Astroglial tau pathology alone preferentially concentrates at sulcal depths in chronic traumatic encephalopathy neuropathologic change

Abstract

Current diagnostic criteria for the neuropathological evaluation of the traumatic brain injury-associated neurodegeneration, chronic traumatic encephalopathy, define the pathognomonic lesion as hyperphosphorylated tau-immunoreactive neuronal and astroglial profiles in a patchy cortical distribution, clustered around small vessels and showing preferential localization to the depths of sulci. However, despite adoption into diagnostic criteria, there has been no formal assessment of the cortical distribution of the specific cellular components defining chronic traumatic encephalopathy neuropathologic change. To address this, we performed comprehensive mapping of hyperphosphorylated tau-immunoreactive neurofibrillary tangles and thorn-shaped astrocytes contributing to chronic traumatic encephalopathy neuropathologic change. From the Glasgow Traumatic Brain Injury Archive and the University of Pennsylvania Center for Neurodegenerative Disease Research Brain Bank, material was selected from patients with known chronic traumatic encephalopathy neuropathologic change, either following exposure to repetitive mild (athletes n = 17; non-athletes n = 1) or to single moderate or severe traumatic brain injury (n = 4), together with material from patients with previously confirmed Alzheimer's disease neuropathologic changes (n = 6) and no known exposure to traumatic brain injury. Representative sections were stained for hyperphosphorylated or Alzheimer's disease conformation-selective tau, after which stereotypical neurofibrillary tangles and thorn-shaped astrocytes were identified and mapped. Thorn-shaped astrocytes in chronic traumatic encephalopathy neuropathologic change were preferentially distributed towards sulcal depths [sulcal depth to gyral crest ratio of thorn-shaped astrocytes 12.84 ± 15.47 (mean ± standard deviation)], with this pathology more evident in material from patients with a history of survival from non-sport injury than those exposed to sport-associated traumatic brain injury (P = 0.009). In contrast, neurofibrillary tangles in chronic traumatic encephalopathy neuropathologic change showed a more uniform distribution across the cortex in sections stained for either hyperphosphorylated (sulcal depth to gyral crest ratio of neurofibrillary tangles 1.40 ± 0.74) or Alzheimer's disease conformation tau (sulcal depth to gyral crest ratio 1.64 ± 1.05), which was comparable to that seen in material from patients with known Alzheimer's disease neuropathologic changes (P = 0.82 and P = 0.91, respectively). Our data demonstrate that in chronic traumatic encephalopathy neuropathologic change the astroglial component alone shows preferential distribution to the depths of cortical sulci. In contrast, the neuronal pathology of chronic traumatic encephalopathy neuropathologic change is distributed more uniformly from gyral crest to sulcal depth and echoes that of Alzheimer's disease. These observations provide new insight into the neuropathological features of chronic traumatic encephalopathy that distinguish it from other tau pathologies and suggest that current diagnostic criteria should perhaps be reviewed and refined.

Keywords: Alzheimer’s disease; ageing-related tau astrogliopathy; chronic traumatic encephalopathy; tau; traumatic brain injury.

Graphical Abstract

Figure 1

Neuronal and astroglial tau pathologies of CTE neuropathologic change. (A) Low power view of cortical material from a former American football player who died in his 70s with a diagnosis of dementia with Lewy bodies (Case C5) reveals a patchy distribution of p-tau-immunoreactive (CP13) profiles, with apparent concentration of pathology to the sulcal depth (outlined in green) compared to the gyral crest (outlined in black). (B, C) There is clustering of p-tau immunoreactive profiles around cortical vessels, (D, E) which on higher power are revealed as typical neurofibrillary tangles (blue circles) and thorn-shaped astrocytes (red circles). Scale bars: (A) 1 mm, (B, C) 500 μm and (D, E) 50 μm

Figure 2

Maps of neurofibrillary tangles and thorn-shaped astrocytes in CTE-NC and ADNC. (A) Reviewing the annotated map of p-tau-immunoreactive (CP13) profiles in CTE-NC reveals numerous neurofibrillary tangles (blue) and thorn-shaped astrocytes (red), (C) with the former showing relatively uniform distribution across the sulcal depth (outlined in green) and gyral crest (outlined in black). (E) In contrast, thorn-shaped astrocytes (red) show marked clustering and concentration to the sulcal depth. (B) In parallel, analysis of ADNC (D) reveals a heavy burden of neurofibrillary tangles arranged in a classical bilaminar distribution across the cortex, with limited concentration to the sulcal depth. (F) No thorn-shaped astrocytes were present in ADNC. (A, C, E) Case C10, a former soccer player age 80s. (B, D, F) Case A6, a patient with known Alzheimer’s disease (age, 80 years)

Figure 3

Sulcal depth to gyral crest distributions of neuronal and astroglial pathologies in each case. (A) In cases with known CTE-NC, the ratio of sulcal depth to gyral crest CP13-positive thorn-shaped astrocyte pathology was typically high, in contrast to neurofibrillary tangles, which showed only limited sulcal concentration. (B) There was a close correlation between density of neurofibrillary tangles immunoreactive for CP13 and neuronal profiles identified using the antibody GT-38, which detects a conformation-dependent epitope of tau present in Alzheimer’s disease. The sulcal depth concentration of these pathologies in cases with CTE-NC was similar to that seen in cases with ADNC. NFT, neurofibrillary tangles; TSA, thorn-shaped astrocytes

Figure 4

Depth to crest ratio of tau pathologies in CTE-NC and ADNC. Quantitative assessment of thorn-shaped astrocytes and neuronal profiles in each case reveals astrocytes with a higher ratio of sulcal depth to gyral crest density (sulcal depth to gyral crest ratio 12.84 ± 15.47; mean ± SD) than co-existing neurofibrillary tangles (1.40 ± 0.74; P < 0.001). There was mild concentration of both CP13- and GT-38-immunoreactive neurofibrillary tangles in CTE-NC, which was similar to that seen in material from patients with ADNC (all analyses not significant). TSA, thorn-shaped astrocytes; NFT, neurofibrillary tangles; open circles, individual data points; crossed circles, outliers

Figure 5

Association of injury exposure, CTE-NC stage and age at death with thorn-shaped astrocyte distribution. (A) Concentration of thorn-shaped astrocytes to the sulcal depth was greater where there was a history of non-sports TBI (depth to crest ratio, 31.21 ± 22.79) than when exposure to TBI was through participation in contact sports (7.44 ± 6.92: P = 0.009). Although there was a greater concentration of thorn-shaped astrocytes to sulcal depths in cases with low (18.90 ± 19.80) versus high (6.78 ± 5.48) stage CTE-NC, this was not significant (P = 0.12). (B) There was no association between age at death and distribution of thorn-shaped astrocytes (R² = 0.063, P = 0.26). TSA, thorn-shaped astrocytes; open circles, individual data points; crossed circles, outliers