Neurodegeneration in the cortical sulcus is a feature of chronic traumatic encephalopathy and associated with repetitive head impacts

Abstract

Neurodegeneration is a seminal feature of many neurological disorders. Chronic traumatic encephalopathy (CTE) is caused by repetitive head impacts (RHI) and is characterized by sulcal tau pathology. However, quantitative assessments of regional neurodegeneration in CTE have not been described. In this study, we quantified three key neurodegenerative measures, including cortical thickness, neuronal density, and synaptic proteins, in contact sport athletes (n = 185) and non-athlete controls (n = 52) within the sulcal depth, middle, and gyral crest of the dorsolateral frontal cortex. Cortical thickness and neuronal density were decreased within the sulcus in CTE compared to controls (p's < 0.05). Measurements of synaptic proteins within the gyral crest showed a reduction of α-synuclein with CTE stage (p = 0.002) and variable changes in PSD-95 density. After adjusting for age, multiple linear regression models demonstrated a strong association between the duration of contact sports play and cortical thinning (p = 0.001) and neuronal loss (p = 0.032) within the sulcus. Additional regression models, adjusted for tau pathology, suggest that within the sulcus, the duration of play was associated with neuronal loss predominantly through tau pathology. In contrast, the association of duration of play with cortical thinning was minimally impacted by tau pathology. Overall, CTE is associated with cortical atrophy and a predominant sulcal neurodegeneration. Furthermore, the duration of contact sports play is associated with measures of neurodegeneration that are more severe in the cortical sulcus and may occur through tau-dependent and independent mechanisms.

Keywords: Chronic traumatic encephalopathy; Contact sports; Cortical sulcus; Cortical thinning; Neurodegeneration; Neuronal loss; Repetitive head impacts; Synaptic loss; Tau pathology.

Fig. 1

Representative images of NeuN staining in CTE. a Cortical thickness was calculated by measuring three lines orthogonal to the pial surface and then computing the average. Analysis was based on three areas: crest, middle, and sulcus. b, c The number of NeuN+ cells in the sulcus of the dorsolateral frontal cortex was greater in control (b) compared to High CTE (c). Scale bars: a 5 mm; b, c 200 μm

Fig. 2

Cortical thickness measurements by pathology group in dorsolateral frontal gray matter in a sulcus, b middle, and c crest. a Cortical thickness within the sulcus was significantly different between groups, as shown by ANCOVA (p = 0.008). Post hoc pairwise comparisons showed that High CTE was significantly less than control (p = 0.015) and RHI (p = 0.04), and Low CTE was reduced compared to the RHI group (p = 0.039). b Within the middle of the gyrus, there were no significant differences between groups. c At the gyral crest, the cortical thickness was significantly different between groups, as shown by ANCOVA (p = 0.01). Post hoc pairwise comparison showed that the RHI group was significantly greater than control (p = 0.021). *p < 0.05, analysis of covariance adjusting for age at death and PMI

Fig. 3

Neuronal density by pathology group in dorsolateral frontal gray matter in a sulcus, b middle, and c crest. a Neuronal density within the sulcus was significantly different between groups, as shown by ANCOVA (p = 0.05). Post hoc pairwise comparisons showed that neuronal density was reduced compared to the control group in both Low CTE (p = 0.03) and High CTE (p = 0.014). b Within the middle of the gyrus there were no significant differences between groups. c At the gyral crest, there were no significant differences between groups. *p < 0.05, analysis of covariance adjusting for age at death and PMI

Fig. 4

α-synuclein and PSD-95 concentrations as measures of synaptic density in dorsolateral frontal gray matter tissue. a α-synuclein levels were significantly different between groups, as shown by ANCOVA (p = 0.028). Post hoc pairwise comparisons showed that RHI, Low CTE, and High CTE group all had significantly less α-synuclein than the control group (p < 0.01). b PSD-95 levels were significantly different between groups, as shown by ANCOVA (p < 0.001). Post-hoc pairwise comparisons showed that the Low CTE group had less PSD-95 than the control group (p = 0.009) and the High CTE group was increased as compared to Low CTE (p = 0.039). *p < 0.05 and **p < 0.01, analysis of covariance adjusting for age at death and PMI

Fig. 5

Schematic representation of mediation analysis modeling associations between repetitive head impacts, age of death, tau pathology, and neuronal density in the sulcus. Black arrows represent significant positive associations, and the red arrow represents significant negative association (p’s < 0.001). Standardized β’s are shown above arrows. Created in BioRender. Stein, T. (2024) BioRender.com/h62i404