Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme

Abstract

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive head impacts (RHI) that has been neuropathologically diagnosed in American football players and other contact sport athletes. In 2013, McKee and colleagues proposed a staging scheme for characterizing the severity of the hyperphosphorylated tau (p-tau) pathology, the McKee CTE staging scheme. The staging scheme defined four pathological stages of CTE, stages I(mild)-IV(severe), based on the density and regional deposition of p-tau. The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging scheme and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman's rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-tau severity and density (p's < 0.001). The severity and distribution of CTE p-tau followed an age-dependent progression: older age was associated with increased odds for having a higher CTE stage (p < 0.001). CTE stage was independently associated with increased odds for dementia (p < 0.001). K-medoids cluster analysis of the semi-quantitative scales of p-tau across 14 regions identified 5 clusters of p-tau that conformed to increasing CTE stage (stage IV had 2 slightly different clusters), age at death, dementia, and years of American football play. There was a predilection for p-tau pathology in five regions: dorsolateral frontal cortex (DLF), superior temporal cortex, entorhinal cortex, amygdala, and locus coeruleus (LC), with CTE in the youngest brain donors and lowest CTE stage restricted to DLF and LC. These findings support the usefulness of the McKee CTE staging scheme and demonstrate the regional distribution of p-tau in CTE.

Keywords: CTE stage; Chronic traumatic encephalopathy; McKee CTE staging scheme; Neurodegenerative disease; Repetitive head impacts; Traumatic brain injury.

Fig. 1.. Box Plots of Quantitative Measurements of Regional P-tau Accumulation by CTE Stage.

Spearman’s rho correlations showed that greater p-tau density was associated with a higher CTE stage for all regions assessed (p’s < 0.001 for all). The sample size was reduced to 176 as this represents the sample with available quantitative data across all 7 brain regions at the time of this data freeze (July 2019). The mid-point line in the box represents the median, the interquartile range box represents the middle 50%, and the whiskers represent the bottom and top 25% of data value. Y-axis values are positive pixels (mm²) and are on a logarithmic scale.

Fig. 2.. Association Between Age at Death and CTE Stage.

Histogram of the distribution of age at death by CTE stage (N = 366). Ordinal logistic regression showed that older age was associated with increased odds for having a higher CTE stage (OR = 1.08, 95% CI = 1.06-1.09, p < 0.001).

Fig. 3.. Association Between Age at Death and Regional P-tau Progression.

Heat map of semi-quantitative p-tau pathology (0 to 3, 3 most severe) for 14 brain regions (N = 287); in addition to exclusion of those for missing data across all regions, the three individuals in the 90-100 decade of age at death were not included in the heat map due to insufficient sample size. In each region, 0= no NFTs, 1= 1 NFT per 20X field, 2= 2-3 NFTs per 20X field, 3 = ≥4 NFTs per 20 x field. Darker color is indicative of greater p-tau pathology. The color scale for the heat map is based on the distribution of all values. The values are averages of semi-quantitative p-tau pathology among the individuals for each age group. Abbreviations: DLF = dorsolateral frontal cortex; RC = Rolandic Cortex; IF = inferior frontal cortex; IP = inferior parietal cortex; EC = entorhinal cortex; SN = substantia nigra; LC = locus coeruleus

Fig. 4.. Scatter Plots of the Association between Age at Death and Quantitative Measurements of P-tau Density.

The sample size was reduced to 176 as this represents the sample with available quantitative data across all three brain regions at the time of this data freeze (July 2019). Older age was associated with greater quantitative p-tau density for each region assessed (p’s < 0.05). For the dorsolateral frontal cortex, p-tau density was measured at the depth of the cortical sulcus (defined as the bottom third of two connecting gyri) and at the gryal crest (defined as the top third of two connecting gyri). For quantitative hippocampal subfield analysis, CA2 and CA3 were combined into one field denoted as CA2/3. Y-axis values are positive pixels (mm²) and are on a logarithmic scale.

Fig. 5.. Dementia Status by CTE Stage and p-tau Accumulation in the Dorsolateral Frontal Cortex and Hippocampus.

Left: Pie chart of the number (%) of brain donors with dementia by CTE stage (N = 359). For percents, denominator is total brain donors with dementia (n = 216). Right: In CTE, p-tau deposition often begins in the dorsolateral frontal cortex (DLF), with the hippocampus becoming involved in later disease stages (i.e., Stage III). The density of p-tau in the DLF and hippocampus and the size of the pathognomonic CTE lesions increases with age. These regions are therefore sensitive markers of the progression and severity of disease. The images on the right are exemplary of the severity of pathology in these regions by age and dementia status. (A) Mild perivascular accumulation of p-tau at the depths of the cortical sulcus in the DLF in a non-demented 30 year old with stage II CTE; (B) Severe perivascular accumulation of p-tau at the depths of the sulcus in the DLF in a demented 80 year old with stage IV CTE; (C) Absence of hippocampal p-tau accumulation in a non-demented 44 year old with stage II CTE; (D) Hippocampal p-tau accumulation in a demented 69 year old with stage III CTE. Positive staining for p-tau is depicted in red while hematoxylin counterstain is in blue. Scale bar represents 200um (A, B) and 2mm (C, D).

Fig. 6.. K-Medoids Cluster Analysis of 14 Semi-Quantitative Rating Scales of Regional P-tau Pathology and their Association with CTE Stage.

A k-medoids cluster analysis with the 14 semi-quantitative rating scales was conducted to determine the different patterns of regional p-tau deposition and to ascertain how these patterns differed by CTE stage. (6a) Using the Gap Statistic method, 5 clusters best fitted the data. (Ten cluster sizes were examined. After 5 clusters, there was minimal difference between the clusters). (6b) Heat map of the medoids of each cluster. The 14 brain regions on the x-axis are those that were rated for p-tau severity using a 0-3 scale, with 0 being none and 3 being severe p-tau involvement. The 5 clusters are represented on the y-axis. The median score of p-tau severity for each brain region is graphed using the shown color scale; darker colors reflecting more severe p-tau. (6c) Association of cluster assignment and CTE stage. Abbreviations: DLF = dorsolateral frontal cortex; RC = Rolandic cortext; IF = inferior orbitofrontal cortex; IP = inferior parietal cortex; ST = superior temporal cortex; EC = entorhinal cortex; SN = substantia nigra; LC = locus coeruleus