Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury

Abstract

Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.

Figure 1

(A–D) Case 1: Whole mount 50-μm coronal sections immunostained for tau with monoclonal antibody AT8 and counterstained with cresyl violet showing irregular, patchy deposition of phosphorylated tau protein in frontal, subcallosal, insular, temporal, and parietal cortices and the medial temporal lobe.

Figure 2

(A–C) Whole mount 50-μm coronal sections of superior frontal cortex from case 1 (A), case 2 (B), case 3 (C) immunostained for tau with monoclonal antibody CP-13 showing extensive immunoreactivity that is greatest at sulcal depths (asterisks) and is associated with contraction of the cortical ribbon. (D–F) Microscopically there are dense tau-immunoreactive neurofibrillary tangles (NFTs) and neuropil neurites throughout the cortex, case 1 (D), case 2 (E) and case 3 (F). There are focal nests of NFTs and astrocytic tangles around small blood vessels (E, arrow) and plaque-like clusters of tau-immunoreactive astrocytic processes distributed throughout the cortical layers (F, arrows).

Figure 3

Whole mount 50-μm sections from cases 1 and 2 immunostained with anti-tau monoclonal antibody AT85. (A) Case 2. There is a prominent perivascular collection of neurofibrillary tangles (NFTs) and astrocytic tangles evident in the superficial cortical layers with lesser involvement of the deep laminae. Prominent neuropil neurites (NNs) are found in the subcortical U-fibers (arrow), original magnification x150. (B) Case 1. There is a preferential distribution of NFTs in layer II and NNs extending into the subcortical white matter even in mildly affected cortex, original magnification x150. (C) Case 1. Focal subpial collections of astrocytic tangles and NFTs are characteristic of chronic traumatic encephalopathy (CTE), original magnification x150. (D) Case 1. The shape of most NFTs and NNs in CTE is similar to those found in Alzheimer disease, original magnification x150. Some NFTs have multiple perisomatic processes (E) and spindle-shaped and dot-like neurites are found in addition to thread-like forms (E, Case 1, original magnification x350. (F) Case 1. Astrocytic tangles are interspersed with NFTs in the cortex (arrows, original magnification x350). (G) Case 1. Tau-immunoreactive astrocytes are common in periventricular regions, original magnification x150. (H, I) Case 1. Tau-immunoreactive astrocytes take various forms; some appear to be protoplasmic astrocytes with short rounded processes (H, I, double immunostained section with AT8 (brown) and anti-glial fibrillary acidic protein (red), (H) original magnification x350, (I) original magnification x945). (J) Case 2: Dot-like or spindle-shaped neurites predominate in the white matter although there are also some threadlike forms, original magnification x150.

Figure 4

(A–C) Whole mount 50-μm-thick coronal sections immunostained for tau (AT8) from case 1 (A), case 2 (B), case 3 (C) (counterstained with cresyl violet) showing extremely dense deposition of tau protein in the amygdala with increasing severity from left to right. (D–F) Microscopically, there is a moderate density of NFTs and astrocytic tangles in case 1 (D), the density is increased in case 2 (E), and extremely marked in case 3 (F), original magnification x350.

Figure 5

Whole mount 50-μm coronal sections of case 2 (A) and case 3 (B), immunostained for tau (AT8) and counter-stained with cresyl violet. There is extremely dense deposition of tau protein in the hippocampus and medial temporal lobe structures. There is also prominent tau deposition in the medial thalamus.

Figure 6

Tau-immunoreactive (AT8) NFTs, astrocytic tangles and neuropil neurites are found in many subcortical nuclei including the substantia nigra (A, case 3, original magnification x350) and nucleus basalis of Meynert (B, case 3, original magnification x350). NFTs are also abundant in the olfactory bulb (C, case 2, Bielschowsky silver method, original magnification x150) and thalamus (case 1, original magnification x350, AT8 immunostain counterstained with cresyl violet).

Figure 7

Whole mount tau (AT8)-immunostained 50-μm coronal sections of the brainstem from case 3 showing severe involvement of the locus ceruleus, pontine tegmentum, pontine base, midline medulla, and hypoglossal nuclei.