Chronic Traumatic Encephalopathy and Primary Age‐Related Tauopathy

Abstract

It was with great interest that we read the article published by Mez et al who determined the relationship between the duration of football played and chronic traumatic encephalopathy (CTE) risk and severity in 266 deceased American football players. The results showed that the duration of football played had a strong dose-response relationship with CTE neuropathology after accounting for brain bank selection bias. 1 In 2016, preliminary consensus criteria were proposed for defining the neuropathology of CTE and concluded that CTE can be distinguished from other neurodegenerative diseases. However, in recent years, emerging evidence has indicated that the neuropathology described as unique to CTE may not be unique or specific to those who have experienced chronic traumatic brain injury. 2 Considering that the mean age at death of participants in this study was 48.9 to 68.7 years old, we raise one concern-that the effects of primary age-related tauopathy (PART) could be taken into consideration. PART is a common pathology associated with aging and presents pathologically as a non-amyloidbeta tauopathy with features overlapping with CTE. 3 A previous study found initial tau deposition in all individuals aged 40 years or older. 4 Our previous study demonstrated that PART was frequently observed in specimens from a Chinese brain bank. 5 Aging and the microtubule-associated protein tau (MAPT) gene H1 haplotype are the known major risk factors for PART. The relationship between the severity of the pathology and the duration of football played might partly be caused by the different distributions of age and MAPT gene H1 haplotype between the 2 groups if the pathology of some participants is PART rather than CTE. Furthermore, the study did not show a relation between cognitive function and the severity of pathology. Compared with patients with CTE, patients with PART usually have a relatively well-preserved cognitive function, but patients with higher neurofibrillary tangle (NFT) stages are more likely to have mild cognitive impairment (MCI). Cognitive impairment correlates with the severity of pathology in both CTE and PART, but it is more obvious in CTE. Thus, in participants with severe pathology in whom cognitive function is preserved, the diagnosis could favor PART rather than CTE. At present, there is no specific marker to pathologically differentiate CTE from PART. Future research is needed to determine whether patients with CTE suffer from a unique progressive neurodegenerative process, genetic predisposition, specific combinations of neuropathologies (eg, tau immunophenotypes, TDP-43, amyloid-β, synaptic dysfunction, and neuronal loss), and regional distribution patterns of pathologies need to be further evaluated for their roles in distinguishing CTE and PART.

Differential Vulnerability of Hippocampal Subfields in Primary Age-Related Tauopathy and Chronic Traumatic Encephalopathy

“…Although there are similarities, these findings suggest that the hippocampal p-tau pathology in CTE and PART can be differentiated neuropathologically, a distinction that has been previously questioned (28). These data also provide more information about the diagnostic features of CTE in addition to the pathognomonic lesion.…”