Tag: Gulf War Illness

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)

TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model

Abstract:

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive.

Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro.

Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.

Source: Bose D, Mondal A, Saha P, Kimono D, Sarkar S, Seth RK, Janulewicz P, Sullivan K, Horner R, Klimas N, Nagarkatti M, Nagarkatti P, Chatterjee S. TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model. Brain Sci. 2020 Aug 8;10(8):532. doi: 10.3390/brainsci10080532. PMID: 32784362; PMCID: PMC7463890. https://www.mdpi.com/2076-3425/10/8/532 (Full text)

Neurotoxicant exposures and rates of Chronic Multisymptom Illness and Kansas Gulf War Illness criteria in Gulf War deployed women veterans

Abstract:

Aims: This study analyzed deployment-related exposures and risk of Persian Gulf War Illness (GWI) in women veterans from the Veterans Affairs (VA) Cooperative Studies Program 585 Gulf War Era Cohort and Biorepository (GWECB CSP#585).

Main methods: We examined the associations between GW deployment-related exposures and case definitions for GWI in deployed GW women. Multivariate regression analyses controlling for demographic outcomes were performed.

Key findings: Surveys were obtained from 202 GW deployed women veterans. Self-reported exposure to smoke from oil well fires as well as chemical and biological warfare were the only exposures significantly associated with the Center for Disease Control and Prevention (CDC) GWI criteria. Seventy-nine women were excluded from the rest of the analyses as they met Kansas GW illness exclusion criteria. Eligible women who self-reported deployment-related exposure to smoke from oil wells, pyridostigmine bromide (PB) pills, pesticide cream, pesticide treated uniforms, and insect baits were significantly more likely to meet the Kansas GWI criteria (n = 123) than those unexposed and exposures were related to Kansas symptom subdomain endorsements.

Significance: These results suggest that women GW veterans reporting deployment related exposures of pesticide, oil well fire and PB pills are significantly more likely to meet the Kansas GWI criteria in this national cohort of GW women suggesting its utility in future studies. In addition, based on these results it appears that women exposed to particular toxicants during the war may benefit from more targeted treatment strategies dependent upon the mechanism of exposure of their toxicant induced outcomes.

Source: Krengel M, Sullivan K, Heboyan V, Zundel CG, Wilson CC, Klimas N, Coughlin SS. Neurotoxicant exposures and rates of Chronic Multisymptom Illness and Kansas Gulf War Illness criteria in Gulf War deployed women veterans. Life Sci. 2021 Sep 1;280:119623. doi: 10.1016/j.lfs.2021.119623. Epub 2021 May 15. PMID: 34004246. https://pubmed.ncbi.nlm.nih.gov/34004246/

Dysregulation of cellular energetics in Gulf War Illness

Abstract:

Gulf War Illness (GWI) is estimated to have affected about one third of the Veterans who participated in the first Persian Gulf War. The symptoms of GWI include chronic neurologic impairments, chronic fatigue syndrome, as well as fibromyalgia and immune system disorders, collectively referred to as chronic multi-symptom illness. Thirty years after the war, we still do not have an effective treatment for GWI. It is necessary to understand the molecular basis of the symptoms of GWI in order to develop appropriate therapeutic strategies. Cellular energetics are critical to the maintenance of cellular homeostasis, a process that is highly dependent on intact mitochondrial function and there is significant evidence from both human studies and animal models that mitochondrial impairments may lead to GWI symptoms.

The available clinical and pre-clinical data suggest that agents that improve mitochondrial function have the potential to restore cellular energetics and treat GWI. To date, the experiments conducted in animal models of GWI have mainly focused on neurobehavioral aspects of the illness. Additional studies to address the fundamental biological processes that trigger the dysregulation of cellular energetics in GWI are warranted to better understand the underlying pathology and to develop new treatment methods. This review highlights studies related to mitochondrial dysfunction observed in both GW veterans and in animal models of GWI.

Source: Raju RP, Terry AV. Dysregulation of cellular energetics in Gulf War Illness. Toxicology. 2021 Aug 10:152894. doi: 10.1016/j.tox.2021.152894. Epub ahead of print. PMID: 34389359. https://pubmed.ncbi.nlm.nih.gov/34389359/

The effect of stress on the transcriptomes of circulating immune cells in patients with Gulf War Illness

Abstract:

Aims: In an effort to gain further insight into the underlying mechanisms tied to disease onset and progression of Gulf War Illness (GWI), our team evaluated GWI patient response to stress utilizing RNA-Seq.

Main methods: The protocol included blood collection before exercise challenge (baseline), at maximal exertion, and after exercise challenge (recovery – four hours post-exercise challenge). Peripheral blood mononuclear cell (PBMC) transcriptomics data were analyzed to understand why GWI patients process stressors differently from their healthy counterparts.

Key findings: Our findings validate previously identified dysregulation of immune and inflammatory pathways among GWI patients as well as highlight novel immune and inflammatory markers of disease activity. These results provide a foundation for future research efforts in understanding GWI pathophysiology and creating targeted treatments.

Significance: Gulf War Illness is a complex, chronic, and debilitating multi-system illness impacting 25%-30% of the U.S. troops deployed to the 1990-1991 Gulf War. The condition is characterized by medically unexplained fatigue and affects multiple organ systems. Because the underlying mechanisms are largely unknown, patients receive symptom-based treatment, rather than targeting fundamental biological processes. To the best of our knowledge, this is the first study that applies RNA-Seq to analyze the effect of GWI, and the response to stressors in GWI, on the transcriptomic changes in circulating immune cells.

Source: Van Booven D, Zarnowski O, Perez M, Sarria L, Collado F, Hansotia K, Riegle S, Finger T, Fletcher MA, Klimas NG, Nathanson L. The effect of stress on the transcriptomes of circulating immune cells in patients with Gulf War Illness. Life Sci. 2021 Sep 15;281:119719. doi: 10.1016/j.lfs.2021.119719. Epub 2021 Jun 16. PMID: 34144055. https://pubmed.ncbi.nlm.nih.gov/34144055/

A randomized phase II remote study to assess Bacopa for Gulf War Illness associated cognitive dysfunction: Design and methods of a national study

Abstract:

Aims: Gulf War Illness (GWI) is a chronic, debilitating, multi-symptom condition affecting as many as one-third of the nearly 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War (GW). The treatment of GWI relies on symptom management. A common challenge in studying the efficacy of interventions for symptom management is participant recruitment related to factors such as the burden of travelling to study sites and the widespread dispersion of Veterans with GWI. The goal of this study is to assess the efficacy of a novel low-risk therapeutic agent, Bacopa monnieri, for cognitive function in Veterans with GWI and to evaluate the utility of a remote patient-centric study design developed to promote recruitment and minimize participant burden.

Main methods: To promote effective participant recruitment, we developed a remote patient-centric study design. Participants will be recruited online through social media and through a web-based research volunteer list of GW Veterans. An online assessment platform will be used, and laboratory blood draws will be performed at clinical laboratory sites that are local to participants. Furthermore, the assigned intervention will be mailed to each participant.

Significance: These study design adaptations will open participation to Veterans nearly nationwide and reduce administrative costs while maintaining methodologic rigor and participant safety in a randomized, placebo-controlled phase II clinical trial.

Source: Cheema AK, Wiener LE, McNeil RB, Abreu MM, Craddock T, Fletcher MA, Helmer DA, Ashford JW, Sullivan K, Klimas NG. A randomized phase II remote study to assess Bacopa for Gulf War Illness associated cognitive dysfunction: Design and methods of a national study. Life Sci. 2021 Oct 1;282:119819. doi: 10.1016/j.lfs.2021.119819. Epub 2021 Jul 10. PMID: 34256038. https://pubmed.ncbi.nlm.nih.gov/34256038/