Exosomal neurofilament light: A prognostic biomarker for remote symptoms after mild traumatic brain injury?

Abstract

Objective: To measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms.

Methods: Exosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1-2 mTBIs, and repetitive (3 or more) mTBIs.

Results: Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF.

Conclusion: Repetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.

Figure 1. Exosomal and plasma levels of biomarkers

(A–J) Participants were divided into 3 groups: control, 1–2 mild traumatic brain injuries (TBIs), and 3 or more TBIs (repetitive mild TBI). Significant group differences were observed for plasma and exosomal neurofilament light (NfL). Biomarker concentrations represented as median + interquartile range. IL = interleukin; TNF-α = tumor necrosis factor–α; VEGF = vascular endothelial growth factor.

Figure 2. Correlations between traumatic brain injury (TBI) characteristics and biomarker levels

(A–I) Only significant correlations are shown. IL = interleukin; NfL = neurofilament light; TNF-α = tumor necrosis factor–α; VEGF = vascular endothelial growth factor.

Figure 3. Correlations between symptoms and biomarker levels within the traumatic brain injury (TBI) group

(A–H) Only significant correlations are shown. IL = interleukin; NfL = neurofilament light; NSI = Neurobehavioral Symptom Inventory; PCL-M = PTSD Checklist Military Version; PHQ-9 = 9-item Patient Health Questionnaire; TNF-α = tumor necrosis factor–α; VEGF = vascular endothelial growth factor.