Reiman, EM

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only postmortem , but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer’s disease (AD) and may lead to comorbid neuropathology. Characterization of the in vivo biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, n = 100) and college (COL, n = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, n = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ 40 , Aβ 42 , tTau, and pTau (pTau 181 , pTau 217 , pTau 231 ) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, APOE -ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ 40 ( p = 0.039) and Aβ 42 ( p = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ 40 ( p = 0.0041) and Aβ 42 ( p = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ 40 ( p = 0.011) and Aβ 42 (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent postmortem studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.

Abstract Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.