What are the Biomarkers of CTE?

June 21, 2020

Introduction

Chronic Traumatic Encephalopathy, also known as CTE is a progressive neurodegeneration disease. The most commonly known neurodegeneration disease is Alzheimer’s disease. Evidence of CTE was first described almost 90 years ago when symptoms were observed among boxers. However, the neuropathology and clinical presentation differ somewhat from how CTE is characterized today.

Although the incidence and prevalence are unknown, it has been diagnosed in former amateur and professional contact sport athletes as well as military veterans. In 2017, a study conducted at Boston University showed that 110 out of 111 brains of deceased former football players showed signs of CTE (Mez et. al, 2017). Given the millions of contact sport athletes and military service members exposed to repetitive head impact each year, CTE has become a major public health concern. New research suggests nearly 6% of the general population may have CTE. Results from the largest and broadest study of CTE to date show that although the highest rates of disease are in athletes, a significant number of non-athletes also have the neurodegenerative disease (Bienek, 2019).

The repetitive head impact linked with CTE impacts the brain

CTE is believed to be triggered by repeated traumatic brain injuries, including concussions and repeated hits to the heads, called sub concussive head impacts (head impacts that do no cause symptoms of concussion) in contact sport athletes and also in military veterans (McKee, 2016).

After a sufficient amount of head trauma, this disease develops in the brain and becomes a progressive widespread brain disease as time goes on. It’s like smoking, it’s not one cigarette that kills you, it’s the repetitive exposure that does.

Risk factors

The only known risk factor in developing CTE is repetitive head injury (Tharmaratnam, 2018). Individuals who engage in activities that increase their chances of sustaining repetitive hits to the head may have a higher risk of developing CTE (Mckee, 2016). In fact, for every 2.6 years of play of American tackle football, the risk of developing CTE doubles. (Mez, 2020). Even a basic tackle causing trauma to the head over and over again appears to be the root of the disease (Stein, 2015). These alarming findings from an analysis of brains of 266 deceased former amateur and profession football players are the first to quantify the strength of the link between playing tackle football and developing CTE.

Researchers currently do not know the incidence and prevalence of CTE, but they do know that CTE does not occur only in athletes. There is no evidence to suggest that one concussion leads to CTE. Research on the role of genetics, sex, other factors such as environmental or life style factors is needed to better understand the risk for CTE.

What actually happens to the brain?

With repeated impact to the head, the brain inside the skull ricochets back and forth. It moves forward, accelerates, decelerates and rotates which causes the brain inside the skull to elongate and stretch. The stretching places excessive physical force on the individual nerve cell and that can lead to the build-up of tau protein (McKee, 2015).

An easy way to understand CTE is by picturing your brain as a wheel of cheese. A normal, undamaged wheel of cheese will be completely solid. All of the neurons will be able to effectively communicate because the wheel is not damaged at all. Someone who suffers from CTE will have a wheel of cheese that more closely resembles swiss cheese.

CTE SYMPTOMS

Symptoms and various behaviours associated of CTE

The symptoms of CTE can vary, but are generally associated with symptoms in cognitive, mood, behaviour and motor domains. (Stern 2013).

  • Cognitive symptoms: Memory, executive dysfunction and dementia

  • Mood and behaviour symptoms: depression, anxiety, irritability, impulsivity, aggression and violent behaviour

  • Motor symptoms: Parkinsonism, dysarthria, ataxia

Stages of CTE

According to a 2012 Boston University study, CTE follow a pattern of phases which reflect the disease course over a period of years to decades. The first phase begins with younger patients and is mostly behaviour/mood related, while the second phase begins later in life and includes cognitive changes. Symptoms may not be visible until years after the trauma, making CTE extremely difficult to diagnose. There are 4 stages of severity of pathology with one being the mildest and 4 being the most severe (McKee, 2012).

  • Stage 1

Symptoms include headaches, loss of attention and concentration. The earliest evidence of CTE was shown in an 18-year-old multi-sport athlete who suffered multiple concussions in high school football (Reference).

  • Stage 2

Symptoms expand to include depression, suicidality, explosivity and short-term memory impairment.

  • Stage 3

Symptoms included cognitive impairment and problems with executive functions, specifically planning, organization, multi-tasking and judgement. 27-year-old NFL tight-end, Aaron Hernandez, shot two people and fatally suicided was later diagnosed with stage 3 CTE (Gregory, 2020).

  • Stage 4

A form of dementia (e.g. memory and cognitive impairments severe enough to impact daily living). Recently, an Australian Football Player diagnosed with Alzheimer’s Disease was also found to have CTE (Pearce, 2020). It was reported that he suffered from personality change, depression, aggression issues and memory loss, that rapidly worsened towards the end of his life.

TAUOPATHY

Tau is a definitive sign of CTE

Tau is a normal protein in brain. Normally, it is inside the nerve cell and it contributes to the cytoskeleton (the skeleton of the cell). It helps hold up the cell shape. The internal skeleton has a tube-liked shaped through which nutrients and other essential substances travel to reach different parts of the neuron. Under abnormal circumstances, such as after trauma, when the nerve cells are damaged, the tau comes off the skeleton. It comes off and it starts clumping up. Eventually it will kill the cell if enough builds up over time (reference)

CTE diagnosis and what makes CTE disease and unlike any neurodegenerative disease?

Currently, CTE cannot be diagnosed in living people (Cantu, 2019). A diagnosis cannot be made without a neuropathological examination of the brain tissue. Examiners look for tau protein deposition in a specific pattern that is not seen in any other disorder:

  • Tau occurs in isolated hot spots that are found deep in the valleys of the brain also known as the sulcus.

  • It uniquely occurs around small blood vessels.

The deposition of an abnormal tau protein that clusters around blood vessels in the brain is a very distinct and specific lesion for CTE. There is no other disease that causes those changes in tau protein and that is how a distinctive diagnosis is made (Katsumoto, 2019).

Due to only a post-mortem diagnosis, developing neuroimaging and blood biomarkers in living individuals are extremely important in order to find a diagnostic marker for CTE.

BIOMARKERS

What is a biomarker?

Biomarkers are measurable substances within our bodies that can indicate, with reasonable accuracy, a disease or condition is present. An example of a common biomarker is our blood sugar levels. By taking a pinprick of blood, we can test the sugar levels in our blood, which is essential for those with diabetes.

In recent years, researchers have made positive advancements in finding CTE biomarkers, however most findings are still guidelines and further investigation and testing is required.

Types of biomarkers:

  1. IMAGING BIOMARKERS - An imaging biomarker is a feature of an image relevant to a patient’s diagnosis. For example, a number of biomarkers are frequently used to determine risk of lung cancer. First, a simple lesion in the lung detected by X-Ray, CT, or MRI can lead to the suspicion of a neoplasm. Imaging tests include PET (Positron Emission Tomography) Scans, EEG (Electroencephalogram), qEEG (Quantitative Electroencephalogram) and MRI (Magnetic Resonance Imaging).

Positive PET Scan for Tau

Recently, researchers from Boston University revealed that an experimental PET scan on living people is able to detect abnormal levels of tau protein in patterns similar to those found in the brains of deceased people diagnosed with CTE after death (Stern et. al, 2019).

The researchers found evidence of abnormal tau proteins in living people by comparing experimental PET scans of 31 control subjects without any history of head trauma or psychological symptoms against 26 former NFL players who have self-reported cognitive, mood and behaviour symptoms associated with CTE. The scan detected greater amounts of abnormal tau protein build-up in the group of living NFL players compared to the control group. Unfortunately, limitations are that it can’t yet be used for individual diagnosis. The study analysed grouped data and not individual findings.

Brain Atrophy

Based on MRI, finding regional brain atrophy on the imaging study suggests that there is some neurodegenerative or other brain disease present, which may or may not be CTE (Cantu, 2019). Hippocampal and cortical atrophy is typically found in the frontal loves in moderate and severe stages of CTE.

Electroencephalogram (EEG)

An EEG is a test used to evaluate the electrical activity in the brain. Using an EEG device such as the eVox system, by Evoke Neuroscience, it can provide a mapping of the brain and clinically actionable objective biomarkers of brain health and function.

EEG Brain Biomarkers:

  • Peak Alpha Frequency (PAF) reflects cognitive capacity. Slow PAF can be seen in patients with Mild Cognitive Impairments and Dementia. Fast PAF can be seen in patients with anxiety, PTSD, Chronic Stress (Dickinson, 2018).

  • Thea Beta Ratio Is another brain biomarker and is cleared by the FDA to aid in the diagnosis of ADHD. High scores reflect inattention (Lenartowicz, 2014).

  • P300 latency (working memory). According to the results of a controlled trial published in Clinical Electroencephalography, P300 latency accurately predicts memory impairment (Braverman, 2003). Low scores reflect an inability to categorize stimuli, problems with information processing, inattention, lack of focus and cognitive decline.

  • Alpha3/Alpha2 is reflective of long-term memory encoding and information processing. A study showed an increase of Alpha3/Alpha 2 ratio is associated with hippocampal atrophy (Moretti et. Al, 2009).

  1. BLOOD BIOMARKERS – Blood biomarkers are characteristic biological properties or molecules that can be detected and measured in parts of the body like the blood or tissue. It may indicate either normal or diseased processes in the body.

Elevated Tau Protein

Researchers exposed rats to a Mild Traumatic Brain Injury (mTBI) once per day for three consecutive days and analysed brain samples taken at 6 and 10 months after the last injury. The level of phosphorylated tau protein was higher in mTBI exposed rats than in control rats at both time points, showing that tau pathology can be detected long after injury (Lempriere, 2020).

In a group of former professional athletes who experienced multiple concussions, a new study has found that approximately half the group had higher than normal levels of tau protein in their cerebrospinal fluid, fluid surrounding the brain and spine (Taghdiri, 2019).

In addition, athletes with elevated tau protein levels compared to athletes with normal levels of tau Individuals scored lower on executive functioning tests – which assessed attention, memory and organizational and planning skills and maybe indicating CTE.

Elevated levels of PROTEIN CC-11

Protein CCL-11 has been identified as a potential biomarker by Boston University researchers. The team studied 23 former college and professional football player’s brains, compared to 50 non athletes Alzheimer’s patient brains and 18 non-athlete control brains (Cherry, 2017).

CCL-11 levels were notably higher in CTE patient brains than in non-athletes Alzheimer’s and control patient brains. They then compared the degree of elevation of CCL11 to the number of years those individuals played football and found that there was a positive correlation between the CCL11 levels and the numbers of years played.

Neurofilament light chain (NfL)

NfL has been highlighted as a biomarker in various neurological diseases in recent studies (Lin, 2019). The work shows that blood levels of NfL indicate disease severity and progression in neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).

CTE MANAGEMENT

Challenges of Finding a Treatment

Diagnosing CTE during life with sensitive and specific biomarkers it the next critical step and only then will its incidence and prevalence, risk factors, and clinical features or other features be known. Presently, there are available therapies and medications that can manage current CTE symptoms and improve the quality of daily life.

Trauma Encephalopathy Syndrome (TES)

At this time the only precisely accurate means of diagnosing CTE Is by post mortem, however Montinegro et al. have proposed new clinical research diagnostic criteria for CTE called Trauma Encephalopathy Syndrome (TES). TES is based on the clinical features reported in neuropathologically confirmed cases of CTE such as behaviour, mood, cognitive or mixed domains. While the validity and accuracy of TES are still a work in progress, it is believed to be useful for the clinician in terms of thinking how likely CTE is to be present.

Exercise

Today physical exercise is being used to treat memory disorders, stroke, post-concussion syndrome and more serious brain injuries (Tiozzo, 2015). A study suggests aerobic exercise can increase neurogenesis and neuroplasticity (Kimhy, 2015).

Diet

A healthy diet is also a general therapy felt useful for those with neurodegenerative as well as other disorders with a stress on high consumption of fruits and vegetables. A diet that promotes monounsaturated fat high in omega 3 is desired (Cantu, 2019).

Cognitive rehabilitation

CTE manifests difficulties with attention, concentration, memory and executive functions. Cognitive therapy. such as FITLIGHT Trainer, has the chance to significantly improve the quality of daily life the earlier it is instituted.

Mood/behaviour therapy

Patients who show symptoms of depression, anxiety, impulsivity, psychological therapy, counselling by a clinical psychologist or psychiatrist is recommended. This form of therapy investigates the relationship between thoughts, feelings and behaviours of the individual.

There are currently no medications for CTE that have been approved by the US Food and Drug Administration (FDA). As a result, treatments are prescribed based on symptoms that are present with the disease. Some medications which have been used for certain disease symptoms include acetylcholinesterase inhibitors for memory related problems and selective serotonin reuptake inhibitors for depression and anxiety. A discussion with the prescribing physician can be productive in determining the right course of symptomatic treatments for CTE (Turk & Budson, 2019).

CONCLUSION

Where are we now?

  • The search to diagnose the disease during life and monitor it will allow for research into prevention and treatment of the disease. A growing amount of new studies are showing promising efforts to develop validated biomarkers.

  • Future efforts need to address the management of acute mTBI as well as treatment, rehabilitation and comprehensive care CTE.

  • Prevention of trauma and continued public education regarding proper detection and management of acute mTBI is currently the best strategy to reduce the development of CTE.

What are the unresolved questions?

  • Incidence and prevalence of CTE. CTE is associated with trauma. There is no evidence to state it is caused by trauma.

  • Further research about the relationship between concussion, sub-concussion and CTE is still unclear

  • Diagnosis of CTE during life with validated biomarkers – blood, CSF, saliva assays. Neuroimaging, DTI, pet tau ligands

  • Validated animal models to understand the pathogenetic mechanisms

  • Other factors, genetic risk factors, other environmental risk factors

While the medical community’s knowledge of this disease is advancing, there is still much research that the medical community is undertaking in order to better understand the nature of this neurodegenerative disease.

References

McKee AC, Alosco ML, Huber BR. Repetitive Head Impacts and Chronic Traumatic Encephalopathy. Neurosurg Clin N Am. 2016;27(4):529‐535. doi:10.1016/j.nec.2016.05.009

McKee, A. C., Stein, T. D., Kiernan, P. T., & Alvarez, V. E. (2015). The neuropathology of chronic traumatic encephalopathy. Brain pathology (Zurich, Switzerland), 25(3), 350–364. https://doi.org/10.1111/bpa.12248

20. Kawata K, Rubin LH, Wesley L, Lee JH, Sim T, Takahagi M, et al. . Acute changes in plasma total tau levels are independent of subconcussive head impacts in college football players. J Neurotrauma (2018) 35:260–6. 10.1089/neu.2017.5376 [PubMed] [CrossRef] [Google Scholar]

Cantu R, Budson A. Management of chronic traumatic encephalopathy. Expert Rev Neurother. 2019;19(10):1015‐1023. doi:10.1080/14737175.2019.1633916

Katsumoto, A., Takeuchi, H., & Tanaka, F. (2019). Tau Pathology in Chronic Traumatic Encephalopathy and Alzheimer's Disease: Similarities and Differences. Frontiers in neurology, 10, 980. https://doi.org/10.3389/fneur.2019.00980

Saulle, M., & Greenwald, B. D. (2012). Chronic traumatic encephalopathy: a review. Rehabilitation research and practice, 2012, 816069. https://doi.org/10.1155/2012/816069

Mez, J., Daneshvar, D. H., Kiernan, P. T., Abdolmohammadi, B., Alvarez, V. E., Huber, B. R., Alosco, M. L., Solomon, T. M., Nowinski, C. J., McHale, L., Cormier, K. A., Kubilus, C. A., Martin, B. M., Murphy, L., Baugh, C. M., Montenigro, P. H., Chaisson, C. E., Tripodis, Y., Kowall, N. W., Weuve, J., … McKee, A. C. (2017). Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA, 318(4), 360–370. https://doi.org/10.1001/jama.2017.8334

Stern, R. A., Adler, C. H., Chen, K., Navitsky, M., Luo, J., Dodick, D. W., Alosco, M. L., Tripodis, Y., Goradia, D. D., Martin, B., Mastroeni, D., Fritts, N. G., Jarnagin, J., Devous, M. D., Sr, Mintun, M. A., Pontecorvo, M. J., Shenton, M. E., & Reiman, E. M. (2019). Tau Positron-Emission Tomography in Former National Football League Players. The New England journal of medicine, 380(18), 1716–1725. https://doi.org/10.1056/NEJMoa1900757

Dickinson, A., DiStefano, C., Senturk, D., & Jeste, S. S. (2018). Peak alpha frequency is a neural marker of cognitive function across the autism spectrum. The European journal of neuroscience, 47(6), 643–651. https://doi.org/10.1111/ejn.13645

Moretti, Davide Vito et al. ‘Increase of Theta/Gamma and Alpha3/Alpha2 Ratio Is Associated with Amygdalo-Hippocampal Complex Atrophy’. 1 Jan. 2009 : 349 – 357.

Braverman, E. R., & Blum, K. (2003). P300 (Latency) Event-Related Potential: An Accurate Predictor of Memory Impairment. Clinical Electroencephalography, 34(3), 124–139. https://doi.org/10.1177/155005940303400306

Lenartowicz, A., & Loo, S. K. (2014). Use of EEG to diagnose ADHD. Current psychiatry reports, 16(11), 498. https://doi.org/10.1007/s11920-014-0498-0

Lemprière S. Brain and blood biomarkers of chronic traumatic encephalopathy. Nat Rev Neurol. 2020;16(4):186. doi:10.1038/s41582-020-0340-8

Cherry JD, Stein TD, Tripodis Y, et al. CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease. PLoS One. 2017;12(9):e0185541. Published 2017 Sep 26. doi:10.1371/journal.pone.0185541

Taghdiri F, Multani N, Tarazi A, et al. Elevated cerebrospinal fluid total tau in former professional athletes with multiple concussions. Neurology. 2019;92(23):e2717‐e2726. doi:10.1212/WNL.0000000000007608

University of Texas Health Science Center at San Antonio. (2019, June 20). Largest study of CTE finds it in 6% of subjects: Interestingly, the traumatic brain disease is identified in both athletes and non-athletes.. ScienceDaily. Retrieved June 12, 2020 from www.sciencedaily.com/releases/2019/06/190620153548.htm

Mez J, Daneshvar DH, Abdolmohammadi B, et al. Duration of American Football Play and Chronic Traumatic Encephalopathy. Ann Neurol. 2020;87(1):116‐131. doi:10.1002/ana.25611

Gregory H. (2020). Making a murderer: Media renderings of brain injury and Aaron Hernandez as a medical and sporting subject. Social science & medicine (1982), 244, 112598. https://doi.org/10.1016/j.socscimed.2019.112598

Tharmaratnam, T., Iskandar, M. A., Tabobondung, T. C., Tobbia, I., Gopee-Ramanan, P., & Tabobondung, T. A. (2018). Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now?. Frontiers in neurology, 9, 445. https://doi.org/10.3389/fneur.2018.00445

Stein, T. D., Alvarez, V. E., & McKee, A. C. (2015). Concussion in Chronic Traumatic Encephalopathy. Current pain and headache reports, 19(10), 47. https://doi.org/10.1007/s11916-015-0522-z

Tiozzo E, Youbi M, Dave K, et al. Aerobic, resistance, and cognitive exercise training poststroke. Stroke. 2015;46(7):2012–2016.

Kimhy D, Vakhrusheva J, Bartels MN, et al. The impact of aerobic exercise on brain-derived neurotrophic factor and neurocognition in individuals with schizophrenia: a single-blind, randomized clinical trial. Schizophr Bull. 2015;41(4):859–868.