Abstract
The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran’s Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.
Highlights
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease associated with a prolonged history of repetitive head impacts (RHI) including concussive and subconcussive hits [1, 2]
Increased neuroinflammation is associated with longer RHI exposure Overall, there was no statistical difference in the density of total Iba1 immunoreactive microglia (Fig. 1a) or GFAP immunoreactive astrocytes (Fig. 1b) between groups
We show that increased neuroinflammation, as evidenced by increased CD68 cell density and enhanced microglia reactive morphology, was associated with more severe AT8 immunopositive ptau pathology in the dorsolateral frontal cortex (DLF) cortex of subjects neuropathologically diagnosed with CTE
Summary
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease associated with a prolonged history of repetitive head impacts (RHI) including concussive and subconcussive hits [1, 2]. We have previously shown in a heterogeneous cohort of deceased contact sport athletes and military personnel that the number of years of exposure to RHI significantly predicts increased CTE stage as defined by the extent of ptau pathology [5, 9]. The reported number of concussions was not significantly correlated with CTE stage [5, 9] and was less predictive than the cumulative head impact index of cognitive and neurobehavioral impairment [8]. 16 % of individuals diagnosed with CTE had no reported history of concussions suggesting subconcussive hits are sufficient for the development of the disease [10]. To date, an association between years of contact sports play and a quantitative measure of ptau pathology in the brain has not been shown, and the underlying factors linking RHI exposure to the development of CTE are unknown
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