Key points

Introduction

There are growing concerns that cumulative repetitive head impact exposure through routine participation in contact and collision sports is associated with increased risk of chronic neurologic and neuropsychiatric problems. Among the issues associated with cumulative repetitive mild traumatic brain injury are persistent postconcussive symptoms and long-term problems in memory and cognition, including the development of chronic traumatic encephalopathy (CTE).

CTE is a unique neurodegenerative disorder that occurs as a latent consequence of cumulative repetitive head impacts (RHIs), including concussion and subconcussion. CTE was first associated with the sport of boxing in 1928, when Harrison Stanford Martland described the clinical features of a neuropsychiatric syndrome that affected pugilists, a condition then known as “punch drunk” or “dementia pugilistica.” Over the following decades, it was gradually recognized that the condition affected men and women with a broad range of exposure to repetitive brain trauma, including physical abuse, head banging, poorly controlled epilepsy, dwarf-throwing, and rugby. The term “chronic traumatic encephalopathy” or “CTE” was introduced by Critchley in his 1949 monograph “Punch drunk syndromes: the chronic traumatic encephalopathy of boxers,” and has subsequently become the preferred designation. Recently, CTE has been described in athletes playing popular modern contact sports including American football, soccer, baseball, wrestling, ice hockey, as well as in military personnel exposed to RHI during military service, including explosive blast. Currently, one of the great concerns to public heath is the identification of CTE in teens and amateur athletes at the high school and collegiate levels. Although this past decade has seen a dramatic increase in public awareness of CTE and an equally dramatic rise in scientific research focused on the long-term effects of RHI, the science to identify the precise risks of RHI exposure and the development of CTE in amateur and professional athletes and military veterans lags behind. Like many neurodegenerative diseases, currently CTE can only be diagnosed after death by neuropathologic examination, and the precise incidence and prevalence of CTE remain unknown. Large-scale, longitudinal prospective studies are needed to directly address these public concerns and close the existing gaps in the basic and clinical science related to the natural history, evaluation and management, and long-term effects of RHI exposure.

Introduction

There are growing concerns that cumulative repetitive head impact exposure through routine participation in contact and collision sports is associated with increased risk of chronic neurologic and neuropsychiatric problems. Among the issues associated with cumulative repetitive mild traumatic brain injury are persistent postconcussive symptoms and long-term problems in memory and cognition, including the development of chronic traumatic encephalopathy (CTE).

CTE is a unique neurodegenerative disorder that occurs as a latent consequence of cumulative repetitive head impacts (RHIs), including concussion and subconcussion. CTE was first associated with the sport of boxing in 1928, when Harrison Stanford Martland described the clinical features of a neuropsychiatric syndrome that affected pugilists, a condition then known as “punch drunk” or “dementia pugilistica.” Over the following decades, it was gradually recognized that the condition affected men and women with a broad range of exposure to repetitive brain trauma, including physical abuse, head banging, poorly controlled epilepsy, dwarf-throwing, and rugby. The term “chronic traumatic encephalopathy” or “CTE” was introduced by Critchley in his 1949 monograph “Punch drunk syndromes: the chronic traumatic encephalopathy of boxers,” and has subsequently become the preferred designation. Recently, CTE has been described in athletes playing popular modern contact sports including American football, soccer, baseball, wrestling, ice hockey, as well as in military personnel exposed to RHI during military service, including explosive blast. Currently, one of the great concerns to public heath is the identification of CTE in teens and amateur athletes at the high school and collegiate levels. Although this past decade has seen a dramatic increase in public awareness of CTE and an equally dramatic rise in scientific research focused on the long-term effects of RHI, the science to identify the precise risks of RHI exposure and the development of CTE in amateur and professional athletes and military veterans lags behind. Like many neurodegenerative diseases, currently CTE can only be diagnosed after death by neuropathologic examination, and the precise incidence and prevalence of CTE remain unknown. Large-scale, longitudinal prospective studies are needed to directly address these public concerns and close the existing gaps in the basic and clinical science related to the natural history, evaluation and management, and long-term effects of RHI exposure.

Neuropathology of chronic traumatic encephalopathy

Microscopic Pathology

The neuropathology of CTE is increasingly well defined. In 2013, in the largest case series study to date, McKee and colleagues reported the spectrum of p-tau pathology in 68 male subjects with a history of exposure to RHI with neuropathological evidence of CTE, ranging in age from 17 to 98 years (mean 59.5 years). In young subjects with the mildest forms of CTE, focal perivascular epicenters of hyperphosphorylated tau (p-tau) immunoreactive neurofibrillary tangles (NFTs) and astrocytic inclusions were found clustered at the depths of the cortical sulci; in subjects with severe disease, a profound tauopathy involved widespread brain regions. Other abnormalities encountered in advanced disease included abnormal deposits of phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) protein, neuroinflammation, varying amounts of beta amyloid plaques, neuronal loss, and white matter degeneration. Based on these findings, preliminary criteria for the neuropathological diagnosis of CTE and a 4-tiered staging system for grading pathologic severity were proposed ( Fig. 1 ).

Stages of hyperphosphorylated tau pathology in CTE. In stage I CTE, p-tau pathology is restricted to isolated foci in the cerebral cortex; the focal lesions consist of perivascular accumulation of p-tau as neuronal and astrocytic inclusions, with NFTs and dot-like structures. In stage II CTE, there are multiple p-tau lesions typically found at the depths of the cerebral sulci. In stage III CTE, p-tau pathology is widespread in the cortex, and the amygdala, hippocampus and entorhinal cortex show neurofibrillary pathology. In stage IV CTE, there is widespread severe p-tau pathology affecting most regions of the cerebral cortex and the medial temporal lobe, with sparing of the calcarine crtex. All images, CP-13 immunostained 50 μm tissue sections.

In 2015, as the first part of a series of consensus panels funded by the National institute of neurological disorders and stroke / National institute of biomedical imaging and bioengineering (NINDS/NIBIB) to define the neuropathological criteria for CTE, these preliminary neuropathological criteria were used by 7 expert neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam without any knowledge of the subjects age, sex, athletic history, clinical symptoms, or gross neuropathological findings. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen kappa: 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen kappa: 0.78) using the preliminary criteria. In addition, the panel refined the preliminary criteria and defined CTE as a distinctive disease with a pathognomonic lesion. The pathognomonic lesion of CTE was defined as an accumulation of abnormal tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern ( Fig. 2 ). The group also defined supportive but nonspecific features of CTE ( Box 1 ) and determined that the diagnostic features of CTE were distinct from the age-related astrocytic p-tau pathology (ARTAG) commonly found in the white matter of the temporal lobe and basal regions of the brain. ARTAG is nonspecific and nondiagnostic, and may be found in a variety of conditions, including aging, CTE, and many others.

The pathognomonic lesion of CTE. The pathognomonic lesion of CTE consists of an accumulation of abnormally phosphorylated tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. There are typically neurofibrillary tangles, p-tau inclusions in thorned astrocytes as well as dot-like structures in the neuropil. ( A ) Magnification X40, ( B ) magnification X 200, ( C ) magnification X 600; all images, CP-13 immunostained 50 μg tissue sections, ( C ) counterstained with cresyl violet.

Box 1

Required for diagnosis of chronic traumatic encephalopathy

The pathognomonic lesion consists of p-tau inclusions in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at the depths of the cortical sulci.

Supportive neuropathological features of chronic traumatic encephalopathy

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  P-tau-related pathologies

  
  
• 1.
  

  Abnormal p-tau immunoreactive pretangles and NFTs preferentially affecting superficial layers (layers II-III)

  
  
• 2.
  

  In the hippocampus, NFTs found preferentially in affecting CA2, CA4, and CA1

  
  
• 3.
  

  NFTs in subcortical nuclei, including the mammillary bodies, hypothalamus, amygdala, thalamus, nucleus basalis of Meynert, raphe nuclei, substantia nigra and locus coeruleus.

  
  
• 4.
  

  P-tau immunoreactive astrocytic inclusions in the subpial and periventricular regions.

  
  
• 5.
  

  P-tau immunoreactive large dot-like structures (in addition to some threadlike neurites)

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  Non-p-tau-related pathologies

  
  
• 1.
  

  Macroscopic features: disproportionate dilatation of the third ventricle, septal abnormalities, mammillary body atrophy, and contusions or other signs of previous traumatic injury.

  
  
• 2.
  

  TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex, and amygdala

Preliminary NINDS criteria for the pathologic diagnosis of chronic traumatic encephalopathy

Adapted from McKee AC, Cairns NJ, Dickson DW, et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 2016;131(1):75–86.

Using the NINDS criteria for CTE, Bieniek and colleagues reviewed the clinical records and brains of 1721 cases donated to the Mayo Clinic Brain Bank over the past 18 years and found 32% of contact sport athletes had evidence of CTE pathology. No cases of CTE were found in 162 control brains without a history of brain trauma or in 33 cases with a history of a single traumatic brain injury (TBI). Of the 21 with CTE pathology, 19 had participated in football or boxing, and many were multiple-sport athletes including rugby, wrestling, basketball, and baseball. One athlete played only baseball, and another athlete only played basketball. Similarly, Ling and colleagues screened 268 cases of neurodegenerative disease and controls in the Queen Square Brain Bank for Neurologic Disorders using the preliminary McKee criteria and found changes of CTE in 11.9% of neurodegenerative disorders and 12.8% of elderly controls. Of the cases with changes of CTE, 93.8% had a history of TBIs; 34% had participated in high-risk sports including rugby, soccer, cricket, lacrosse, judo and squash; and 18.8% were military veterans.