.7% identified as male, 58.1% as White, and 39.5% as Hispanic. Ocular symptoms were more severe in the ME/CFS (n = 32) and IF (n = 48) groups compared to controls (n = 44) across dry eye (DE; Ocular Surface Disease Index [OSDI]: 48.9 ± 22.3 vs. 38.8 ± 23.3 vs. 19.1 ± 17.8, p < 0.001; 5 item Dry Eye Questionnaire [DEQ-5]: 10.8 ± 3.9 vs. 10.0 ± 4.6 vs. 6.6 ± 4.2, p < 0.001) and pain-specific questionnaires (Numerical Rating Scale 1-10 [NRS] right now: 2.4 ± 2.8 vs. 2.4 ± 2.9 vs 0.9 ± 1.5; p = 0.007; Neuropathic Pain Symptom Inventory modified for the Eye [NPSI-E]: 23.0 ± 18.6 vs. 19.8 ± 19.1 vs. 6.5 ± 9.0, p < 0.001). Ocular surface parameters and blood markers of inflammation were generally similar across groups.

Conclusion: Individuals with ME/CFS report increased ocular pain but similar DE signs, suggesting that mechanisms beyond the ocular surface contribute to symptoms.

Source: Victor Sanchez BS, Colin K. Kim BS, Elyana V. T. Locatelli BS, Adam K. Cohen, Kimberly Cabrera MS, Kristina Aenlle PhD, Nancy G. Klimas MD, Robert O’Brien PhD, Anat Galor MD, MSPH. Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome. First published: 12 November 2023 https://doi.org/10.1111/ceo.14313 https://onlinelibrary.wiley.com/doi/10.1111/ceo.14313 (Full text)

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity

Abstract:

Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI).

We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls.

Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis.

In conclusion, impaired mitochondrial function—but not peripheral inflammation—predicts greater GWI symptoms and severity.

Source: Golomb, B.A., Sanchez Baez, R., Schilling, J.M. et al. Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity. Sci Rep 13, 10739 (2023). https://doi.org/10.1038/s41598-023-35896-w https://www.nature.com/articles/s41598-023-35896-w (Full text)

Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS) and Fibromyalgia are chronic illnesses that, despite their prevalence in society, are still of unknown aetiology. All three conditions present similar clinical symptoms and are difficult to diagnose due to a lack of appropriate biomarkers. Currently, diagnosis consists of satisfying clinical criteria and eliminating other conditions, a lengthy and often costly process for patients. The discovery of biomarkers would significantly speed up patient diagnosis and allow the development of pharmacological therapies that target the underlying metabolic causes of these diseases.

Metabolomics is an emerging research area used to characterise the metabolites present within biological specimens. Developments within this field now allow the analysis of thousands of metabolites within different samples and model systems, and have the potential to aid in unravelling the metabolic phenotypes that underpin complex metabolic diseases. ME/CFS, GWS and Fibromyalgia are three conditions that could benefit from a plasma/tissue metabolomics analysis, allowing a greater understanding of their aetiology and identify common pathways. An analysis of the literature in these conditions reveals alterations within pathways associated with energy and lipid metabolism with alterations in key metabolites associated with elevated oxidative stress. Understanding what might drive the elevated oxidative stress within all three illnesses will not only be important in future research but could also be a potential therapeutic target for antioxidant medications which could be implemented to reduce the symptom burden in these illnesses.

Source: MORTEN, Karl Jonathan and Davis, Leah and Lodge, Tiffany A. and Strong, James and Espejo-Oltra, José Andrés and Zalewski, Pawel and Pretorius, Etheresia, Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions. Available at SSRN: https://ssrn.com/abstract=4455366 or http://dx.doi.org/10.2139/ssrn.4455366 (Full text available as PDF file)

At the Root of 3 “Long” Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome

Abstract:

Several foreign antigens such as those derived from viruses and bacteria have been linked to long-term deleterious effects on the brain and other organs; yet, health outcomes subsequent to foreign antigen exposure vary depending in large part on the host’s immune system, in general, and on human leukocyte antigen (HLA) composition, in particular.

Here we first provide a brief description of 3 conditions characterized by persistent long-term symptoms, namely long-COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and Gulf War Illness (GWI), followed by a brief overview of the role of HLA in the immune response to foreign antigens. We then discuss our Persistent Antigen (PA) hypothesis and highlight associations between antigen persistence due to HLA-antigen incongruence and chronic health conditions in general and the 3 “long” diseases above in particular. This review is not intended to cover the breadth and depth of symptomatology of those diseases but is specifically focused on the hypothesis that the presence of persistent antigens underlies their pathogenesis.

Source: James LM, Georgopoulos AP. At the Root of 3 “Long” Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome. Neurosci Insights. 2022 Jul 22;17:26331055221114817. doi: 10.1177/26331055221114817. PMID: 35910083; PMCID: PMC9335483. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335483/ (Full text)

The impact of post-traumatic stress on quality of life and fatigue in women with Gulf War Illness

Abstract:

Background: Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder characterized by fatigue, muscle pain, cognitive problems, insomnia, rashes, and gastrointestinal issues affecting an estimated 30% of the ~ 750,000 returning military Veterans of the 1990-1991 Persian Gulf War. Female Veterans deployed to combat in this war report medical symptoms, like cognition and respiratory troubles, at twice the rate compared to non-deployed female Veterans of the same era. The heterogeneity of GWI symptom presentation complicates diagnosis as well as the identification of effective treatments. This is exacerbated by the presence of co-morbidities. Defining subgroups of the illness may help alleviate these complications. One clear grouping is along the lines of gender. Our aim is to determine if women with GWI can be further subdivided into distinct subgroups based on post-traumatic stress disorder (PTSD) symptom presentation.

Methods: Veterans diagnosed with GWI (n = 35) and healthy sedentary controls (n = 35) were recruited through the Miami Veterans Affairs Medical Health Center. Symptoms were assessed via the RAND short form health survey, the multidimensional fatigue inventory, and the Davidson trauma scale. Hierarchal regression modeling was performed on measures of health and fatigue with PTSD symptoms as a covariate. This was followed by univariate analyses conducted with two separate GWI groups based on a cut-point of 70 for their total Davidson trauma scale value and performing heteroscedastic t-tests across all measures.

Results: Based on the distinct differences found in PTSD symptomology regarding all health and trauma symptoms, two subgroups were derived within female GWI Veterans. Hierarchical regression models displayed the comorbid effects of GWI and PTSD, as both conditions had measurable impacts on quality of life and fatigue (ΔR2 = 0.08-0.672), with notable differences in mental and emotional measures. Overall, a cut point analysis indicated poorer quality of life and greater fatigue within all measures for women with GWI and PTSD symptoms in comparison to those women with GWI without PTSD symptoms and healthy controls.

Conclusions: Our current findings support the understanding that comorbid symptoms of GWI and PTSD subsequently result in poorer quality of life and fatigue, along with establishing the possibility of varying clinical presentations.

Source: Shastry N, Sultana E, Jeffrey M, Collado F, Kibler J, DeLucia C, Fletcher MA, Klimas N, Craddock TJA. The impact of post-traumatic stress on quality of life and fatigue in women with Gulf War Illness. BMC Psychol. 2022 Feb 25;10(1):42. doi: 10.1186/s40359-022-00752-5. PMID: 35216624; PMCID: PMC8876751. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876751/ (Full text)

Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM)

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction.

Methods: Activated midbrain nuclei were inferred by a re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network.

Results: Before exercise, control and GWI subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI, indicating reciprocal patterns of activation. The controls had no changes.

Conclusions: Exercise caused the opposite effects with increased activation in ME/CFS but decreased activation in GWI, indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

Source: Baraniuk JN, Amar A, Pepermitwala H, Washington SD. Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM). Brain Sci. 2022 Jan 5;12(1):78. doi: 10.3390/brainsci12010078. PMID: 35053821. https://pubmed.ncbi.nlm.nih.gov/35053821/

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms.
These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.
Source: James N. Baraniuk. Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM) Brain Sci. 2022, 12(2), 132; https://doi.org/10.3390/brainsci12020132 (registering DOI) https://www.mdpi.com/2076-3425/12/2/132/htm (Full text)