Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports

Abstract

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

FIGURE 1.

Lewy body disease type is altered in participants with CTE (CTE-LBD) compared to AD (AD-LBD). The distribution of LBD type within each pathological group is shown. A chi-squared test between participants with Lewy body disease (LBD), CTE with LBD (CTE-LBD), AD with LBD (AD-LBD), and CTE with AD and LBD (CTE-AD-LBD) shows a significantly different distribution of LBD type between pathological groups (χ² = 45.6, p < 0.001). Participants with LBD alone or with CTE-LBD have significantly more brainstem LBD and significantly less amygdala-predominant LBD than AD-LBD (*p < 0.05 adjusted with the Bonferroni method for multiple comparisons). CTE-AD-LBD participants have a greater frequency of neocortical LBD than the other groups, but this difference did not achieve significance (χ² = 4.1, p = 0.129 for adjusted comparison to AD-LBD).

FIGURE 2.

Regional distribution of Lewy body deposition by unsupervised cluster analysis. A cluster heatmap shows the Lewy body pathology distribution within clusters. The column on the left indicates the cluster identity, and the column on the right represents the pathological diagnoses. The color scale indicates the semiquantitative severity of Lewy body pathology.

FIGURE 3.

Comparison of neurodegenerative protein density between pathological groups. Between participants with neocortical LBD and without LBD: (A) α-synuclein levels varied significantly between pathological groups (control, CTE, or AD; p = 0.025) and by the presence of neocortical LBD (p = 0.018, ANOVA). (B) Aβ_1-40 levels were not significantly different by pathological group or neocortical LBD. (C) Aβ_1-42 levels varied significantly by pathology (p = 0.009) and by the presence of neocortical LBD (p = 0.040, ANOVA). Multiple comparison testing (Bonferroni) showed significantly increased Aβ_1-42 in neocortical LBD compared to participants without LBD for both controls (p = 0.02) and CTE (p = 0.05). (D) Levels of pTau231 were different between pathological groups with increased levels in AD (p = 0.032) but did not differ with LBD. (E) Levels of pTau181 (U/mL) were different between pathological groups with increased levels in AD (p = 0.041) but did not differ with LBD. (F) The density of neurofibrillary tangles (NFT) by AT8 immunostaining was increased in CTE and further increased in CTE with neocortical LBD compared to controls (p = 0.038, ANOVA).