Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex illness which disproportionally affects females. This illness is associated with immune and metabolic perturbations that may be influenced by lipid metabolism. We therefore hypothesized that plasma lipids from ME/CFS patients will provide a unique biomarker signature of disturbances in immune, inflammation and metabolic processes associated with ME/CFS. Methods Lipidomic analyses were performed on plasma from a cohort of 50 ME/CFS patients and 50 controls (50% males and similar age and ethnicity per group). Analyses were conducted with nano-flow liquid chromatography (nLC) and high-performance liquid chromatography (HPLC) systems coupled with a high mass accuracy ORBITRAP mass spectrometer, allowing detection of plasma lipid concentration ranges over three orders of magnitude. We examined plasma phospholipids (PL), neutral lipids (NL) and bioactive lipids in ME/CFS patients and controls and examined the influence of sex on the relationship between lipids and ME/CFS diagnosis. Results Among females, levels of total phosphatidylethanolamine (PE), omega-6 arachidonic acid-containing PE, and total hexosylceramides (HexCer) were significantly decreased in ME/CFS compared to controls. In males, levels of total HexCer, monounsaturated PE, phosphatidylinositol (PI), and saturated triglycerides (TG) were increased in ME/CFS patients compared to controls. Additionally, omega-6 linoleic acid-derived oxylipins were significantly increased in male ME/CFS patients versus male controls. Principal component analysis (PCA) identified three major components containing mostly PC and a few PE, PI and SM species—all of which were negatively associated with headache and fatigue severity, irrespective of sex. Correlations of oxylipins, ethanolamides and ME/CFS symptom severity showed that lower concentrations of these lipids corresponded with an increase in the severity of headaches, fatigue and cognitive difficulties and that this association was influenced by sex. Conclusion The observed sex-specific pattern of dysregulated PL, NL, HexCer and oxylipins in ME/CFS patients suggests a possible role of these lipids in promoting immune dysfunction and inflammation which may be among the underlying factors driving the clinical presentation of fatigue, chronic pain, and cognitive difficulties in ill patients. Further evaluation of lipid metabolism pathways is warranted to better understand ME/CFS pathogenesis.

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Introduction Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. Methods Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. Results Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07–3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23–3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12–7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56–6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07–5.62], p ≤ 0.05) among those who met the GWI case criteria. Conclusion These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

BackgroundThe apolipoprotein E e4 allele (APOE4) is a major risk factor, contributing to vascular pathologies in AD which include CAA, BBB dysfunction and reduced cerebral vascular integrity. The diminished capacity of APOE4 to transport docosahexaenoic acid (DHA), an essential fatty acid required for the structural and functional maintenance and vascular integrity of the brain, could also contribute to AD pathogenesis. However, it remains undetermined if changes in the brain DHA content of phospholipids (PL) and DHA transporters exist in relation to APOE4, AD diagnosis and CAA pathology.MethodWe performed liquid chromatography/mass spectrometry‐based PL analysis of the cerebrovascular and parenchymal fractions from autopsied human brain of pathologically confirmed AD cases and controls. We performed an antibody‐based examination of the major facilitator superfamily domain containing 2A (mfsd2a) protein in the cerebrovasculature from these subjects and brain homogenates from transgenic mice with human APOE (APOE‐TR) and APOE‐TR crossed with mice with five AD mutations (EFAD). We performed proteomic analyses of the cerebrovascular and parenchymal fractions of the brains from 50‐week‐old APOE‐TR.ResultIn the cerebrovasculature and parenchyma, DHA containing PL species were lower in ε4 carriers with AD compared to control ε4 carriers. We observed an ε4‐dependent decrease in mfsd2a level in the cerebrovasculature of ε4 carriers compared to non‐carriers. Stratification of DHA containing PL by CAA showed that these PL levels were reduced in ε4 positive AD patients with severe CAA. In addition, brain levels of DHA containing PC species and mfsd2a were lower in APOE4‐TR and E4FAD mice compared to other genotypes in each mouse model. Furthermore, protein levels of glucose transporter 1 (Glut1) and a metabolite transporter, monocarboxylate transporter 1 (MCT1), were lower in the cerebrovasculature of APOE4‐TR relative to APOE3‐TR and APOE2‐TR mice.ConclusionThese findings demonstrate that brain DHA deficiencies in ε4 carriers may be due to reduced mfsd2a expression and partly associated with severe CAA. Thus, targeting this transport mechanism may improve the bioavailability of DHA into the brains of ε4 carriers who are at risk of developing AD.