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 severity of the hyperphosphorylated tau (p-tau) pathology, the McKee CTE staging scheme. The staging scheme defined four pathological stages of CTE, stages I(mild)–IV(severe), based on the density and regional deposition of p-tau. The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging scheme and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman’s rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-tau severity and density (p’s < 0.001). The severity and distribution of CTE p-tau followed an age-dependent progression: older age was associated with increased odds for having a higher CTE stage (p < 0.001). CTE stage was independently associated with increased odds for dementia (p < 0.001). K-medoids cluster analysis of the semi-quantitative scales of p-tau across 14 regions identified 5 clusters of p-tau that conformed to increasing CTE stage (stage IV had 2 slightly different clusters), age at death, dementia, and years of American football play. There was a predilection for p-tau pathology in five regions: dorsolateral frontal cortex (DLF), superior temporal cortex, entorhinal cortex, amygdala, and locus coeruleus (LC), with CTE in the youngest brain donors and lowest CTE stage restricted to DLF and LC. These findings support the usefulness of the McKee CTE staging scheme and demonstrate the regional distribution of p-tau in CTE.
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We would like to acknowledge the many families who contributed to this work, Christopher Nowinski, Ph.D. and Lisa McHale from the Concussion Legacy Foundation, and the clinical and neuropathology research staff of the BU CTE Center, VA Boston Healthcare System and Edith Nourse Rogers VA Medical Center This work was supported by grant funding from: NIA (AG057902, AG06234, RF1AG054156, K23AG046377), NINDS (U54NS115266, U01NS086659, and K23NS102399), National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345-5); Department of Veterans Affairs Merit Award (I01-CX001038), the Nick and Lynn Buoniconti Foundation, and BU-CTSI Grant Number 1UL1TR001430. JC is funded by the Alzheimer’s Association (AARF-17-529888). The views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official Veterans Affairs or Department of Defense position, policy, or decision, unless so designated by other official documentation. Funders did not have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
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Alosco, M.L., Cherry, J.D., Huber, B.R. et al. Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme. Acta Neuropathol 140, 495–512 (2020). https://doi.org/10.1007/s00401-020-02197-9
- Chronic traumatic encephalopathy
- CTE stage
- McKee CTE staging scheme
- Repetitive head impacts
- Neurodegenerative disease
- Traumatic brain injury