Chronic Traumatic Encephalopathy (CTE)

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder thought to be associated with exposure to repetitive head trauma. CTE is characterized neuropathologically by hyperphosphorylated tau (p- tau) deposition throughout the brain. The first reported clinical cases were described in boxers in the early 1900’s and described as “punch drunk” and since that time the terminology has evolved and is currently referred to as chronic traumatic encephalopathy or “CTE.” Over the last decade, there has been increased awareness of the long term effect of mild traumatic brain injury (mTBI) in both the military and sports populations.  Clinically, these individuals may present with constellation of chronic symptoms including mood, cognitive, behavioral and motor disturbances. A definitive diagnosis of CTE is made by post mortem macroscopic and histopathological accumulation of p-tau. Genetic influences such as apolipoprotein E ε4 (APOE ε4) have been suggested to increase susceptibility to CTE after repetitive head trauma. ^[1] Future studies for clinical studies should focus on identification of diagnostic tools such as biomarkers, advanced neuroimaging, and neuropsychological testing to provide a diagnosis for CTE.

Traumatic brain injury (TBI) is a major health concern that is a leading cause of mortality, morbidity, and disability worldwide.  Annually, in the United Sates there are over 1.7 million cases TBI of varying severities, ranging from mild to severe TBI. ^[2] In addition, with the recent US military conflicts, TBI has been deemed the "signature injury" of Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND), affecting up to 20% of all service members deployed in theatre with more than 339,000 TBIs reported in OIF/OEF/OND between 2000 and 2015, ^[3] over 75% of which are mild. ^[4]

TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions. ^[5] TBI can be classified as mild, moderate, or severe, based on initial Glasgow coma scale (GCS), ^[6] duration of loss of consciousness, and duration of post-traumatic amnesia. ^[7]

Mild TBI or concussion can result in changes in cognitive function. Athletes and trauma patients often report diverse physical, behavioral, cognitive and emotional symptoms in the initial days and weeks following the injury.  The most frequently endorsed symptoms include headaches, fatigue, attention/concentration, irritability, and dizziness. Most mTBI patients appear to recover within the first 2 weeks after injury, though there are a few where the symptoms evolve into a more persistent pattern (> 3 months). Subconcussive events or subclinical concussion results when impact to the head does not result in the clinical signs or symptoms of a concussion but it postulated that repetitive subclincal concussions can have a “deleterious” effect. ^[8] Repetitive closed head injury occurs in a wide variety of contact sports, including American football, hockey, soccer, lacrosse with thousands of subconcussive hits during the course of a single season.

The effects of single or multiple TBIs in later-life are poorly understood, particularly in mild TBI (mTBI). Recent studies suggest that even mTBI can lead to an increased risk of later-life cognitive impairment and neurodegenerative disease, especially when repeated injuries are involved. ^{[9, 10, 11]}

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CTE is a chronic slowly progressive disease which can begin years to decades after acute exposure and recovery from repetitive head trauma and is distinct from persistent postconcussion symptoms.

Clinically, CTE is thought to be divided into three categories of impairment including: neuropsychiatric (increased impulsivity, explosivity, violence, rage, depression, apathy, substance abuse, suicidal behavior), cognitive (impaired attention, executive function, memory) and motor (Parkinsonism, dysphagia, dysarthria, poor coordination).

The early symptoms of CTE include short-term memory problems, irritability, executive function impairments, depression, emotional lability, impulse/anger control, suicidal behaviors, and substance abuse. In later stages CTE can progress to worsening memory and executive function, worsening aggression, motor impairments and dementia. Stern et al suggests there are two major presentations of CTE with one being a behavior/mood variant occurring at a younger age (mean age 35) and the other being a cognitive variant occurring at an older age (mean age 60). ^[32]  

The neuropathology of CTE can be broken up into gross and microscopic changes. The gross neuropathologic change in early CTE, if any, is mild enlargement of the fontal and temporal horns of the lateral and third ventricles. In advanced CTE gross changes include gray and white matter atrophy of the frontal and temporal lobes, decreased brain weight, enlargement of the fontal and temporal horns of the lateral and third ventricles, cavum pellucidum with fenestrations, atrophy of the thalamus, hypothalamus and mamillary bodies, thinning of the corpus callosum, and pallor of the locus coeruleus and substantia nigra.

McKee at al ^[26]  established pathological staging criteria (I - IV) for CTE based on 85 subjects with history of repetitive head trauma and evidence of CTE. The criteria are based on location, pattern and pathological progression of tau accumulation. Stage I  is characterized by isolated perivascular focal epicenters of p-tau neurofibrillary tangles and neuropil neurites, which is, localized to the sulcal depths of the cerebral cortex. Stage II  is characterized by perivascular multiple epicenters of p-tau neurofibrillary tangles and neuropil neurites at the sulcal depths of the cerebral cortices. Stage III  is characterized by widespread dense p- tau located in the frontal, septal, temporal. Stage IV is the most severe and advanced stage with widespread tau accumulation in the diencephalon, brain stem and cerebellum.

Microscopic neuropathology of CTE is characterized by deposition of hyperphosphorylated tau (p-tau) as neurofibrillary tangles, neuropil threads and astrocytic tangles. Tau is a protein that modulates the stability of axonal microtubules and maintains the shape of the neuron. The deposition of tau is seen in normal aging and as a feature of Alzheimer’s and other neurodegenerative disorders, but CTE has a distinct pattern and location of tau deposition and is pathognomic for CTE.

The preliminary NINDS/NIBIB consensus panel criteria required for pathologic diagnosis of CTE is: “The pathognomic lesion consists of p-tau aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at the depths of the sulci.” In addition, the consensus panel provided supportive neuropathological features of CTE but that are were nonspecific for CTE. ^[33]

CTE has also been characterized by widespread TDP-43 proteinopathy in more than 80% of patients with CTE. ^[34] TDP-43 is involved in regulating translation in mitochondrial RNA in the brain. It has been associated with the physiological response to traumatic axotomy. ^[35] Blood levels of TDP-43 are elevated in association with a variety of neurodegenerative conditions, to include frontotemporal lobar degenerations, amyotrophic lateral sclerosis (ALS) and Alzheimer’s Disease. In some cases the TDP-43 proteinopathy extends to involve the spinal cord and may present as motor neuron disease similar to ALS. As in the case of tau, TDP-43 fibrillaries accumulate at anatomical points of geometric inflection in the brains of CTE subjects. Given that trauma focuses deformation forces in these areas, it is highly plausible that TDP-43 accumulation is in contact with the compromised microvasculature and, as such, would be present in the blood of trauma patients with latent CTE.

Beta-amyloid (Aβ) peptides have diagnostic and prognostic utility for a broad number of neurodegenerative disorders and can be found in 52% of individuals with CTE. ^[36] Aβ plaques are common immediately after TBI, ^[24] and Aβ continues to accumulate in traumatized axons that survive. ^[37] When Aβ plaques are present in CTE predominantly in a fibrillary form that resembles AD pathology more than acute TBI, but more  diffuse and less dense than Alzheimer’s.  Importantly, diffuse, widespread fibrillary Aβ accumulation resembles CTE pathology. ^[38]   

Possession of the APOE-ε4 allele is a risk factor for dementia. ^[39]  Carriers may  have altered brain activity, even at a young age. ^[40]  Long-term, but not short-term, effects of TBI may be influenced by APOE. APOE was not associated with poorer neuropsychological performance 1 month after mild or moderate TBI. ^[41]  However, TBI was found to increase AD risk of APOE 10-fold. ^[42]  A study by Atherton et al showed that APOEe4 carriers were more than twice as likely to have severe CTE as those without the APOEe4 gene. ^[43]

Environmental factors, in particular multiple concussions, may influence the effects of APOE. Boxers with the APOE-ε4 allele who had participated in many bouts were more likely to have CTE, while the allele was not a risk factor in boxers who had only experienced a few fights. ^[21]

Structural neuroimaging such as CT and MRI are non-specific for CTE. Currently, there are no validated advanced neuroimaging techniques to provide a confirmatory diagnosis of CTE. Positron emission tomography (PET) ligands for p-tau, diffuse tensor imaging (DTI), magnetic resonance spectroscopy and functional MRI may have some potential benefit in the future.

A study by Alosco et al showed that a distinct pattern of frontal-temporal atrophy on MRI may suggest CTE. Compared with persons with normal cognition, those with CTE had significantly greater atrophy in several brain regions, including the orbital-frontal cortex, dorsolateral frontal cortex, superior frontal cortex, anterior temporal lobes, and medial temporal lobe. ^[44]

Currently, there are no fluid biomarkers that can predict the presence of CTE.