Emerging advances of in vivo detection of chronic traumatic encephalopathy and traumatic brain injury

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder that is of epidemic proportions in contact sports athletes and is linked to subconcussive and concussive repetitive head impacts (RHI). Although postmortem analysis is currently the only confirmatory method to diagnose CTE, there has been progress in early detection techniques of fluid biomarkers as well as in advanced neuroimaging techniques. Specifically, promising new methods of diffusion MRI and radionucleotide PET scans could aid in the early detection of CTE.

The authors examine early detection methods focusing on various neuroimaging techniques. Advances in structural and diffusion MRI have demonstrated the ability to measure volumetric and white matter abnormalities associated with CTE. Recent studies using radionucleotides such as flortaucipir and ¹⁸F-FDDNP have shown binding patterns that are consistent with the four stages of neurofibrillary tangle (NFT) distribution postmortem. Additional research undertakings focusing on fMRI, MR spectroscopy, susceptibility-weighted imaging, and singlephoton emission CT are also discussed as are advanced MRI methods such as diffusiontensor imaging and arterial spin labeled. Neuroimaging is fast becoming a key instrument in early detection and could prove essential for CTE quantification. This review explores a global approach to in vivo early detection.

Limited data of in vivo CTE biomarkers with postmortem confirmation are available. While some data exist, they are limited by selection bias. It is unlikely that a single test will be sufficient to properly diagnosis and distinguish CTE from other neurodegenerative diseases such as Alzheimer disease or Frontotemporal Dementia. However, with a combination of fluid biomarkers, neuroimaging, and genetic testing, early detection may become possible.

Introduction

In the 21st century, a global health concern regarding the consequences of contact sports has taken place. Predominantly in the United States, professional athletes are retiring early in fear of permanent brain injury¹ and organizations are advocating and attempting to enhance protective equipment. Traumatic brain injury can be divided into three main categories: severe, moderate, and mild. Mild traumatic brain injury (mTBI) is also often referred to as concussion but can include both subconcussive or concussive impacts to the head. These injuries occur as either a single event or are repetitive as commonly seen in contact sports and often go undiagnosed and untreated. While single sport-related mTBIs often result in short neurological impairment without visible structural injury,² severe TBI can lead to intracranial hemorrhage, cerebral contusions, and axonal damage which can therefore be detected by standard neuroimaging techniques.^3,4 Traumatic brain injuries have also been associated with an increased risk of suicide⁵ and are a major risk factor for the development of epilepsy.⁶ The number of sport-associated mTBIs is estimated to be between 1.6 million and 3.8 million annually.⁷ A recent study that used helmet sensors to measure the number of head impacts in 50 football players under age 18 recorded more than 11,900 impacts in one season.⁸ Repetitive head impacts (RHI) are associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease. Between 2005 and 2018, the number of published articles relating to CTE and RHI has increased. Chronic traumatic encephalopathy is a tauopathy that is pathologically characterized by an abnormal aggregation of hyperphosphorylated tau in the brain.⁹ CTE has been reported in athletes from a variety of contact sports,^10,11 military personnel,⁹ and in a professional bull rider,¹² all in which repetitive concussive and subconcussive head trauma are common.¹³ The prevalence of CTE, however, remains largely unknown due to the relatively new diagnostic criteria. A deeper understanding of the mechanism in which RHI lead to CTE is crucial for in vivo diagnosis of suspected cases. The need to quantify the health impacts related to head impacts calls for further studies.

The history of RHI and their relationship to brain damage has been explored throughout the 20th century. In 1928, Martland explored the long-term effects of repetitive brain trauma describing a “punch drunk” syndrome in 23 retired boxers.¹⁴ Researchers continue to disagree on whether “punch drunk” and CTE are the same disease. Regardless of their differences, in both cases, clinical and pathological degradation occurs due to RHI. Case studies of retired National Football League (NFL) players in the 21st century have rekindled medical interest.^15,16 Serious questions and a lack of clarity still exist on early-detection methods, pathological hallmarks, and post-diagnostic management of the disease.

Postmortem histopathological analysis is currently the only confirmatory method of CTE diagnosis. However, between 2015 and 2019, a considerable amount of literature has been published on in vivo detection of CTE and acute traumatic brain injury. These studies suggest promising advances in early detection methods. Histopathological analysis of CTE shows abnormally hyperphosphorylated tau in neurons and astroglia specifically around small blood vessels at the depths of the cortical sulci.^17–20 Due to the unique pattern of tau aggregation, CTE is distinguishable from other clinically similar neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD).²¹

In the opinion of the authors, a detailed diagnostic strategy must be developed to characterize CTE severity in living patients and cellular damage following RHI. Such information would contribute to educated decision-making regarding return-to-play following concussion, and characterization of risk factors that suggest total abstinence from contact sports. With the recent surge of CTE research, in vivo early detection methods may be achievable. The specific objective of this review is to evaluate the implications and limitations of the current advances in neuroimaging techniques for the diagnosis of CTE. The main methods reviewed in this article include structural MRI, diffusion tensor imaging (DTI), and positron emission tomography (PET). Research undertakings in MR spectroscopy (MRS), single photon emission CT (SPECT), susceptibility-weighted imaging (SWI), and functional MRI (fMRI) are briefly mentioned.

RHI, TBI & CTE

Chronic traumatic encephalopathy is a neurodegenerative tauopathy that is believed to clinically manifest itself 8–10 years after RHI, but also a single TBI may progress into CTE.^22,23 Studies have examined long-term exposure to RHI and the development of CTE. Since both RHI from contact sports and single event TBI have been associated with the development of CTE, the authors chose to explore existing literature related to both. A 2015 study conducted by Bieniek et al examined postmortem brains with a history of contact sports and found that 21 of 66 (31.8%) showed pathological signs of CTE.¹⁷ Furthermore, 198 brains that had no history of exposure to contact sports were analyzed and no trace of pathological CTE was found.¹⁷ A small subset including 33 of the 198 brains examined was from individuals with a history of a single-incident TBI occurring from accidents or violence; the brains did not show any pathological signs of CTE.¹⁷ Using the McKee criteria²⁴ for CTE in 2015, Ling et al investigated 268 cases of neurodegenerative disease in the Queen Square Brain Bank and found that 32 (11.9%) of the donors had pathological CTE with 93.8% of donors having had a history of TBIs.¹⁸ The most ominous aspect of CTE is the connection to subconcussive blows.^25–29 Compared to concussive trauma, subconcussive blows rarely are treated and athletes often continue to play without reconsideration. It is important to note that while repetitive head trauma is a prerequisite for CTE, not cases lead to CTE and the mechanism of degeneration and risk remains unclear.

Considerable heterogeneity exists between the mechanisms of injury between sports. Although many considerations must be considered when examining the biomechanics of injury, force and direction are two principle aspects worth noting. In boxing, the impacts are of lesser force but occur frequently whereas, in football, the impacts usually occur less periodically but have a superior impact. Further differences exist within each sport. In football, injury mechanics can vary depending on position which can result in both linear and rotational impacts. Injury in boxing can occur from coup countercoup injuries, which come from a linear impact resulting from a jab, or from torque injuries, which are rotational impacts that result from an uppercut or hook. The latter put boxers in jeopardy due to the twist and stretch and damage the brainstem. Viano et aldemonstrated that the rotational forces that boxers absorb can cause axonal damage.³⁰ This axonal damage is mainly located in the white matter tracts. Advanced neuroimaging techniques measuring cerebral white matter are discussed later. By contrast, football players mainly sustain linear helmet-to-helmet impacts but can also experience rotational forces. Viano et al also compared the inertial forces produced by boxers and football players and concluded that the forces produced by football players can be up to 30% greater than those by boxers.³⁰

The clinical presentations of CTE vary depending on the contact sport practiced by each individual. Stern et al performed a study examining 36 confirmed CTE cases, mostly focusing on retired NFL athletes.³¹ Stern et al found that while practically all experienced cognitive deficits, two distinct groups emerged.³¹ Stern found one group developed behavioral/mood disturbances at a relatively young age whereas the other group cognitive impairment at an older age. Differences in the clinical manifestation are often associated with the mechanism of trauma; with the most prominent clinical differences exist between boxers and football players. It has been previously observed that boxers tend to have more motor-related symptoms due to an increased number of torque injuries (rotational or twist force); motor-related symptoms are infrequently seen in football players. Due to the heterogeneity of contact-sport injuries, CTE has a complicated clinical presentation. CTE has mainly been diagnosed in football and boxing participants, but also in athletes in soccer, wrestling, rugby, and hockey.⁷ The clinical presentation includes neurobehavioral and neurocognitive changes that vary from case to case.^21,32 The most common neurobehavioral changes include severe depression, substance abuse, emotional instability, aggressiveness, impulsivity, irritability, and dementia.^32–34

Table 1.

Summary of clinical features according to McKee²⁴

Stage	Clinical presentation
1	Headache, inattention, loss of concentration
2	Depression, explosivity, impairment of short-term memory
3	General cognitive impairment
4	Dementia, language impairment

^a https://www.ncbi.nlm.nih.gov/pubmed/23208308

Clinically, CTE can be complicated to diagnose due to a presentation similar to that of other neurodegenerative disorders such as FTD, AD, and dementia. Continuous, steady neurocognitive changes often manifest themselves with symptoms similar to FTD, such as memory impairment, inattention, and executive dysfunction.⁷ Symptoms vary from case to case depending on the mode of acquisition. Boxers diagnosed with CTE generally have Parkinson’s disease-like symptoms including motor deficits, language disturbances, dysarthria, spasticity, ataxia, tremors, and gait disturbance.²¹ Affected football players, by contrast, tend to have predominantly neurobehavioral and cognitive aspects with few motor symptoms.

Due to the considerable heterogeneity of the clinical representation of CTE, debate exists regarding the connection between pathological CTE and the clinical features. Grant et al argue that in order to accelerate research, there is a need to separate neuropathological changes from the broad spectrum of clinical features.³⁵ Furthermore, with such diversity in the symptomology of CTE, further studies are needed to assess the role of comorbid diseases and performance-enhancing drugs (PEDs) use that is often common in contact sports cohorts.^7,21 Another concern and potential biomarker is the effect of TBI on the blood brain barrier. It is thought that TBI not only acutely disrupts the blood brain barrier after traumatic brain injury, but persists later on in life.^36,37 Additionally, an increase in blood brain barrier permeability has been noted.³⁸

The influence of genetic risk factors in the development of CTE and the functional recovery post-TBI has also been explored.^39,40 The apolipoprotein E allele 4 (ApoE4) is a significant risk factor for AD⁴¹ and could be involved with CTE development. A recent systematic literature review that explored the role of APOe4 allele on the outcome following TBI concluded incongruously.⁴⁰ In 2017, Cao et al demonstrated that the ApoE4 allele contributes to the development of hyperphosphorylated Tau post-TBI.⁴² In 2018, Cherry et al examined the association between CTE and gene variation TMEM106B, a transmembrane protein previously associated with TDP-43 related diseases and neuroinflammation.⁴³ Cherry found an association between the minor allele and reduced tau pathology and neuroinflammation in the dorsolateral frontal cortex. Additionally, Cherry noted associations between minor allele and increased synaptic density and reduced ante-mortem dementia. While promising, current research on the relationship between CTE development and gene variations ApoE4 and TMEM106B remains inconclusive and further studies are needed.

STRUCTURAL MRI

If it is possible to quantify RHI in individuals, it then becomes important to also quantify the amount of damage and potential CTE risk. These advanced neuroimaging techniques are comprehensively described elsewhere.⁴⁴ The use of MRI to detect CTE is an attractive option due to its widespread clinical use and availability of various techniques. There has been a notable progression in neuroimaging technology and research in the past years.

Conventional MRI is the preferred structural brain imaging technique due to its resolution and specificity. The contrast between white and gray matter provide useful insight in many neurological conditions where white or gray matter are affected. Brain volume and microhemorrhages can also be measured allowing for detection of atrophy or ruptured blood vessels. Two observations in postmortem CTE are ventricular enlargement and cerebral atrophy²⁰ which can be detected using conventional MRI. Evans index (EI) is a nonspecific measurement which indicates the ventricular size and is observed in various pathologies. Various studies have examined EI in athlete populations and suspected CTE cases. When the brain atrophies, the ventricles increase in size. Due to cerebral atrophy, an increased EI may be present in CTE.^45,46 One study performed by Wilde et al, performed structural MRI scans on a group of 10 boxers and nine controls.⁴⁷ The group of boxers had a significantly larger EI than that of the group of noncombat sports controls, suggesting boxing related cerebral atrophy. Since cerebral atrophy is a hallmark of Alzheimer disease, EI detection would only determine atrophy, not the pathological cause. Ventricular enlargement is only seen in 53% of CTE verified cases,²⁰ reducing the clinical specificity of EI measurements. One longitudinal MRI study that followed collegiate females soccer players over the course of 4 years found several significant alterations including an increase in the width of the sulci in the frontal and occipital cortices, subtle hemorrhagic changes, and in some players, and a decrease in overall brain volume during what is generally a developmental phase of growth for young adults.⁴⁸ Despite documented physical brain alterations, none of the athletes demonstrated long-term clinical deficits.⁴⁸ A recent study by Churchill explored the long-term effects of sport-related concussions by performing comprehensive MRI techniques by comparing 21 athletes with a history of concussions with 22 concussive free athletes of both contact and non-contact sports.⁴⁹ To characterize brain abnormalities associated with concussions, Churchill measured structural changes, cerebral blood flow, and gray matter abnormalities. Churchill found significant volumetric differences in the right hippocampus, left caudate, and cuneus. Correlated with the number of concussions, Churchill observed a decrease in perfusion in the temporal and frontal lobes. A promising longitudinal case study performed by Raji et al followed an ex-high school football player with suspected CTE due to a history of concussions.⁵⁰ Raji et al performed two MRI brain scans over the course of four years and found a 14% decrease in total gray matter, particularly in the midbrain, ventral diencephalon, and frontal lobes.

Table 2.

Summary of pathological changes proposed by McKee²⁴

Stage	Pathological changes
1	Tauopathy solely in the depths of the sulci in the frontal cortex
2	Tau aggregation in the cerebral cortex spreads to multiple layers.
3	Dispersed tauopathy not only affecting the frontal and temporal cortices but also degeneration of the insula, amygdala, and hippocampus
4	Neuronal loss and a widespread tauopathy across the cerebral cortex

^a https://www.ncbi.nlm.nih.gov/pubmed/23208308

Although volumetric MRI is an attractive option, limitations exist. Ross et al have investigated limitations related to pre-TBI brain volume estimation and less reliable radiologists’ visual interpretations.^51–53 Promising advancements in technology and machine learning techniques are improving accuracy in the detection of brain abnormalities. Ross et al demonstrated that NeuroQuant (medical software for quantification of MRI measurements) was significantly better at detecting atrophy, abnormal asymmetry, and progressive atrophy (95.8%) than that of the traditional radiologists’ interpretation.⁵²

Another potential in vivo neuroimaging marker for at-risk CTE is the presence of cavum septum pellucidum (CSP). The CSP is a minor opening in the septum pellucidum that usually fuses early in life. The existence of CSP has also been associated with schizophrenia,⁵⁴ as well as among participants of contact sports.^55,56 One study by Smith revelated that CSP was present in 65% of cases of post-mortem CTE.⁵⁷ Regarding in vivo reports of CSP, Aviv performed MRI scans on 164 active boxers and discovered a 49% prevalence of CSP, with some boxers revealing CSP solely on their second scan.⁵⁸ Another important study investigated by Koerte explored the association of CSP parameters and symptomology in former professional NFL players.⁵⁶ Koerte found that a greater length of CSP was associated with decreased performance on learning tasks and a decrease in test scores regarding verbal intelligence.⁵⁶ Although non- specific to CTE, the presence of in vivo CSP could aid in diagnosing at-risk individuals.

DIFFUSION MRI

DTI is technique that uses diffusion-weighted imaging to detect changes in white and gray matter. While conventional MRI detects macroscopic abnormalities, DTI is sensitive to the characteristics of microscopic fiber tracts. DTI uses the diffusion of water as a measurement tool: the direction of the water flow indicates the type of tissue.^59,60 A three-dimensional ellipsoid is created within each region of interest or voxel which demonstrates the shape of water diffusion. In cerebral spinal fluid (CSF), e.g. the water diffuses in all directions, whereas in dense tissues such as fiber tracts, the water is forced to diffuse along the axon, changing the shape of the ellipsoid. Distinct flow patterns allow for identification of damaged tissue. Many scalar metrics are used to measure the direction of diffusion. Another feature seen in TBI is axonal injury, mainly degeneration of the white matter (WM) tracts, making DTI scans a suitable option for injury detection.^61–65 Although promising, considerable controversy exists regarding the significance of the scalar metrics. Various literature review articles have been published exploring DTI in contact sport athlete populations with mixed results.^66,67

The main diffusion metric employed is fractional anisotropy (FA). FA is a general measurement that characterizes the extent of directionality of diffusion. One recent study explored FA abnormalities in boxers.⁶⁵ Herweh et al performed DTI scans on 31 amateur boxers and 31 controls and found that FA was significantly reduced in the boxers group, partially associated with the number of fights.⁶⁵ In 2017, one post-mortem study aimed to explore the radiological-pathological correlation of white and gray matter abnormalities in neurogenerative diseases. Using samples from the superior frontal cortex of previously diagnosed CTE individuals they compared high special resolution diffusion MRI metrics, specifically FA, in areas adjacent to histopathological hallmarks of CTE.⁶⁸ Holleran et al was able to discriminate between disrupted and normal regions of white matter, where higher FA was associated with increased levels of disruption. Furthermore, they found a strong association between axonal disruption and the location of hyperphosphorylated tau aggregation.⁶⁸

Another general DTI metric is MD, which is the average rate of diffusion in all directions. Bazarian et al performed a longitudinal study on 10 football players and five controls using DTI neuroimaging to analyze RHI-related white matter changes over the course of one football season.⁶⁴ Bazarian focused on FA and MD scalar metrics to determine diffusion alterations pre and post-season. Although no athlete suffered from a clinically positive concussion, the total number of head impacts throughout the season ranged from 431 to 1,850 per athlete. Bazarian et al found greater changes in both FA and MD in the athlete group compared to the control group. Additionally, Bazarian concluded that repeated head impacts independent of concussions, from just one football season, resulted in WM changes within athletes that persisted after 6 months of contact-free rest. Although both FA and MD are both sensitive biomarkers for white matter injury, they are unable to differentiate between damage to the axon and loss of myelin.

To differentiate between these two types of injury, the use of more specific diffusion MRI scalars including axial diffusivity (AD) and radial diffusivity (RD) is needed. AD is the magnitude of diffusion along the fiber tracts whereas RD is the average diffusion perpendicular to the fiber tracts. Reductions in AD are associated with axonal injury whereas increases in RD are associated with demyelination. Regarding AD, one study performed by Multani et al compared diffusion MRI scalar metrics between retired Canadian football players and age-matched controls.⁶⁹ Multani revealed a significant increase in AD, primarily in the right hemisphere, in the group of retired football players.⁶⁹ One study by Koerte investigated the white matter integrity of soccer players without symptomatic concussion by comparing against a swimmer cohort.²⁵ Koerte found increased RD in soccer players across various white matter structures. Koerte also found higher AD in the corpus collosum in soccer players but insignificant differences in FA and MD. Various other studies have found significant alterations in both RD⁷⁰ and AD⁷¹ when comparing TBI patients to controls. Although controversy over the significance of DTI metrics exists, Table 3 shows the suggested significance of alterations in each scalar metric.

Table 3.

Interpretation of diffusion MRI scalar metrics

Diffusion metric	Measurement	Significance of alteration
FA	Directionality of diffusion	↓ or ↑ suggests WM alteration with decreases suggesting damage and increases suggesting microstructural scarring
MD	Mean diffusion in all directions	↑ suggests WM total diffusion alteration, often inverse with FA changes
AD	Diffusion along axon	↓ suggests axonalinjury but can increase with axonal recovery
RD	Diffusion perpendicular to axon	↑ suggests myelin impairment, such as demyelinaton or dysmyelination

AD, axial diffusivity; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, ; RD, radial diffusivity.

Advanced diffusion MRI techniques are promising for detection of subtle structural changes related to CTE.

Neurite orientation dispersion and density imaging (NODDI) is a diffusion MRI technique that is sensible to the microstructure of axons and dendrites and provides information regarding neurite density and orientation dispersion.⁷² In 2019, Churchill et al measured DTI and NODDI in athletes following sport-related concussion.⁷³ Churchill et al found that decreases in FA and increases in AD and RD were associated with reduced intraneurite water volume. Athletes experiencing more symptoms had greater changes in FA, AD, and RD accompanied with increased neurite dispersion.

Despite many significant findings in DTI metrics, not all studies share similar results and various limitations exist. One principle drawback to DTI is the inter site variability between diffusion metrics. Changes are thought to be relative to each study and cannot be compared between different sites and systems (GE, Siemens, Phillips, etc). Fortunately, advances in diffusion MRI data pre-processing have led to harmonization algorithms which aim to allow comparison of acquired diffusion metrics.^74,75 Karayumak et al demonstrates a method that can be used to harmonized diffusion data across sites despite different acquisition parameters while maintaining inter subject variability.⁷⁴ Although promising, the contradictory findings regarding DTI scalar metrics highlight the need for further research and validation in single TBI, RHI, and CTE.

FUNCTIONAL MRI

Cerebrovascular injury is a common consequence of TBI and due to cerebral blood flow alterations, could be a potential neuroimaging potential biomarker. Numerous studies have explored fMRI abnormalities in mTBI patients, due to its ability to evaluate cerebral blood flow.^67,76–79 Both acute and long-term changes have been identified following RHI. Irregularity in the default mode network following concussion can be observed.⁷⁹ Long-term abnormalities also exist in post-mTBI,⁷⁸ with one study identifying a post-concussion “brain strain” effect in young athletes.⁷⁷ While alterations exist, further studies are needed to validate these results. Han et al used resting state fMRI to examine network disruptions following chronic TBI.⁸⁰ Significant group changes in connectivity were found in the default, dorsal attention, and frontoparietal control networks, highlighting the concern for TBI-related network disruption. Nordin et al used resting-state fMRI to investigate functional connectivity in chronic mTBI patients after the completion of a psychomotor vigilance task.⁸¹ A significant correlation between mental fatigue and functional connectivity was found, specifically in the thalamus and middle frontal cortex. Amyot et al measured cerebrovascular reactivity and cerebral blood flow in chronic TBI patients by MRI BOLD analysis.⁸² Significant reductions in cerebrovascular reactivity were found in mean global, gray matter, and white matter areas.

MRS

MRS is an advanced neuroimaging technique which measures human brain tissue metabolism in vivo, primarily neurometabolines such as glutamine, choline, creatine, and N-acetyl aspartate. Abnormalities in MRS metabolites are sensitive to neuroinflammation, neuronal loss, and axonal injury, which are observed in CTE. In 2017, a seminal literature review by Alosco et al examined the use of MRS as a biomarker for CTE.⁸³ Alosco et al concluded that while empirical evidence exists in the detection of neurological impairment, further research and post-mortem confirmation is needed. In 2019, Alosco et al performed a large-scale study using MRS to measure neurochemistry in 77 symptomatic former NFL players.⁸⁴ Alosco et al found a correlation between neurochemicals associated with neuroinflammation and behavioral/mood symptoms. Alosco et al also found that a higher cumulative head impact index was correlated with lower parietal white matter creatine levels. Promising advances in two-dimensional MRS provide substantially more information about metabolites and neurotransmitters which will improve MRS research on CTE. The disadvantage of one-dimensional MRS is the neurochemical overlap, which complicates the single chemical measurement precision. The use of Localized Correlated Spectroscopy solves this issue and allows for distinct detection of various metabolites, lipids and macromolecules. One pilot study by Lin investigated neurochemical levels using Localized Correlated Spectroscopy in five former professional athletes.⁸⁵ Lin found significantly higher values in glutamine/glutamate, choline, fucosylated molecules, and phenylalanine in the athlete group compared to controls.

SWI

Susceptibility weighted imaging (SWI), also known as BOLD venography, uses magnetic susceptibilities to produce a high contrast MR image. SWI is sensitive to venous blood and is used to detect hemorrhage or microbleeds in TBI injuries of all severities in childern.⁸⁶ Studies have demonstrated the usefulness of SWI in predicating cognitive outcomes, where volume of microhemorrhages correlate with neurological outcome.⁸⁶ Since SWI principally measures hemorrhages, their use is ideal in acute TBI injuries but not necessarily as a CTE diagnostic tool.

SPECT

SPECT is an imaging technique that requires the injection of a radionuclide and uses γ rays to quantify regional cerebral blood flow. SPECT is a relatively low cost and available technique that is methodologically similar to PET. However, while PET is utilized for evaluating glucose metabolism SPECT instead evaluates regional cerebral blood flow. In TBI, particularly mTBI, a systematic review showed that frontal lobe hypoperfusion was the most common finding in the literature even in absence of structural lesions.^87,88

PET AND RADIONUCLEOTIDES

Chronic traumatic encephalopathy is similar to other neurodegenerative diseases in its pathology. The literature on CTE has highlighted several pathological hallmarks that differentiate it from other neurodegenerative diseases such as AD, FTD, amyotrophic lateral sclerosis and Parkinson’s disease.^89–91

The hallmark of CTE in its histopathology is phosphorylated tau aggregates in neurons, astrocytes, and in the depths of the cortical sulci.^19,24,33 Although the structure of the tau aggregates is the same, in CTE, it has a unique pattern of distribution. In CTE, aggregates are primarily found in the outer layers II and III whereas layers III and V in AD.⁷ Tangles are found olfactory bulb, hippocampus, amygdala, entorhinal cortex, mammillary bodies, SR, and locus coeruleus.⁷ Common supportive pathological features of CTE include inclusions of transactive response DNA binding protein 43 kDa (TDP-43) and in around 50% of the cases, amyloid plaques. Motor symptoms seen in boxers could be a result of TDP-43 proteinopathy⁷ and the marked increase in cerebellar scarring²¹ which is not commonly seen in football players.

Advances in neuroimaging using radionucleotides have proven to be a promising method in the early detection of CTE. A recent systematic review published in 2017 by Sparks et al explored the recent advances in the diagnosis of CTE; however, postmortem confirmation was absent.⁹ Sparks et al noted that the most promising neuroimaging technique is the τ-binding radionuclide 18F-FDDNP because it binds to τ,⁹² the neuropathological hallmark of CTE. Preliminary work investigating the efficacy of the radionuclide ¹⁸F-FDDNP PET scan by Barrio et al demonstrated four distinct patterns of ¹⁸F-FDDNP in the brainstem white matter tracts and cortical and subcortical layers.⁹³ Barrio et al compared 14 retired NFL players with 28 healthy controls and 24 patients with AD and according to the binding patterns.⁹³ The patterns found distinguished suspected CTE patients from controls and AD patients and the τ deposition was consistent with post-mortem autopsies of confirmed CTE. These patterns of deposition were also consistent with models of concussion, and, due to localization in the brainstem and diencephalon, would help explain behavioral and mood symptomology commonly seen in CTE. Additionally, these findings were similar to the volumetric results of Raji, who found regional volume loss in the brainstem.⁵⁰ A follow-up study demonstrated the effectiveness of the antemortem ¹⁸F-FDDNP PET scan through a postmortem autopsy of a football player with CTE that had previously received a PET scan.⁹⁴ The postmortem confirmation is an important step in the validation of ¹⁸F-FDDNP PET scans for CTE diagnosis.

A growing body of literature has investigated other potential TAU-binding ligands such as flortaucipir ([18 F]T807/AV1451).^95–98 Dickstein et al performed a flortaucipir PET scan on a 39-year-old retired NFL player with progressive neuropsychiatric symptoms.⁹⁵ Dickstein found a retention pattern resembling pathogenic CTE, specifically at the white matter–gray matter cortical junctions. In 2019, Stern et al measured τ and amyloid deposition in 26 former NFL players using flortaucipir.⁹⁹ Stern reported higher tau levels in the former players, particularly in CTE affected brain regions including the bilateral superior frontal, bilateral medial temporal, and left parietal areas. While postmortem correlation is lacking, this study demonstrates the promising attributes of TAU-binding ligands.

Although promising, radionucleotide PET scans possess numerous limitations. In 2018, Lee et al conducted a massive systematic review of PET imaging in CTE and concluded that although enormous potential exists, the field remains in its infancy.¹⁰⁰ Limitations include non-specific binding of potential ligands, radioactive tracer safety, and the availability and financial coverage of these highly specific PET scans. Such methods can potentially complement traditional FDG PET methods that have shown metabolic abnormalities in conjunction with abnormalities on SPECT. For example, one study examined 13 patients with mild TBI using both SPECT perfusion neuroimaging and FDG-PET metabolic neuroimaging. Approximately 85% of the patients with a mild magnitude of TBI had decreased perfusion on SPECT and decreased metabolism on PET in the frontal and temporal lobes.¹⁰¹ This is in line with previously discussed studies showing TBI-related damage to these areas with other imaging modalities and demonstrated the high degree of concordance between these neuro-nuclear methods.⁸⁷

ASL MRI

It should be noted that an advanced MRI corollary to the neuro-nuclear techniques discussed is arterial spin labeled (ASL) MRI. ASL utilizes magnetization of hydrogen in the water of blood flowing through both the carotid and vertebral–basilar arteries.¹⁰² This labeling produces a map of regional cerebral blood flow that is fully quantitative and, as SPECT, is a perfusion imaging technique—a metric that is itself coupled to metabolism as imaged with FDG PET. Unlike these methods though, ASL MRI does not use any radiation nor does it require any gadolinium or other exogenous contrast agents. Its utility in TBI has been demonstrated across all severities of TBI including mild TBI when visual evaluations of concurrently acquired MR images may be negative and thus interpreted by radiologists as “normal.”¹⁰³ Newer pipelines are available that can analyze ASL MRI scans to provide quantitative evaluations of regional cerebral blood flow compared to a normal database that statistically accounts for age and gender.¹⁰⁴

CONCLUSION

A validated, in vivo method of early diagnosis is essential for CTE. Early diagnosis will lead to preventative recommendations, rule and equipment modifications and early retirement from high impact sports for at-risk individuals. Available evidence for CTE in living patients is limited and its use is challenging due to the clinical and pathological heterogeneity. An issue that has not been addressed in the literature was whether behavioral and cognitive symptoms are influenced by comorbid steroid use that is common among some professional athletes and which can influence similar symptomology. Another major limitation is that the majority of the literature is performed by means of group comparisons, with little translation to individual patients. Furthermore, research to date has not yet determined the number of subconcussive and concussive blows or other forms of RHI and TBI that form a risk factor for the development of CTE.

To date, insufficient evidence exists to diagnose CTE in living patients although neuroimaging does show capiblity of identifying TBI. It is unlikely that a single test will be sufficient to effectively diagnose and distinguish CTE from other neurodegenerative diseases and a combination of fluid biomarkers, neuroimaging, and validated risk factors will be necessary for in vivo confirmation.