Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury

Abstract

Almost a century ago, the first clinical account of the punch-drunk syndrome emerged, describing chronic neurological and neuropsychiatric sequelae occurring in former boxers. Thereafter, throughout the twentieth century, further reports added to our understanding of the neuropathological consequences of a career in boxing, leading to descriptions of a distinct neurodegenerative pathology, termed dementia pugilistica. During the past decade, growing recognition of this pathology in autopsy studies of nonboxers who were exposed to repetitive, mild traumatic brain injury, or to a single, moderate or severe traumatic brain injury, has led to an awareness that it is exposure to traumatic brain injury that carries with it a risk of this neurodegenerative disease, not the sport or the circumstance in which the injury is sustained. Furthermore, the neuropathology of the neurodegeneration that occurs after traumatic brain injury, now termed chronic traumatic encephalopathy, is acknowledged as being a complex, mixed, but distinctive pathology, the detail of which is reviewed in this article.

Keywords: CTE; amyloid; axons; neurodegeneration; tau; traumatic brain injury.

Figure 1

Proposed evolution of axonal and microglial pathologies contributing to late neurodegeneration following traumatic brain injury (TBI). In the intact, uninjured axon (a) microtubules composed of tubulin dimers bound by tau protein (h) transport cargo along the axon, including amyloid precursor protein (APP) and the enzymes responsible for its cleavage to amyloid β (Aβ) (e). As a consequence of dynamic stretch during injury, there is a change in the physical properties of tau protein, resulting in the mechanical breaking of microtubules, tau liberation, and its subsequent phosphorylation (i). At these sites of microtubule breakage, transport interruption follows, with the accumulation of transported cargo (f) resulting in axonal swelling (b), degeneration (c), and the liberation of large pools of Aβ, leading to plaque formation (g), a process that continues beyond the acute phase in a proportion of survivors (d). In parallel with this axonal pathology, there is a notable neuroinflammatory response marked by quiescent, ramified microglia (j) becoming activated (k); these activated and amoeboid microglia (l) persist beyond the acute phase in a proportion of survivors.

Figure 2

Neocortical tau pathology in chronic traumatic encephalopathy. Tau immunoreactive profiles are distributed throughout the neocortex, although they typically show a preferential distribution toward the superficial neocortical layers and depths of sulci [a, 49-year-old male 12 months following single, severe traumatic brain injury (TBI)], with a distinctive and characteristic perivascular accentuation of immunoreactive neurons and glia, whether exposed to repetitive, mild TBI (b, 56-year-old male, former rugby player) or a single, moderate or severe TBI (c, 48-year-old male 3 years following a single, severe TBI). The accumulations of subpial thorn-shaped astrocytes may also be observed (d, 59-year-old male, former soccer player). All sections stained for phosphorylated tau using antibody CP-13 (courtesy of Dr. P. Davies).

Figure 3

Tau pathology in chronic traumatic encephalopathy (CTE). In addition to neocortical tau pathology, tau-immunoreactive profiles are common in the hippocampus in CTE, with preferential involvement of sector CA2 by neurofibrillary tangles and extracellular tangles, as well as astroglial tau pathology (a, 59-year-old male, former soccer player). Elsewhere, tau pathologies are described in the deep gray nuclei and brainstem, where tau-immunoreactive substantia nigra neurons and neurites may be present, together with a degree of pigment incontinence (b, same case as in a). Scattered tau-immunoreactive axonal profiles are also common in subcortical and midline white matter (c, same case as a; d, 60-year-old male, former boxer). All sections stained for phosphorylated tau using antibody CP-13 (courtesy of Dr. P. Davies).

Figure 4

Axonal pathology in the corpus callosum with varying durations of survival after traumatic brain injury (TBI). A constant in all severities of TBI is diffuse axonal injury (DAI) with associated interruption of axonal transport. In tissue sections, DAI is typically revealed by staining for amyloid precursor protein (APP) and is detectable in under an hour following injury as immunoreactive axonal profiles with varying abnormal morphologies (a, 18-year-old male 11 h after severe TBI). Beyond this acute-phase axonal injury, evidence of ongoing interruption of axonal transport is marked by scattered, morphologically abnormal axons; staining for APP remains present in survivors 1 year or more after a single, moderate or severe TBI (b, 24-year-old male 8 years after a single, severe TBI) and in material from individuals exposed to repetitive, mild TBI (c, 59-year-old male, former soccer player). All sections stained for an antibody to the N-terminal amino acids 66–81 of APP (EMD Millipore).

Figure 5

Amyloid β (Aβ) plaque pathologies following traumatic brain injury (TBI). Diffuse Aβ plaques can be identified in autopsy and surgical material from approximately 30% of TBI patients during the acute phase post-injury (a, 51-year-old male 24 h following severe TBI). In the following weeks to months, these diffuse plaques resolve, only to reemerge in approximately 30% of survivors 1 year or more after a single, moderate or severe TBI as both neuritic and diffuse Aβ plaques (b, 55-year-old female 47 years after a single, severe TBI). Aβ plaques are also present in a majority of cases of chronic traumatic encephalopathy following exposure to repetitive, mild TBI; these are typically, although not exclusively, diffuse in subtype (c, 60-year-old male, former boxer; d, 59-year-old male, former soccer player). All sections stained using antibody 6F/3D, specific for the N-terminal epitope of Aβ (Dako, Agilent Technologies).

Figure 6

Neuroinflammation and degradation of white matter in the corpus callosum occurring with survival following traumatic brain injury (TBI). Material from approximately 30% of survivors at 1 year or more after a single, moderate or severe TBI shows evidence of white matter degradation as rarefaction in staining with Hematoxylin and eosin (d) when compared with material from uninjured controls (a). Accompanying this is evidence of ongoing neuroinflammation in the form of numerous amoeboid, activated microglia (e) in contrast to the quiescent, ramified microglia in uninjured controls (b). Staining for myelin with Luxol fast blue–Cresyl violet demonstrates an associated loss of myelin with evidence of continued myelin degradation after trauma (f). (a–c) Sections from the corpus callosum of a 38-year-old male non-TBI control whose cause of death was sudden, unexpected death in epilepsy. (d–f) Sections from the corpus callosum of a 56-year-old male with 3-year survival after a single, severe TBI. (b) and (e) stained for HLA-DP, -DQ, and -DR using antibody CR3/43 (Dako, Agilent Technologies) to reveal activated microglia.