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.