Evidence suggests that repetitive disturbance of axons along with altered neurotransmission is linked to widespread glutamate release, ionic fluxes, and metabolic uncoupling.15 These changes may generate a chain of events leading to CTE.15
Animal models have shown decreased serum and cerebrospinal fluid (CSF) levels and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that dephosphorylates the p-Tau protein essential for microtubule assembly. Accumulation of p-Tau eventually causes neuronal death.16
A recent consensus conference defined the irregular pattern of p-Tau immunoreactivity deposition surrounding microvasculature in the depths of cortical sulci as pathognomonic for CTE, a distinction from other tauopathies.
Supportive features include abnormal p-Tau neurofibrillary tangles (NFTs) distributed in layers I-II of the cortex; p-Tau thorn-like astrocytes in the subpial and periventricular regions of the cortex; pretangles, extracellular tangles, or NFTs; and dendritic swellings in the hippocampus.
Also supportive of CTE are dot-like structures and TDP-43 immunoreactive neuronal inclusions in the antromedial temporal cortex, amygdala, and the hippocampus, as well as septal abnormalities, atrophy of mammillary bodies, and third ventricle dilation.17 Staging for CTE pathology has been proposed.10
There are some similarities between Alzheimer’s disease (AD) and CTE, suggesting a separate classification of CTE-AD; the presence of Aβ plaques correlates with more severe p-Tau pathology and advanced stages and clinical presentations.18
Plaques in CTE-AD are more likely to be found within the sulci, contrasting with the gyral depositions observed in AD. Death tends to occur 10 years earlier, suggesting that repetitive mTBI may accelerate and change the deposition and accumulation of Aβ; presence of Aβ plaques may correlate with CTE progression and may speed up the aging process of the brain. The presence of Aβ plaques is believed to increase the odds of developing cognitive dysfunction in CTE by 4.5 times in individuals with Aβ pathology.18
Although CTE cannot currently be diagnosed via imaging, there are a few PET ligands for p-Tau that show some promise. [F-18]FDDNP consistently identifies p-Tau deposits in brains with clinically-suspected CTE in the same distribution of p-Tau NFTs on autopsy, and the ligand [11C]DPA-713 has detected TBI-related neuronal inflammation in 9 former NFL players with clinically-suspected CTE. The PiB amyloid ligand is also being investigated for utility in PET neuroimaging.19
Image 1 depicts the different stages of CTE.
The average age of symptom onset is between 30 and 64 years of age. Within the first 48 hours to 2 weeks after an mTBI, cognitive deficits are common.20 Four stages of neuropsychiatric symptoms were proposed in 201310, and are similar to the posthumous progression described in 2011 by Omalu et al.5
Stage I symptoms include memory loss, executive dysfunction, difficulty concentrating, inattention, aggression, depression, explosivity, and suicidality. Headache is fairly common. At this stage, very few individuals will see a psychiatrist.