Chronic Traumatic Encephalopathy: Update on Current Clinical Diagnosis and Management

Chronic traumatic encephalopathy is a disease afflicting individuals exposed to repetitive neurotrauma. Unfortunately, diagnosis is made by postmortem pathologic analysis, and treatment options are primarily symptomatic. In this clinical update, we review clinical and pathologic diagnostic criteria and recommended symptomatic treatments. We also review animal models and recent discoveries from pre-clinical studies. Furthermore, we highlight the recent advances in diagnosis using diffusor tensor imaging, functional magnetic resonance imaging, positron emission tomography, and the fluid biomarkers t-tau, sTREM2, CCL11, NFL, and GFAP. We also provide an update on emerging pharmaceutical treatments, including immunotherapies and those that target tau acetylation, tau phosphorylation, and inflammation. Lastly, we highlight the current literature gaps and guide future directions to further improve clinical diagnosis and management of patients suffering from this condition.


Innovations in Diagnosis
The diagnostic criteria and neuropathologic features of CTE are well defined but perfecting in-vivo diagnosis of CTE remains elusive; CTE is only definitively diagnosed at autopsy. Studies into neurobehavioral commonalities, neuropathology, cognitive and functional symptomatology, imaging findings, and biomarkers illuminate our perspective on in-vivo diagnosis and facilitate improved characterization of the spectrum of CTE. These diagnostic innovations are summarized in Table 1.

Diagnostic Imaging
While CTE remains a histologic diagnosis, identification of radiographic signs and correlates of disease severity remains a high priority. MRI is the imaging modality of choice for evaluating structural changes in chronic TBI and CTE due to superior sensitivity compared to computed tomography (CT) and the ability to detect diffuse axonal injury. Unfortunately, recurrent structural findings, such as grey matter atrophy, ventricular enlargement, and cavum septum pellucidum, are not specific to CTE [25] and structural findings are therefore not sufficient to diagnose CTE.
Use of diffusion tensor imaging (DTI) to assess white matter integrity has become a popular tool for assisting in the diagnosis of CTE [26]. Research indicates it may be useful in determining the relationship between cognitive deficits and TBI and in distinguishing the spectrum of brain injury, even when the injury was sustained years prior [27]. Post-mortem analysis has confirmed the relationship between axonal damage and decreased fractional anisotropy (FA) [28].
Blood oxygenation level-dependent MRI, also known as functional (fMRI) can detect changes in the oxygenation of hemoglobin while correlating to brain function during a specific task. Although the use of BOLD fMRI for the study of TBI presents challenges due decreased cerebral blood flow found in TBI, it remains a novel tool for analyzing the activity of specific regions of the brain [27]. Significant developments are taking place with the use of PET for diagnosing CTE [12] using ligands that bind pathology in CTE. The most well-studied is FDDNP, which binds to neurofibrillary tangles. However, it is non-specific because it binds to β-amyloid in addition to hyperphosphorylated tau [29]. Other tracers include T807, AV1451, and flortaucipir. Though nascent in their development, they are emerging as promising tools within the field of imaging biomarkers for CTE. While studies investigating this imaging modality have shown varied regions of uptake, they have consistently demonstrate increased tracer uptake in the limbic system and temporal lobe. However, evidence for tracer uptake in cortical regions widely varies [29].

Fluid Biomarkers
The identification of fluid biomarkers from blood or CSF is under active investigation for pre-morbid diagnosis of CTE. While no single fluid biomarker is sufficient or approved for diagnosis, several studies are continually investigating further fluid biomarker candidates [1]. Although also associated with chronic neurodegenerative disease such as AD, preliminary research supports the use of plasma t-tau as a marker of injury severity following repetitive head trauma [1,30]. Total plasma and CSF tau concentrations have been shown to correlate with increased exposure to athletic head impacts in multiple studies, and a plasma concentration ≥3.56 pg/mL has been suggested as a threshold to reliably distinguish NFL players from healthy controls [30-32]. Stern et al. demonstrated that exosomal tau could also reliably differentiate former NFL players from healthy controls and that levels correlate with cognitive and psychomotor decline [33]. Triggering receptor expressed on myeloid cells 2 (TREM2) is a protein involved in microglia resolution of CNS inflammation and is a known correlate of AD severity [34,35]. Microglia are known mediators of neurinflammation and have been found to contribute to the accumulation of tau in CTE [36]. Examining soluble TREM2 (sTREM2) concentrations in the CSF as a marker of microglial activation, Alosco et al. found sTREM2 correlated with total tau levels, and strengthened the relationship with tau and head trauma when included in regression models. Microglia also express cognate receptors for the chemokine CCL11/eotaxin, an inflammatory marker associated with neurodegeneration. CCL11 has been shown to be significantly elevated within the dorsolateral frontal cortex (DLFC) of former American football players, with a non-significant increase within the CSF, and could reliably differentiate CTE from AD [20]. Other promising fluid biomarkers under investigation include neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP).

Innovations in Clinically Oriented Treatment
Prevention of TBI remains the only method of prevention. Within the contact sports, which are common facilitators of repetitive mild TBI (rmTBI), preventative measures include contact rule changes and protective equipment, with an acknowledgement that no protective equipment can prevent a concussion [18]. Immediate removal from play with strict supervised return to play guidelines and proper medical management remains a crucial element in prevention of second impact syndrome and other sequalae [33].
Treatment of CTE is currently mainly supportive. However, recently elucidated understandings of neurobiological mechanisms in rodent models have led to advances in treatment development. We summarize the currently recommended treatments and promising innovations in the following paragraphs and Table 2.

Recommended Supportive Treatments
Non-pharmaceutical management recommendations include cognitive rehabilitation, motor therapy, mood and behavior therapy, mindfulness, the Mediterranean diet, and aerobic exercise. Vestibular rehabilitative therapy is also recommended for those with inner ear injury resultant from repetitive TBI. Occupational-ocular therapy is recommended for those with visual disturbances. There are no FDA-approved medications for CTE. They are used "off-label" and primarily target symptomology. Drugs used for memory impairment parallel those used in Alzheimer's disease like galantamine, donezepil, and rivastigmine. In addition to stimulants like methylphenidate, dopamine agonists like carbidopa/levodopa, pramipexole amantadine, memantine, may treat apathy. Furthermore, these stimulants can treat impaired attention. Depression and anxiety medications include sertraline and escitalopram, though they with caution considering its side effect of suicidality as suicide is well-documented in CTE.
Furthermore, it is recommended to optimize drug regimens to minimize drugs interactions and reduce those that may exacerbate symptoms and cause further cognitive impairments, like sedatives and anticholinergics [37].
Considering the recent advances in the understanding of the molecular and inflammatory cascades leading to progressive neurodegeneration, pre-clinical studies paving the way for clinical trials for patients with CTE [12].

Review of Pre-Clinical Animal Models
CTE is characterized by progressive neurodegeneration in the absence of further trauma through incompletely understood secondary injury cascades. A better understanding of these molecular pathways and optimized treatment development would be facilitated using animal models representing CTE. While several well-characterized animal models, like the non-impact head acceleration, blast wave, weight drop, fluid percussion, and controlled cortical impact (CCI) models exist for traumatic brain injury, animal model development for CTE is still in the early stages as none fully reflect the known progressive pathological, neurocognitive, and psychiatric findings. Still, many models inflicting repetitive mild TBI reflect some findings like neurofibrillary tangles, Aβ, phosphorylated tau, and TDP-43 deposition, microgliosis, astrogliosis, ER stress, glutamate excitotoxicity, and white matter changes, as well as the sequelae involving progressive cognitive impairment and mood changes [38-53].
Several studies demonstrated that roscovitine and its derivative CR-8, cyclin dependent kinase (CDK) inhibitors, reduced neuroinflammation and neurodegeneration while improving functional outcomes in TBI rat models [83]. A study showed that the combined use of Lithium and roscovitine had more profound reductions in cortical and blood p-tau when used in combination rather than when used alone in a mouse model of repetitive mild TBI [50].

Immunotherapy
Immunotherapy by the use of monoclonal antibodies has also been studied in preclinical studies investigating tauopathies. Notably, a recent study demonstrated that the delivery of an adeno-associated virus (AAV) vector coding for an anti-pTau antibody reduced CNS pTau levels in rodent models of repeated traumatic brain injury [84]. An in-vitro study demonstrated that several tau antibodies successfully prevented neuronal tau uptake. The antibody 6C5 prevented interneuronal spreading and progression of aggregation after cellular uptake [85]. In an effort to avoid targeting the trans isoform of p-tau that is important for normal cellular activity, antibodies developed specific to the pathogenic cis-P-tau that develops after TBI demonstrated reductions in tauopathy and improved structural and functional outcomes [86][87][88].

Targeting Inflammation
Studies have also targeted the complex inflammatory cascade and metabolic changes occurring in CTE. A recent study investigated the use of 4-{2-[2-(3,4-dimethoxyphenyl)vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-il}benzsulfamide (OCH, a pyrimidine derivative) which is proposed to preserve mitochondrial function and proper ATP synthesis following TBI. In rodent models of repetitive TBI, OCH improved ATP-generation, respiratory intensity, and cerebral blood flow while decreasing glycolysis intensity, CTE biomarker concentrations, and β-amyloid levels. It also preserved sensorimotor function [89]. Administration of the salubrinal (SAL), a stress modulator, significantly reduced ER stress, oxidative stress, pro-inflammatory cytokines, and inducible nitric oxide synthase while preventing impulsive-like behavior in rodent models of repetitive TBI [90]. Calpain-2 is proposed to contribute to neurodegeneration following TBI. The use of a selective calpain-2 inhibitor, (C2I) significantly reduced calpain-2 activation, prevented increased tau phosphorylation and TDP-43 changes, prevented astrogliosis and microgliosis, and eliminated cognitive impairment in a rodent model of repeated traumatic brain injury [91]. Several studies have shown that the ketogenic diet enhances cognitive, motor, and pathological outcomes in rodent TBI models [92]. Pre-clinical studies have also indicated that increased recovery times in rodents improve outcomes, consistent with similar studies in human populations [93,94].

Future Discoveries
CTE has gained significant media attention in recent years. Despite significant effort, methods for pre-mortem diagnosis and treatment remain elusive. While there are several proposed clinical diagnostic criteria, there is unfortunately no consensus among the scientific community on which to use. Furthermore, there is little research assessing these criteria's diagnostic validity.
Imaging modalities are also similarly limited. While radiographic findings are consistently identified in patients with overt clinical disease, their diagnostic utility remains unclear considering small sample sizes, inconsistent use of imaging modality, little histological correlation, and confounding and unknown effects (e.g., gender, intelligence quotient, education, genetic polymorphisms). Small sample sizes are a particularly limiting factor considering the heterogeneity of CTE among individuals. Diagnostic studies vary widely in analysis methodology, making interpretation and inter-study comparison difficult. Only two studies have directly compared histologic and imaging analyses [28,97], which would support validation of imaging-based diagnostics. Many studies do not use age-matched control groups, rendering differentiation of normal-aging associated neurological changes from CTE difficult. Many studies, particularly those analyzing contact sports, do not include females, preventing the study of gender-based outcomes of chronic TBI. Therefore, future directions to improve radiographic diagnosis of patients with CTE include: validation of diagnostic criteria; adequately controlled imaging studies with increased sample sizes and greater statistical power; inclusion of female study participants; consistent imaging methodologies; consistent use of age-matched control groups; and neuropathological evaluation to directly correlate imaging and pathologic findings. Furthermore, more studies investigating additional, more specific tau ligands like flortaucapir are needed [98]. We look forward to the results of the DIAGNOSE-CTE project, which will perform longitudinal investigations in athletes to validate various diagnostic tests [99].
While many blood and CSF biomarkers are well-characterized for TBI, few biomarkers have been studied specifically for CTE [100]. Identification of reliable biomarkers may support early diagnosis, prognostication, monitoring of disease progression, evaluation of treatment response, and support linking pathological disease burden with clinical symptomology. Considering that the pathology of CTE significantly overlaps with other tauopathies, investigating validated biomarkers in the context of CTE is a reasonable next approach [101]. While still premature, next-generation imaging modalities, such as engineered macrophages used to image micro-metastases, have potential applications to any disease state involving an inflammatory state and may have applicability to neurodegenerative diseases such as CTE [102].
Currently, there are no approved drugs that improve pathological and functional outcomes in patients with CTE. Preclinical studies have largely shown promising results in the treatment of CTE. While there are ongoing clinical trials for treatments in other tauopathies like Alzheimer's, there are very little for CTE. Furthermore, very few pre-clinical studies explore these treatments in rodent models specific for CTE, likely due to their recent advent. Therefore, in addition to the need for continued research for rodent models accurately reflecting CTE pathology, there is a need for further treatment studies using these animal models. There is an increasingly appreciated role of the immune system in traumatic brain injury. Microglia have remained the predominant focus, however, the relative involvement of peripheral immune cells recruited to CNS after traumatic injury is unknown and further investigations into this component of disease pathogenesis may reveal novel therapeutics [97]. Other topics worthy of future investigation include development of humanized monoclonal antibodies and enhancement of blood brain barrier permeability through unilateral focused and low-intensity pulsed ultrasound methods [103].
Considering a lack of treatment options, the best treatment method for CTE remains prevention. Therefore, continued research on the efficacy of protective equipment, development of enhanced protective equipment, continued enforcement and further development of sport contact roles, and improvements and enforcement of return to play protocols is needed [104].