Inflammatory-neurodegenerative crosstalk in pediatric severe traumatic brain injury: a multi-domain plasma proteomic study.

BACKGROUND

Pediatric severe traumatic brain injury (sTBI) remains a leading cause of death and long-term disability, yet its molecular characterization is incomplete. Single-biomarker approaches fail to capture the biological heterogeneity underlying variable clinical outcomes. Comprehensive proteomic profiling across neuropathologic domains to identify clinical endotypes has not been performed in pediatric sTBI. This study addresses this gap using high-throughput plasma neuro-proteomic profiling during the acute injury phase.

METHODS

We conducted an exploratory case-control study enrolling 23 pediatric sTBI patients (median age 15 years, 70% male) admitted to a Level 1 Trauma Center and 20 age- and sex-matched healthy controls. Plasma samples were collected on pediatric intensive care unit (PICU) Day 1 and Day 3. Proteomic analysis using the Nucleic Acid-Linked Immuno-Sandwich Assay quantified 120 proteins spanning five neuropathologic domains: neuroinflammation, neurodegeneration, amyloid/tau pathology, synaptic regulation, and vascular/metabolic pathways. Differential expression analysis identified dysregulated proteins in sTBI, facilitating interrogation of protein-protein interaction networks and protein-clinical variable correlations.

RESULTS

Proteomic analysis on PICU Day 1 identified 67 differentially expressed proteins (DEPs): 46 increased and 21 decreased. Inflammatory mediators (n = 31/51) dominated the response, with marked elevations in acute-phase reactants (SAA1, CRP), pro-inflammatory cytokines (IL-6, IL-33), and the anti-inflammatory marker IL-10. Network analysis revealed IL-6 as a central hub linking inflammatory and neurodegenerative pathways. Brain-specific proteins showed distinct temporal patterns: CRH, GFAP, S100B, pTau-231, pTau-181, REST, and TAFA5 displayed biphasic trajectories, whereas NEFH, NEFL, and NGF exhibited sustained increases through PICU Day 3. Enrichment analyses localized DEPs predominantly to inflammatory or neuronal compartments and tissues. Significant correlations emerged between multiple proteins and clinical outcomes.

CONCLUSIONS

This exploratory study provides the first comprehensive, multi-domain neuro-proteomic characterization of acute pediatric sTBI, revealing molecular disruptions beyond the scope of traditional single-biomarker approaches. We identified 67 DEPs spanning five neuropathologic domains, with network analysis revealing co-enrichment of inflammatory and neurodegeneration-related programs, consistent with known connectivity patterns. These findings establish a biological foundation for biomarker validation studies and inform precision medicine strategies in pediatric neurotrauma.