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.
Highlights
Traumatic brain injury (TBI) is recognized as a major risk factor for a range of neurodegenerative diseases, including Alzheimer’s disease and chronic traumatic encephalopathy (CTE) (Johnson et al, 2017; Smith et al, 2019)
While p-tau-immunoreactive thorn-shaped astrocytes were not observed in sections with Alzhemier’s disease neuropathologic changes (ADNC), these were abundant in cases with CTE neuropathologic change (CTE-NC) (Fig. 1)
P-tau immunoreactive thorn-shaped astrocytes in cases with CTE-NC were present in sub-pial locations and extending into deeper cortical layers (Fig. 2), with clustering around intracortical vessels
Summary
Traumatic brain injury (TBI) is recognized as a major risk factor for a range of neurodegenerative diseases, including Alzheimer’s disease and chronic traumatic encephalopathy (CTE) (Johnson et al, 2017; Smith et al, 2019). Several decades ago, as dementia pugilistica of former boxers (Millspaugh, 1937; Critchley, 1949; Critchley, 1957; Corsellis et al, 1973), consensus criteria for the neuropathological assessment of what is recognized as CTE only emerged in the last decade (McKee et al, 2016) These criteria define the pathognomonic lesion of CTE neuropathologic change (CTE-NC) as p-tau aggregates in neurons, astrocytes and Cortical tau in chronic traumatic encephalopathy. Earliest accounts of the neuropathology of CTE ( dementia pugilistica) described abundant neuronal profiles in the form of neurofibrillary tangles, with a noted preferential involvement of superficial cortical layers and patchy distribution of pathology Documented in these early reports was the subjective impression of an apparent concentration of tangles to the depths of cortical sulci (Hof et al, 1992; Geddes et al, 1996; Geddes et al, 1999), this was never formally quantified. In addition to neurofibrillary tangle pathology, tau-immunoreactive, thorn-shaped astrocytes (TSAs) are increasingly recognized as a prominent feature of CTE (Ikeda et al, 1995; Ikeda et al, 1998; McKee et al, 2009; McKee et al, 2013; McKee et al, 2016), with the combination of these glial and neuronal pathologies defining the pathognomonic lesion of CTE-NC (McKee et al, 2016); a pathology that has been documented in boxers, but in non-boxer athletes (Omalu et al, 2005; McKee et al, 2009; McKee et al, 2013; Smith et al, 2013; Stewart et al, 2016; Ling et al, 2017; Mez et al, 2017; Lee et al, 2019), military veterans (Goldstein et al, 2012; Stein et al, 2014) and individuals exposed to a single moderate or severe TBI (Johnson et al, 2012; Zanier et al, 2018; Tribett et al, 2019; Arena et al, 2020)
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