Traumatic brain injury or head impacts from contact sports are associated with tau astrogliopathy

John D Arena; William Stewart; Gabor G Kovacs; Edward B Lee; John L Robinson; Virginia M-Y Lee; John Q Trojanowski; Andrea L C Schneider; Douglas H Smith; Victoria E Johnson

doi:10.1093/brain/awaf073

Traumatic brain injury or head impacts from contact sports are associated with tau astrogliopathy

Brain. 2025 Apr 2:awaf073. doi: 10.1093/brain/awaf073. Online ahead of print.

Authors

John D Arena¹, William Stewart^{2

3}, Gabor G Kovacs^{4

5

6}, Edward B Lee^{7

8}, John L Robinson⁷, Virginia M-Y Lee⁷, John Q Trojanowski⁷, Andrea L C Schneider^{9

10}, Douglas H Smith¹, Victoria E Johnson¹

Affiliations

¹ Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
² Department of Neuropathology, Queen Elizabeth University Hospital, Glasgow, UK, G51 4TF.
³ Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK, G51 4TF.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, Toronto, ON, M5T 0S8, Canada.
⁵ Krembil Brain Institute, University Health Network, Toronto, ON, Canada, M5T 0S8.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A8.
⁷ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
⁸ Translational Neuropathology Research Laboratory, University of Pennsylvania, Philadelphia, 19104, USA.
⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
¹⁰ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.

PMID: 40171950
DOI: 10.1093/brain/awaf073

Abstract

Exposure to traumatic brain injury (TBI) and/or repetitive head impacts (RHI) increases the risk of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy neuropathologic change (CTE-NC). Astrocytic tau pathology reminiscent of aging-related tau astrogliopathy (ARTAG) is a component feature of CTE-NC in many cases. Yet the relationship between TBI/RHI exposure and wider tau astrogliopathy, beyond that of CTE-NC, remains poorly characterized. Autopsy derived material from 556 individuals was selected to include cases with: a history of moderate or severe traumatic brain injury (survival >6 months; n=77) or a history of contact sports participation (n=45); for comparison with uninjured controls with (n=397) or without (n=37) neuropathologically confirmed neurodegenerative disease (NDD). Representative tissue sections from multiple brain regions were then immunostained for hyperphosphorylated tau (p-tau; PHF-1) and assessed in accordance with the harmonized evaluation criteria for ARTAG. PHF-1 immunoreactive thorn-shaped astrocytes (TSA) were observed more frequently in contact sports participants (75.6%) versus controls with (32.5%; p<0.001) and without (8.1%; p<0.001) NDD. In addition, while the prevalence of TSA following moderate/severe TBI (32.5%) was similar to NDD controls, regression analyses demonstrated increased odds of TSA, when adjusting for age and sex (OR 2.42; 95% CI 1.29-4.54). These findings were observed regardless of whether the pathognomonic lesion of CTE-NC was present in the regions examined. Intriguingly, while subpial TSA at sulcal depths were occasionally observed in aged controls with (3.6%) and without (2.8%) NDD, this pathology was considerably more common following RHI/TBI (42.2%; p<0.001). These findings support history of RHI and TBI as independent risk factors for the development of thorn-shaped tau astrogliopathy, over and above ARTAG observed in aging and wider neurodegenerative disease. Moreover, trauma may be associated with TSA within specific distributions, including the subpial region of the cortical sulcal depths. The clinical significance of these observations will be important to determine.

Keywords: ARTAG; aging-related tau astrogliopathy; chronic traumatic encephalopathy; thorn-shaped astrocytes; traumatic brain injury; traumatic brain injury related neurodegeneration.

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