Gulf War illness (GWI) encompasses a constellation of persistent debilitating symptoms associated with significant changes in central nervous system (CNS) and immune functioning. Currently, there is no validated biomarker for GWI risk susceptibility. Given the impact of immune responses linked to GWI symptomology, genetic variability that causes persistent inflammatory/immune alterations may be key. This Boston University-based Gulf War Illness Consortium (GWIC) study investigated the impact of single nucleotide polymorphisms (SNPs) in variants of immune and pain genetic markers IL1B, IL2, IL6, IL6R, IL10, TNF, TGF, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, COMT and OPRM1 on GWI occurrence in a Caucasian subset of Gulf War (GW) veterans with (cases, n = 170) and without (controls, n = 34) GWI. Logistic regression modeling created a prediction model of GWI risk that associated genetic variability in TGF (rs1800469, p = 0.009), IL6R (rs8192284, p = 0.004) and TLR4 (rs4986791, p = 0.013) with GWI occurrence. This prediction model was specific and sensitive, with a receiver operator characteristic area under the curve of 71.4%. This is the first report of immune genetic variability being predictive of GWI and warrants validation in larger independent cohorts. Future reports will present interactions of these genetic risk factors with other characteristics of GW service.

To introduce a resource supporting research on Gulf War illness (GWI) and related disorders, the Gulf War Veterans' Illnesses Biorepository (GWVIB).

More than 230,000 veterans-about 1/3 of US personnel deployed in the 1990-1991 Persian Gulf War-developed chronic, multi-symptom health problems now called "Gulf War illness" (GWI), for which mechanisms and objective diagnostic signatures continue to be sought.

Gulf War Illness (GWI) is a condition that affects about 30 % of veterans who served in the 1990-91 Persian Gulf War. Given its broad symptomatic manifestation, including chronic pain, fatigue, neurological, gastrointestinal, respiratory, and skin problems, it is of interest to examine whether GWI is associated with changes in the brain. Existing neuroimaging studies, however, have been limited by small sample sizes, inconsistent GWI diagnosis criteria, and potential comorbidity confounds.

Across diverse groups of Gulf War (GW) veterans, reports of musculoskeletal pain, cognitive dysfunction, unexplained fatigue, chronic diarrhoea, rashes and respiratory problems are common. GW illness is a condition resulting from GW service in veterans who report a combination of these symptoms. This study integrated the GW literature using meta-analytical methods to characterise the most frequently reported symptoms occurring among veterans who deployed to the 1990-1991 GW and to better understand the magnitude of ill health among GW-deployed veterans compared with non-deployed GW-era veterans.

Low level sarin nerve gas and other anti-cholinesterase agents have been implicated in Gulf War illness (GWI), a chronic multi-symptom disorder characterized by cognitive, pain and fatigue symptoms that continues to afflict roughly 32% of veterans from the 1990-1991 Gulf War. How disrupting cholinergic synaptic transmission could produce chronic illness is unclear, but recent research indicates that acetylcholine also mediates communication between axons and oligodendrocytes. Here we investigated the hypothesis that oligodendrocyte development is disrupted by Gulf War agents, by experiments using the sarin-surrogate acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP). The effects of corticosterone, which is used in some GWI animal models, were also investigated. The data show that DFP decreased both the number of mature and dividing oligodendrocytes in the rat prefrontal cortex (PFC), but differences were found between PFC and corpus callosum. The differences seen between the PFC and corpus callosum likely reflect the higher percentage of proliferating oligodendroglia in the adult PFC. In cell culture, DFP also decreased oligodendrocyte survival through a non-cholinergic mechanism. Corticosterone promoted maturation of oligodendrocytes, and when used in combination with DFP it had protective effects by increasing the pool of mature oligodendrocytes and decreasing proliferation. Cell culture studies indicate direct effects of both DFP and corticosterone on OPCs, and by comparison with in vivo results, we conclude that in addition to direct effects, systemic effects and interruption of neuron-glia interactions contribute to the detrimental effects of GW agents on oligodendrocytes. Our results demonstrate that oligodendrocytes are an important component of the pathophysiology of GWI.

Gulf War Illness (GWI) remains a serious health consequence for at least 11,000 veterans of the first Gulf War in the early 1990s. Our understanding of the health consequences that resulted remains inadequate, and this is of great concern with another deployment to the same theater of operations occurring now. Chronic immune cell dysfunction and activation have been demonstrated in patients with GWI, although the literature is not uniform. We exposed GWI patients and matched controls to an exercise challenge to explore differences in immune cell function measured by classic immune assays and gene expression profiling.

Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes.

This review paper summarizes the accumulation of research investigating neuropsychological outcomes in veterans with Gulf War illness (GWI). Earlier research focused on Gulf War veterans (GW) who were deployed versus non-deployed, as well as those who were symptomatic versus asymptomatic, or compared neuropsychological test results to published norms. Further research became more sophisticated, investigating specific GWI criteria, as well as the result of neurotoxicant exposure and the relationship to possible neurocognitive outcomes. As the early research supported both psychological and physiological effects on GWI; current research as summarized in this literature review supports the presence of neuropsychological deficits, particularly in the domains of attention, executive functioning, memory, and motor functioning related to chemical exposures that can be exacerbated by comorbid mood-related conditions. The same test battery has not been used consistently making it difficult to compare results among studies. Therefore, researchers created a resource to provide recommendations for the recently listed Neuropsychological Tests for Common Data Elements (CDEs) for use in all future GWI studies. Future research is necessary to further understand patterns of neuropsychological test data and how these decrements may relate to immunological or other biological markers, and the impact of trauma from physical and psychological stressors. In conclusion, there is consistent evidence that GWI is characterized by neuropsychological decrements - with future research these findings may aid in the diagnosis and assessment of treatment trial efficacy of GW veterans.

The Persian Gulf War of 1990 to 1991 involved the deployment of nearly 700,000 American troops to the Middle East. Deployment-related exposures to toxic substances such as pesticides, nerve agents, pyridostigmine bromide (PB), smoke from burning oil wells, and petrochemicals may have contributed to medical illness in as many as 250,000 of those American troops. The cluster of chronic symptoms, now referred to as Gulf War Illness (GWI), has been studied by many researchers over the past two decades. Although over $500 million has been spent on GWI research, to date, no cures or condition-specific treatments have been discovered, and the exact pathophysiology remains elusive.Using the 2007 National Institute of Health (NIH) Roadmap for Medical Research model as a reference framework, we reviewed studies of interventions involving GWI patients to assess the progress of treatment-related GWI research. All GWI clinical trial studies reviewed involved investigations of existing interventions that have shown efficacy in other diseases with analogous symptoms. After reviewing the published and ongoing registered clinical trials for cognitive-behavioral therapy, exercise therapy, acupuncture, coenzyme Q10, mifepristone, and carnosine in GWI patients, we identified only four treatments (cognitive-behavioral therapy, exercise therapy, CoQ10, and mifepristone) that have progressed beyond a phase II trial.We conclude that progress in the scientific study of therapies for GWI has not followed the NIH Roadmap for Medical Research model. Establishment of a standard case definition, prioritized GWI research funding for the characterization of the pathophysiology of the condition, and rapid replication and adaptation of early phase, single site clinical trials could substantially advance research progress and treatment discovery for this condition.

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

Gulf War illness (GWI) is a disorder related to military service in the 1991 GW. Prominent symptoms include fatigue, pain and cognitive problems. These symptoms were reported by GW Veterans (GWV) immediately after the war and were eventually incorporated into case definitions of GWI. Neuropsychological function in GW veterans has been studied both among deployed GWV and in GWV diagnosed with GWI. Results have been inconsistent between and across GW populations. The purpose of the present investigation was to better characterize neuropsychological function in this veteran population.

Gulf War Illness (GWI) has affected many Gulf War veterans. It involves several organs, most notably the brain. Neurological-cognitive-mood-related symptoms frequently dominate and are at the root of chronic ill-health and disability in GWI. Here we investigated the neural mechanisms underlying brain dysfunction in GWI in the absence of mental health disorders.

Introduction: Approximately 25-30% of veterans deployed to Kuwait, 1990-91, report persistent multi-symptom Gulf War Illness (GWI) likely from neurotoxicant exposures. Photobiomodulation (PBM) in red/near-infrared (NIR) wavelengths is a safe, non-invasive modality shown to help repair hypoxic/stressed cells. Red/NIR wavelengths are absorbed by cytochrome C oxidase in mitochondria, releasing nitric oxide (increasing local vasodilation), and increasing adenosine tri-phosphate production. We investigated whether PBM applied transcranially could improve cognition, and health symptoms in GWI. Materials and Methods: Forty-eight (40 M) participants completed this blinded, randomized, sham-controlled trial using Sham or Real, red/NIR light-emitting diodes (LED) applied transcranially. Fifteen, half-hour transcranial LED (tLED) treatments were twice a week (7.5 weeks, in-office). Goggles worn by participant and assistant maintained blinding for visible red. Pre-/Post- testing was at Entry, 1 week and 1 month post- 15th treatment. Primary outcome measures were neuropsychological (NP) tests; secondary outcomes, Psychosocial Questionnaires, including PTSD. Results: Primary Analyses (all participants), showed improvement for Real vs. Sham, for Digit Span Forwards (p < 0.01); and a trend for Trails 4, Number/Letter Sequencing (p < 0.10). For secondary outcomes, Real group reported more improvement on the SF-36V Plus, Physical Component Score (p < 0.08). Secondary Analyses included only subjects scoring below norm (50%ile) at Entry, on specific NP test/s. Real and Sham improved at 1 week after 15th treatment; however, at 1 month, only those receiving Real improved further: Digit Span Total, Forwards and Backwards; Trails 4, Number/Letter Sequencing; California Verbal Learning Test-II, long delay free recall; Continuous Performance Test-II, False Alarm Rate; and Color-Word Interference, Stroop, Trial 3, Inhibition; Sham group worsened, toward Entry values. Only those with more post-traumatic stress disorder (PTSD) symptomatology at Entry, receiving Real, continued to have additional PTSD reduction at 1 month; Sham regressed. Conclusion: This study was underpowered (n = 48), with large heterogeneity at Entry. This likely contributed to significance or trend to significance, for only two of the NP tests (Digit Span Forwards; Trails 4, Number/Letter Sequencing) and only one general health measure, the SF-36V Plus, Physical Component Score. More subjects receiving Real, self-reported increased concentration, relaxation and sleep. Controlled studies with newer, transcranial LED home treatment devices are warranted; this is expected to increase enrollment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01782378.

Military service and deployment affect women differently than men, underscoring the need for studies of the health of women veterans and their receipt of health care services. Despite the large numbers of women who served during the 1990-1991 Gulf War, few studies have evaluated Gulf War illness (GWI) and other medical conditions specifically as they affect women veterans of the 1991 Gulf War. The objectives of the Gulf War Women's Health Cohort study are: (1) to establish the Gulf War women's cohort (GWWC), a large sample of women veterans who served in the 1990-1991 Gulf War and a comparison group of women who served in other locations during that period; and (2) to provide current, comprehensive data on the health status of women who served during the 1990-1991 Gulf War, and identify any specific conditions that affect Gulf War women veterans at excess rates. The study will utilize both existing datasets and newly collected data to examine the prevalence and patterns of Gulf War Illness symptoms, diagnosed medical conditions, reproductive health, birth outcomes and other health issues among women who served during the Gulf War. The Gulf War Women's Health Cohort study will address the need for information about the comprehensive health of women veterans who were deployed to the Gulf War, and other wars during the Gulf War era.

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990-1991 Persian Gulf War (GW). Eligible Veterans were invited via mail to complete a survey assessing health conditions as well as GW-specific deployment characteristics and exposures. We evaluated the representativeness of this GW-era cohort relative to the broader population by comparing demographic, military, and health characteristics between respondents and non-respondents, as well as with all GW-era Veterans who have used Veterans Health Administration (VHA) services and the full population of U.S. GW-deployed Veterans. A total of 109,976 MVP GW-era Veterans were invited to participate and 45,270 (41%) returned a completed survey. Respondents were 84% male, 72% White, 8% Hispanic, with a mean age of 61.6 years (SD = 8.5). Respondents were more likely to be older, White, married, better educated, slightly healthier, and have higher socioeconomic status than non-respondents, but reported similar medical conditions and comparable health status. Although generally similar to all GW-era Veterans using VHA services and the full population of U.S. GW Veterans, respondents included higher proportions of women and military officers, and were slightly older. In conclusion, sample characteristics of the MVP GW-era cohort can be considered generally representative of the broader GW-era Veteran population. The sample represents the largest research cohort of GW-era Veterans established to date and provides a uniquely valuable resource for conducting in-depth studies to evaluate health conditions affecting 1990-1991 GW-era Veterans.

Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs).

Gulf War Illness (GWI) currently has no known cure and affects soldiers deployed during the Persian Gulf War. It is thought to originate from exposure to neurotoxicants combined with battlefield stress, and previous research indicates that treatment first involves inhibition of interleukin-2 and tumor necrosis factor alpha, followed by the glucocorticoid receptor. However, the off-target effects of pharmaceuticals hinder development of a drug treatment therapy.

Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder affecting an estimated 25-32% of the returning military veterans of the 1990-1991 Persian Gulf War. GWI presents with a wide range of symptoms including fatigue, muscle pain, cognitive problems, insomnia, rashes and gastrointestinal issues and continues to be a poorly understood illness. This heterogeneity of GWI symptom presentation complicates diagnosis as well as the identification of effective treatments. Defining subgroups of the illness may help alleviate these complications. Our aim is to determine if GWI can be divided into distinct subgroups based on PTSD symptom presentation.

Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI) by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory, and reproductive problems. The symptoms have persisted for 30 years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in the war zone have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence of symptoms, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water for 7 days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genome-wide DNA methylation analysis using high-throughput sequencing. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans.