# Metabolic pathway dysregulation in diffuse axonal injury: a multimodal biomarker approach for early diagnosis and mechanistic insights

## TL;DR

This study identifies metabolic pathway disruptions in diffuse axonal injury, offering new biomarkers for early diagnosis and treatment insights.

## Contribution

The study introduces pathway-based biomarkers for diagnosing diffuse axonal injury and highlights mitochondrial and lipid metabolism as therapeutic targets.

## Key findings

- DAI patients show significant dysregulation in mitochondrial fatty acid oxidation and phospholipid metabolism.
- A multi-parameter model integrating metabolic markers achieved high diagnostic accuracy (AUC = 0.927).
- Pathway disruptions predicted 3-month functional outcomes with high accuracy (GOSE AUC = 0.912).

## Abstract

Diffuse axonal injury (DAI), a severe subtype of traumatic brain injury (TBI), lacks reliable early diagnostic biomarkers, contributing to poor clinical outcomes. Systemic metabolic pathway dysregulation in DAI remains poorly characterized, limiting targeted therapeutic strategies.

Identify DAI-specific metabolic network disruptions and evaluate their diagnostic and prognostic utility.

In this prospective cohort study, serum metabolomics profiling, pathway enrichment analysis, and machine learning were integrated with clinical assessments in 64 adults with acute TBI (30 DAI, 34 non-DAI). Untargeted metabolomics via UPLC-LTQ-Orbitrap MS identified differential metabolites, which were mapped to biological pathways using MetaboAnalyst 5.0. Diagnostic and prognostic performance of pathway-based models was assessed using ROC analysis.

DAI patients exhibited distinct metabolic perturbations, with significant dysregulation in mitochondrial fatty acid oxidation (FAO) and phospholipid metabolism. Key discriminative metabolites included carnitine C8:1 (VIP = 3.26) and lysophosphatidylcholine 22:3 sn-2, which correlated with Marshall CT scores (ρ = 0.62, p < 0.001) and pupillary reflex loss. A multi-parameter model integrating FAO and phospholipid degradation markers achieved superior diagnostic accuracy (AUC = 0.927, 95% CI: 0.86–0.98) compared to clinical models (AUC = 0.744). Pathway disruptions further predicted 3-month functional outcomes (GOSE AUC = 0.912).

DAI involves systemic metabolic network dysfunction centered on mitochondrial energetics and lipid metabolism. Pathway-centric biomarkers enhance diagnostic precision and prognostication, offering a novel framework for biomarker-driven management of TBI. These findings highlight mitochondrial FAO and phospholipid homeostasis as potential therapeutic targets, addressing a critical gap in DAI care.