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Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness.

ABSTRACT: BACKGROUND:25% to 30% of Veterans deployed to the 1990 to 1991 Persian Gulf War exhibit an idiopathic syndrome of chronic fatigue, exertional exhaustion, pain, hyperalgesia, cognitive and affective dysfunction known as Gulf War Illness (GWI). METHODS:Gulf War veterans (n=15) and sedentary veteran and civilian controls (n=11) completed a 2-back working memory test in an fMRI before and after two bicycle exercise stress test. We performed single voxel (1)H MRS to evaluate brain metabolic differences in the left anterior cingulate cortex and the changes associated with exercise. RESULTS:Eight GWI subjects increased their 2-back scores after exercise (labelled increasers) and seven GWI subjects decreased their 2-back scores after exercise (labelled decreasers). These phenotypic responses were absent for controls. Decreasers had significantly elevated prefrontal lactate levels compared to Increasers prior to completion of the exercise stress tests. Evaluation of prefrontal lactate levels prior to exercise demonstrated predictability (ROC analysis) of the two diametrically opposed subgroups. CONCLUSION:Prefrontal lactate levels may be a potential biomarker for exercise-induced subgroups in GWI. The alterations in brain energetics may be in part responsible for a subgroup of GWI and underlie some of the symptoms present in the patient population.

SUBMITTER: Rayhan RU

PROVIDER: S-EPMC3612516 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness.

Rayhan Rakib U RU Raksit Megna P MP Timbol Christian R CR Adewuyi Oluwatoyin O Vanmeter John W JW Baraniuk James N JN

American journal of translational research 20130328 2

<h4>Background</h4>25% to 30% of Veterans deployed to the 1990 to 1991 Persian Gulf War exhibit an idiopathic syndrome of chronic fatigue, exertional exhaustion, pain, hyperalgesia, cognitive and affective dysfunction known as Gulf War Illness (GWI).<h4>Methods</h4>Gulf War veterans (n=15) and sedentary veteran and civilian controls (n=11) completed a 2-back working memory test in an fMRI before and after two bicycle exercise stress test. We performed single voxel (1)H MRS to evaluate brain meta ...[more]

PMID: 23573365

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Project description:Gulf War Illness (GWI), a chronic multisymptom health problem, afflicts ~30% of veterans served in the first GW. Impaired brain function is among the most significant symptoms of GWI, which is typified by persistent cognitive and mood impairments, concentration problems, headaches, chronic fatigue, and musculoskeletal pain. This review aims to discuss findings from animal prototypes and veterans with GWI on mechanisms underlying its pathophysiology and emerging therapeutic strategies for alleviating brain dysfunction in GWI. Animal model studies have linked brain impairments to incessantly elevated oxidative stress, chronic inflammation, inhibitory interneuron loss, altered lipid metabolism and peroxisomes, mitochondrial dysfunction, modified expression of genes relevant to cognitive function, and waned hippocampal neurogenesis. Furthermore, the involvement of systemic alterations such as the increased intensity of reactive oxygen species and proinflammatory cytokines in the blood, transformed gut microbiome, and activation of the adaptive immune response have received consideration. Investigations in veterans have suggested that brain dysfunction in GWI is linked to chronic activation of the executive control network, impaired functional connectivity, altered blood flow, persistent inflammation, and changes in miRNA levels. Lack of protective alleles from Class II HLA genes, the altered concentration of phospholipid species and proinflammatory factors in the circulating blood have also been suggested as other aiding factors. While some drugs or combination therapies have shown promise for alleviating symptoms in clinical trials, larger double-blind, placebo-controlled trials are needed to validate such findings. Based on improvements seen in animal models of GWI, several antioxidants and anti-inflammatory compounds are currently being tested in clinical trials. However, reliable blood biomarkers that facilitate an appropriate screening of veterans for brain pathology need to be discovered. A liquid biopsy approach involving analysis of brain-derived extracellular vesicles in the blood appears efficient for discerning the extent of neuropathology both before and during clinical trials.

Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.

Dataset Information

Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness.

Publications

Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness.

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