CTE - Think aBout It
By Kevin Johnston, AGPC-NP
(Image courtesy of ABC Fresno News)
Introduction
Chronic Traumatic Encephalopathy (CTE) is a type of dementia that is found in individuals with repeated head injuries. In this segment of our Think About It series we cover CTE, a progressive neurodegenerative disease. We will discuss the CTE phenomenon that affects the patient’s short and long-term memory, and thought processes, moods, and behaviors.
History of CTE
This disease was originally termed as being punch drunk or later, dementia pugilistica, to describe boxers that were experiencing motor and mental deficits after repeated strikes to the head. Dr. Harrison Martland, a highly esteemed scientist and neurologist described dementia pugilistica after studying and disagreeing with the published works of Dr. Wilfred Trotter, a British surgeon, who described concussions as an “essentially transient state” in his talk, On Current Minor Injuries of the Brain in 1924 (Changa, Vietrogoski, & Carmel, 2017).
Dr. Martland volunteered to serve as a surgeon during the First World War, serving with the Bellevue Unit Medical Corps at a hospital in Vichy, France. After the war, he was appointed to be the first Medical Examiner in New Jersey state and later became the head of New York University’s Department of Forensic Medicine. He observed and documented damages to brains during 309 autopsies. 300 of these autopsies involved cases of hemorrhages immediately prior to the subject’s deaths, but nine cases with that no immediate causes. He investigated and discovered that all nine had been boxers or men that suffered repeated head injuries and displayed symptoms of being Punch Drunk after years of repeated head traumas (Changa, et al, 2017).
He described their behaviors as post-concussion neurosis and psychoses and wrote papers about so-called “post-traumatic encephalitis”. He documented 23 cases in total (5 he autopsied personally) that described boxers as having immediate symptoms after fights, including minute changes in gait or staggering, parkinsonian gait (walking with stiff joints), tremulousness, vertigo, and cognitive symptoms. Several suffered “mental deterioration” that resulted in asylum institutionalization. Dr. Martland studied boxing and boxers and, as a result, realized heavier and slower boxers were more often sufferers. Those that fought longer or later in life also were more apt to develop symptoms. He felt that perivascular microhaemorrhages caused replacement gliosis within the brain (Changa, et al, 2017).
Another study of boxers helped discover more about this traumatic brain injury disease. J. A. Millspaugh, a naval lieutenant, published an article in 1937 describing examples of cognitive dysfunction in naval boxers. He relied heavily on the published papers of Dr. Martland and coined the medical term dementia pugilistica. He recommended that all sanctioned fights include a medical attendant that would assess the fighters between rounds and after knockdowns to ensure that the boxers were not showing signs of concussions. This was the first attempt at promoting safety in sports by using medical professionals in the immediate vicinity of the contestants (Changa, et al, 2017).
With the advancement in brain imaging Dr. Corsellis used advanced diagnostic technology and found cerebral degeneration with histopathological changes secondary to protein depositions in 1973. He found this after studying the brains of 15 retired boxers that all suffered from multiple symptoms, such as parkinsonism, personality changes and cognitive alterations. This proteinopathy theory is the most comprehensive explanation of the causes of CTE to date. Further studies have yet to confirm, or refute, the role of microhaemorrhages in CTE. Dr. Martland has published a similar point in a paper published in 1928 (Changa, et al, 2017).
Parkinson and movement disorders gained public attention with the boxer Muhammad Ali. Ali became an advocate for Parkinson disease during his cognitive decline after his long career fighting. The punishment that his body and head absorbed over his 21-year boxing career and a professional record of 56 and 5, with an amateur record of as much as 161 and 6 between the ages of 15 and 18. He may have won 37 professional fights by knock out (TKO), but suffered apparent concussions by Sonny Banks (1961) and Henry Cooper (1962), both of which left him staggering early in their matches. He recovered and won both matches. He was noted to have developed a pronounced stutter and trembling hands as early as 1979, but continued to be medically cleared and entering the fighting ring until December, 1981. It is estimated that his body absorbed some 200,000 hits during his boxing career (Wikipedia, 2024).
The most public exposure to date however only recently (2005) when CTE was reported to be connected to the autopsies of two retired National Football League (NFL) players. Both players had long careers without reports of acute concussions. Both had been diagnosed with severe major depressive disorder without psychosis after retirement. At autopsy, the only abnormal finding that repeated in the two brains was the presence of diffuse abnormal accumulations of sparse to frequent tau-positive neurofibrillary tangles and neuropil threads in all regions of the brain. These findings resulted in head trauma safety protocols being adopted and continuously revised in the NFL to this day (Omalu, Dekosky, Minster, Kamboh, Hamilton, et al, 2005).
In the early 20th century, football players wore brown or black leather head coverings for safety. This started to change in the 1960’s when Riddell began making plastic helmets that carried team logos and later were equipped with face cages and the solid eye protection used today. For the 2024 season, the NFL has approved using padded helmet accessories known as Guardian Caps, which are reportedly able to reduce head contact force by up to 20%. These helmets have been used in college and high school football games since 2010. The Guardian Caps are now required for use in scrimmage and practice games, but not for actual games. The NFL has reported that preseason practices with these new protections show a decline of 52% in concussion incidence reporting. These numbers and methods of study are closely guarded secrets of the NFL and not independently confirmable. Many players complain that the new helmets are ugly, heavy (the guards add about 7 ounces to the total weight of the helmet), make their heads look obnoxiously large, and interfere with their “swag”. Promoters of the game fear that the helmets will cost the teams money earned through promotional markings on the helmets. Newer versions make the protection less noticeable, but the debate continues (Cohan, 2024).
The National Hockey League (NHL) started to mandate helmets during games in 1974, though active players were grandfathered in and were allowed to decide whether or not to wear helmets. The helmets have been revised and improved multiple times since then. This change has resulted in reduced head injuries and shortened times spent on disabled and injured lists (Rogers, 2024).
Aaron Hernanadez played 3 years of football for NFL’s New England Patriots before being arrested for murdering the man dating his fiance’s sister in 2013. He was convicted of the murder in 2015, and died by suicide in prison in 2017 after being acquitted of two other murders that occurred in 2012. He was 27 when he died. His brain was autopsied and it was found to have one of the most advanced cases of CTE disease ever seen in such a young person. The CTE Center at Boston University has found that 92% of all ex-NFL player’s brains studied suffered from CTE. Autopsied brains from athletes as young as 17 years old have been found with CTE changes. (Callahan, 2024).
Boston University (BU) has become a world leader in research into predicting, diagnosing, treating and preventing CTE’s. The CTE Center is an independent research facility attached to the Boston University Chobanian and Avedisian School of Medicine. It was founded in 1996 and is part of the BU Alzheimer’s Disease Research Center. They conduct leading edge research in CTE and other consequences of repetitive brain trauma in at risk patients. They have collected and are continuing to study over 1,500 brains, with 800 diagnosed with CTE using the NINDS criteria. They are working to find ways to diagnose the disease in living people (Yarin, 2023).
The CTE Center has studied brains of athletes (boxers, hockey players, soccer players, BMX cyclists, wrestlers, and rodeo cowboys) and people that had poorly controlled epilepsy, victims of domestic violence, and others that suffered from repeated blows to the head. They have received over 2,000 donated brains and correlated tackle football to increased Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Repeated hits to the head lead to loss of white matter in the brain. Their next big goal is to create a diagnostic tool that can find CTE and other brain damage early, when the patient is still living and before it becomes debilitating (Callahan, 2024).
The largest global sport is also not immune to head trauma risk. Soccer players are at high risk due to the habit of passing the ball by hitting the ball with their heads. Soccer is the most popular team sport worldwide and is played by all ages. Since it is an inexpensive game- you need a flat field and a soccer ball, it is played in every nation on Earth. Cases of CTE have been reported in amateur players in their teens, after sudden deaths (Hageman, Hageman, & Nihom, 2024)
In research, the head of the BU CTE Center, Dr. McKee, has found microscopic abnormal proteins, called Tau, filling the tissue of the damaged brains. She and her team would like to come up with clinical way of diagnosing CTE. They are interviewing the families of donated brains. They collect information from medical records, history of exposure to head injuries, sports played and at what level, when and for how long. Once the information is compiled, it is compared to the findings of the pathological team. The pathology is currently the gold standard for diagnosing. The data also helps with studies of other neurodegenerative diseases, such as Alzheimer’s disease. Early signs of CTE include dizziness, loss of concentration, and headaches. Impulse control is also affected early on. The BU CTE Center is funded by awards by the National Institute of Health, the Department of Veterans Affairs, industry groups, foundations, and private donors (Callahan, 2024).
Recently football fans have seen in real time the effects of head trauma in football. Tua Tagovailoa, who signed a $212 million dollar contract extension starting in 2025, is the starting quarterback for the Miami Dolphins. He suffered his third (or more) concussion during an NFL game in the past 24 months. He also had at least one concussion during his college carrier. It was noted that in this last injury, his body went into the “fencers pose” immediately after being hit. This is an automatous movement wherein one arm moves forward and up, with a clenched fist and the other arm goes limp. The player has no memory of either hit or the immediate aftermath. He has been placed on a 4 game “concussion protocol” before he can return to actively playing. As of the writing of this paper, he has not announced what his future intentions are (CBS News Miami 2024).
CTE Etiology, treatment, and progression
Currently, the only definitive way to diagnose CTE is through an autopsy and the use of microscopic study of the brain tissues. Researchers are exploring various methods of diagnosing CTE, including detailed examinations of the medical history, exposure to head trauma, CT/MRI studies, cognitive, and skill testing, (Bieniek, Cairns, Crary, et al., 2021).
Remarkably, there is no present treatment for CTE only prevention methods. The best way to avoid CTS is to prevent head trauma. The CTE Center and other groups studying CTEs found that as few as three concussions may start the progression of this disease (Mayo Staff, 2023). Wearing helmets while playing sports and practicing is one of the most basic methods of preventing CTE. In the early 20th century, the football helmets were simply a leather head covering. It has morphed into a space-age plastic dome. As of the 2024 season, the league is trying to implement Guardian Caps- knowing that they can reduce the force of head contract by approximately 20%. Players are complaining about the look and added weight. The NFL keeps their own records on the effectiveness of their concussion reduction methods. They claim that there has been a 52% decline in concussions during pre-season practices since mandating the pads during practice. All players, except kickers and quarterbacks, are mandated to wear these Caps during practice. Many players complain about the weight, the feel, and the look of these protective devices. The NFL has stated that the fans are also largely against the coverings. In the 1960’s, the NFL Commissioner stated that the helmets are important branding tools- prior to that they were plain and did not differ between teams. Now, because of the high-definition televisions and close ups of hits on the field, even the fabric covered Caps on the helmets offer poor definition and the logos look “muddy”. The NFL is also looking into six other helmet models that offer additional protection without changing the visuals of the game (Cohan, 2024).
In 2015, a panel of neuropathologists funded by the NINDS/NIBIB met and defined a preliminary consensus for the neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," after reviewing 25 tauopathy cases. The panel met again in 2016 to review and refine the initial criteria, with consideration around a minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), using double blinded clinical and demographic information. Generalized estimating equation analyses showed statistically significant associations between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on these challenges in assigning CTE stages, the panel proposed working protocols including minimum thresholds for the diagnosis of CTE and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies (Bieniek, et al, 2021).
The chemokine CCL11 (CCL11), also known as eotaxin-1, was first identified in the peripheral immune system as a potent eosinophil chemoattractant in allergic inflammation, asthma, atopic dermatitis, and inflammatory bowel disease. Although CCL11 has been previously observed to be produced and act mainly in the periphery, studies in mice have shown that CCL11 is capable of both penetrating the blood-brain barrier (BBB) and, in aged mice, can be directly produced by the choroid plexus epithelial cells suggesting direct central nervous system (CNS) effects. CCL11, a protein previously associated with age-associated cognitive decline, is observed to be increased in the brain and cerebrospinal fluid (CSF) in CTE compared to Alzheimer’s disease (AD). Using a cohort of 23 deceased American football players with neuropathologically verified CTE, 50 subjects with neuropathologically diagnosed AD, and 18 non-athlete controls, CCL11 levels were significantly increased in the dorsolateral frontal cortex (DLFC) in subjects with CTE compared to non-athlete controls and AD subjects without a history of head trauma. This increase was also seen to correlate with years of exposure to American football. A recent analysis of the brains from 111 NFL players observed 110 (99%) had evidence of CTE, further suggesting how prevalent the disease might be. Currently, CTE can only be diagnosed by post-mortem examination of brain tissue. The diagnostic hallmark of CTE is the accumulation of hyperphosphorylated tau (as neurofibrillary tangles (NFT)) in neurons and astrocytes present around small blood vessels at the sulcal depths of the cerebral cortex. The development of perivascular tau pathology in CTE is associated with a robust and persistent inflammatory microglial response that significantly increases with the pathological severity of CTE. The pathology of CTE differs in several substantive ways from AD. AD is characterized by the accumulation of beta-amyloid (Aß) plaques as well as the deposition of aggregates of hyperphosphorylated tau (ptau) as NFTs, however in AD there is no accentuation of ptau deposition around small blood vessels and there are differences in the tau epitopes expressed in AD and CTE. Although AD and CTE are both characterized by disruption of the BBB and neuroinflammation, the BBB disruption and neuroinflammation in CTE appear to predate ptaudeposition. A detailed analysis of the select cytokines and chemokines involved in CTE and AD has yet to be performed.
The neuropathological features of CTE have become increasingly well-defined, including recently developed diagnostic criteria. However, there is an urgent need for a method to detect CTE during life. One reason that precludes that ability to diagnose CTE in life at this time is the lack of in vivo biomarkers that accurately detect CTE pathology. PET imaging of tau is expected to be the gold standard biomarker for CTE, however, analysis of plasma and CSF proteins is a more practical alternative that can also accurately detect the presence of neurodegenerative diseases (i.e., AD). CCL11 may be one potential candidate biomarker for CTE. In humans, altered CSF and plasma levels of CCL11 have been observed in AD, ALS, Huntington's disease (HD) and secondary progressive multiple sclerosis (SPMS) when compared to age-matched, healthy controls. Notably, in AD and HD, increased plasma CCL11 expression is associated with more advanced disease, while in ALS and SPMS, lowered CCL11 expression is associated with increased disease severity. The observed differences in CCL11 expression with certain neurodegenerative diseases suggest that CCL11 is differentially regulated across disease states and may prove useful as a novel biomarker candidate to detect distinctive neurodegenerative diseases. Clinical assessment occurred as previously described. During a telephone interview, athletic history, military service history, demographic information, and education, were assessed. An informant versions of the Ohio State University TBI Identification Method Short Form and two questionnaires adapted from published studies that address military-related head injuries and concussions was used to determine TBI history. For analysis on how the number of years exposed to playing football relates to CCL11, subjects in the CTE group were further divided into two groups based on the group median number of years playing football (16 years). An identical clinical assessment was performed using the Framingham Heart Study cohert. Pathological processing, immunohistochemistry, and evaluation were conducted using previously published methodology. Briefly, all brain tissue was processed identically by fixation in periodate-lysine-paraformaldehyde (PLP) and stored at 4°C. During the initial processing, macroscopic features and brain volume were recorded. Tissue was blocked and cut at 10 μm thickness. To identify the CTE specific features required for a positive neuropathologic diagnosis, 22 sections from multiple tissue regions were stained for Luxol fast blue, hematoxylin and eosin (LHE), Bielschowsky’s silver, phosphorylated tau (ptau) (AT8), alpha-synuclein (αs), amyloid-ß (Aß), and phosphorylated TDP-43 (pTDP-43). For histologic antibody staining, section underwent antigen retrieval using citrate buffer (pH 6.0) and boiling in the microwave for 10 mins. Primary antibodies were applied and incubated overnight at 4°C. The next day, biotinylated secondary antibodies and 3-amino-9-ethylcarbazol HRP substrate kit (Vector Laboratories H-3401) were used for visualization of staining. Sections were coverslipped for long term storage using Permount mounting medium. Aneuropathological diagnosis of CTE was made using criteria recently defined by the 2015 NINDS-NIBIB Consensus Conference. Other neurodegenerative diseases were diagnosed using well-established criteria for AD, Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), and motor neuron disease (MND). To diagnose CTE, the criteria requires at least one perivascular ptau lesion that consisting of ptau aggregates in neurons, astrocytes, and cell processes around a small vessel. The deposition of ptau is most commonly observed at the depths of the cortical sulci in the cerebral cortex. The CTE ptau deposition is distinct from the lesions of aging-related tau astrogliopathy. For analysis of CTE pathologic severity, AT8 (ptau) immunostained slides from the DLFC were scanned and digitized at 20x magnification using the Aperio ScanScope (Leica) as previously described. Identification, selection, and analysis of the regions of interest were performed as previously described. Briefly, the depth of the cortical sulcus, which was defined as the bottom third of two connecting gyri, was selected and circled in ImageScope (Lecia). Only gray matter was highlighted. A modified version of the Aperio positive pixel count algorithm (Version 9) was used to determine the total area of AT8 positive staining. Quantifications were standardized to the area measured and presented as density per analyzed area as previously described. Flash frozen brain tissue was obtained from the sulcus of the DLFC, weighed, and placed on dry ice. Freshly prepared, ice cold 5M Guanidine Hydrochloride in Tris-buffered saline (20 mM Tris-HCl, 150 mM NaCl, pH 7.4 TBS) containing 1:100 Halt protease inhibitor cocktail (ThermoScientific) and 1:100 Phosphatase inhibitor cocktail 2 & 3 (Sigma) was added to the brain tissue at 5:1 and homogenized with Qiagen Tissue Lyser LT, at 50Hz for 5 minutes. The homogenate was then incubated while rocking overnight at room temperature. Lysate was diluted according to manufacture protocol and spun down at 17,000 g, 4°C, for 15 minutes. The supernatant was then applied to Meso Scale Discovery (MSD) Chemokine Panel 1 (human) Kit V-PLEX Plus (Thermo Scientific) and run according to manufactures protocol. Plates were run on MSD plate reader model 1250. Plates were run in three separate batches. In order to account for inter-batch variability, values were normalized to controls present on each respective batch to generate a “fold change” value compared to the controls. A significant increase in CCL11 levels was observed in individuals with CTE and 16 years or more exposure to football compared to controls with no exposure to sports and individuals with CTE and less than 16 years exposure. Furthermore, when looking only at individuals with CTE, multiple linear regression analysis demonstrated that CCL11 levels were significantly predicted by the number of years of exposure to football (β = 0.426, p = 0.048) independent of age (β = -0.046, p = 0.824). The number of reported concussions were not able to predict CCL11 levels (β = -0.230, p = 0.357) independently of age (β = -0.128, p = 0.605). In preliminary analysis using a small cohort of cases with available post-mortem CSF (Control = 4, CTE = 7, AD = 4), there was a trend towards increased CCL11 levels in CTE, but not AD, compared to controls. Multiple linear regression analysis also demonstrated that CCL11 levels in the CSF were associated with greater exposure to repeated head injuries (β = 0.685, p = 0.040) independent of age (β = -0.103, p = 0.716). Furthermore, despite the limited sample size, receiver operating characteristic (ROC) curve analysis demonstrated that CSF CCL11 levels significantly discriminated participants with CTE from controls and individuals with AD (AUC = 0.839, 95% CI 0.62–1.058, p = 0.028). A cutoff value of 5.630 pg/ml was determined to have a maximum sensitivity and specificity of 71.43% and 87.5% respectively. Finally, although CSF CCL11 could significantly predict a diagnosis of CTE, CCL11 levels in the CSF were not able to predict severity of disease as measured by AT8 density in the DLFC (β = 0.424, p = 0.247). Overall, preliminary analysis demonstrated that levels of CCL11 were significantly elevated in the DLFC of former NFL football players with CTE compared to controls and individuals with AD without exposure to football. Furthermore, in individuals with CTE, CCL11 levels correlated with increased density of AT8 immunopositive tau pathology in the DLFC independently of age. Additionally, greater total number of years of football participation was significantly associated increased levels of CCL11 in subjects with CTE. Finally, CCL11 was increased in the CSF of participants with CTE and significantly predicted a positive diagnosis of CTE when compared to the CSF of controls and individuals with AD. Due to the limited sample size, this study was most likely too underpowered to observe an effect of CSF CCL11 on CTE severity. Although additional studies are needed, these preliminary data suggest that CCL11 may be a novel biomarker to aid in the detection of CTE neuropathology and to discriminate CTE from AD. While repeated concussions are thought to be the primary predictor for CTE, there is growing evidence that CTE may also be caused by sub-concussion head injuries (Thurston, 2023).
Conclusion
Chronic Traumatic Encephalopathy is the new name for an injury that was described over 100 years ago. It has been poorly understood and has proven to be difficult to diagnose and treat. Researchers are studying multiple methods to reduce the risk, diagnose early before damage becomes apparent and how to repair the damage.
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