Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy

TL;DR

The study finds that spinal cord tau and other protein pathologies are common in individuals with chronic traumatic encephalopathy, suggesting a broader condition called encephalomyelopathy.

Contribution

The study provides new evidence that spinal cord pathologies are prevalent in CTE-NC cases, expanding the understanding of trauma-related neurodegeneration.

Findings

All CTE-NC cases with RHI showed spinal cord p-tau pathology, with higher prevalence of p-TDP-43, Aβ, and α-synuclein compared to controls.

Spinal p-tau pathology was associated with microglial activation and motor symptoms in older individuals with RHI.

CTE-NC cases with RHI aged 65 or older frequently exhibited multiple co-occurring protein pathologies in the spinal cord.

Abstract

Are phosphorylated tau (p-tau) and other misfolded protein pathologies present in the spinal cord of individuals with repetitive head impact (RHI) exposure or chronic traumatic encephalopathy neuropathologic change (CTE-NC)?

In this case-control study, p-tau pathology in the spinal cord was observed in all CTE-NC cases with RHI, and older cases frequently exhibited phosphorylated TAR DNA-binding protein 43 (64%), amyloid-β (93%), and α-synuclein (50%) pathology; all these pathologies were more prevalent than in controls. Severity of p-tau pathology was associated with clinical symptoms and microglial activation in the spinal cord.

These findings suggest that the concept of CTE-NC may need to be expanded to encompass chronic trauma–induced encephalomyelopathy.

Exposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood.

To evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain.

This case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025.

RHI history and CTE-NC presence.

Informant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ), as well as amyloid precursor protein and human leukocyte antigen DR.

Of 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n = 14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), Aβ deposits (13 of 14 cases [93%]), and α-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE.

This case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.

This case-control study evaluates spinal cord pathologies associated with exposure to repetitive head impacts or chronic traumatic encephalopathy neuropathologic change in the brain among autopsied individuals.

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