Tag: Gulf War Illness

Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls

Abstract:

Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS).

The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls. In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups.

Source: Abou-Donia MB, Krengel MH, Lapadula ES, Zundel CG, LeClair J, Massaro J, Quinn E, Conboy LA, Kokkotou E, Nguyen DD, Abreu M, Klimas NG, Sullivan K. Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls. Brain Sci. 2021 Jan 23;11(2):148. doi: 10.3390/brainsci11020148. PMID: 33498629. https://pubmed.ncbi.nlm.nih.gov/33498629/

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share many symptoms of fatigue, pain, and cognitive dysfunction that are not relieved by rest. Patterns of serum metabolites in ME/CFS and GWI are different from control groups and suggest potential dysfunction of energy and lipid metabolism. The metabolomics of cerebrospinal fluid was contrasted between ME/CFS, GWI and sedentary controls in 2 sets of subjects who had lumbar punctures after either (a) rest or (b) submaximal exercise stress tests. Postexercise GWI and control subjects were subdivided according to acquired transient postexertional postural tachycardia. Banked cerebrospinal fluid specimens were assayed using Biocrates AbsoluteIDQ® p180 kits for quantitative targeted metabolomics studies of amino acids, amines, acylcarnitines, sphingolipids, lysophospholipids, alkyl and ether phosphocholines.

Glutamate was significantly higher in the subgroup of postexercise GWI subjects who did not develop postural tachycardia after exercise compared to nonexercise and other postexercise groups. The only difference between nonexercise groups was higher lysoPC a C28:0 in GWI than ME/CFS suggesting this biochemical or phospholipase activities may have potential as a biomarker to distinguish between the 2 diseases. Exercise effects were suggested by elevation of short chain acylcarnitine C5-OH (C3-DC-M) in postexercise controls compared to nonexercise ME/CFS. Limitations include small subgroup sample sizes and absence of postexercise ME/CFS specimens. Mechanisms of glutamate neuroexcitotoxicity may contribute to neuropathology and “neuroinflammation” in the GWI subset who did not develop postural tachycardia after exercise. Dysfunctional lipid metabolism may distinguish the predominantly female ME/CFS group from predominantly male GWI subjects.

Source: Baraniuk JN, Kern G, Narayan V, Cheema A. Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome. PLoS One. 2021 Jan 13;16(1):e0244116. doi: 10.1371/journal.pone.0244116. PMID: 33440400. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244116 (Full text)

An analysis of 2‐day cardiopulmonary exercise testing to assess unexplained fatigue

Abstract:

Two consecutive maximal cardiopulmonary exercise tests (CPETs) performed 24 hr apart (2-day CPET protocol) are increasingly used to evaluate post-exertional malaise (PEM) and related disability among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This protocol may extend to other fatiguing illnesses with similar characteristics to ME/CFS; however, 2-day CPET protocol reliability and minimum change required to be considered clinically meaningful (i.e., exceeding the standard error of the measure) are not well characterized. To address this gap, we evaluated the 2-day CPET protocol in Gulf War Illness (GWI) by quantifying repeatability of seven CPET parameters, establishing their thresholds of clinically significant change, and determining whether changes differed between veterans with GWI and controls.

Excluding those not attaining peak effort criteria (n = 15), we calculated intraclass correlation coefficients (ICCs), the smallest real difference (SRD%), and repeated measures analysis of variance (RM-ANOVA) at the ventilatory anaerobic threshold (VAT) and peak exercise in 15 veterans with GWI and eight controls. ICC values at peak ranged from moderate to excellent for veterans with GWI (mean [range]; 0.84 [0.65 – 0.92]) and were reduced at the VAT (0.68 [0.37 – 0.78]).

Across CPET variables, the SRD% at peak exercise for veterans with GWI (18.8 [8.8 – 28.8]) was generally lower than at the VAT (28.1 [9.5 – 34.8]). RM-ANOVAs did not detect any significant group-by-time interactions (all p > .05). The methods and findings reported here provide a framework for evaluating 2-day CPET reliability, and reinforce the importance of carefully considering measurement error in the population of interest when interpreting findings.

Source: Lindheimer JB, Alexander T, Qian W, et al. An analysis of 2-day cardiopulmonary exercise testing to assess unexplained fatigue. Physiol Rep. 2020;8(17):e14564. doi:10.14814/phy2.14564 (Full text) https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy2.14564

Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

Abstract:

For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder.

Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)). Specifically, we compared plasma markers of CNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS).

For veterans with GWI, the results showed statistically increased levels of nine of the ten autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW controls as well as civilians with ME/CFS and IBS.

Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups. The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups.

Source: Mohamed B. Abou-Donia, Elizabeth S. Lapadula, Maxine H. Krengel, Emily Quinn, Jessica LeClair, Joseph Massaro, Lisa A. Conboy, Efi Kokkotou, Maria Abreu, Nancy G. Klimas, Daniel D. Nguyen and Kimberly Sullivan.  Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls. Brain Sci. 2020, 10(9), 610; https://doi.org/10.3390/brainsci10090610  https://www.mdpi.com/2076-3425/10/9/610/htm (Full text)

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses.

Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients.

Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Source: Stuart D Washington, Rakib U Rayhan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John W VanMeter, James N Baraniuk, Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brain Communications, Volume 2, Issue 2, 2020, fcaa070, https://doi.org/10.1093/braincomms/fcaa070 https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074 (Full text)

Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI)

Abstract:

Background: Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) are two debilitating disorders that share similar symptoms of chronic pain, fatigue, and exertional exhaustion after exercise. Many physicians continue to believe that both are psychosomatic disorders and to date no underlying etiology has been discovered. As such, uncovering objective biomarkers is important to lend credibility to criteria for diagnosis and to help differentiate the two disorders.

Methods: We assessed cognitive differences in 80 subjects with GWI and 38 with CFS by comparing corresponding fMRI scans during 2-back working memory tasks before and after exercise to model brain activation during normal activity and after exertional exhaustion, respectively. Voxels were grouped by the count of total activity into the Automated Anatomical Labeling (AAL) atlas and used in an “ensemble” series of machine learning algorithms to assess if a multi-regional pattern of differences in the fMRI scans could be detected.

Results: A K-Nearest Neighbor (70%/81%), Linear Support Vector Machine (SVM) (70%/77%), Decision Tree (82%/82%), Random Forest (77%/78%), AdaBoost (69%/81%), Naïve Bayes (74%/78%), Quadratic Discriminant Analysis (QDA) (73%/75%), Logistic Regression model (82%/82%), and Neural Net (76%/77%) were able to differentiate CFS from GWI before and after exercise with an average of 75% accuracy in predictions across all models before exercise and 79% after exercise. An iterative feature selection and removal process based on Recursive Feature Elimination (RFE) and Random Forest importance selected 30 regions before exercise and 33 regions after exercise that differentiated CFS from GWI across all models, and produced the ultimate best accuracies of 82% before exercise and 82% after exercise by Logistic Regression or Decision Tree by a single model, and 100% before and after exercise when selected by any six or more models. Differential activation on both days included the right anterior insula, left putamen, and bilateral orbital frontal, ventrolateral prefrontal cortex, superior, inferior, and precuneus (medial) parietal, and lateral temporal regions. Day 2 had the cerebellum, left supplementary motor area and bilateral pre- and post-central gyri. Changes between days included the right Rolandic operculum switching to the left on Day 2, and the bilateral midcingulum switching to the left anterior cingulum.

Conclusion: We concluded that CFS and GWI are significantly differentiable using a pattern of fMRI activity based on an ensemble machine learning model.

Source: Provenzano D, Washington SD, Rao YJ, Loew M, Baraniuk J. Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI). Brain Sci. 2020;10(7):E456. Published 2020 Jul 17. doi:10.3390/brainsci10070456 https://www.mdpi.com/2076-3425/10/7/456 (Full text)

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

Abstract:

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise.

One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI).

The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks.

These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction.

Source: Clarke T, Jamieson JD, Malone P, Rayhan RU, Washington S, VanMeter JW, et al. (2019) Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention. PLoS ONE 14(12): e0226481. https://doi.org/10.1371/journal.pone.0226481 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226481 (Full text)

Systemic Hyperalgesia in Females with Gulf War Illness, Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Pain is a diagnostic criterion for Gulf War Illness (GWI), Chronic Fatigue Syndrome (CFS), and fibromyalgia (FM). The physical sign of systemic hyperalgesia (tenderness) was assessed in 920 women who were stratified by 2000 Kansas GWI, 1994 CFS, and 1990 FM criteria.

Pressure was applied by dolorimetry at 18 traditional tender points and the average pressure causing pain determined. GWI women were the most tender (2.9 ± 1.6 kg, mean ± SD, n = 70), followed by CFS/FM (3.1 ± 1.4 kg, n = 196), FM (3.9 ± 1.4 kg, n = 56), and CFS (5.8 ± 2.1 kg, n = 170) compared to controls (7.2 ± 2.4 kg, significantly highest by Mann-Whitney tests p < 0.0001, n = 428). Receiver operating characteristics set pressure thresholds of 4.0 kg to define GWI and CFS/FM (specificity 0.85, sensitivities 0.80 and 0.83, respectively), 4.5 kg for FM, and 6.0 kg for CFS.

Pain, fatigue, quality of life, and CFS symptoms were equivalent for GWI, CFS/FM and CFS. Dolorimetry correlated with symptoms in GWI but not CFS or FM. Therefore, women with GWI, CFS and FM have systemic hyperalgesia compared to sedentary controls.

The physical sign of tenderness may complement the symptoms of the Kansas criteria as a diagnostic criterion for GWI females, and aid in the diagnosis of CFS. Molecular mechanisms of systemic hyperalgesia may provide new insights into the neuropathology and treatments of these nociceptive, interoceptive and fatiguing illnesses.

Source: Surian AA, Baraniuk JN. Systemic Hyperalgesia in Females with Gulf War Illness, Chronic Fatigue Syndrome and Fibromyalgia. Sci Rep. 2020 Apr 1;10(1):5751. doi: 10.1038/s41598-020-62771-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113257/ (Full text)

Brain studies show chronic fatigue syndrome and Gulf War illness are distinct conditions

CHICAGO (October 23, 2019) — Gulf War Illness (GWI) and chronic fatigue syndrome (CFS) share symptoms of disabling fatigue, pain, systemic hyperalgesia (tenderness), negative emotion, sleep and cognitive dysfunction that are made worse after mild exertion (postexertional malaise). Now, neuroscientists at Georgetown University Medical Center have evidence, derived from human brain studies, that GWI and CFS are two distinct disorders that affect the brain in opposing ways.

The findings, presented in two related studies at the annual meeting of the Society for Neuroscience (SFN) in Chicago, offer a new perspective on neurotoxicity and suggest that methods to effectively diagnose and treat these disorders could be developed, says the studies’ senior author, James Baraniuk, MD, a Georgetown professor of medicine.

GWI affects veterans of the 1990-1991 Persian Gulf War who were exposed to a toxic environment of nerve agents, pesticides and other neurotoxins, while the etiology of CFS is unknown. The overlapping symptoms suggest they may share some common mechanisms of disease.

Baraniuk was first to find unique physical changes in the brains of patients with GWI, and he and his colleagues have also found changes in brain chemistry between GWI and CFS. “This new work further emphasizes that chronic fatigue syndrome and Gulf War Illness are two very real, and very distinct, diseases of the brain,” he says.

The two SFN studies were led by investigators in Baraniuk’s lab. One, being presented by neuroscientist Stuart Washington, PhD, details how specific areas in the brain are affected by the disorders, and the second, led by student Haris Pepermintwala, MS, takes a deep dive into one of those areas, the brain stem, to illustrate the degree to which these conditions have differing effects.

Chronic fatigue syndrome/myalgic encephalomyelitis affects between 836,000 and 2.5 million Americans, according to a 2015 report by the National Academy of Medicine. Gulf War Illness developed in about one-third of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War. Baraniuk says that during Operation Desert Storm, these veterans were exposed to combinations of nerve agents, pesticides and other toxic chemicals that may have triggered the chronic pain and cognitive and gastrointestinal problems.

Both GWI and CFS share common features: cognitive dysfunction, pain and fatigue primarily following physical exercise. To determine how these conditions affect brain function, investigators studied neuronal activation using functional MRI (fMRI) during a cognitive task a day before and a day after bicycle exercise stress tests in their different groups: 38 CFS patients, 80 GWI patients, and a control group of 23 healthy sedentary volunteers. Brain activation during a working memory task was compared between the pre- and post-exercise fMRI studies, and between CFS and GWI groups.

Before exercise, brain activation was similar between groups. However, after exercise the CFS group showed significantly increased activation of the midbrain, while GWI had the opposite effect, with decreased activation in this vital region of the arousal network. CFS also had increased activation in the insula. In contrast, GWI, but not CFS, had a decrease in activation of the cerebellum after exercise. The findings show that specific brain regions acted in opposing ways, representing a differentiation between GWI and CFS.

While these areas are involved in pain perception, among their many other tasks, “this doesn’t mean more or less activity is directly related to pain,” says Washington. “What it does show is that the two conditions are distinct from each other and involve different cellular/molecular mechanisms.”

The second study, led by Pepermintwala, looked more closely at specific regions within the brain stem and confirmed that CFS had significantly increased activation during the cognitive task after the exercise provocations, while GWI had significantly reduced activation.

These regions are involved in vital functions for instantaneous assessments of threats, predator-prey decisions, arousal, modulation of chronic pain, sleep and other neurobehavioral functions, Pepermintwala says. But after exercise, the CFS group had significantly increased activity in the majority of regions evaluated, while the GWI patients experienced significantly decreased activation.

The results support other research, conducted post-mortem in veterans with PTSD, suggesting that the brain stem in these veterans may have physical abnormalities, such as a loss of neurons, Pepermintwala says. “The midbrain is affected by the exercise and cognitive challenges, but CFS and GWI react in opposite ways, showing that they are related, but distinctly different disorders.”

For the study led by Washington, additional co-authors include Rakib Rahan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John VanMeter and Baraniuk.

For the study led by Pepermintwala, additional co-authors include Washington, Addiego, Rayhan and Baraniuk.

The authors report having no personal financial interests related to the studies.

These studies were supported by funding from The Sergeant Sullivan Circle, Barbara Cottone, Dean Clarke Bridge Prize, Department of Defense Congressionally Directed Medical Research Program (W81XWH-15-1-0679 and W81-XWH-09-1-0526), and the National Institute of Neurological Disorders and Stroke (R21NS088138 and RO1NS085131). The project has been funded in whole or in part with federal funds (UL1TR000101 previously UL1RR031975) from the National Center for Advancing Translational Sciences, National Institutes of Health, through the Clinical and Translational Science Awards Program.

Neuroinflammation disorders exacerbated by environmental stressors

Abstract:

Neuroinflammation is a condition characterized by the elaboration of proinflammatory mediators within the central nervous system. Neuroinflammation has emerged as a dominant theme in contemporary neuroscience due to its association with neurodegenerative disease states such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

While neuroinflammation often is associated with damage to the CNS, it also can occur in the absence of neurodegeneration, e.g., in association with systemic infection. The “acute phase” inflammatory response to tissue injury or infections instigates neuroinflammation-driven “sickness behavior,” i.e. a constellation of symptoms characterized by loss of appetite, fever, muscle pain, fatigue and cognitive problems. Typically, sickness behavior accompanies an inflammatory response that resolves quickly and serves to restore the body to homeostasis. However, recurring and sometimes chronic sickness behavior disorders can occur in the absence of an underlying cause or attendant neuropathology.

Here, we review myalgic enchepalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Illness (GWI), and chemobrain as examples of such disorders and propose that they can be exacerbated and perhaps initiated by a variety of environmental stressors. Diverse environmental stressors may disrupt the hypothalamic pituitary adrenal (HPA) axis and contribute to the degree and duration of a variety of neuroinflammation-driven diseases.

Source: O’Callaghan JP, Miller DB. Neuroinflammation disorders exacerbated by environmental stressors. Metabolism. 2019 Nov;100S:153951. doi: 10.1016/j.metabol.2019.153951. https://www.ncbi.nlm.nih.gov/pubmed/31610852