Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy: A Detailed Clinical-Pathological Analysis

Introduction

Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease associated with exposure to repetitive head impacts (RHI), such as those sustained in contact sports or military service. While the diagnostic hallmark of CTE—the perivascular accumulation of phosphorylated tau (p-tau) in the cerebral cortex—is well-established, the extent of neurodegeneration outside the brain has remained largely overlooked. Emerging evidence suggests that the neurodegenerative process in RHI-exposed individuals may extend to the spinal cord, potentially explaining the motor symptoms often observed in these patients. This case-control study explores the prevalence and nature of spinal cord protein pathologies associated with CTE neuropathologic change (CTE-NC).

Patient Information

The study analyzed a retrospective autopsy series of 70 individuals (62 male, 8 female) with a mean age of 64.40 years (SD 13.94). The cohort was selected from a multicenter brain bank collaboration focused on individuals exposed to RHI. Of these 70 cases, 20 were confirmed to have CTE-NC in the brain. A significant history of repetitive head impacts was a common demographic feature among the cases, and informant-reported clinical histories were utilized to identify motor symptoms and other functional declines during life.

Diagnosis

The diagnosis of CTE-NC was confirmed through standardized brain autopsy protocols. For the spinal cord analysis, immunohistochemistry was performed for several key pathological proteins: phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ). Additionally, markers for microglial activation (human leukocyte antigen DR) and axonal injury (amyloid precursor protein) were assessed.

Key Diagnostic Findings:
1. Spinal p-tau Presence: 100% of cases with brain CTE-NC (n=20) exhibited spinal cord p-tau deposits. These deposits were most prevalent in individuals aged 65 or older with prior RHI.
2. Localization: In the older cohort (n=14), spinal tau pathology was extensive, presenting as both neuronal (100% of cases) and astrocytic (86% of cases) p-tau deposits.
3. Microglial Activation: Spinal p-tau pathology was significantly associated with microglial activation, suggesting an ongoing inflammatory response linked to the proteinopathy.
4. Clinical Correlation: The presence of these spinal pathologies was strongly associated with informant-reported motor symptoms prior to death.

Differential Diagnosis

In patients presenting with motor symptoms and a history of RHI, several differential diagnoses must be considered:
– Amyotrophic Lateral Sclerosis (ALS): While p-TDP-43 is a hallmark of ALS, in this cohort, p-TDP-43 was often confined to the spinal cord in CTE-NC cases, differing from the typical brain-and-spine progression of classic ALS.
– Alzheimer’s Disease (AD): While Aβ deposits were present in 93% of the older CTE-NC group, the specific perivascular pattern of tau in the brain distinguished these cases as CTE rather than primary AD.
– Parkinson’s Disease / Lewy Body Dementia: α-synuclein deposits were present in 50% of the older CTE-NC group, suggesting a complex overlapping proteinopathy rather than a single idiopathic disease.

Pathological Findings and Management

There is currently no cure for CTE-NC or its associated spinal pathologies. Management focuses on symptomatic relief and longitudinal monitoring. The study highlights the complexity of the pathology in older patients (65+). Among these individuals with CTE-NC and RHI history, multiple proteinopathies co-occurred:
– p-TDP-43 Inclusions: Present in 64% of cases.
– Aβ Deposits: Present in 93% of cases.
– α-synuclein: Present in 50% of cases.
– Multimorbidity: 29% of these individuals exhibited all four pathologies (tau, TDP-43, Aβ, and α-synuclein) simultaneously.

Interestingly, in 50% of the individuals with spinal p-TDP-43 pathology, the inclusions were restricted solely to the spinal cord and were not observed in the brain, suggesting the spinal cord may be uniquely vulnerable or an early site of protein misfolding in trauma-related cases.

Outcome and Prognosis

The presence of complex spinal proteinopathy indicates a more severe and widespread neurodegenerative process. The association with motor symptoms suggests that spinal cord pathology is a significant contributor to the clinical morbidity seen in RHI-exposed individuals. In contrast, individuals without CTE-NC (n=50) showed significantly fewer and sparser protein deposits, with p-tau seen in only 54% and generally at much lower severity. The presence of astrocytic tau pathology in RHI-exposed individuals even without brain CTE-NC suggests that the spinal cord may reflect trauma-induced changes earlier or differently than the brain.

Discussion

This study provides robust evidence for the concept of “trauma-related encephalomyelopathy.” The findings suggest that repetitive head impacts do not merely affect the brain but can trigger a cascade of misfolded protein aggregation throughout the central nervous system, including the spinal cord.

Clinical Significance: The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein in older patients with CTE-NC suggests that cumulative trauma may lower the threshold for multiple proteinopathies, leading to a complex clinical picture that may mimic or exacerbate other neurodegenerative diseases. The finding that p-TDP-43 was sometimes confined to the spinal cord is particularly noteworthy, as it suggests that clinicians should look beyond the brain when evaluating the neurological impacts of RHI.

Expert Commentary: The high prevalence of spinal pathology in this cohort supports the need for comprehensive neuroanatomical assessments in patients with a history of RHI. Future research should focus on identifying biomarkers that can detect these spinal changes in vivo to improve diagnosis and develop targeted therapies for those suffering from the long-term consequences of repetitive head trauma.

References

1. Tanaka H, Black LE, Forrest SL, et al. Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy. JAMA neurology. 2026;83(3):231-241.
2. McKee AC, Stein TD, Kiernan PT, Alvarez VE. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. 2015;25(3):350-364.
3. Stern RA, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81(13):1122-1129.