Table 1

Features of classic versus modern CTE

CharacteristicClassic CTEModern CTE
Number of reported casesApproximately 250 (11 detailed)27
Approximately 1530
Approximately 1041
Approximately 642
Approximately 343
85 (17 not considered CTE pathology)8 11
17 (6 not considered CTE pathology)35
Age of onsetLate 50s—early 60s22Staging of the disease11
Stage I: 22.2 years (SD=5.6 years)
Stage II: 39.0 years (9.3 years)
Stage III: 44.3 years (10.7 years)
Stage IV: 57.2 years (15.4 years)
Early 40s35

Age at death
range (mean)
57–91 years3014–98 years (mean: 54.1 years±23.3 years)11
18–52 years (mean: 41 years)35
Exposure60–700+ bouts and/or 7–25 years’ boxing27
>50% of sample had 300+ bouts and/or 15 years’ boxing. A number of cases also fought in an unknown number of booth contests30
5 and 24 years as a professional boxer; unreported number of bouts & 48 professional bouts, respectively8; otherwise unreported career lengths/exposure; primarily American football, hockey, and military exposure11;
No data on the career lengths/exposure; level of play—high school, collegiate and NFL football; professional boxing; wrestling; MMA35
Progression30% progress—physical symptoms may progressYes, mean 18.6 years8; Yes; noted in first three cases, but no progression reported in other cases35
Clinical featuresDysarthria, movement difficulties (slowing and ‘unsteady on feet’), tremor, later onset of memory problems, alcohol sensitivityNeuropsychiatric and behavioural symptoms prominent. Cognitive deficits and dementia with progression
Genotype riskApoE 428No ApoE 4 genotype risk11
DiagnosisClinically: clinical assessment and limited radiological evaluation27 30Neuropathologically confirmed on autopsy
Classic neuropathologySeptal fenestration, cerebellar scarring (inferior surface of the lateral lobes), degeneration of the substantia nigra and locus coeruleus, diffuse neurofibrillary tangle inclusion (medial temporal region, uncus, amygdala, hippocampus, parahippocampal gyrus, fusiform gyrus, lateral temporal, insular and frontal cortices). NFTs spread diffusely through the cerebral cortex and brainstem, with vast concentrations in the medial temporal grey, uncus, corticomedial part of the amygdala nucleus, hippocampus, parahippocampal nucleus, fusiform gyrus, lateral temporal area, insula and frontal cortex, with an absence of senile plaques30
Modern neuropathologyContingent upon stage of disease:
Stage I: mild lateral ventricular enlargement, focal epicentres of perivascular p-τ NFTs and astrocytic tangles (prominent in the sulcal depths and superior in the dorsolateral frontal cortices), rare isolated NFTs in the superficial laminae; low density NFTs in the locus coeruleus (2/7 cases); TDP-43 in the frontal subcortical white matter and fornix (4/7 cases)
Stage II: mild enlargement of the frontal horn of the lateral ventricles or third ventricle (6/11 cases), a small cavum septum (4/11 cases), the third ventricle was enlarged and slightly concave (3/11 cases), pallor of the locus coeruleus and substantia nigra (3/11 cases), severe gliosis and atrophy of one mamillary body (1/11 cases), p-τ pathology commonly in the superior, dorsolateral, lateral, inferior, and subcallosal frontal; anterior, inferior, and lateral temporal; inferior parietal; insular and septal cortices. NFTs in the superficial layers of the cortex, moderate density in tge locus coeruleus, nucleus basalis of Meynert, and amygdala, low densities p-τ NFTs in the hypothalamus, CA1 hippocampus, entorhinal cortex, thalamus, substantia nigra, dorsal and medial raphe nuclei of the midbrain, distorted axonal varicosities in the frontal and temporal cortices and white matter tracts, TDP-43 present (11/14 cases), found in the cerebral subcortical white matter, brainstem or medial temporal lobe (8/14 cases), severe TDP-43 (3/14 cases)
Stage III: mild cerebral atrophy with dilation of the lateral and third ventricles, septal abnormalities (5/12 cases), ranging from the cavum septum, septal perforation or absence, moderate depigmentation of the locus coeruleus (7/12 cases), mild depigmentation of the substantia nigra (6/12 cases), atrophy of the mamillary bodies, thalamus, sharply convex contour of the medial thalamus, thinning of the hypothalamic floor and thinning of the corpus callosum, NFTs widespread throughout the superior frontal, dorsolateral frontal, inferior orbital, septal, insular, temporal pole, superior middle and inferior temporal, and inferior parietal cortices, extensive NFTs in the hippocampus, entorhinal cortex, amygdala, nucleus basalis of Meynert and the locus coeruleus, frequent NFTs in the olfactory bulbs, hypothalamus, mamillary bodies, substantia nigra and dorsal and dorsal motor nucleus of the vagus, dentate nucleus of the cerebellum and spinal cord, severe axonal loss and distortion in the frontal and temporal cortices, TDP-43 in the cerebral cortex, medial temporal lobe or brainstem of most cases, more widespread in three cases
Stage IV: atrophy of the cerebral cortex and white matter, marked in the medial temporal lobe, thalamus, hypothalamus and mamillary bodies, ventricle enlargement, sharp concave contour of the third ventricle, cavum septum pellucidum, septal perforations or absence, pallor of the locus coeruleus and substantia nigra, striking neuronal loss in the cortex, hippocampal sclerosis affecting the CA1 and subiculum and astrocytic p-τ, p-τ abnormalities throughout the cerebrum, diencephalon, basal ganglia, brainstem and spinal cord, dense TDP-43 in the cerebral cortex, medial temporal lobe, diencephalon, basal ganglia, brainstem and, less frequently, the spinal cord
  • CTE, chronic traumatic encephalopathy; NFTs, neurofibrillary tangles; p-τ, phosphorylated τ protein.