Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100μg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.     

Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models: Modulation by the immunotherapeutic LNFPIII

Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990–1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6 J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethyl-methylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8–14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-HT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.     

Brainstem atrophy in Gulf War Illness

BackgroundGulf 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.ObjectivesUsing a large cohort of US veterans with GWI, we assessed regional brain volumes for their associations with GWI, and quantified the relationships between any regional volumetric changes and GWI symptoms.MethodsStructural magnetic resonance imaging (MRI) scans from 111 veterans with GWI (Age = 49 ± 6, 88 % Male) and 59 healthy controls (age = 51 ± 9, 78 % male) were collected at the California War Related Illness and Injury Study Center (WRIISC-CA) and from a multicenter study of the Parkinson’s Progression Marker Initiative (PPMI), respectively. Individual MRI volumes were segmented and parcellated using FreeSurfer. Regional volumes of 19 subcortical, 68 cortical, and 3 brainstem structures were evaluated in the GWI cohort relative to healthy controls. The relationships between regional volumes and GWI symptoms were also assessed.ResultsWe found significant subcortical atrophy, but no cortical differences, in the GWI group relative to controls, with the largest effect detected in the brainstem, followed by the ventral diencephalon and the thalamus. In a subsample of 58 veterans with GWI who completed the Chronic Fatigue Scale (CFS) inventory of Centers for Disease Control and Prevention (CDC), smaller brainstem volumes were significantly correlated with increased severities of fatigue and depressive symptoms.ConclusionThe findings suggest that brainstem volume may be selectively affected by GWI, and that the resulting atrophy could in turn mediate or moderate GWI-related symptoms such as fatigue and depression. Consequently, the brain stem should be carefully considered in future research focusing on GWI pathology.     

A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain

More than a quarter of veterans of the 1990–1991 Persian Gulf War suffer from Gulf War Illness (GWI), a chronic, multi-symptom illness that commonly includes musculoskeletal pain. Exposure to a range of toxic chemicals, including sarin nerve agent, are a suspected root cause of GWI. Moreover, such chemical exposures induce a neuroinflammatory response in rodents, which has been linked to several GWI symptoms in rodents and veterans with GWI. To date, a neuroinflammatory basis for pain associated with GWI has not been investigated. Here, we evaluated development of nociceptive hypersensitivity in a model of GWI. Male Sprague Dawley rats were treated with corticosterone in the drinking water for 7 days, to mimic high physiological stress, followed by a single injection of the sarin nerve agent surrogate, diisopropyl fluorophosphate. These exposures alone were insufficient to induce allodynia. However, an additional sub-threshold challenge (a single intramuscular injection of pH 4 saline) induced long-lasting, bilateral allodynia. Such allodynia was associated with elevation of markers for activated microglia/macrophages (CD11b) and astrocytes/satellite glia (GFAP) in the lumbar dorsal spinal cord and dorsal root ganglia (DRG). Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1β and IL-6 were elevated in the lumbar dorsal spinal cord, DRG, and gastrocnemius muscle. Demonstrating a casual role for such neuroinflammatory signaling, allodynia was reversed by treatment with either minocycline, the TLR4 inhibitor (+)-naltrexone, or IL-10 plasmid DNA. Together, these results point to a role for neuroinflammation in male rats in the model of musculoskeletal pain related to GWI. Therapies that alleviate persistent immune dysregulation may be a strategy to treat pain and other symptoms of GWI.     

Exposure to an organophosphate pesticide,individually or in combination with other Gulf War agents,impairs synaptic integrity and neuronal differentiation,and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure

Gulf War illness (GWI) is a currently untreatable multi‐symptom disorder experienced by 1990–1991 Persian Gulf War (GW) veterans. The characteristic hallmarks of GWI include cognitive dysfunction, tremors, migraine, and psychological disturbances such as depression and anxiety. Meta‐analyses of epidemiological studies have consistently linked these symptomatic profiles to the combined exposure of GW agents such as organophosphate‐based and pyrethroid‐based pesticides (e.g. chlorpyrifos (CPF) and permethrin (PER) respectively) and the prophylactic use of pyridostigmine bromide (PB) as a treatment against neurotoxins. Due to the multi‐symptomatic presentation of this illness and the lack of available autopsy tissue from GWI patients, very little is currently known about the distinct early pathological profile implicated in GWI (including its influence on synaptic function and aspects of neurogenesis). In this study, we used preclinical models of GW agent exposure to investigate whether 6‐month‐old mice exposed to CPF alone, or a combined dose of CPF, PB and PER daily for 10 days, demonstrate any notable pathological changes in hippocampal, cortical (motor, piriform) or amygdalar morphometry. We report that at an acute post‐exposure time point (after 3 days), both exposures resulted in the impairment of synaptic integrity (reducing synaptophysin levels) in the CA3 hippocampal region and altered neuronal differentiation in the dentate gyrus (DG), demonstrated by a significant reduction in doublecortin positive cells. Both exposures also significantly increased astrocytic GFAP immunoreactivity in the piriform cortex, motor cortex and the basolateral amygdala and this was accompanied by an increase in (basal) brain acetylcholine (ACh) levels. There was no evidence of microglial activation or structural deterioration of principal neurons in these regions following exposure to CPF alone or in combination with PB and PER. Evidence of subtle microvascular injury was demonstrated by the reduction of platelet endothelial cell adhesion molecule (PECAM)‐1 levels in CPF+PB+PER exposed group compared to control. These data support early (subtle) neurotoxic effects on the brain following exposure to GW agents.     

Psychiatric diagnoses in Gulf War veterans with fatiguing illness

The purpose of this study was to determine whether Gulf War Illness (GWI) can be explained by the presence of psychiatric disorders as assessed by DSM-III-R. To reduce the heterogeneity amongst Persian Gulf War veterans with GWI (PGV-F), only those were studied who presented with severe fatigue as a major complaint and also fulfilled clinical case definitions for Chronic Fatigue Syndrome, Idiopathic Chronic Fatigue, and/or Multiple Chemical Sensitivity. A total of 95 Registry PGVs were examined; 53 presented with GWI and 42 did not report any post-war health problems (PGV-H). All subjects were assessed for the presence of DSM-III-R Axis I psychiatric disorders. Compared to PGV-Hs, 49% of PGV-Fs had similar post-war psychiatric profiles: either no, or only one, psychiatric disorder was diagnosed. Psychiatric profiles of the remaining 51% of PGV-Fs were significantly different from PGV-Hs in that most of these veterans suffered from multiple post-war psychiatric diagnoses. The presence of psychiatric disorders as assessed by DSM-III-R criteria cannot explain symptoms of Gulf War Illness among all Persian Gulf veterans with severe fatiguing illness.     

Olfactory functioning in Gulf War-era veterans: relationships to war-zone duty, self-reported hazards exposures, and psychological distress.

To explore possible neurotoxic sequelae of Gulf War (GW) participation, olfactory identification performance, neurocognitive functioning, health perceptions, and emotional distress were assessed in 72 veterans deployed to the GW and 33 military personnel activated during the GW but not deployed to the war zone. Findings revealed that war-zone-exposed veterans reported more concerns about health, cognitive functioning, and depression than did their counterparts who did not see war-zone duty. There was no evidence that performances on olfactory or neurocognitive measures were related to war-zone duty or to self-reported exposure to GW toxicants. However, symptoms of emotional distress were positively correlated with self-report of health and cognitive complaints. Results do not provide support for the hypothesis that objectively-measured sensory (i.e., olfactory) or cognitive deficits are related to war-zone participation but do underscore the increasingly demonstrated association between self-reported health concerns and symptoms of emotional distress.     

Deployment stressors and a chronic multisymptom illness among Gulf War veterans

Unusual health problems have been reported by Gulf War (GW) veterans, but no single etiology has been linked to these illnesses. This study was conducted to determine the association between self-reported GW deployment stressors and an illness defined by a combination of fatigue, mood-cognition, and musculoskeletal symptoms. A total of 1002 GW veterans from this cross-sectional survey of four Air Force units completed a self-administered questionnaire that asked about symptoms, demographic and military characteristics, and stressors during deployment. Severe and mild-moderate illness was positively associated with self-reports of pyridostigmine bromide use, insect repellent use and belief in a threat from biological or chemical weapons. Injuries requiring medical attention were only associated with severe illness. These results suggest a link between self-reported chemical, emotional, and physical exposures, and GW veterans' illness. Further research is needed to determine physiological and psychological mechanisms through which such stressors could have contributed to this symptom complex.     

Proteomic CNS Profile of Delayed Cognitive Impairment in Mice Exposed to Gulf War Agents

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.     

Perfusion deficit to cholinergic challenge in veterans with Gulf War Illness

A highly plausible etiology for Gulf War Illness (GWI) is that the neural damage and cognitive deficits are associated with excessive exposure to cholinesterase-inhibiting cholinergic stimulants. Our previous SPECT study provided strong indication that cerebral blood flow (CBF) in veterans with GWI may be different from those of unaffected control veterans. The present study confirmed and extended previous findings that patients with GWI have abnormal response to an inhibitory cholinergic challenge, physostigmine infusion, when compared to age-gender-education matched control veterans. The MRI-based arterial spin labeling (ASL) and phase-contrast techniques have several key advantages over SPECT, including shorter experiment duration, complete non-invasiveness, and higher spatial and temporal resolutions, and therefore may provide a cost-effective biomarker for characterization of GWI.     

Stressors, personality traits, and coping of Gulf War veterans with chronic fatigue

Objectives: preliminary surveys of Persian Gulf veterans revealed a significant prevalence of self-reported symptoms consistent with chronic fatigue syndrome (CFS). The purpose of this study was to compare self-reported life stressors, combat, and chemical exposures, personality and coping between Gulf War veterans with CFS and healthy veterans.Methods: following a complete physical, psychiatric, and neuropsychological evaluation, 45 healthy veterans, 35 veterans with CFS and co-morbid psychiatric disorder, and 23 veterans with CFS and no co-morbid psychiatric disorder completed questionnaires assessing war and non-war-related life stressors, self-reports of environmental exposure (e.g. oil well fires, pesticides), personality, and coping.Results: measures of personality, self-reported combat and chemical exposures, and negative coping strategies significantly differentiated healthy veterans from those with CFS.Conclusion: a biopsychosocial model of veterans' illness was supported by the fact that personality, negative coping strategies, life stress after the war, and environmental exposures during the war were significant predictors of veterans' current physical function.     

Effects of low-level sarin and cyclosarin exposure on white matter integrity in Gulf War Veterans

BackgroundWe previously found evidence of reduced gray and white matter volume in Gulf War (GW) veterans with predicted low-level exposure to sarin (GB) and cyclosarin (GF). Because loss of white matter tissue integrity has been linked to both gray and white matter atrophy, the current study sought to test the hypothesis that GW veterans with predicted GB/GF exposure have evidence of disrupted white matter microstructural integrity.MethodsMeasures of fractional anisotropy and directional (i.e., axial and radial) diffusivity were assessed from the 4 T diffusion tensor images (DTI) of 59 GW veterans with predicted GB/GF exposure and 59 “matched” unexposed GW veterans (mean age: 48 ± 7 years). The DTI data were analyzed using regions of interest (ROI) analyses that accounted for age, sex, total brain gray and white matter volume, trauma exposure, posttraumatic stress disorder, current major depression, and chronic multisymptom illness status.ResultsThere were no significant group differences in fractional anisotropy or radial diffusivity. However, there was increased axial diffusivity in GW veterans with predicted GB/GF exposure compared to matched, unexposed veterans throughout the brain, including the temporal stem, corona radiata, superior and inferior (hippocampal) cingulum, inferior and superior fronto-occipital fasciculus, internal and external capsule, and superficial cortical white matter blades. Post hoc analysis revealed significant correlations between higher fractional anisotropy and lower radial diffusivity with better neurobehavioral performance in unexposed GW veterans. In contrast, only increased axial diffusivity in posterior limb of the internal capsule was associated with better psychomotor function in GW veterans with predicted GB/GF exposure.ConclusionsThe finding that increased axial diffusivity in a region of the brain that contains descending corticospinal fibers was associated with better psychomotor function and the lack of significant neurobehavioral deficits in veterans with predicted GB/GF exposure hint at the possibility that the widespread increases in axial diffusivity that we observed in GW veterans with predicted GB/GF exposure relative to unexposed controls may reflect white matter reorganization after brain injury (i.e., exposure to GB/GF).     

Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness

Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. Here, using our established GWI mouse model, we investigated the effects of CORT and DFP exposure, with or without a chronic application of pyridostigmine bromide (PB) and N,N-diethyl-meta-toluamide (DEET), on cytokines in the liver and serum. While CORT primed DFP-induced neuroinflammation, this effect was largely absent in the periphery. Moreover, the changes found in the peripheral tissues do not correlate with the previously reported neuroinflammation. These results not only support GWI as a neuroimmune disorder, but also highlight the separation between central and peripheral effects of these exposures.     

Lipidomic Profiling of Phosphocholine Containing Brain Lipids in Mice with Sensorimotor Deficits and Anxiety-Like Features After Exposure to Gulf War Agents

The central nervous system (CNS)-based symptoms of Gulf War Illness (GWI) include motor dysfunction, anxiety, and cognitive impairment. Gulf War (GW) agents, such as pyridostigmine bromide (PB), permethrin (PER), N,N-diethyl-meta-toluamide (DEET), and stress, are among the contributory factors to the pathobiology of GWI. This study characterizes disturbances in phosphocholine-containing lipids that accompany neurobehavioral and neuropathological features associated with GW agent exposure. Exposed mice received PB orally, dermal application of PER and DEET and restraint stress daily for 28?days, while controls received vehicle during this period. Neurobehavioral studies included the rotarod, open field, and Morris water maze tests. Histopathological assessments included glial fibrillary acid protein, CD45, and Nissl staining. Liquid chromatography/mass spectrometry with source collision-induced dissociation in negative and positive ionization scanning modes was performed to characterize brain phosphatidylcholine (PC) and sphingomyelin (SM). A significant increase in ether containing PC (ePC34:0, ePC36:2, and ePC36:1) or long-chain fatty acid-containing PC (38:1, 40:4, 40:2) was observed in exposed mice compared with controls. Among differentially expressed PCs, levels of those with monounsaturated fatty acids were more affected than those with saturated and polyunsaturated fatty acids. Sensorimotor deficits and anxiety, together with an increase in astrocytosis, were observed in exposed mice compared with controls. These lipid changes suggest that alterations in peroxisomal pathways and stearoyl-CoA desaturase activity accompany neurobehavioral and neuropathological changes after GW agent exposure and represent possible treatment targets for the CNS symptoms of GWI.     

Oligodendrocyte involvement in Gulf War Illness

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.     

Enhanced cortisol suppression to dexamethasone associated with Gulf War deployment

OBJECTIVE: To examine whether PTSD or post-deployment health symptoms in veterans of the first Gulf War (Operation Desert Shield/Storm) are associated with enhanced suppression of the pituitary-adrenal axis to low-dose dexamethasone (DEX). METHOD: Plasma cortisol and lymphocyte glucocorticoid receptor (GR) number were measured at 08:00 h on two consecutive days, before and after administration of 0.5mg of DEX at 23:00 h in 42 male Gulf War veterans (14 without psychiatric illness, 16 with PTSD only, and 12 with both PTSD and MDD) and 12 healthy male veterans not deployed to the Gulf War or another war zone. RESULTS: In the absence of group differences in basal cortisol levels or GR number, Gulf War veterans without psychiatric illness and Gulf War veterans with PTSD only had significantly greater cortisol suppression to DEX than non-deployed veterans and Gulf War veterans with both PTSD and MDD. Gulf War deployment was associated with significantly greater cortisol suppression to DEX controlling for weight, smoking status, PTSD, and MDD; PTSD was not associated with response to DEX. Among Gulf War veterans musculoskeletal symptoms were significantly associated with cortisol suppression and those who reported taking anti-nerve gas pills (i.e., pyridostigmine bromide) during the war had significantly greater DEX-induced cortisol suppression than those who did not. CONCLUSIONS: The data demonstrate that alterations in neuroendocrine function are associated with deployment to the Gulf War and post-deployment musculoskeletal symptoms, but not PTSD. Additional studies are needed to examine the relationship of enhanced glucocorticoid responsivity to deployment exposures and chronic unexplained medical symptoms in Gulf War veterans.     

Cognitive Functioning in Gulf War Illness

A comprehensive neuropsychological battery was administered to 48 veterans with Gulf War Illness (GWI) characterized by severe fatigue (GV-F) and 39 healthy veterans (GV-H). Subjects were matched on intelligence and did not differ on age, gender, race, and alcohol consumption. Compared to GVs-H, GVs-F were significantly impaired on four tasks: three attention, concentration, information processing tasks and one measure of ion and conceptualization. After considering the presence of post-war Axis I psychopathology, GWI remained a significant predictor of cognitive performance on one of the attention, concentration, and information processing tasks and one abstraction and conceptualization measure. Performance on the remaining two attention, concentration, and information processing tasks was only significantly predicted by Axis I psychopathology with post-war onset. The results suggest that Gulf War Illness is associated with some aspects of cognitive dysfunction in Gulf Veterans, over and above the contribution of psychopathology.     

Cognitive functioning in Gulf War Illness

A comprehensive neuropsychological battery was administered to 48 veterans with Gulf War Illness (GWI) characterized by severe fatigue (GV-F) and 39 healthy veterans (GV-H). Subjects were matched on intelligence and did not differ on age, gender, race, and alcohol consumption. Compared to GVs-H, GVs-F were significantly impaired on four tasks: three attention, concentration, information processing tasks and one measure of abstraction and conceptualization. After considering the presence of post-war Axis I psychopathology, GWI remained a significant predictor of cognitive performance on one of the attention, concentration, and information processing tasks and one abstraction and conceptualization measure. Performance on the remaining two attention, concentration, and information processing tasks was only significantly predicted by Axis I psychopathology with post-war onset. The results suggest that Gulf War Illness is associated with some aspects of cognitive dysfunction in Gulf Veterans, over and above the contribution of psychopathology.     

Neurotoxicity in Gulf War Illness and the potential role of glutamate

Shortly after the Gulf War in 1990–1991, service men and women began reporting multiple symptoms ranging from persistent headaches, widespread pain, chronic fatigue, cognitive dysfunction, mood dysregulation, gastrointestinal issues, skin abnormalities, and respiratory problems. This prompted the Centers for Disease Control and Prevention (CDC) to initially classify the disorder as chronic multi-symptom illness (CMI), where it later became known as Gulf War Illness (GWI). Researchers and healthcare professionals since the early 1990s have been working extensively on alleviating the symptoms expressed in GWI as well as attempting to understand the mechanisms behind this illness. Scientific literature as well as reports from GWI veterans indicate that the toxic exposures during deployment may be responsible for the symptoms. These toxic exposures potentially include nerve agents, pyridostigmine bromide pills, pesticides, munitions with depleted uranium, and burning oil well fires. GWI currently affects 25–32 % of the 697,000 American troops who were stationed overseas during the short conflict. The purpose of this paper is to review the literature on neurotoxic exposures in Gulf War Illness, to explain how these exposures may lead to glutamate excitotoxicity, which has been implicated in the majority of the symptoms characterizing the illness, and to propose a novel treatment option for GWI.     

White matter abnormalities associated with military PTSD in the context of blast TBI

Mild traumatic brain injury (mTBI) and post‐traumatic stress disorder (PTSD) are common among recent military veterans and involve substantial symptom overlap, making clinical distinction and effective intervention difficult. Emerging evidence of cerebral white matter abnormalities associated with mTBI may provide a biological measure to inform diagnosis and treatment, but the potentially confounding effects between PTSD and mTBI have largely gone unexamined. We collected diffusion imaging data from 133 recently‐deployed American service members who developed PTSD and/or sustained mTBI, or had neither condition. Effects of PTSD and mTBI on traditional tensor‐based measures of cerebral white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) were compared in anatomical regions of interest and individual voxels throughout the brain. Generalized FA (GFA), which allows for multiple fiber orientations per voxel, was also included to improve sensitivity in white matter areas containing crossing or diverging axon bundles. PTSD was consistently associated with high GFA in select brain regions, greater likelihood of regions and voxels with abnormally low MD, and a greater number of voxels with abnormally high FA, while mTBI was associated with fewer high MD regions. Overall, PTSD was associated with more restricted diffusion (low MD) and greater anisotropy (high GFA) in regions of crossing/diverging fibers poorly characterized by a single tensor (FA), suggesting that interstitial fibers may be involved. Contrary to earlier results in a sample without PTSD, mTBI was not associated with anisotropy abnormalities, perhaps indicating the cooccurrence of PTSD and mTBI requires special consideration with regard to structural brain connectivity. Hum Brain Mapp 36:1053–1064, 2015. © 2014 Wiley Periodicals, Inc.