Diffusion MRI Profiles Map onto Distinct Inflammatory States After Adolescent Concussion: A CARE4Kids Study

Importance: Neuroinflammation is a key component of the response to injury after concussion, but direct links between diffusion MRI metrics and specific plasma inflammatory pathways in human concussion have not been established. Objective: To examine associations between diffusion MRI metrics and pathway-level inflammatory proteomic signatures in adolescents during the subacute period after concussion. Design, Setting, and Participants: Cross-sectional analysis of data from the CARE4Kids Consortium, a six-site prospective study. Participants were English-speaking adolescents ages 11-17.99 with concussion and symptoms at 7-35 days post-injury. Data were collected between 2022-2024. Of 370 enrolled participants, 122 had both diffusion MRI and plasma proteomics available for analysis. Exposure: Advanced diffusion MRI metrics were converted to z-scores and participants were grouped by the spatial extent of outlier values (potholes and peaks) across 15 white matter regions of interest. Nine non-redundant groupings were selected for primary analysis. Main Outcomes and Measures: Pathway-level inflammatory profiles derived from gene set enrichment analysis (GSEA) of ~5,400 plasma proteins measured by Olink proximity extension assay, targeting nine hallmark inflammatory pathways spanning initiation through resolution. Persistent symptoms were assessed 64-115 days post-injury. Results: Diffusion metrics reflecting tissue disorganization were associated with upregulation of the coagulation pathway, consistent with hemostatic-inflammatory signaling. Metrics reflecting reduced tissue complexity and neurite density were associated with upregulation of interferon- and interferon-{gamma} response pathways, consistent with microstructural remodeling driven by cellular immune activation. Elevated free water content was associated with downregulation of most inflammatory pathways and trend-level transforming growth factor - {beta} upregulation, reflecting inflammatory resolution. Time since injury did not differ between groups based on free water (Kolmogorov-Smirnov p = 0.97), suggesting these differences reflect individual variability in recovery pace. Exploratory analyses showed a trend toward lower odds of persistent symptoms in the group with elevated free water content (odds ratio = 0.51, p = 0.18). Conclusions and Relevance: Multiple diffusion MRI metrics are differentially sensitive to distinct neuroinflammatory states in the subacute period after adolescent concussion. These findings suggest that diffusion imaging could serve as a non-invasive tool for inflammatory phenotyping, with potential implications for identifying patients who may benefit from targeted immunomodulatory intervention.