Table 2

Histopathological classification of modern CTE

BU CSTE criteria—four stages of disease11Omalu et al—four phenotypes35
Stage 1
Normal brain weight. Focal epicentres of perivascular p-τ and NFTs and astrocytic tangles involving the sulcal depths and typically affecting the superior and dorsolateral frontal cortices
Phenotype I
Sparse to frequent NFTs and neuritic threads in the cerebral cortex and brainstem but without involvement of the subcortical nuclei (basal ganglia) and cerebellum. No diffuse amyloid plaques in the cerebral cortex
Stage 2
Normal brain weight. Multiple epicentres at the depths of the sulci with localised spread from epicentres to the superficial layers of the adjacent cortex. No NFTs or p-τ involvement in the medial temporal lobe
Phenotype II
Sparse to frequent NFTs and neuritic threads in the cerebral cortex and brainstem with or without such pathology in the subcortical nuclei (basal ganglia) and cerebellum. Diffuse amyloid plaques in the cerebral cortex
Stage 3
Mild reduction in brain weight. Mild cerebral atrophy with dilation of the lateral and third ventricles. Septal abnormalities. Moderate depigmentation of the locus coeruleus and mild depigmentation of the substantia nigra. Atrophy of the mamillary bodies and thalamus. Widespread p-τ pathology in the frontal, insula, temporal and parietal lobes. NF pathology in the amygdala, hippocampus and entorhinal cortex
Phenotype III
Brainstem predominant: moderate to frequent NFTs and neuritic threads in the brainstem nuclei, absent or sparse NFTs and neuritic threads in the cerebral cortex, subcortical nuclei (basal ganglia) and cerebellum. No amyloid plaques in the cerebral cortex
Stage 4
Marked reduction in brain weight with atrophy of the cerebral cortex. Marked atrophy of the medial temporal lobe, thalamus, hypothalamus and mamillary bodies. Severe p-τ pathology affecting most regions of the cerebral cortex and the medial temporal lobe, sparing the calcarine cortex. Severe p-τ pathology in the diencephalon, basal ganglia, brainstem and spinal cord. Marked axonal loss of subcortical WM tracts
Phenotype IV
Absent or sparse NFTs and neuritic threads in the cerebral cortex, brainstem, and subcortical nuclei (basal ganglia). No cerebellar involvement. No diffuse amyloid plaques in the cerebral cortex
  • CTE, chronic traumatic encephalopathy; LC, locus coeruleus; NF, neurofibrillary; NFTs, neurofibrillary tangles; p-τ, phosphorylated τ; SNr, substantia nigra; WM, white matter.