Authored By: Jaeuk Shin
Art By: Carla Hu
Abstract
Traumatic brain injury (TBI) affects about 1.5 million Americans each year. Recent studies have shown that repetitive head trauma can lead to chronic traumatic encephalopathy (CTE), a neurodegenerative disease that has been linked with suicides within the NFL, contributing to its recently growing popularity. Symptoms of CTE include mood disorders, memory loss, cognitive impairment, and motor dysfunction. Currently, however, there is no cure for CTE and it can only be diagnosed post-mortem via [complete]. Researchers have explored imaging techniques to diagnose CTE in vivo, such us MRI, fMRI, DTI, and CT scans. Studies show that MRI is the most established method,. Imaging to diagnose CTE is vital for the safety of athletes and people prone to head injury, including those in the military. so research for imaging methods is necessary.
Introduction
There has been growing concern about the long-term effects of traumatic head injuries such as concussions on the brain [43]. Traumatic brain injury (TBI) affects about 1.5 million Americans annually [34]. Head injuries occur in contact sports like American football, featuring dangerous tackles and helmet-to-helmet contact, where athletes are regularly exposed to repetitive head trauma associated with a neurodegenerative disease called chronic traumatic encephalopathy (CTE) [1]. However, CTE can be developed in anyone who has experienced head trauma [2]. CTE is also seen in individuals who play hockey and boxing, for instance, and those who are in the army [6].
CTE is a progressive and fatal brain disease whose symptoms include mood disorders, memory loss, cognitive impairment, and motor dysfunction [1]. Further symptoms of CTE are commonly linked with suicide and impaired cognition throughout the rest of a CTE-diagnosed patient’s life [26]. CTE occurs in those who have experienced severe brain damage and who have been exposed to minor injuries, so it is important to establish more knowledge about the disease to understand CTE. As CTE results in several disabilities, diagnosis techniques must be found as helping prevent the spreading of CTE can potentially put a stop to the symptoms that come with CTE and even save lives. A person who has developed CTE has experienced a form of repetitive head trauma, emphasizing the link between the two [2]. Thus, it can be implied that experiencing repetitive head trauma makes one more susceptible to developing CTE; however, more studies must be conducted to confirm this [2]. The main issues related to CTE are that it is currently an incurable disease and that it can only be diagnosed postmortem [27].
The fact that CTE cannot be currently diagnosed in vivo stresses the urgent need for an in vivo diagnosis method and calls for further research to be done [3]. CTE has been the cause of many suicides: out of 7 articles that reported on retired National Football League (NFL) athletes and their CTE diagnosis, the calculated expected number of deaths by suicide is 21.8%, a study found [26]. Out of 376 deceased former NFL players, 345 were diagnosed with CTE, about 92% [33]. So, clarification on the diagnosis of CTE is needed to truly understand what must be done to help stop the development of CTE in brains. As of now, CTE can currently be diagnosed only through brain tissue analysis, where brain tissue is sliced and chemicals are used to make the abnormal tau protein visible, whilst analyzing a pattern unique to CTE in the tauopathy [7]. To address this, researchers have explored different techniques to develop a method to diagnose CTE. While several imaging methods (CT, PET scans) have been used to explore the possibility of a diagnosis, magnetic resonance imaging, MRI, has been reported to be the most promising one [8].
Funding for CTE is growing, with many large corporations providing grants for researchers to find a way to diagnose CTE in vivo [35]. In 2015, the National Institutes of Health and the National Institute of Neurological Disorders and Stroke awarded researchers with a $16 million grant. In 2016, the NFL joined and promised to pledge $100 million to neuroscience research to make football a safer game [36]. With the growing support of big companies, awareness of the dangers of CTE will become more widespread and researchers will be given the opportunity to explore an unknown disease [37].
This review paper aims to explore CTE in vivo diagnosing methods, with a focus on MRI. The first section of the manuscript provides an essential background of CTE. The second section, the core of the manuscript, reviews the state-of-the-art methods to diagnose CTE in-vivo and summarizes relevant studies that have used these methods to diagnose CTE in different ways. Finally, the promises and limitations of CTE diagnosis in-vivo are discussed to conclude with a suggestion on what the best imaging technique might be.
Discussion Background of Chronic Traumatic Encephalopathy
Through brain dissections of CTE-diagnosed patients, the accumulation of tau protein in the brain has been connected with CTE (see Figure 1) [5]. In healthy brains, tau proteins are necessary for the proper functioning of the brain’s nerve cells, which transmit signals throughout the body. However, in individuals with CTE, tau protein becomes abnormally phosphorylated and forms insoluble aggregates, leading to the development of neurofibrillary tangles (NFTs) and the disruption of normal brain function [23]. NFTs are a hallmark of CTE and are found in various regions of the brain, including the cortex, hippocampus, and amygdala [24]. The accumulation of NFTs is associated with the degeneration of neurons and subsequent brain damage that leads to the clinical symptoms of CTE [24]. The severity and distribution of NFTs in the brain correlate with the severity of clinical symptoms, with more severe cases of CTE associated with a higher number of NFTs. McKee et al. described the fact that tau protein accumulation leads to the development of CTE through the abnormal phosphorylation of tau which disrupts the protein’s normal function and leads to the formation of NFTs [25].
The 4 stages shown in Figure 1 are the 4 ‘steps’ of CTE, where clusters of NFTs gradually spread throughout the whole cross-section. Stage I CTE is characterized by 1 or 2 isolated perivascular epicenters of NFTs in the cortical sulci. In stage II, it can be observed that 3 additional cortical CTE lesions are found. This can be connected to an early site of tau phosphorylation in NFT formation. In stage III, multiple CTE lesions and diffuse neurofibrillary degeneration of the medial temporal lobe are found. Multiple lesions are also found in the frontal cortex and insula and there is neurofibrillary degeneration of the hippocampus. In stage IV, large groups of CTE lesions in the frontal, temporal, and insular cortices can be found and there is diffuse neurofibrillary degeneration of the amygdala.
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Figure 1 - Depiction of Dr. Ann McKee’s four stages of CTE through tau accumulation adapted under an Open Access license from Mez et al. [28], |
According to McKee’s classification [28], in stage I, a typical CTE patient is asymptomatic or may complain of mild short-term memory deficits and depressive symptoms. In Stage II, the mood and behavioral symptoms could include behavioral outbursts and more severe depressive symptoms. In Stage III, patients typically present with more cognitive deficits, including memory loss, executive functioning deficits, visuospatial dysfunction, and apathy. In Stage IV, patients present with advanced language deficits, and psychotic symptoms including paranoia, motor deficits, and parkinsonism. As CTE progressively gets worse through each stage, NFT formation is widespread in specific locations of the brain, which evidently has an impact on the cognition and function of the brain.
The presence of white matter abnormalities in the brain has been connected to CTE [30]. White matter is found in the subcortical region of the brain, comprised of axons (nerve fibers), and neurons. It is also composed of glial cells which form the connections between regions of the brain [30]. These connections are called white matter tracts, which help the communication between the regions and the brain to function. Research has shown that there may be a correlation between CTE and the deposition of abnormal tau in the white matter of CTE, showing that white matter undergoes important alterations as well.
Medical Imaging and In Vivo Diagnosis of CTE
While there is no definitive way to diagnose CTE in vivo currently, techniques to diagnose CTE in vivo have been used through MRI and CT scans as well as other imaging methods. The current hypothesis predicts that there is a relationship between micro changes within white matter and tau proteins that reflect changes at the macro level which can be captured using medical imaging which would correlate with CTE [5, 11]. Studies have used this approach to use imaging to attempt to diagnose CTE in vivo, where features of both the brain tissue after death and imaging scans are used to try to build a connection between specific features.
The different techniques that have been used include standard MRI, diffusion tensor imaging (DTI) MRI, functional MRI (fMRI), and CT. Standard MRI is used to capture changes in the brain’s structure and function through tau protein accumulation [11]. Tau protein accumulation is a micro change that affects macro changes in the brain that standard MRI scans are able to detect. MRI scans are useful for detecting changes in the white matter of the brain, the tissue that connects different regions of the brain, often affected in people with CTE [11, 14]. An advanced MRI technique, DTI, has been used in studies to provide information of white matter in the brain, sensitive to axonal injury and changes in white matter [17]. DTI measures the direction and rate of water diffusion in brain tissue to examine microstructural changes such as white matter in the brain [21]. Resting-state fMRI measures the spontaneous, low-frequency activity of the brain at rest and can identify networks of brain regions that are connected [40]. The main difference between standard MRI and fMRI is that MRI scans show structural details of the brain, while fMRI is able to show structure and activity levels [41]. Finally, CT uses x-rays to detect acute bleeding or skull fractures in those with recent head trauma [13]. However, CT scans are radioactive and less accurate than MRI at providing detailed information about the size, location, and severity of brain damage [8]. Out of all 3 techniques, standard MRI is the most established as it has been historically used to diagnose other progressive brain diseases similar to CTE such as Alzheimer’s disease [39].
Standard MRI techniques were used to analyze the brains of 55 CTE-confirmed men and 31 men with normal cognition at the time of the scan [11]. MRI was able to discover that those with CTE had experienced macro changes, reduced brain volume and cortical thinning, which reflected micro changes in white matter, compared to those without CTE. Another study compared the MRI scans of 21 former NFL players diagnosed with CTE to 14 former NFL players without CTE and 11 non-athlete controls [22]. The scans showed that the players with CTE had significantly smaller hippocampal volumes and reduced cortical thickness in several brain regions when compared with the 11 non-athlete controls and players without CTE. While changes specific to CTE were not able to be found due to its small size in nature, a connection between structural changes in the brain and CTE was suggested. Both studies were able to detect brain volume loss of the brain and cortical thinning through an MRI scan.
Another study involving 53 patients with a history of multiple concussions and cognitive symptoms used diffusion tensor imaging (DTI) MRI, to examine changes in the white matter of the brain [21]. The 53-patient breakdown was 34 males and 19 females, with 27 patients having a history of concussion from football. The results showed that the patients had significantly lower fractional anisotropy (FA) values in several brain regions than healthy controls. FA is a measure of the degree of organization of white matter fibers and lower FA values indicate disruption of white matter structure [21]. The use of DTI in identifying white matter abnormalities in professional fighters with a history of repetitive head trauma was also investigated by Wilde et al [18]. The study included 22 professional fighters (mean age 35 years and mean career length 11 years) as well as 11 age-matched, healthy controls. Results showed that professional fighters had a significantly lower FA value than controls in white matter regions including the cingulate gyrus, corpus callosum, and uncinate fasciculus [18]. The study also found a significant correlation between the number of fights and the extent of white matter abnormalities, suggesting that DTI may be useful in monitoring the progression of brain injury in professional fighters. Therefore, it can be concluded that according to these studies DTI is a useful tool for detecting white matter abnormalities to diagnose CTE, potentially identifying early markers of CTE in individuals with head trauma [18, 21].
A study with 26 former NFL players with multiple concussions and 31 control participants used resting-state fMRI to investigate changes in brain connectivity [29]. Results showed that the NFL players had decreased functional connectivity in several brain regions, including the default mode network (DMN), a network of brain regions involved with thinking and memory, and the salience network (SN), involved in detecting and responding to stimuli, compared to healthy controls [29]. Researchers concluded that resting-state fMRI had promising results enough to be useful for identifying changes in brain connectivity associated with CTE.
While standard MRI, DTI, fMRI and CT imaging have been used to identify structural changes in the brains of individuals with a history of repetitive head trauma, the practicality of an already well-known and established technique of standard MRI is most promising. A study found that MRI imaging was more accurate than any other imaging techniques that have been used in detecting brain abnormalities in individuals with a history of repetitive head trauma [38]. The non-invasive nature of standard MRI and its practical suitability to diseases similar to CTE makes it considered to be the more accurate form of imaging diagnosis.
Table 1: Summary relevant state-of-the-art studies exploring in vivo diagnosis of CTE
Study | Method of Diagnosis | Sample Size | Results |
Diffusion Tensor Imaging Correlates of Concussion Related Cognitive Impairment, Gonzalez, et al. [21] | Diffusion tensor imaging (DTI) | 53 patients with a history of multiple concussions; 34 males, 19 females; 27 out of 53 were former football players. | Concussed patients have a lower value of organized white matter fibers, implying that the white matter structure is disrupted. |
Severe Suicidality in Athletes with Chronic Traumatic Encephalopathy: A Case Series on Putative Ethiopathogenetic Mechanisms, Costanza [22] | Functional MRI (fMRI) | 21 former NFL players diagnosed with CTE to 14 former NFL players without CTE and 11 non-athlete controls. | Scans were able to detect and distinguish brain volume loss and structural shrinkage in CTE diagnosed patients compared to controls. |
Structural MRI profiles and tau correlates of atrophy in autopsy-confirmed CTE [11] | Standard MRI | 55 CTE-confirmed men, 31 normal cognition controls | Those patients with CTE had reduced brain volume, cortical thinning, and white matter changes. |
Chronic Effects of Boxing: Diffusion Tensor Imaging and Cognitive Findings [18] | DTI | 22 professional fighters, 11 age-matched, healthy controls. The mean age is 35 years old and the mean career length is 11 years | The fighters had lower FA values in white matter regions. There is a correlation between the number of fights and the extent of white matter abnormalities. |
Characterizing the Link Between Glial Activation and Changed Functional Connectivity in National Football League Players Using Multimodal Neuroimaging [29] | Resting-state fMRI | 26 former NFL players with multiple concussions and 31 healthy controls | fMRI showed that players had decreased functional connectivity in DMN and SN. Brain injury is connected with decreased cognition, memory, and self-referential thinking. |
This table summarizes the diagnose technique, the sample size and the main results of a selection of relevant state-of-the-art studies that explore the diagnosis of CTE in vivo
Limitations and Gaps to be Addressed
Among the three studies, all have small sample sizes (the largest sample size is 57 patients). Similarly, the selection of patients to be involved in the studies was selective and varying; the majority of the sample size was male athletes who played football and had a history of concussions. Patients’ history of other contact sports or activities were not taken into account or other underlying conditions besides concussions. The only study that truly includes athletes who have been diagnosed with CTE post-mortem is the second study featuring 21 former NFL players with CTE. However, all three studies are able to draw a clear connection between the severity of concussions and their relationship to CTE-related features in a patient’s MRI scan.
While many other studies have been conducted about the diagnosability of CTE in vivo, commonly cited studies are limited by methodological biases, pathological inconsistencies, insufficient data, and reliance on post-mortem data [32]. Due to the nature of the diagnosis of CTE, it is difficult to get a large sample size and an unbiased data set. Because of this, data and assumptions are exaggerated, causing unnecessary fear for individuals who believe they have CTE simply because they have a history of concussions. While this may be the case, there is also a possibility that individuals who have had concussions do not develop CTE and are fearful only because of studies that show concussed athletes with CTE. A method to include a much larger number of participants with varying backgrounds of different head injuries and contact sports must be developed to get a deeper understanding of the true neuropathological nature of CTE. This will allow people to if they are at risk of developing CTE and understand symptoms that may relate to its development.
The diagnosis of CTE in vivo is important to allow people to take precautions to prevent CTE from developing in their brains. . As there is no knowable cure for CTE, the process of finding a method for the diagnosis of CTE is urgent.
All that can be done as of now to stop the development of CTE is prevention. As the characteristics of CTE is currently unknown, it is believed that the only way to lower the risk of getting CTE is to avoid repeated head injuries [37]. For example, if playing contact sports, wearing the correct protective equipment can be helpful. Furthermore, making sure head injuries are treated and checked on properly can help the prevention of CTE [37].
Conclusion
This study highlights the importance of diagnosing CTE in vivo and reviews the state-of-the-art methods to diagnose this disease in vivo. Several imaging methods to diagnose CTE have been used in the past and include CT, PET, and MRI. In this regard, MRI is the most established technique showing promising results through the use of DTI and fMRI. MRI has been able to take brain scans of athletes diagnosed with CTE as well as people who have had a history of concussions and draw a consistent link between CTE/brain injury and disorganized white matter, brain shrinkage and volume loss, and decreased functional connectivity between brain regions. However, these studies had limitations which included a small sample size and biased selections of subjects. An analysis of the use of MRI for in-vivo diagnosis of CTE implied that studies should be conducted more thoroughly to get a clear understanding of the process to diagnose CTE in-vivo.
The use of MRI is still being tested as it is unclear how sensitive and specific these techniques are for detecting the disease. The development of imaging techniques that can detect CTE at earlier stages and prevent it from spreading is crucial. It is even more crucial to be able to use MRI to detect features in a living patient that signifies CTE development and prevent it from spreading further.
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