Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

Abstract

In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, football, football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression.

GM1 ganglioside prevents axonal regeneration inhibition and cognitive deficits in a mouse model of traumatic brain injury

“…Considering all the studies presented above, there is a strong basis to assume that the administration of GM1 ganglioside can inhibit the AOI mechanism following traumatic brain injury, thereby serving as a neuroprotective agent in various brain injuries. Since in the past decade or even earlier, TBI has been established as a major cause to CTE (chronic traumatic encephalopathy) 44 – 46 new and novel potential treatments are needed to address this destructive process. Although GM1 have previously been used as a potential treatment for neurodegenerative diseases like PD and HD 40 , 47 , it is important to emphasize that in contrast to these reports where a high dose of GM1 or a longer range of treatment was needed to obtain desired results, this low-single dose was sufficient to prevent cognitive and biochemical damage.…”

Inhibition of Glycogen Synthase Kinase 3β as a Treatment for the Prevention of Cognitive Deficits after a Traumatic Brain Injury

“…Excessive p-tau is a major contributor to CTE. 36 This has been seen in sports such as boxing and football. 37 p-GSK-3b is the primary kinase that phosphorylates tau, and p-tau is known to increase following a TBI.…”

A Clinicopathological Report of a 93-Year-Old Former Street Boxer With Coexistence of Chronic Traumatic Encephalopathy, Alzheimer's Disease, Dementia With Lewy Bodies, and Hippocampal Sclerosis With TDP-43 Pathology

“…In 2016, the first NINDS/NIBIB consensus meeting defined the neuropathological criteria of CTE and confirmed that the pathognomonic lesions in CTE are accumulations of abnormally hyperphosphorylated tau (p-tau) in astrocytes and neurons located around small blood vessels and at the depths of the cortical sulci (10). CTE, a new neurodegenerative tauopathy, was reported in athletes who played soccer, baseball, ice hockey, and rugby, as well as in military personnel exposed to explosive blasts (5)(6)(7)11). Clinical presentation of CTE was divided into three phases: behavioral/psychiatric, cognitive, and motor (12,13).…”

“…Traumatic brain injury (TBI) was long recognized as a risk factor for dementia (1)(2)(3)(4)(5). Chronic traumatic encephalopathy (CTE) refers to the neuropathological changes resulting from repeated episodes of TBI (3,(5)(6)(7). In the early twentieth century, the terms "punch-drunk" or "dementia pugilistica" were used to describe the clinical features of a distinct neuropsychiatric syndrome that affected boxers.…”