Basic Science and Pathogenesis

Background: Traumatic brain injury (TBI) is recognized as one major, potentially modifiable risk factor for neurodegenerative disease (NDD). Autopsy studies describe a range of neuropathologies in a proportion of individuals surviving late after TBI, most frequently the tau associated pathology, chronic traumatic encephalopathy neuropathologic change (CTE-NC). In addition to tau, other NDD pathologies are described. Of these, deposition of abnormally phosphorylated transactive response DNA-binding protein 43 (pTDP-43) has been reported in association with CTE-NC. However, to date the prevalence and distribution of pTDP-43 in CTE-NC and its distinction from pathology of wider NDD has not been formally assessed.

Method: Patients with history of exposure to repetitive mild traumatic brain injury (rmTBI) and documented NDD (n = 30), together with age-matched controls with no known TBI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT-TBI archive. Whole slide digital images of standardized brain tissue sections stained for pTDP-43 (1D3) were reviewed, and the pattern and distribution of pathology mapped.

Result: Overall, prevalence of pTDP-43 pathology was similar among rmTBI patients (40%) and their age-matched controls with NDD (33%; p = 0.7778). However, while pTDP-43 was typically localized in controls with NDD and in rmTBI patients without CTE-NC (limbic-predominant age-related TDP-43 encephalopathy [LATE] stage 1-2), in patients with CTE-NC this pathology was more often widespread and high stage (LATE stage 3; p = 0.0045).

Conclusion: These results demonstrate rmTBI is associated with higher stage LATE pathology than in equivalent age matched controls and individuals with wider, non-TBI related NDD. Further studies are required to characterize the association between TBI and TDP-43 proteinopathy, including the contribution, if any, of this pathology to clinical sequelae of TBI related neurodegenerative disease.