[1] Symptoms of CTE, which occur in four stages, generally appear eight to ten years after an individual experiences repetitive mild traumatic brain injuries.

[16] Other physical manifestations of CTE include anterior cavum septi pellucidi and posterior fenestrations, pallor of the substantia nigra and locus ceruleus, and atrophy of the olfactory bulbs, thalamus, mammillary bodies, brainstem and cerebellum.

[6] On a microscopic scale, a pathognomonic CTE lesion involves p-tau aggregates in neurons, with or without thorn-shaped astrocytes, at the depths of the cortical sulcus around a small blood vessel, deep in the parenchyma, and not restricted to the subpial and superficial region of the sulcus; the pathognomonic lesion must include p-tau in neurons to distinguish CTE from aging-related tau astrogliopathy (ARTAG).

[18] A small group of individuals with CTE have chronic traumatic encephalomyopathy (CTEM), which is characterized by symptoms of motor-neuron disease and which mimics amyotrophic lateral sclerosis (ALS).

[20] Loss of neurons, scarring of brain tissue, collection of proteinaceous senile plaques, hydrocephalus, attenuation of the corpus callosum, diffuse axonal injury, neurofibrillary tangles, and damage to the cerebellum are implicated in the syndrome.

Research studies are examining whether neuroimaging can detect subtle changes in axonal integrity and structural lesions that can occur in CTE.

[27] In a small study of 5 retired NFL players with cognitive and mood symptoms, the PET scans revealed accumulation of the tracer in their brains.

The autoantibodies were detected in football players who experienced a large number of head hits but no concussions, suggesting that even sub-concussive episodes may be damaging to the brain.

The autoantibodies may enter the brain using a disrupted blood-brain barrier, and attack neuronal cells which are normally protected from an immune onslaught.

[30] Given the large numbers of neurons present in the brain (86 billion), and considering the poor penetration of antibodies across a normal blood-brain barrier, there is an extended period between the initial events (head hits) and the development of any signs or symptoms.

[34] The use of helmets and mouth guards has been put forward as a possible preventative measure; though neither has significant research to support its use,[35] both have been shown to reduce direct head trauma.

[33] Because repeated impacts are thought to increase the likelihood of CTE development, a growing area of practice is improved recognition and treatment for concussions and other head trauma; removal from sport participation during recovery from these traumatic injuries is essential.

[41] There are also antidepressants like selective serotonin reuptake inhibitors (SSRIs), which can potentially help manage some of the behavioral and emotional symptoms associated with chronic traumatic encephalopathy (CTE) and may have a small improvement in memory function, mood, and alertness.

[43] Professional level athletes are the largest group with CTE, due to frequent concussions and sub-concussive impacts from play in contact sport.

[54] The initial diagnosis of dementia pugilistica was derived from the Latin word for boxer, pugil (akin to pugnus 'fist', pugnāre 'to fight').

[3] British neurologist, Macdonald Critchley, wrote a 1949 paper titled "Punch-drunk syndromes: the chronic traumatic encephalopathy of boxers".

As evidence pertaining to the clinical and neuropathological consequences of repeated mild head trauma grew, it became clear that this pattern of neurodegeneration was not restricted to boxers, and the term chronic traumatic encephalopathy became most widely used.

[63] In October 2022, the United States National Institutes of Health formally acknowledged there was a causal link between repeated blows to the head and CTE.

[64] In 2005, forensic pathologist Bennet Omalu, along with colleagues in the Department of Pathology at the University of Pittsburgh, published a paper, "Chronic Traumatic Encephalopathy in a National Football League Player", in the journal Neurosurgery, based on analysis of the brain of deceased former NFL center Mike Webster.

[65] In 2008, the Center for the Study of Traumatic Encephalopathy at the BU School of Medicine (now the BU CTE Center) started the VA-BU-CLF Brain Bank at the Bedford Veterans Administration Hospital to analyze the effects of CTE and other neurodegenerative diseases on the brain and spinal cord of athletes, military veterans, and civilians.

Also in 2010, MLS player Taylor Twellman, who had to retire from the New England Revolution because of post-concussion symptoms, agreed to donate his brain upon his death.

In 2018, NASCAR driver Dale Earnhardt Jr., who retired in 2017 citing multiple concussions, became the first auto racing competitor to agree to donate his brain upon his death.

[74] In related research, the Center for the Study of Retired Athletes, which is part of the Department of Exercise and Sport Science at the University of North Carolina at Chapel Hill, is conducting research funded by National Football League Charities to "study former football players, a population with a high prevalence of exposure to prior Mild Traumatic Brain Injury (MTBI) and sub-concussive impacts, in order to investigate the association between increased football exposure and recurrent MTBI and neurodegenerative disorders such as cognitive impairment and Alzheimer's disease (AD)".

[77] The family got in touch with representatives of the Boston University center studying the condition, said Robert Stern, the co-director of the research group.

Tissue for the study was donated by twelve athletes and their families to the VA-BU-CLF Brain Bank at the Bedford, Massachusetts VA Medical Center.

[94] After a competitive application process, a consortium led by Virginia Commonwealth University was awarded funding to study brain injuries in military veterans.

][88][95][96] The project principal investigator for the CENC is David Cifu, chairman and Herman J. Flax professor[97] of the Department of Physical Medicine and Rehabilitation (PM&R) at Virginia Commonwealth University (VCU) in Richmond, Virginia, with co-principal investigators Ramon Diaz-Arrastia, Professor of Neurology, Uniformed Services University of the Health Sciences,[88] and Rick L. Williams, statistician at RTI International.

[101] In 2023, Australian rules football player Heather Anderson became the first female athlete diagnosed with CTE after her death by suicide on 13 November 2022, at the age of 28.

[103] In March 2024, former rugby union player Billy Guyton became the first New Zealand-based athlete diagnosed with CTE following his forced retirement in 2018, due to the complications of multiple concussions, and his death by suspected suicide in 2023.

[104][105] His brain had been donated by his family to the Neurological Foundation Human Brain Bank at the University of Auckland,[104] with post-mortem analyses conducted in New Zealand and Australia eventually finding "background changes consistent with global hypoxic ischaemic encephalopathy",[104] as well as trauma-induced cavum septum pellucidum and age-related tau deposits.