Plasma Neurofilament Light Chain (NF-L) Is a Prognostic Biomarker for Cortical Damage Evolution but Not for Cognitive Impairment or Epileptogenesis Following Experimental TBI

Abstract

Plasma neurofilament light chain (NF-L) levels were assessed as a diagnostic biomarker for traumatic brain injury (TBI) and as a prognostic biomarker for somatomotor recovery, cognitive decline, and epileptogenesis. Rats with severe TBI induced by lateral fluid-percussion injury (n = 26, 13 with and 13 without epilepsy) or sham-operation (n = 8) were studied. During a 6-month follow-up, rats underwent magnetic resonance imaging (MRI) (day (D) 2, D7, and D21), composite neuroscore (D2, D6, and D14), Morris-water maze (D35–D39), and a 1-month-long video-electroencephalogram to detect unprovoked seizures during the 6th month. Plasma NF-L levels were assessed using a single-molecule assay at baseline (i.e., naïve animals) and on D2, D9, and D178 after TBI or a sham operation. Plasma NF-L levels were 483-fold higher on D2 (5072.0 ± 2007.0 pg/mL), 89-fold higher on D9 (930.3 ± 306.4 pg/mL), and 3-fold higher on D176 32.2 ± 8.9 pg/mL after TBI compared with baseline (10.5 ± 2.6 pg/mL; all p < 0.001). Plasma NF-L levels distinguished TBI rats from naïve animals at all time-points examined (area under the curve [AUC] 1.0, p < 0.001), and from sham-operated controls on D2 (AUC 1.0, p < 0.001). Plasma NF-L increases on D2 were associated with somatomotor impairment severity (ρ = −0.480, p < 0.05) and the cortical lesion extent in MRI (ρ = 0.401, p < 0.05). Plasma NF-L increases on D2 or D9 were associated with the cortical lesion extent in histologic sections at 6 months post-injury (ρ = 0.437 for D2; ρ = 0.393 for D9, p < 0.05). Plasma NF-L levels, however, did not predict somatomotor recovery, cognitive decline, or epileptogenesis (p > 0.05). Plasma NF-L levels represent a promising noninvasive translational diagnostic biomarker for acute TBI and a prognostic biomarker for post-injury somatomotor impairment and long-term structural brain damage.

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

“…Across multiple models of single TBI, including closed head injury, controlled cortical impact, penetrating injury, blast injury and CHIMERA, NfL peaks in the days following injury ( Fig. 4A-C ) (7,39,40,46,50,52), with an injury-severity-dependent elevation (7) indicating that axonal injury/damage is a common pathophysiological mechanism. Notably, following rmTBI, NfL responds to cumulative injuries (45,46,49) and injury intervals (45,47), suggesting that NfL levels could inform on susceptibility to subsequent mild TBIs.…”

“…The overall temporal pattern of NfL blood levels closely aligns with studies in gyroencephalic models in pigs (109), and with the human data (7,20). However, there is a difference in the time-to-first-peak between rodents (days 1-3, (39,40,52)), pigs (days 5-10,(109)), and humans (days 14-21; (20)) ( Fig. 5 ), possibly related to species-specific differences in protein turnover rates or clearance mechanisms (110), anatomical differences in white matter (111), and differences in BBB dysfunction or permeability (112).…”

Review on the Role of Salivary Biomarkers in the Diagnosis of Mild Traumatic Brain Injury and Post-Concussion Syndrome

“…The molecular pathways through which NfL participates are mainly addressing the structural integrity of the neuronal cytoskeleton. Despite being an intracellular structural constituent of neurons, NfL could also be found in synaptic space, where they supposedly interact with NMDA GluN1 receptors by influencing their distribution [ 38 ]. Their local or systemic increased levels could indicate axonal injury and degeneration [ 39 ].…”

Neurofilament light chain: A possible fluid biomarker in the intrahippocampal kainic acid mouse model for chronic epilepsy?

“…Since 2020, a handful of (pre)clinical studies investigated the correlation between NfL levels and seizures as well. [13][14][15][16][17][18] Lybeck et al showed that patients with electrographic SE, due to brain injury after cardiac arrest, had elevated serum NfL levels compared to patients who did not develop SE after cardiac arrest. They suggest a correlation of SE with the development of additional secondary neuronal injury, predicted by higher serum NfL levels.…”

“…However, this does not reflect quantification in blood or cerebrospinal fluid (CSF). Since 2020, a handful of (pre)clinical studies investigated the correlation between NfL levels and seizures as well 13‐18 . Lybeck et al showed that patients with electrographic SE, due to brain injury after cardiac arrest, had elevated serum NfL levels compared to patients who did not develop SE after cardiac arrest.…”