Characterizing 1991 Gulf War women veterans from the Boston Biorepository and Integrative Network for Gulf War Illness: demographics, exposures, neuroimaging and cognitive outcomes.

Objective: Gulf War Illness (GWI) is a debilitating multisymptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include pain, fatigue, gastrointestinal issues, and cognitive decrements. Our work has shown that GWI rates and potential causes for symptoms vary between men and women veterans. Studies have documented neuropsychological and neuroimaging findings mostly in men or combined sex datasets. Data are lacking for women veterans due to lack of power and repositories of women veteran samples. Methods: We characterized GW women veterans in terms of demographics, exposures, neuropsychological and neuroimaging outcomes from the newly collated Boston, Biorepository and Integrative Network (BBRAIN) for GWI. Results: BBRAIN women veterans are highly educated with an average age of 54 years. 81% met GWI criteria, 25% met criteria for current PTSD, 78% were white, and 81% served in the Army. Exposure to combined acetylcholinesterase inhibitors (AChEi) including skin pesticides, fogs/sprays and/or pyridostigmine bromide (PB) anti-nerve gas pill exposure resulted in slower processing speed on attentional tasks and a trend for executive impairment compared with non-exposed women. Brain imaging outcomes showed lower gray matter volumes and smaller caudate in exposed women. Conclusions: Although subtle and limited findings were present in this group of women veterans, it suggests that continued follow-up of GW women veterans is warranted. Future research should continue to evaluate differences between men and women in GW veteran samples. The BBRAIN women sub-repository is recruiting and these data are available to the research community for studies of women veterans.

Early-life manganese exposure during multiple developmental periods and adolescent verbal learning and memory.

BACKGROUND: Manganese (Mn) is both an essential and toxic metal, and associations with neurodevelopment depend on exposure timing. Prospective data examining early life Mn with adolescent cognition are sparse. METHODS: We enrolled 140 Italian adolescents (10-14 years old) from the Public Health Impact of Metals Exposure study. Mn in deciduous teeth was measured using laser ablation-mass spectrometry to represent prenatal, postnatal and early childhood exposure. The California Verbal Learning Test for Children (CVLT-C) was administered to assess adolescent verbal learning and memory. Multivariable regression models estimated changes in CVLT-C scores and the odds of making an error per doubling in dentine Mn in each exposure period. Multiple informant models tested for differences in associations across exposure periods. RESULTS: A doubling in prenatal dentine Mn levels was associated with lower odds of making an intrusion error (OR = 0.23 [95% CI: 0.09, 0.61]). This beneficial association was not observed in other exposure periods. A doubling in childhood Mn was beneficially associated with short delay free recall: (ß = 0.47 [95% CI: -0.02, 0.97]), which was stronger in males (ß = 0.94 [95% CI: 0.05, 1.82]). Associations were null in the postnatal period. CONCLUSION: Exposure timing is critical for understanding Mn-associated changes in cognitive function.

Transcranial Photobiomodulation Treatment: Significant Improvements in Four Ex-Football Players with Possible Chronic Traumatic Encephalopathy.

Background: Chronic traumatic encephalopathy, diagnosed postmortem (hyperphosphorylated tau), is preceded by traumatic encephalopathy syndrome with worsening cognition and behavior/mood disturbances, over years. Transcranial photobiomodulation (tPBM) may promote improvements by increasing ATP in compromised/stressed cells and increasing local blood, lymphatic vessel vasodilation. Objective: Aim 1: Examine cognition, behavior/mood changes Post-tPBM. Aim 2: MRI changes - resting-state functional-connectivity MRI: salience, central executive, default mode networks (SN, CEN, DMN); magnetic resonance spectroscopy, cingulate cortex. Methods: Four ex-players with traumatic encephalopathy syndrome/possible chronic traumatic encephalopathy, playing 11- 16 years, received In-office, red/near-infrared tPBM to scalp, 3x/week for 6 weeks. Two had cavum septum pellucidum. Results: The three younger cases (ages 55, 57, 65) improved 2 SD (p < 0.05) on three to six neuropsychological tests/subtests at 1 week or 1 month Post-tPBM, compared to Pre-Treatment, while the older case (age 74) improved by 1.5 SD on three tests. There was significant improvement at 1 month on post-traumatic stress disorder (PTSD), depression, pain, and sleep. One case discontinued narcotic pain medications and had reduced tinnitus. The possible placebo effect is unknown. At 2 months Post-tPBM, two cases regressed. Then, home tPBM was applied to only cortical nodes, DMN (12 weeks); again, significant improvements were seen. Significant correlations for increased SN functional connectivity (FC) over time, with executive function, attention, PTSD, pain, and sleep; and CEN FC, with verbal learning/memory, depression. Increased n-acetyl-aspartate (NAA) (oxygen consumption, mitochondria) was present in anterior cingulate cortex (ACC), parallel to less pain and PTSD. Conclusion: After tPBM, these ex-football players improved. Significant correlations of increased SN FC and CEN FC with specific cognitive tests and behavior/mood ratings, plus increased NAA in ACC support beneficial effects from tPBM.

The prevalence of mild cognitive impairment in Gulf War veterans: a follow-up study.

Introduction: Gulf War Illness (GWI), also called Chronic Multisymptom Illness (CMI), is a multi-faceted condition that plagues an estimated 250,000 Gulf War (GW) veterans. Symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. We previously reported that 12% of a convenience sample of middle aged (median age 52 years) GW veterans met criteria for mild cognitive impairment (MCI), a clinical syndrome most prevalent in older adults (e.g., ≥70 years). The current study sought to replicate and extend this finding. Methods: We used the actuarial neuropsychological criteria and the Montreal Cognitive Assessment (MoCA) to assess the cognitive status of 952 GW veterans. We also examined regional brain volumes in a subset of GW veterans (n = 368) who had three Tesla magnetic resonance images (MRIs). Results: We replicated our previous finding of a greater than 10% rate of MCI in four additional cohorts of GW veterans. In the combined sample of 952 GW veterans (median age 51 years at time of cognitive testing), 17% met criteria for MCI. Veterans classified as MCI were more likely to have CMI, history of depression, and prolonged (≥31 days) deployment-related exposures to smoke from oil well fires and chemical nerve agents compared to veterans with unimpaired and intermediate cognitive status. We also replicated our previous finding of hippocampal atrophy in veterans with MCI, and found significant group differences in lateral ventricle volumes. Discussion: Because MCI increases the risk for late-life dementia and impacts quality of life, it may be prudent to counsel GW veterans with cognitive dysfunction, CMI, history of depression, and high levels of exposures to deployment-related toxicants to adopt lifestyle habits that have been associated with lowering dementia risk. With the Food and Drug Administration's recent approval of and the VA's decision to cover the cost for anti-amyloid ß (Aß) therapies, a logical next step for this research is to determine if GW veterans with MCI have elevated Aß in their brains.

Preliminary Findings from the Gulf War Women's Cohort: Reproductive and Children's Health Outcomes among Women Veterans.

Reproductive outcomes, such as preterm birth, miscarriage/stillbirth, and pre-eclampsia, are understudied in veterans, particularly among Gulf War veterans (GWVs). During deployment, women GWVs were exposed to toxicant and nontoxicant exposures that may be associated with adverse reproductive and developmental outcomes. The data come from a survey of 239 participants from northeastern and southern U.S. cohorts of women veterans. The questionnaire collected information about the service history, current and past general health, reproductive and family health, demographic information, and deployment exposures. Odds ratios were computed with 95% confidence intervals between exposures in theater and reproductive/children's health outcomes. GWVs experienced adverse reproductive outcomes: 25% had difficulty conceiving, and 31% had a pregnancy that ended in a miscarriage or stillbirth. Pregnancy complications were common among GWVs: 23% had a high-risk pregnancy, and 16% were diagnosed with pre-eclampsia. About a third of GWVs reported their children (38%) had a developmental disorder. Use of pesticide cream during deployment was associated with higher odds of all reproductive and developmental outcomes. The results demonstrate that GWVs experienced reproductive and children's health outcomes at potentially high rates, and exploratory analyses suggest pesticide exposure as associated with higher odds of adverse reproductive outcomes. Future longitudinal studies of women veterans should prioritize examining reproductive and children's health outcomes.

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness.

BACKGROUND: Nearly 250,000 veterans from the 1990-1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. METHODS: Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. RESULTS: An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. CONCLUSION: Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

The impact of neurotoxicant exposures on posttraumatic stress disorder trajectories: The Ft. Devens Gulf War Veterans Cohort.

Gulf War veterans (GWVs) were exposed to neurotoxicants, including sarin nerve gas, anti-nerve agent pills, pesticides, oil well fires, and fumes from unvented tent heaters, all of which have been associated with subsequent adverse health. Posttraumatic stress disorder (PTSD) symptoms have also been associated with GW deployment; however, associations between exposures and PTSD symptoms have not been investigated. We assessed PTSD symptom trajectories and associations with neurotoxicant exposures in Ft. Devens Cohort (FDC) veterans (N = 259) who endorsed trauma exposure during deployment and completed the PTSD Checklist at three follow-ups (1992-1993, 1997-1998, 2013-2017). Results indicate that among veterans with more severe initial PTSD symptoms, symptoms remained significantly higher across follow-ups, Bs = -1.489-1.028, whereas among those with low initial PTSD symptoms, symptom severity increased significantly over time, Bs = 1.043-10.304. Additionally, neurotoxicant exposure was associated with a significant increase in PTSD symptoms, Bs = -1.870-9.003. Significant interactions between time and exposures were observed for PTSD symptom clusters, suggesting that among participants with high initial PTSD symptom, unexposed veterans experienced symptom alleviation, whereas exposed veterans' PTSD symptoms remained high. In GWVs with low initial PTSD symptoms, both unexposed and exposed veterans experienced PTSD symptom exacerbations over time; however, this occurred at a faster rate among exposed veterans. These findings suggest that in the years following deployment, GWVs who were exposed to both traumatic events and neurotoxicants may experience more severe and chronic PTSD symptoms than those without neurotoxicant exposures.

Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.

BACKGROUND: Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years. METHODS: Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures. RESULTS: Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time. CONCLUSION: This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.

A common language for Gulf War Illness (GWI) research studies: GWI common data elements.

AIMS: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. MAIN METHODS: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. KEY FINDINGS: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. SIGNIFICANCE: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing.

Brain-Immune Interactions as the Basis of Gulf War Illness: Clinical Assessment and Deployment Profile of 1990-1991 Gulf War Veterans in the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990-1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S. sites that included clinical assessments, brain imaging, neuropsychological testing, and analyses of a broad range of immune and immunogenetic parameters. GWI cases were similar to controls on most demographic, military, and deployment characteristics although on average were two years younger, with a higher proportion of enlisted personnel vs. officers. Results of physical evaluation and routine clinical lab tests were largely normal, with few differences between GWI cases and healthy controls. However, veterans with GWI scored significantly worse than controls on standardized assessments of general health, pain, fatigue, and sleep quality and had higher rates of diagnosed conditions that included hypertension, respiratory and sinus conditions, gastrointestinal conditions, and current or lifetime depression and post-traumatic stress disorder. Among multiple deployment experiences/exposures reported by veterans, multivariable logistic regression identified just two significant GWI risk factors: extended use of skin pesticides in theater (adjusted OR = 3.25, p = 0.005) and experiencing mild traumatic brain injury during deployment (OR = 7.39, p = 0.009). Gulf War experiences associated with intense stress or trauma (e.g., participation in ground combat) were not associated with GWI. Data and samples from the GWIC project are now stored in a repository for use by GWI researchers. Future reports will present detailed findings on brain structure and function, immune function, and association of neuroimmune measures with characteristics of GWI and Gulf War service.

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

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.

Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC): A collaborative research infrastructure for intervention and implementation.

AIMS: There is an inadequate portfolio of treatments for Gulf War Illness (GWI), a complex disease involving multiple organ systems, and early-phase clinical trials are hampered by many logistical problems. To address these challenges, the Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC) was formed with the aims of (i) creating a collaborative consortium of clinical and scientific researchers that will rapidly implement rigorous and innovative phase I and II clinical trials for GWI, (ii) perform at least four phase I or II clinical trials, (iii) provide a foundation of scalable infrastructure and management in support of the efficient and successful operation of the GWICTIC, and (iv) partner with the Boston Biorepository, Recruitment & Integrated Network for GWI and other GWI investigators to develop a common data element platform for core assessments and outcomes. MAIN METHODS: The GWICTIC brings together a multidisciplinary team of researchers at several institutions to provide scientific innovation, statistical and computational rigor, and logistical efficiency in the development and implementation of early-phase low-risk clinical trials for GWI. The GWICTIC core trials adhere to a Veteran-centered philosophy and focus on interventions with multiple mechanistic targets to maximize the likelihood of efficacy. To support rapid and efficient study startup and implementation across the GWI research community, the GWICTIC will share infrastructure with investigator-initiated research studies funded under separate mechanisms. SIGNIFICANCE: The GWICTIC will leverage the efficiencies of centralized research support and innovative trial designs to address several longstanding needs in the GWI interventions research community.

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

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.

Neuroimaging Markers for Studying Gulf-War Illness: Single-Subject Level Analytical Method Based on Machine Learning.

Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed that the severity of these symptoms often remain unchanged even years after the GW, and these veterans with GWI continue to have poorer general health and increased chronic medical conditions than their non-deployed counterparts. For better management and treatment of this condition, there is an urgent need for developing objective biomarkers that can help with simple and accurate diagnosis of GWI. In this study, we applied multiple neuroimaging techniques, including T1-weighted magnetic resonance imaging (T1W-MRI), diffusion tensor imaging (DTI), and novel neurite density imaging (NDI) to perform both a group-level statistical comparison and a single-subject level machine learning (ML) analysis to identify diagnostic imaging features of GWI. Our results supported NDI as the most sensitive in defining GWI characteristics. In particular, our classifier trained with white matter NDI features achieved an accuracy of 90% and F-score of 0.941 for classifying GWI cases from controls after the cross-validation. These results are consistent with our previous study which suggests that NDI measures are sensitive to the microstructural and macrostructural changes in the brain of veterans with GWI, which can be valuable for designing better diagnosis method and treatment efficacy studies.

Changes in Health Status in the Ft. Devens Gulf War Veterans Cohort: 1997-2017.

Gulf War veterans (GWVs) were exposed to numerous neurotoxicants during deployment. Upon returning home, many reported a multitude of symptoms including fatigue, pain, gastrointestinal and respiratory issues, and neurological, cognitive, and mood complaints, collectively termed "Gulf War Illness (GWI)." Now, nearly 30 years post-war, many GWVs continue to suffer from these symptoms, in addition to health concerns associated with normal aging. While most research on GWVs has been cross-sectional, it is important to evaluate the progression and onset of new GWI symptoms longitudinally. The current study investigated the health of GWVs 25+ years after the war by resurveying the Ft. Devens Cohort and comparing their current health to their health reported 15 to 20 years earlier. The sample consists of 317 GWVs (~54 years old at the latest survey, 38 women) who responded to both surveys (1997-1998 and 2013-2017). Multivariable regression analyses were used to assess changes in GWI symptomatology and prevalence of medical conditions. The rates of 12 of 25 health symptoms increased significantly from the prior 1997-1998 survey. Anxiety, numbness in extremities, depressed mood, and joint pain had the greatest increase in endorsement. The rates of 7 of 16 medical conditions increased significantly from the prior 1997-1998 survey. High blood pressure, diabetes, and cancer had the greatest increase in prevalence. In summary, this study demonstrates that both symptoms and physician-diagnosed medical conditions associated with GW deployment/exposure increased in prevalence. For GWVs, focus by providers on the treatment of cognitive and mental health issues as well as cardiovascular and cerebrovascular risk factors is warranted. Targeting symptom alleviation would help improve the quality of life in these veterans until treatments addressing the entire illness become available.

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

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.

Longitudinal Assessment of Health Symptoms in Relation to Neurotoxicant Exposures in 1991 Gulf War Veterans: The Ft. Devens Cohort.

OBJECTIVE: This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans. METHODS: Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates. RESULTS: Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily. CONCLUSION: This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.

Alterations in high-order diffusion imaging in veterans with Gulf War Illness is associated with chemical weapons exposure and mild traumatic brain injury.

The complex etiology behind Gulf War Illness (GWI) has been attributed to the combined exposure to neurotoxicant chemicals, brain injuries, and some combat experiences. Chronic GWI symptoms have been shown to be associated with intensified neuroinflammatory responses in animal and human studies. To investigate the neuroinflammatory responses and potential causes in Gulf War (GW) veterans, we focused on the effects of chemical/biological weapons (CBW) exposure and mild traumatic brain injury (mTBI) during the war. We applied a novel MRI diffusion processing method, Neurite density imaging (NDI), on high-order diffusion imaging to estimate microstructural alterations of brain imaging in Gulf War veterans with and without GWI, and collected plasma proinflammatory cytokine samples as well as self-reported health symptom scores. Our study identified microstructural changes specific to GWI in the frontal and limbic regions due to CBW and mTBI, and further showed distinctive microstructural patterns such that widespread changes were associated with CBW and more focal changes on diffusion imaging were observed in GW veterans with an mTBI during the war. In addition, microstructural alterations on brain imaging correlated with upregulated blood proinflammatory cytokine markers TNFRI and TNFRII and with worse outcomes on self-reported symptom measures for fatigue and sleep functioning. Taken together, these results suggest TNF signaling mediated inflammation affects frontal and limbic regions of the brain, which may contribute to the fatigue and sleep symptoms of the disease and suggest a strong neuroinflammatory component to GWI. These results also suggest exposures to chemical weapons and mTBI during the war are associated with different patterns of peripheral and central inflammation and highlight the brain regions vulnerable to further subtle microscale morphological changes and chronic signaling to nearby glia.

The Gulf War Women's Health Cohort: Study Design and Protocol.

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.

Prevalence and Patterns of Symptoms Among Female Veterans of the 1991 Gulf War Era: 25 Years Later.

Background: A new national cohort of Gulf War (GW) veterans of 1,318 participants was created from the Veterans Affairs Cooperative Studies Program 585 Gulf War Era Cohort and Biorepository (GWECB) pilot study. However, female veteran health outcomes have not been reported separately for those deployed versus nondeployed to the 1990-1991 GW. Methods: Using data from the cooperative studies program (CSP) #585 GWECB, this study examined whether excess prevalence and patterns of Gulf War Illness (GWI) symptoms were present among female veterans who served during the GW compared with female veterans who did not deploy to the GW (GW-Era). Results: A total of 301 women veterans participated in the survey (203 GW, 98 GW-era). Mean ages in 2016 were 53 years among GW women veterans and 54 years among GW-era women. Participant groups did not differ by age, race, ethnicity, or education, but GW women were more likely to have served in the army or navy and less likely to have served in the air force. Compared with GW-era women, GW-deployed women were significantly more likely to report 7 out of 34 symptoms related to cognitive, neurological, and mood problems and respiratory complaints when controlling for age, race, GW deployment, branch of service, and smoking status in logistic regression analyses. Ordered logistic regression was also used to estimate the association between the total number of self-reported symptoms and deployment status, age, race, branch of service, and smoking status. Results showed deployed GW veterans to have a nearly twofold risk of reporting more symptoms than GW-era women, with younger, nonwhite, army-enlisted GW women significantly more likely to report more total symptoms. Discussion: Twenty-five years after the war, GWECB women GW veterans continued to report a wide variety of symptoms at a significantly higher excess frequency prevalence than GW-era women. Our results showed at least a 14% excess frequency prevalence in all seven significantly different symptoms encompassing two out of the six Kansas GWI criteria, including neurological/mood/cognition, and respiratory domains. These results suggest that further study of these symptom domains is warranted in GW women veterans.