Plasma Lipidomic Profiling in a Military Population of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder with Apolipoprotein E ɛ4–Dependent Effect

Abstract

In the military population, there is high comorbidity between mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) due to the inherent risk of psychological trauma associated with combat. These disorders present with long-term neurological dysfunction and remain difficult to diagnose due to their comorbidity and overlapping clinical presentation. Therefore, we performed cross-sectional analysis of blood samples from demographically matched soldiers (total, n = 120) with mTBI, PTSD, and mTBI+PTSD and those who were considered cognitively and psychologically normal. Soldiers were genotyped for apolipoprotein E (APOE) ɛ4, and phospholipids (PL) were examined using liquid chromatography/mass spectrometry analysis. We observed significantly lower levels of several major PL classes in TBI, PTSD, and TBI+PTSD, compared with controls. PTSD severity analysis revealed that significant PL decreases were primarily restricted to the moderate-to-severe PTSD group. An examination of the degree of unsaturation showed that monounsaturated fatty acid-containing phosphatidylcholine (PC) and phosphatidylinositol (PI) species were lower in the TBI and TBI+PTSD groups. However, these PLs were unaltered among PTSD subjects, compared with controls. Similarly, ether PC (ePC) levels were lower in PTSD and TBI+PTSD subjects, relative to controls. Ratios of arachidonic acid (AA) to docosahexaenoic acid (DHA)-containing species were significantly decreased within PC and phosphatidylethanolamine (PE) classes. APOE ɛ4 (+) subjects exhibited higher PL levels than their APOE ɛ4 (-) counterparts within the same diagnostic groups. These findings suggest that PL profiles, together with APOE genotyping, could potentially aid to differentiate diagnosis of mTBI and PTSD and warrant further validation. In conclusion, PL profiling may facilitate clinical diagnosis of mTBI and PTSD currently hindered by comorbid pathology and overlapping symptomology of these two conditions.

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

“…We also examined lipid species to determine whether specific lipid signatures could differentiate our three diagnostic groups. Functional magnetic resonance imaging and positron emission tomography have suggested metabolic changes in TBI (Dadas et al, 2018) and we have previously shown in these cohorts that several classes of plasma phospholipids including phosphatidylcholine (PC), lysoPC, phosphatidylethanolamine (PE), and lysoPE as well as sphingomyelin (SM) were all decreased in mTBI, PTSD, and mTBI + PTSD groups compared to controls (Emmerich et al, 2016). In the current study, we examined PS an additional PL as well as neutral lipids generally found in plasma lipid-rich lipoprotein particles responsible for transporting these lipids between various tissue including the brain and liver (Jonas and Phillips, 2008;Tracey et al, 2018).…”

“…The recruitment details of these military cohorts have been previously described in Emmerich et al (2016), where basic demographics as well as deployment related history, psychological health questionnaires and neurobehavioral symptoms data were collected from two cohorts of 120 active duty male soldiers, pre-deployment to the Middle East for Operation Iraqi Freedom/Operation Enduring Freedom, who participated on a voluntary basis under IRB approved consent. For the Army, a non-deployable status in relation to a psychiatric condition requires a clinician diagnosis in their medical record.…”

“…Samples were stored in dry ice before transport to a −80 • C medical specimen freezer at the end of each day. Additionally, samples from whole blood aliquots were APOE genotyped in our laboratory, by purifying the DNA (Gentra Puregene Blood Kit, Gentra Systems), then using standard polymerase chain reaction as described by Emi et al (1988) followed by electrophoresis with experimenters blinded to participants' group membership and other group characteristics (all procedures described in more details in Emmerich et al, 2016). Due to low numbers when stratifying by specific genotype in addition to diagnosis (six possible allele combination for four different diagnostic groups) and since most participants had either an ε3/ε3 or ε3/ε4 genotype, participants were grouped into ε4− and ε4+ groups where the ε4− group was composed of participants who did not have any ApoE ε4 allele and the ε4+ group of participants who had one or two ApoE ε4 alleles.…”

“…Blood lipids are emerging as candidate biomarkers of neurological disorders given their important role in the maintenance of brain health through their contributions to metabolic, inflammatory and neuro-signaling processes (Piomelli et al, 2007). Recent studies suggest that blood and brain lipids are chronically disturbed in both mTBI and PTSD (Hauer et al, 2013;Emmerich et al, 2016). Further, we and others have shown that major phospholipid (PL) classes involved in providing both structural and functional support to the brain are chronically altered in both brain and blood of mouse models of severe and mTBI (Abdullah et al, 2014;Ojo et al, 2018;Thau-Zuchman et al, 2019), in the blood of soldiers with mTBI (Emmerich et al, 2016) and in CSF of civilians after severe TBI (Pasvogel et al, 2010).…”

“…Recent studies suggest that blood and brain lipids are chronically disturbed in both mTBI and PTSD (Hauer et al, 2013;Emmerich et al, 2016). Further, we and others have shown that major phospholipid (PL) classes involved in providing both structural and functional support to the brain are chronically altered in both brain and blood of mouse models of severe and mTBI (Abdullah et al, 2014;Ojo et al, 2018;Thau-Zuchman et al, 2019), in the blood of soldiers with mTBI (Emmerich et al, 2016) and in CSF of civilians after severe TBI (Pasvogel et al, 2010). Many of the post-TBI changes in lipids that have been described involve alterations in blood and brain polyunsaturated fatty acids (PUFA)-containing PLs required for maintaining membrane integrity and synaptogenesis (Liu et al, 2015;Emmerich et al, 2017;Knobloch, 2017;Fiandaca et al, 2018).…”