Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive head impacts (RHI) that has been neuropathologically diagnosed in American football players and other contact sport athletes. In 2013, McKee and colleagues proposed a staging scheme for characterizing the

Introduction:Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed.Methods: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on NeurologicalThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

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Objective:To test the hypothesis that repetitive head impacts (RHI), like those from contact sport play, and traumatic brain injury (TBI) have long-term neuropsychiatric and cognitive consequences, we compared middle-age and older adult participants who reported a history of RHI and/or TBI to those without this history on measures of depression and cognition.Methods:This cross-sectional study included 13,323 individuals (mean age=61.95, 72.5% female) from the Brain Health Registry who completed online assessments, including the Ohio State University TBI Identification Method; the Geriatric Depression Scale (GDS-15); and the CogState Brief Battery and Lumos Labs NeuroCognitive Performance Tests. Inverse propensity weighted linear regressions accounting for age, sex, race/ethnicity, and education tested the effects of RHI and TBI compared to a non-RHI/TBI group.Results:725 reported RHI exposure (mostly contact sport play and abuse) and 7,277 reported TBI (n=2,604 with LOC). RHI (beta=1.24, 95% CI=0.36,2.12), TBI without LOC (beta=0.43, 95% CI=0.31,0.54), and TBI with LOC (beta=0.75, 95% CI=0.59,0.91) corresponded to higher GDS-15 scores. While TBI with LOC had the most neuropsychological associations, TBI without LOC had a negative effect on CogState Identification (beta=0.004, 95% CI=0.001,0.01) and CogState One Back Test (beta=0.004, 95% CI=0.0002,0.01). RHI predicted worse CogState One Back Test scores (beta=0.02, 95% CI =-0.01,0.05). There were RHIxTBI interaction effects on several neuropsychological subtests, and participants who had a history of both RHI and TBI with LOC had the worse depression symptoms and cognition.Conclusions:RHI and TBI independently contributed to mid- to worse mid- to later-life neuropsychiatric and cognitive functioning.