By Arielle Lehman, MD
Synopsis: This study demonstrates that both traumatic brain injury and participation in contact sports are independently associated with increased tau astrogliopathy, particularly thorn-shaped astrocytes, even when cases of chronic traumatic encephalopathy neuropathologic change are excluded.
Source: Arena JD, Stewart W, Kovacs GG, et al. Traumatic brain injury or head impacts from contact sports are associated with tau astrogiopathy. Brain. 2025;148(8):2671-2683.
Repetitive head impacts (RHI) and traumatic brain injury (TBI) are known risk factors for neurodegenerative disease later in life, including chronic traumatic encephalopathy (CTE). CTE neuropathologic change (CTE-NC) is characterized by hyperphosphorylated tau (p-tau) deposits in neurons and astrocytes at the depths of cortical sulci in a perivascular distribution. The tau pathology in CTE-NC primarily is neuronal but often is accompanied by p-tau immunoreactive thorn-shaped astrocytes (TSA). This distinctive pattern of p-tau in CTE-NC distinguishes it from aging-related tau astrogliopathy (ARTAG), where p-tau astrocytes, including TSA, are more widespread.
The authors of this study sought to investigate the association between TBI and contact sports-related RHI and the development of p-tau astrogliopathy, independent of CTE-NC and age. Specifically, the study assessed autopsy-derived brains and divided them into four groups: history of moderate/severe TBI, history of contact sports participation, and controls with or without neuropathologically confirmed neurodegenerative disease. A history of contact sports participation and TBI was gathered from available medical records and/or next of kin. Participation in contact sports included any level of play and did not delineate based on duration. Immunohistochemical staining with PHF-1 antibody was performed across four standardized brain regions targeting p-tau. Harmonized criteria for ARTAG were used to identify the presence of tau astrogliopathy and further categorize it by subtype and location.
A total of 556 post-mortem brains were analyzed. Considering differences across groups, contact sports had the highest proportion of men (97.8%) compared to 56.9% in the neurodegenerative disease group. In the trauma-exposed groups, 17% of the contact sports participants and 16% of the moderate/severe TBI individuals had a history of an additional TBI exposure. Overall, the study found that tau astrogliopathy was present in 75.6% of contact sports participants, 41.3% of controls with neurodegenerative disease, and 10.8% of healthy controls without neurodegenerative disease (P < 0.001). Moderate/severe TBI was associated with 2.08-fold increased odds of tau astrogliopathy compared to healthy controls (95% confidence interval, 1.13-3.84). The prevalence of tau astrogliopathy between the TBI cohort and controls with neurogenerative disease was similar; however, the TBI group typically was younger.
Regarding morphology, TSA was more common in contact sports participants and TBI subjects compared to both groups of controls, even when excluding CTE-NC cases. Analysis by location found that contact sports and TBI cases exhibited more frequent distribution of subpial TSA at sulcal depths (42.2% and 9.2%, respectively) compared to controls (< 3.6%). Lastly, the contact sports group showed a higher prevalence of TSA in all screened anatomical regions compared to the other groups.
Commentary
This study adds to the growing body of evidence linking both RHI from contact sports and TBI to the development of tau astrogliopathy. Although most research on neurodegenerative tauopathies has focused on CTE-NC, this study demonstrates that both contact sports participation and TBI are independently associated with increased tau astrogliopathy, with TSA being more prevalent in individuals exposed to RHI and TBI even after controlling for CTE-NC. This suggests that trauma exposure is an independent risk factor for tau astrogliopathy not solely explained by CTE-NC.
The preferential location of TSA at sulcal depths, regions known to be susceptible to mechanical strain during impact, supports a mechanistic link between TSA and trauma exposure. Importantly, the findings indicate that contact sports participation is more strongly associated with tau astrogliopathy than isolated TBI, although both exposures are significantly elevated compared to controls. These results suggest that frequent, subclinical head impacts may have a greater cumulative effect on the development of tau astrogliopathy than fewer, more clinically significant head injuries.
However, the clinical implications of tau astrogliopathy remain unclear. Although tau astrogliopathy is common in older adults and those with neurodegenerative disease, its increased frequency and unique distribution in trauma-exposed individuals suggest a distinct mechanism, with uncertain effect on cognitive or neuropsychiatric outcomes. In CTE, the specificity of clinical symptoms is low and often overlaps with other neuropathologies. A recent meta-analysis found that all CTE cases with premorbid cognitive deficits had comorbid non-CTE neuropathologies, and there was no consistent pattern of neuropsychological impairments.1 This underscores the ambiguous clinical significance of these neuropathologic results and the need for larger studies to elucidate clinical profiles associated with tau astrogliopathy.
Future research should stratify contact sports participation by duration of play, since longer exposure is a known risk factor for the development of CTE, with evidence supporting a dose-response relationship between years of contact sports involvement and risk of CTE pathology.
In summary, the findings of this study suggest that tau astrogliopathy, particularly TSA, may represent a neuropathological consequence of trauma. However, the clinical implications of these findings have not yet been established.
Arielle Lehman, MD, is a Neurologist at New York Presbyterian/Weill Cornell.
Reference
1. LoBue C, Bickart KC, Bieniek KF, et al. Cognitive impairment and dementia-related diagnoses in chronic traumatic encephalopathy: A systematic review and meta-analysis. Neurology. 2025;105(4):e213934.
