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

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.