Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

Abstract

Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS–NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose–response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS–NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose–response relationship between RHI and CTE.

Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts

“…No p-tau astrocytes were found in the parenchyma or subpial region. The lack of p-tau astrocytes was surprising because subpial p-tau thorn-shaped astrocytes are a frequent finding in older individuals with CTE . Their absence indicates that p-tau astrocytes are not an early or essential feature of CTE.…”

Chronic traumatic encephalopathy neuropathologic change in former Australian rugby players

“…The TES criteria acknowledge that neurobehavioural dysregulation alone limits the diagnostic certainty of CTE‐NC to ‘suggestive of CTE’ [22]. However, a recent study of 152 young contact and collision sport athletes under 30 years of age also did not find an association between clinical symptoms, including neurobehavioral dysregulation, and CTE‐NC status (41.4% had CTE‐NC), despite a high frequency of cognitive and neurobehavioural symptoms in this convenience sample [49]. Similarly, psychiatric features are also used to draw inferences relating to provisional levels of certainty that a research subject might harbour CTE‐NC.…”

Update on modifiable risk factors for Alzheimer's disease and related dementias

“…Epidemiological research on the association between traumatic brain injury (TBI) and ADRD has been reignited by the delineation of chronic traumatic encephalopathy (CTE) – a neurodegenerative disease neuropathologically defined by a neuronal and astrocytic tauopathy preferentially located in perivascular areas in the depth of cortical sulci, clinically manifested with progressive cognitive decline and prominent behavioral disturbances, and typically affecting professional athletes of contact sports who sustain repetitive head impacts, both concussions and nonconcussive [56,77 ▪ ]. However, whether one or more TBIs in mid-life can increase the risk of late-onset ADRD remains controversial, partly due to substantial heterogeneity in study design.…”