Key points

Introduction

Chronic traumatic encephalopathy (CTE) is a recently defined neuropathologic entity (although, probably, a very old but unrecognized pathologic entity) that describes a constellation of brain lesions associated with a history of previous head trauma. Sudden and injurious events affecting the central nervous system (CNS) are clinically termed, altogether, traumatic brain injury (TBI). TBIs are events known since human beings have been able to report accidents of the head or how people have changed after such traumatic events. Although not always reported, TBIs have affected humanity because accidents to the head have been possible either as naturally occurring accidents (eg, casual cranial fractures, falls) or human-created connected risks (eg, automobiles, weapons). Peculiar types of TBI, especially for their association with specific neuropsychiatric consequences, are represented by traumatic brain events that cause immediate and often delayed motor, cognitive, and behavioral changes in war veterans coming back from war zones and combat operations. Although an antique issue present in human society for millennia, it was only during the late nineteenth century that TBIs and their medical sequelae were considered possibly linked to specific neuropathologic phenomena. Moreover, it was not until the 1920s and 1930s that systematic attempts, although still sporadic, were made to analyze the neuropathologic effects of single TBI (sTBI) and repetitive TBI (rTBI).

Considering the enormous long-lasting personal and socioeconomic impact of TBI for civilians and military personnel, it is surprising that, apart from those initial sporadic studies performed more than a century ago, the possible spectrum of brain disorders associated with TBI has scarcely been investigated in both civilians and military personnel until recent years. For example, the first systematic criteria to define CTE (a term initially introduced by Critchley in 1957) were only published in 2016 based on multiple collaborative efforts of a team of investigators participating in the First National Institutes of Health Consensus Conference to Define the Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy ( http://www.ninds.nih.gov/research/tbi/ReportFirstNIHConsensusConference.htm ). These multi-institutional decennial efforts to develop preliminary postmortem diagnostic criteria for CTE represent an important landmark in the study of TBI neuropathology. TBI investigators began then to systematically analyze and better describe those possible neuropathologic lesions that could be exclusively, or primarily, associated with TBI. Furthermore, the long-term clinicopathologic consequences of TBI as subjacent to CTE and other possible modifying cofactors (ie, aging, genetic background, environmental risks) also started to be more carefully considered.

The rapidly growing focus on CTE in the scientific and clinical communities as a disorder subjacent to TBI (and more specifically to mild TBI cases) has been stimulated by 2 recent historical events:

• 1.
  

  The unusual presence (for age, anatomic localization, and histologic distribution) of intracellular hyperphosphorylated tau–positive lesions in an autopsy brain of a professional American football player reported by Omalu and colleagues in 2005. Omalu and colleagues report, and its relevant mediatic and sociopolitical impact (even to the point of stimulating the making of a movie concerning contact sports activities and related brain issues: Concussion [ http://www.sonypictures.com/movies/concussion , 2016]), led other investigators to reconsider prior reports describing findings similar to the so-called punch-drunk syndrome described by Harrison S. Martland almost 90 years ago. Martland referred to previous studies published by Cassasa in 1924 and Osnato and Giliberti in 1927, which already described peculiar neuropathologic lesions in patients with concussion and hypothesized possible explanatory pathophysiologic mechanisms. Osnato and Giliberti had referred to even earlier works published by Tanzi and Lugaro in 1914, who began, for the first time in the published medical literature, to inquire about the possible chronic effects of concussion on the human brain. The reconsideration of the punch-drunk syndrome, followed by sporadic clinical and pathologic investigations on TBI, and of the more recent Omalu and colleagues report, triggered a series of studies designed to analyze possible clinical and pathologic consequences of various contact sports practices. For more than half a century, the prototype of all contact sports–related neurodegenerative syndromes has been dementia pugilistica (DP), a term coined first in 1937 by JA Millspaugh, a lieutenant of the Medical Corp of the US Navy. In his original manuscript, Millspaugh recognized that Jokl and Guttmann had already proposed a distinct form of dementia caused by pugilism. However, DP has been considered for many decades to be a unique posttraumatic brain syndrome almost, if not exclusively, confined to retired professional boxers and so reducing the chance for it to be considered and analyzed as part of a wider spectrum of possible TBI-related disorders.

  
  
• 2.
  

  The second relevant historical event linked to the renaissance of TBI-related neuropathologic studies has been the increased number of United States and United States allies’ veterans returning home from long-lasting war operations, namely Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND). Some of these veterans have experienced a wide range of postwar disorders, possibly related to TBI and posttraumatic stress disorder (PTSD). Specifically, these recent war conflicts have been characterized by the widespread use of improvised explosive devices (IEDs). Veterans from OEF/OIF/OND, although better protected and more likely to survive TBI than soldiers in past wars, are now facing different types of long-term sequelae possibly caused by IEDs and other related blast-type explosives. Blast TBI is considered the signature injury of current warfare, which has also been referred to as an invisible wound. The original invisibility of this wound has been mainly attributable to the fact that in most of these veterans, the medical and neuropsychiatric consequences are not associated with any specific serologic, neurophysiologic, or neuroimaging biomarker. Moreover, initial neuropsychiatric signs and symptoms may not appear until soldiers exposed to IED/blasts return home. Whether and how IEDs, and blast TBI in general, directly affect the CNS in humans is the main topic of ongoing intense clinical, neuroimaging, and neuropathologic investigations.

The 2 events described earlier have stimulated the scientific community to increase the investigative efforts to define the neuropathologic consequences of TBI either in terms of short-term or long-term effects. The renewed and growing interest in TBI-related disorders research has also been reinforced by recent epidemiologic studies showing a significant association between a history of TBI and an increased risk of dementia, parkinsonism, and more general neurodegenerative disorders.

This article summarizes the neuropathologic knowledge about CTE as acquired until June 2016.