Cognitive, biomarker, and neuroimaging indices associated with traumatic encephalopathy syndrome across two independent athlete cohorts

Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC = 0.91, PPV = 0.80; DIAGNOSE CTE: AUC = 0.84, PPV = 0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.