Extracellular Vesicle Proteins and MicroRNAs Are Linked to Chronic Post-Traumatic Stress Disorder Symptoms in Service Members and Veterans With Mild Traumatic Brain Injury.

Vivian A Guedes,Heather L Rusch,William C Walker,Carina A Martin,Dilorom Sass,Christina Devoto,Bao-Xi Qu,Kimbra Kenney,Chen Lai,Katie A Edwards,Sara Mithani,Ramon Diaz-Arrastia,Rany Vorn,Elisabeth A Wilde,Jessica M Gill

doi:10.3389/fphar.2021.745348

Abstract

Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants (n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aβ) 42, Aβ40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls (p = 0.024) and mTBI participants with less severe PTSD symptoms (p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139–5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.

Highlights

Post-traumatic stress disorder (PTSD) is highly prevalent in military populations and frequently associated with deployment-related mild traumatic brain injury (Hoge et al, 2008; Schneiderman et al, 2008)
These findings contribute to the efforts to develop prognostic biomarkers of traumatic brain injury (TBI)-related behavioral health disorders, and shed light on possible molecular mechanisms associated with the development of persistent PTSD symptoms in TBI populations
We observed an association between persistent PTSD symptoms and the Extracellular vesicles (EVs) levels of miRNAs, especially hsa-miR-139–5p

Summary

Introduction

Post-traumatic stress disorder (PTSD) is highly prevalent in military populations and frequently associated with deployment-related mild traumatic brain injury (mTBI) (Hoge et al, 2008; Schneiderman et al, 2008). EVs have a lipid bilayer and contain a cargo that includes proteins (e.g., cytokines and growth factors) and microRNAs (miRNAs) (Taylor and Gercel-Taylor 2013; Snijders et al, 2018), which are small non-coding RNAs that are thought to play a major role in the regulation of gene expression and epigenetic alterations (Taylor and GercelTaylor, 2013). Neuroinflammatory activity can be initiated by EVs, which contain biologically active cytokines in their cargo and surface (Gupta and Pulliam, 2014; Fitzgerald et al, 2018). EVs readily cross the blood brain barrier (BBB) to the peripheral circulation, where they can be accessed and isolated, allowing for the quantification of their protein and miRNA content (Gupta and Pulliam, 2014; Fitzgerald et al, 2018)

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