Total Blitz on the Brain: The Elusive Tactics of Chronic Traumatic Encephalopathy

Dan Bader

Illustrations by Alexandra Adsit

In the early 1900s, ‘punch drunk syndrome’ was used to describe a pattern of unusual behaviors observed amongst boxers, including emotional volatility and cognitive impairments [1]. As awareness of the condition increased, the disease was more accurately renamed chronic traumatic encephalopathy (CTE) [1]. CTE is a progressive neurodegenerative condition resulting from various types of head trauma or injuries [2]. Neurodegenerative diseases are characterized by cognitive and motor deficits due to nervous system damage and neuronal death [2, 3, 4]. While CTE was originally documented in boxers, it has recently gained notoriety due to its prevalence in former National Football League (NFL) players, particularly following its identification in NFL Hall of Famer ‘Iron’ Mike Webster [5, 6]. After his 19-year career, Webster experienced a rapid deterioration in health that was characterized by persistent difficulty with attention, severe depression, and unexplained fits of rage, ultimately culminating in his death at 50 years old [5, 6]. CTE’s diverse range of symptoms makes the disease complicated to identify, and to this day, CTE remains diagnosable only post-mortem, or after death [3, 7]. Advancing our understanding of how CTE develops is paramount as the condition continues to affect athletes and non-athletes alike [3, 7]. 

A Crash Course: Who is at Risk for Developing CTE 

Repeated exposure to head trauma, such as collisions in American football, can contribute to the onset of CTE [8]. In fact, the likelihood of developing CTE is thought to double with every additional 2.6 years of playing American football due to the prevalence of forceful contact to the head associated with the sport [8]. Frequent instances of milder impacts can also induce the development of CTE [9,10]. For example, a soccer player heading a ball might experience only a minor impact with each hit, but repeated occasions of these seemingly harmless blows could contribute to CTE development [9,10]. While popular media typically portrays repeated patterns of head injuries as the only sources of CTE, the disease can also be caused by a single, severe impact, also known as a traumatic brain injury [3, 11, 12]. Importantly, a single traumatic brain injury can cause immediate, significant damage to brain tissue and surrounding blood vessels [13]. Long-term inflammation from the initial injury can continue to harm the brain tissue for years [11, 13].  

Although CTE is commonly linked to athletes involved in contact sports, various risk factors can increase the likelihood of developing the condition [3]. For example, CTE is frequently observed in military veterans, as repeated blast damage can cause significant head trauma [3]. Maladaptive behaviors that often begin in childhood, such as headbanging and other forms of self-injury, can also increase the likelihood of developing CTE [14]. Following the onset of CTE, several factors influence the speed of progression and the subsequent age at which people begin to experience symptoms [15]. Alcohol and drug abuse can accelerate neurodegeneration in individuals with CTE, causing symptoms to manifest earlier in life [15]. Likewise, genetics can also play a role in the progression of CTE [15, 16]. The TMEM106B gene encodes for the TMEM106B protein, which contributes to the regulation of lysosomes in the brain [15, 17]. In cells, lysosomes digest cellular waste, recycle cell components, and manage neuroinflammation [15, 17, 18]. Neuroinflammation is a part of the brain’s natural immune response to injury, and prolonged inflammation is detrimental to brain function as it causes structural changes and neuronal cell death [18, 19]. Variants of the TMEM106B gene can affect the regulation of lysosome activity, potentially increasing neuroinflammation [15, 17, 18]. Since TMEM106B regulates brain inflammation and health, individuals with CTE who have unfavorable TMEM106B gene mutations may be prone to experiencing clinical symptoms earlier in life [15, 16]. 

From Yellow Card to Red Alert: Symptoms of CTE 

CTE symptoms can be strikingly varied and often remain hidden for years, sometimes taking up to a decade to fully surface [20]. Many people with CTE experience chronic headaches, diminished cognitive function, and language difficulties [21, 22, 23]. CTE can also impact an individual’s behavior, often causing increased impulsivity and aggression, as observed in ‘Iron’ Mike Webster [7, 22]. Behavioral alterations are thought to arise from CTE-induced neuronal death in the amygdala, a brain region involved in processing emotional stimuli and regulating decision-making behaviors [24, 25, 26]. As CTE develops, mental health problems such as depression and suicidal ideation may also result from dysfunction in the brain [22, 27]. CTE is a progressive disease, meaning that older individuals typically experience more severe cases with different symptoms as the disease damages the brain further [3, 7]. Cognitive deficits such as memory loss and difficulty with attention are more prevalent in older individuals with CTE compared to younger ones [3, 7]. Parkinsonism, which describes the tremors and walking abnormalities characteristic of individuals with Parkinson's disease, is also common among older people with severe cases of CTE [1, 3]. CTE presents a complex array of symptoms that progressively worsen over time, affecting not only physical and cognitive functions but also behavior and mental health [1, 3].  

Change in Formation: Structural Alterations Induced by CTE

CTE is characterized by physical and functional changes involving tau, a protein responsible for providing structural stability to the brain [3, 10, 28]. Tau plays a crucial role in the assembly and stabilization of microtubules, which are components of the cell essential for its development, maintenance, structure, and communication [28, 29]. CTE is classified as a tauopathy, an umbrella term used to describe neurodegenerative diseases characterized in part by the abnormal accumulation of tau in the brain [30]. A typical tau protein bound to a microtubule contains two or three phosphate groups, which are negatively charged molecules that influence protein folding and function [31, 32]. However, severe head trauma can damage axons — thin fibers involved in neuron communication — leading to the addition of excess phosphate groups to tau in a process called hyperphosphorylation [30, 33, 34]. Hyperphosphorylated tau detaches from microtubules and becomes misfolded, altering the structure and function of the protein, preventing tau from being used in the cell [35, 36, 37]. As a result, hyperphosphorylated tau aggregates, or clumps together, to form abnormal clusters called neurofibrillary tangles (NFTs) [10, 30, 38]. The accumulation of NFTs destabilizes microtubules and disrupts communication between neurons, leading to neuronal death and ultimately contributing to cognitive impairment [10, 36, 37]. 

Neurodegeneration resulting from NFT aggregates is also a hallmark of other tauopathies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1, 20]. Although the location and specifics of NFTs differ across CTE and AD, individuals with either CTE or AD experience cognitive impairments, including learning and memory deficits [1, 20, 39]. Furthermore, both CTE and AD are characterized by neuronal death and decreased production of proteins involved in neuronal communication [20]. The accumulation of hyperphosphorylated tau and subsequent NFT formation observed in CTE are also features of PD [10, 39]. Additionally, there is a positive correlation between the concentration of hyperphosphorylated tau and the severity of PD symptoms like motor dysfunction and cognitive decline [10, 39]. While there is some overlap, the differences between AD, PD, and CTE are substantial, both in their underlying causes and in the specific symptoms experienced by affected individuals [1, 20, 39]. Nonetheless, understanding the common features these tauopathies share can help us understand more about tau-related neurodegeneration and guide the development of common treatment strategies [39]. 

Flag on the Play: Missed Calls of CTE Diagnosis 

Currently, there are many barriers that make CTE diagnosis challenging [3, 7]. Modern imaging technologies, such as magnetic resonance imaging (MRI), are not sensitive enough to detect NFTs in living people, so clinical diagnosis pre-mortem remains impossible [3, 7]. There are, however, some ways that CTE may be visualized in the brain after death [3, 7]. The locations of NFTs and the magnitude of neuronal damage, for example, are trademark indicators that can help differentiate CTE from similar tauopathies [3]. The current method of CTE diagnosis involves performing an autopsy of brain tissue to reveal the presence of hyperphosphorylated tau in brain regions such as the amygdala and hippocampus ([3, 7]. Similar tauopathies, such as AD and PD, are often also confirmed through post-mortem brain analysis, but clinical diagnoses can be made before death based on symptoms, neuroimaging, and biomarkers — indicators of disease that can be detected through medical testing [40]. Biological fluids like saliva, blood, and urine are commonly used for biomarker detection, as the presence of specific proteins or substances in these fluids can often be indicative of disease [41]. Since CTE has no established biomarkers and its symptoms, such as cognitive decline, mood changes, and tremors, are not unique to the disease, it is impossible to definitively diagnose the condition in living people [7]. Extensive research has been dedicated toward establishing diagnostic criteria for CTE in living individuals by assessing factors like mood, behavior, and cognitive function [2, 7]. However, such diagnostic approaches currently lack the necessary specificity and accuracy for reliably identifying CTE [2, 7]. Continued research into advanced neuroimaging techniques and biomarkers is essential to establish effective diagnostic criteria for detecting CTE in living individuals [2, 7].

Since CTE can only be diagnosed post-mortem, people suffering from CTE are often misdiagnosed [2, 21]. The misdiagnosis of CTE is common because CTE symptoms share common characteristics with numerous medical conditions [1]. For example, CTE is often mistaken for depression, as symptoms like anger, aggression, and impulsive behaviors — such as gambling and substance abuse — are common in both conditions [1]. Since CTE often manifests with cognitive decline and tremors, a misdiagnosis of AD or PD is also typical [2]. Detailed consideration of medical history is of the utmost importance for CTE diagnosis, as seemingly inconsequential head trauma can have debilitating effects later in life [21]. Understandably, it may not be someone’s first instinct to attribute memory loss and motor impairment to a singular brain injury from years past, yet this disconnect is just another reason why CTE can go unrecognized [2]. Even if diagnosing CTE in living people were possible, such a diagnosis alone would not significantly improve symptom management or treatment [2]. Understanding the unique elements that contribute to the development of CTE on a case-by-case basis is beneficial because it elucidates potential risk factors of CTE, which can help prevent future cases [4]. 

On the Offensive: Tackling Treatment Options

Given the limitations of diagnosing CTE, treatments are often not specific to the disease itself and primarily focus on symptom management rather than preventing further damage in the brain [2]. Depressive symptoms associated with CTE are typically treated with a combination of antidepressants and mood-stabilizing medications used to treat clinical depression [2]. Likewise, motor disorders linked to CTE are treated with medications conventionally used to manage Parkinson’s disease [2]. The utilization of depression and Parkinson’s medications in treating CTE demonstrates how CTE treatment often does not address the root cause of the disease, but rather attempts to alleviate symptoms to improve quality of life [2]. Treatments for similar diseases, such as AD, may be effective in CTE as they target a hallmark of the disease: hyperphosphorylated tau aggregates [1, 2, 20]. For example, kinase inhibition could potentially treat both CTE and AD by preventing excess phosphates from binding to tau [42, 43, 44]. Kinase enzymes moderate the addition of phosphate groups to proteins, so impeding kinase activity could prevent the accumulation of hyperphosphorylated tau by regulating phosphorylation [43, 44, 45]. Lithium salts, a standard treatment for bipolar disorder, have also emerged as potential agents for kinase inhibition [43, 44, 46]. Although it has not yet been tested in humans, research in animal models of AD has shown that lithium can prevent the formation of new NFTs and potentially prevent subsequent neuronal death [43, 44]. Promising treatments like kinase inhibition may offer potential strategies to slow CTE progression in individuals suspected to be living with the disease [43, 44].

While kinase inhibition and treatments aimed at alleviating symptoms of CTE have shown some promise, prevention remains the most effective strategy to combat the disease [45, 47]. Ice hockey has mandated the use of mouthguards in some high schools, which are believed to reduce the likelihood of concussion by 57% [48, 49] Other contact sports such as American football, rugby, and soccer have implemented soft shell padding to reduce head impact and the incidence of concussions [47, 50]. The NFL in particular has faced significant criticism for its lack of proactive measures regarding player safety [51]. For years, the NFL attempted to downplay and deny the connection between its players and CTE, only finally acknowledging the connection in 2016 [51, 52]. The NFL has since been forced to make changes to the sport to improve player safety and reduce head trauma, though concerns about transparency and integrity of the NFL’s handling of CTE remain [47, 53]. In 2022, the NFL introduced the Guardian Cap, a soft padding placed over the exterior of helmets designed to decrease the amount of impact force absorbed by the helmet [47]. Players in high-risk positions for repeated head trauma were required to wear Guardian Caps during the 2024 preseason, and the NFL reported a 50% reduction in concussions during that period [47]. However, clinical research regarding the Guardian Cap tells a different story, as impact testing has revealed that the device does not significantly reduce the force of head impact [47, 54]. Although the data do not directly dispute concussion incidence, it is clear that the NFL publicizes that the Guardian Cap has significantly greater efficacy than what is supported by clinical research, again calling into question the league’s supposed devotion to player safety [47]. 

Apart from attempts at physical protection, the NFL has also implemented concussion protocols to promote player safety [53]. For example, the NFL recently installed guidelines to prioritize accurate diagnosis of concussions and prevent injured players from returning to athletic activities until they are medically cleared [53]. Additionally, ‘spotters’ are employed to monitor games and utilize replay review to identify players displaying concussion-like symptoms, which could indicate a head injury [53]. Rule changes have also been introduced to discourage head-to-head contact, such as the ‘targeting’ rule, which penalizes defensive players for initiating contact with their helmet when making a tackle [55]. As a result of these rule changes, equipment variations, and other preventative measures, the NFL reported a 17% reduction in concussions in the 2024 season [56]. However, this statistic notably does not exist outside NFL publications and was not subject to common scientific publishing standards, raising questions about the validity and integrity of the data [47]. 

Final Whistle: Prevention is the Best Play 

CTE is a complex and devastating disease with widespread implications for those at risk, which includes anyone who has experienced a significant head injury or patterns of mild brain trauma [3, 11, 12] Individuals with CTE often develop severe cognitive impairment, motor issues, and headaches, as well as personality changes such as increased aggressiveness, depression, and even suicidal ideation [7, 21, 22]. Unfortunately, CTE often goes undetected due to its overlapping symptoms with other conditions and the lack of effective diagnostic criteria for living individuals [7]. Limitations in diagnosis and the lack of treatment strategies render CTE irreversible once established in the brain, so advocating for CTE prevention in the sports world and beyond remains paramount [2, 7]. Increased CTE awareness pushed the NFL to enact significant changes to rules and equipment, although the effectiveness of the alterations remains inconclusive as questions continue to surround the integrity of the NFL and its data claims [51, 54]. Changes to safety regulations in notoriously concussion-heavy sports are necessary and have considerable merit, but concussions in everyday life through car crashes, military service, and ordinary accidents will persist in the future [3, 57]. Therefore, efforts to address CTE in the future must include a multifaceted approach, including advocating for preventive measures, continued research into diagnostic systems, and further studies regarding CTE treatment plans [2, 22, 47]. 

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