Fluid Biomarkers for Neurobehavioral Dysregulation in Former American Football Players

Background The NINDS criteria define Traumatic Encephalopathy Syndrome (TES) as the clinical manifestation of the neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The core clinical features of TES include both cognitive and neuropsychiatric symptoms, the latter termed neurobehavioral dysregulation (NBD). We explored potential biological correlates of NBD by investigating fluid biomarkers of neuronal damage, astrogliosis, phosphorylated tau (pTau), neuroinflammation, and catecholamines in former American football players. Method Our cohort consisted of former professional (PRO) and college (COL) American football players from the DIAGNOSE CTE Research Project. NBD was measured by four subscales (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability) and a total NBD score, derived by factor analysis of multiple self‐report neuropsychiatric measures. Plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), CSF total tau and pTau181/231/217, as well as CSF biomarkers related to neuroinflammation (IL‐6, CRP, TNF‐α, VEGF‐A), were measured with various well‐validated immunoassay methods. Catecholamines in CSF (dopamine, 3,4‐dihydroxyphenylacetic acid, 3,4‐dihydroxyphenylalanine, noradrenaline, 3,4‐dihydroxyphenylglycol) were measured with HPLC. Multivariate linear regression models assessed the relationships between biomarkers and NBD scales, adjusted for age, BMI, race, and APOE e4, including stratification by exposure group, i.e., PRO, COL. Result Demographics and biomarker levels are displayed in Table 1. High levels of IL‐6 were significantly associated with higher scores of all NBD subscales, independent of exposure group. Other significant relationships included plasma NfL with emotional dyscontrol and impulsivity. Within the college group, CSF pTau181 was significantly associated with emotional dyscontrol and CSF noradrenaline with explosivity, emotional dyscontrol, impulsivity, and total NBD score. (Table 2 & Figure 1). IL‐6 models were repeated with measures of cognitive dysfunction (another core feature of TES) added as covariates; these analyses again found significant relationships between IL‐6 and NBD, irrespective of cognitive functioning. Conclusion We observed specific fluid biomarkers related to NBD in former American football players. Of note were the associations between IL‐6 and all NBD subscales (and not with cognitive functioning), suggesting that neuroinflammation may be a specific