Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis

Raymond Nicks, Nathan F. Clement, Victor E. Alvarez, Yorghos Tripodis, Zachery H. Baucom, Bertrand R. Huber, Jesse Mez, Michael L. Alosco, Nurgul Aytan, Jonathan D. Cherry, Kerry A. Cormier, Carol Kubilius, Rebecca Mathias, Sarah E. Svirsky, Morgan J. Pothast, Audrey M. Hildebrandt, Jaeyoon Chung, Xudong Han, John F. Crary, Ann C. McKeeMatthew P. Frosch, Thor D. Stein

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10 Scopus citations


Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

Original languageEnglish
Pages (from-to)395-408
Number of pages14
JournalActa Neuropathologica
Issue number4
StatePublished - Apr 2023


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