Neural exposome burden stratifies cognitive trajectories in a subacute-to-chronic mild TBI outpatient cohort: an exploratory dimension-reduction study

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Aim To translate the National Institute of Neurological Disorders and Stroke (NINDS) neural exposome framework into a clinically measurable model for 6-month cognitive trajectory after mild traumatic brain injury (mTBI) using principal component analysis (PCA).Methods Forty-four adults with mTBI (GCS 13–15; 50% female) were prospectively enrolled at an academic TBI clinic. Fifteen a priori variables spanning Exogenous, Endogenous, and Behavioral exposure categories were assessed. First, an outcome-informed forward-selection procedure identified a coherent 13-variable exposome set, summarized using PCA to derive a cumulative exposome burden score. Cognitive outcome was defined by residualized 6-month Montreal Cognitive Assessment (MoCA) performance dichotomized into worse-than-expected (WTE; ≤ −1 point) and not-worse-than-expected (nWTE) recovery groups. Second, separate PCA analyses were performed within each exposure category, without reference to cognitive outcome, to evaluate internal coherence and directional associations with cognitive recovery.Results Cross-category PCA identified a latent exposome axis explaining 16.0% of overall variance, driven primarily by education, area deprivation, insurance coverage, PM2.5 exposure, and adverse childhood events. Cumulative exposome burden scores were significantly higher in the WTE group (n = 15) versus nWTE (n = 29) (median PC1: 1.34 vs −0.76; p = 0.010), with similar findings on permutation testing (p = 0.037). Category-level PCA demonstrated coherent internal structure, with first principal components explaining 30.1% (Exogenous), 34.7% (Endogenous), and 39.7% (Behavioral) of within-category variance. Associations with residualized 6-month MoCA were directionally negative across all three categories.Conclusions Neural exposome burden composites stratified 6-month cognitive trajectories after mTBI. Coherent PCA structure across NINDS-informed exposure categories supports the feasibility of exposome-informed approaches for post-mTBI cognitive risk stratification.

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