Answers to the 8 most pressing questions about Chronic Traumatic Encephalopathy (CTE)

1. WHAT IS CTE?
2. WHAT ARE THE SYMPTOMS?
3. HOW CAN CTE BE DIAGNOSED?
4. HOW CAN THE FOUR STAGES OF CTE BE DISTINGUISHED?
5. WHO IS AT RISK?
6. HOW COULD CTE BE TREATED?
7. WHAT RESEARCH HAS ALREADY BEEN DONE AND WHAT AREAS OF RESEARCH SHOULD FUTURE STUDIES FOCUS ON?
8. WHY IS IT IMPORTANT TO DO MORE RESEARCH ON THE TOPIC?

Have you ever hit your head hard enough to see stars? Maybe you have played contact sports or witnessed a friend or loved one suffer a concussion.

We often think of these injuries as temporary setbacks, but what if the effects are more profound and long-lasting? This brings us to a genuinely concerning, but also complex issue. 

Therefore, this blog will provide answers to the eight most pressing questions about CTE. 

1. What is CTE?

CTE is a neurodegenerative disease, meaning it causes progressive damage to brain cells over time. The primary cause of CTE is repeated blows to the head, often seen in athletes involved in contact sports like American football, boxing, and ice hockey. These repeated impacts, even those not resulting in a diagnosed concussion, can trigger a cascade of events in the brain leading to the aggregation of the abnormal, hyperphosphorylated form of a protein called tau (p-tau).

Figure 1: Image of tau protein structure (source: Protein Data Bank).

2. What are the symptoms?

The resulting damage can manifest as various symptoms, affecting mood, behaviour, thinking, and movement. Do you recognize any of the following symptoms: apathy, depression, mania, anxiety, and related diseases (like obsessive-compulsive disorder), loss of impulse control and/or aggression? Have you also noticed a loss of attention, episodic memory, and executive, language, and visuospatial functioning?
Early- to mid-life behavioural and mood disturbances and later-life cognitive impairment can be a sign that you or a person you know might suffer from CTE.

3. How can CTE be diagnosed?

These symptoms in conjunction with a history of repetitive head impacts (RHI) can be taken as an indicator for CTE, but up until today a diagnosis can only be made postmortem.
Neuropathological examinations of the brain typically show aggregations of hyperphosphorylated tau, astrocytes at the depths of the cerebral sulci, neurofibrillary tangles concentrated around the penetrating parenchymal vessels, and diffuse amyloid plaques.
Another condition associated with high levels of cerebral tau-aggregation is Alzheimer’s disease (AD), which explains the similarity of the observed cognitive symptoms and why AD is considered one of the most frequent comorbid neurodegenerative diseases in relation to CTE.

4. How can the four stages of CTE be distinguished?

Before it received an official scientific name and defined diagnostic criteria, CTE had initially been described as “being punch-drunk” in boxers since the 1920s. In 2013, after a lot more research had been done, neuropathologist Dr. Ann McKee and her colleagues have identified four stages of this neurodegenerative disease, based on the density and regional deposition of hyperphosphorylated tau (p-tau) pathology.

Stage 1
In stage 1, some isolated spots of p-tau can be found around the frontal lobe or the crown of the head. The patient usually does not show any symptoms.

Stage 2
In stage 2, more p-tau can be found in the frontal lobes. More brain cells are affected, and the patient begins to show symptoms such as rage, impulsivity, and depression.

Stage 3
In stage 3, the temporal lobes are also affected by p-tau deposition. Since the amygdala and the hippocampus, which play a key role in emotions and memory, are affected, the patient shows signs of confusion and memory loss.

Stage 4
In stage 4, p-tau has been deposited throughout the whole brain. Many nerve cells have been killed, shrinking the brain, and making it deformed and brittle. The patient has advanced dementia, their cognitive function is severely limited.

Figure 2: Schematic drawing of the brain regions affected by tau pathology in the four neuropathological stages of CTE (source: Stein et al., Alzheimer’s Research and Therapy, 2014).

5. Who is at risk?

Especially athletes in contact sports like American football, rugby, and ice hockey or in combat sports like boxing or Mixed Martial Arts are at risk of developing CTE during or after their career. Since the disease is associated with exposure to RHI, athletes that regularly suffer from concussion or mild traumatic brain injury are in acute danger of being affected by the symptoms associated with CTE.
However, professional athletes are not the only recorded cases of people that have been diagnosed with CTE. There have also been cases of CTE in victims of domestic violence. Although it is rarely talked about, longstanding intimate partner violence can lead to repetitive head impacts just as much as a career in contact/combat sports.

6. How could CTE be treated?

The treatment to cure CTE by reversing the underlying pathology has yet to be found. Thus, we should consider different ways to prevent, detect, and manage CTE.

What can be done to prevent CTE?

Until a treatment has been established, CTE pathology may be prevented, or at least diminished, by adhering to some lifestyle modifications. It has been suggested that regular exercise and cognitive training can help maintain brain health and potentially slow down cognitive decline, while a healthy diet rich in antioxidants could also support brain health.
Those that are exposed to the risk of developing CTE because of their career in contact or combat sports should also wear protective gear to minimize the risk of concussion, or even wear smart mouthguards that measure forces to the head, like it is being established in rugby, to ensure assessment after experiencing a high acceleration event. Moreover, rule changes, such as a rule to limit heading in football players under the age of 12, could also help protect young players from being exposed to RHI on a regular basis.

How could CTE potentially be detected in vivo?

The apparent similarity of CTE symptoms to symptoms of other neurodegenerative diseases such as AD further complicates the search for diagnostic criteria that can be used during life. Currently, there are different biomarkers and imaging techniques being investigated.

Cerebrospinal fluid (CSF) is a clear fluid that circulates around the brain and spinal cord, providing protection, transporting nutrients, and removing waste products. CSF analysis through a lumbar puncture is a valuable diagnostic tool for various neurological conditions.

Current research is exploring the potential of CSF biomarkers for CTE diagnosis. Some of the most promising biomarkers are tau proteins, the Neurofilament light chain protein, and a marker for microglial activation called soluble triggering receptor expressed on myeloid cells 2 (sTREM2).

Researchers are also investigating whether biomarkers currently used for diagnosing Alzheimer’s disease, such as amyloid beta and phosphorylated tau (p-tau), can be applied to CTE detection. However, due to potential differences in the underlying tau pathologies between the two diseases, CTE-specific biomarker tests may be necessary.

Apart from that, advanced imaging techniques, such as diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), are being used to detect microstructural brain changes associated with CTE. Studies using these techniques have shown white matter alterations and blood-brain barrier dysfunction in athletes who have experienced repetitive head trauma. Furthermore, imaging techniques like positron emission tomography (PET) or electroencephalography (EEG) are used to provide insight into the development or tracking of CTE.

Overall, the development of reliable in vivo diagnostic tools for CTE is crucial for early detection and intervention, allowing for lifestyle and career changes, potential therapeutic interventions to slow disease progression, and even the development of more effective treatments.

What can be done to manage CTE symptoms?

Directly targeting tau pathology, reducing neuroinflammation, or protecting neurons could potentially help with the treatment of CTE, although most methods that have been proposed only help with symptom management rather than reversing the underlying pathology.
Developing drugs that inhibit the aggregation of tau protein could halt or delay CTE progression. Moreover, medications that reduce inflammation in the brain, such as certain non-steroidal anti-inflammatory drugs, could mitigate CTE-related damage, though the long-term effects of these medications on CTE progression require further investigation. Neuroprotective agents like antioxidants and growth factors, which protect neurons from damage and promote their survival, could slow down CTE progression.

What could a future treatment look like?

Antibodies that target and clear abnormal tau, which are already being investigated in the context of other neurodegenerative diseases, could hold promise for CTE treatment by reversing the pathology.
Likewise, customized nano chaperones enhancing pathological tau clearance, which are already showing promising results in AD mice, could be adapted for CTE. This approach aims to clear the accumulated tau protein, potentially halting or slowing the progression of the disease.

Another novel approach could be to combine minocycline treatment, which can be used to reduce neuroinflammation, with a prescribed exercise regimen and a strict Mediterranean diet for overall brain health. This multi-faceted approach could potentially address both the neuroinflammation and the overall neuronal health, offering a more comprehensive treatment strategy.

While genetic risk factors for CTE are not fully understood, another potential approach could be to use CRISPR-Cas9 to target and modify specific genes that increase the risk of developing CTE. However, this is a highly speculative and ethically complex approach that requires extensive research into the genetic basis of CTE.
Some of the genes worth researching would be the transmembrane protein 106B gene (associated with increased CTE pathology, neuroinflammation, and the presence of dementia amongst athletes with CTE), the MAPT gene (coding for tau protein), the CDLN5 gene (associated with blood-brain-barrier integrity), and genes such as TNF-alpha or IL-1 (involved in inflammation following brain injuries).

Nevertheless, genetic modifications present an ethical dilemma that is often talked about and for which it is nearly impossible to find an answer that most of the general population would feel comfortable with. That is why, future research should focus primarily on finding more conventional treatment methods, enabling patients from all kinds of backgrounds to receive an effective treatment.

7. What research has already been done and what areas of research should future studies focus on?

As CTE attracts the attention of researchers worldwide, there have already been a good number of studies done on former American football players. Nevertheless, many questions remain.

How is aging related to CTE development and severity?

A study of 246 American football players, of whom 211 had been diagnosed with CTE, has shown that the age of first exposure to American football does not appear to correlate with CTE pathological severity. Increasing age, however, has been suggested to lead to more severe pathology in some other studies.
Nevertheless, a younger age of first exposure seems to be significantly associated with an earlier onset of both behavioural/mood and cognitive symptoms. For every year younger a player began playing American football, symptom onset occurred 2.93 years earlier for cognitive and 2.66 years earlier for behavioural/mood symptoms. For players that began their career before the age of 12, the onset of symptoms has even been advanced by approximately 13 years for behavioural/mood symptoms and approximately 16 years for cognitive symptoms.
Therefore, while age could be considered as a potential factor in CTE development and symptom severity, more research is needed to confirm these findings and clarify the exact mechanisms by which age influences CTE.

What are the differences between the two sexes?

Up until today, CTE research has been focusing primarily on men. This does not mean that women are less susceptible to the disease. In fact, studies suggest that female athletes may exhibit greater symptom severity and slower recovery from concussions compared to males. Also, the phase of the menstrual cycle at the time of head injury could also influence the severity of the symptoms. Since progesterone can have a protective effect after traumatic brain injury (TBI), TBI leads to a poorer outcome during the follicular phase of the menstrual cycle compared to the luteal phase because progesterone will be withdrawn in the days after the incident.On the other h and, the Professional Fighters Brain Health Study has found that women sustained fewer knockouts, or technical knockouts compared to men, indicating potential differences in the type and severity of head impacts experienced.

Apart from that, intimate partner violence (IPV) is increasingly recognized as a potential cause of RHI in women, which in turn could lead to CTE development. It should be mentioned that women are not the only ones experiencing IPV. In fact, with 1 in 3 women and 1 in 4 men having experienced physical violence by an intimate partner, these cases far outpace the number of individuals with prolonged exposure to contact or combat sports.
On that note, if you ever witness or even just have a suspicion about domestic violence, please do not hesitate to act. Moral courage goes a long way!

In the future, more studies are needed to examine larger, more diverse samples, including both males and females from various backgrounds and with different RHI exposure to investigate the interplay of biological, hormonal, social, and environmental factors.

How could “everyday medication” affect CTE symptom management?

It is unclear how medications like anticoagulants affect CTE symptom management. It has been suggested that patients should not stop taking their anticoagulation medication after TBI because the risk of thromboembolic events, such as strokes, is higher than the risk of bleeding. Anticoagulants, by affecting blood clotting, could also influence the microvascular changes that occur after receiving repetitive head impacts.
Thus, it is essential to do further research to determine the complex interplay of factors involved in CTE development and to assess whether anticoagulants could play a role in managing or mitigating its symptoms.

What should future studies look like and what should they focus on?

Turner et al. have laid out the ideal workflow for future clinical CTE studies in 2013 already. Researchers should focus on an at-risk patient population and do baseline measurements before an incident occurs. This pre-screening should include imaging, biomarker levels, and neuropsychological testing. After a suspected injury or after receiving a predefined high magnitude or quantity of head impacts, the post-injury screening should be used to keep track of the changes, again using imaging, biomarker levels, and neuropsychological testing. Finally, post-mortem histological studies should include biomarker levels and the presence of tauopathies and other neuropathology.
Others have highlighted the importance of longitudinal studies considering parameters such as age of injury, cognitive reserve, genetics, medical history, influence of gonadal sex hormones and their changes (i.e. in women during menopause), menstrual cycle function post-injury, lifestyle choices, and many more to fully investigate the relationship between CTE and aging as well as the difference between male and female patients and how those parameters influence the severity of the long-term consequences of brain trauma.

What are the challenges researchers are facing?

Since a definitive diagnosis of CTE is only possible after death, it is extremely challenging to intervene early and prevent neuronal damage. By the time CTE is confirmed, it is too late, and the brain has already changed irreversibly.

The absence of reliable in vivo biomarkers for CTE poses a significant challenge in identifying individuals in the early stages and monitoring treatment effectiveness. Current research is exploring potential biomarkers and advanced imaging techniques, but these are still under development.
While the literature acknowledges RHI as a key risk factor, the precise mechanisms by which they lead to CTE are not fully understood. This incomplete understanding hinders the development of targeted therapies.
CTE presents with a wide range of symptoms, varying in severity and type from person to person. This makes it difficult to design treatments that address the diverse clinical manifestations of the disease.

8. Why is it important to do more research on the topic?

If you look at the figure below and notice the enormous differences between a normal brain and a brain in an advanced CTE stage, it becomes obvious that scientists should not stop researching until the factors influencing CTE are better understood.

Figure 3: Comparison of the image of a healthy brain (on the left) with the image of a brain showing signs of advanced CTE (on the right) (source: Wexler, Frontline, 2013).

In the end, an effective diagnostic and treatment strategy, which works for both men and women without severe side effects, can only be found after conducting more conclusive research that allows for a deep understanding of how CTE development, progression, and severity can be influenced by a multitude of factors.