Extracellular vesicle neurofilament light is elevated within the first 12-months following traumatic brain injury in a U.S military population

Vivian A Guedes,Megan M Wright,Rael T Lange,Jessica M Gill,Sara Mithani,Samantha M Baschenis,Sara M Lippa,Angela E Driscoll,Carina A Martin,Kisha Greer,Christina Devoto,Kelly C Gillow,Katie A Edwards,Louis M French,Tracey A Brickell,Chen Lai,Chelsea L Wagner

doi:10.1038/s41598-022-05772-0

Abstract

Traumatic brain injury (TBI) can be associated with long-term neurobehavioral symptoms. Here, we examined levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in extracellular vesicles isolated from blood, and their relationship with TBI severity and neurobehavioral symptom reporting. Participants were 218 service members and veterans who sustained uncomplicated mild TBIs (mTBI, n = 107); complicated mild, moderate, or severe TBIs (smcTBI, n = 66); or Injured controls (IC, orthopedic injury without TBI, n = 45). Within one year after injury, but not after, NfL was higher in the smcTBI group than mTBI (p = 0.001, d = 0.66) and IC (p = 0.001, d = 0.35) groups, which remained after controlling for demographics and injury characteristics. NfL also discriminated the smcTBI group from IC (AUC:77.5%, p < 0.001) and mTBI (AUC:76.1%, p < 0.001) groups. No other group differences were observed for NfL or GFAP at either timepoint. NfL correlated with post-concussion symptoms (rs = − 0.38, p = 0.04) in the mTBI group, and with PTSD symptoms in mTBI (rs = − 0.43, p = 0.021) and smcTBI groups (rs = − 0.40, p = 0.024) within one year after injury, which was not confirmed in regression models. Our results suggest the potential of NfL, a protein previously linked to axonal damage, as a diagnostic biomarker that distinguishes TBI severity within the first year after injury.

Highlights

Over the last decade, almost 250,000 US service members and veterans (SMVs) have sustained a traumatic brain injury (TBI), with the vast majority classified as mild Traumatic brain injury (TBI)[1]
TBI neuropathology consists of a primary injury that results of the traumatic insult, and secondary processes that may lead to glial and neuronal changes, and increased risk for later-in-life neurodegenerative conditions[3]
Biomarker studies in TBI have focused on circulating levels of proteins associated with pathological processes within the brain, including neurofilament light chain (NfL), a neurofilament protein highly expressed in large-caliber myelinated axons, and glial fibrillary acidic protein (GFAP), a component of the cytoskeleton of astrocytes[4–7]

Summary

Introduction

Almost 250,000 US service members and veterans (SMVs) have sustained a traumatic brain injury (TBI), with the vast majority classified as mild TBI (mTBI)[1]. EVs play a role in cell signaling and in the removal of unwanted proteins of the brain, and their cargo can functionally change the recipient cells[25,26]. They have been linked to the pathology of age-related neurodegenerative conditions such as Alzheimer’s Disease (AD)[27–29]. Elevated EV levels of GFAP, but not NfL, have been observed in a civilian population with history of moderate or severe TBI one year post-injury[33]. To the best of our knowledge, no study has evaluated EV NfL or EV GFAP levels across TBI severities (i.e., mild, moderate, and severe) at distinct chronic timepoints after TBI (i.e., ≤ 1 year, and > 1 year). No study has evaluated the potential of EV biomarkers in the stratification of mild injuries in uncomplicated and complicated mTBIs

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