A Quest for Biomarkers and Diagnostic Criteria for Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that affects people who have been exposed to repetitive head impacts, such as athletes, military personnel, and domestic violence survivors. CTE can cause various symptoms, such as cognitive impairment, mood disorders, behavioral changes, and dementia. However, there is no definitive way to diagnose CTE during life, as the diagnosis can only be confirmed by examining the brain tissue after death.

To address this challenge, a team of researchers from different disciplines and institutions across the US has launched the DIAGNOSE CTE research project, a multi-center, multi-disciplinary, 7-year grant funded by the National Institute of Neurological Disorders and Stroke (NINDS). The project aims to develop methods of detecting and diagnosing CTE during life, including the development and examination of neuroimaging and fluid biomarkers, establishing and validating diagnostic criteria for traumatic encephalopathy syndrome (TES), and studying potential risk factors of the disease.

In addition to the conventional methods of diagnosis and treatment, the project also explores the use and investigation of alternative therapies for CTE that are being investigated by other researchers and practitioners. These alternative therapies include hyperbaric oxygen therapy (HBOT), amino acid supplementation, brain restoration therapy (BRT), and home remedies. The project aims to evaluate the effectiveness and safety of these alternative therapies for CTE and its related conditions.

The Methods

The DIAGNOSE CTE research project involves four main components:

Component 1: The development and validation of diagnostic criteria for TES, the clinical syndrome of CTE during life. A panel of experts from various fields has conducted a consensus workshop and an iterative process to define the criteria for TES based on current knowledge and evidence. The criteria include the history of exposure to repetitive head impacts, the presence of cognitive impairment, neurobehavioral dysregulation, or both, and the exclusion of other possible causes. The criteria also specify the level of certainty for having CTE pathology based on the available biomarkers.
Component 2: The recruitment and examination of 240 former NFL players, 240 former college football players, and 120 control participants between the ages of 45 and 74 for a comprehensive assessment at one of four locations: Boston, New York, Las Vegas, or Scottsdale/Phoenix. The assessment includes neuropsychological testing, neurological examination, psychiatric evaluation, genetic testing, blood and cerebrospinal fluid sampling, magnetic resonance imaging (MRI), positron emission tomography (PET), and magnetoencephalography (MEG). The participants will be followed up annually for three years to monitor their changes in symptoms and biomarkers.
Component 3: The development and validation of neuroimaging biomarkers for CTE using MRI, PET, and MEG. The researchers will use advanced techniques to measure various aspects of brain structure and function, such as gray matter volume, white matter integrity, amyloid plaques, tau tangles, glucose metabolism, blood flow, oxygen extraction fraction, network connectivity, and neural oscillations1. The researchers will compare the neuroimaging findings among the three groups of participants and correlate them with their clinical features and fluid biomarkers.
Component 4: The development and validation of fluid biomarkers for CTE using blood and cerebrospinal fluid samples. The researchers will analyze various molecules that may reflect the pathological processes of CTE, such as tau protein, neurofilament light chain, glial fibrillary acidic protein, amyloid beta peptide, inflammatory cytokines, microRNAs, and exosomes1. The researchers will compare the fluid biomarker levels among the three groups of participants and correlate them with their clinical features and neuroimaging biomarkers.
Component 5: The exploration and evaluation of alternative therapies for CTE using various sources of information. The researchers will review the literature on alternative therapies for CTE that are being investigated by other researchers and practitioners. These alternative therapies include hyperbaric oxygen therapy (HBOT), amino acid supplementation, brain restoration therapy (BRT), and home remedies. The researchers will also conduct surveys and interviews with former NFL players who have used or are using these alternative therapies to obtain their feedback on their experiences and outcomes. The researchers will compare the results of these alternative therapies with those of conventional methods in terms of effectiveness and safety.

The Objectives

The DIAGNOSE CTE research project has several objectives that aim to advance the scientific understanding of CTE and its clinical manifestations:

To develop reliable and valid diagnostic criteria for TES that can be used in clinical practice and research settings.
To identify novel neuroimaging and fluid biomarkers that can detect CTE pathology during life.
To determine the prevalence and incidence of TES among former NFL players, former college football players, and control participants.
To examine the longitudinal changes in symptoms and biomarkers among the participants over three years.
To explore the genetic and environmental factors that may influence the risk or progression of CTE.
To provide guidance for future prevention and treatment strategies for CTE.
To evaluate the effectiveness and safety of alternative therapies for CTE and its related conditions.
To increase awareness and education about alternative therapies for CTE among health care providers, policymakers, sports organizations, military personnel, and the general public.

The Implications

The DIAGNOSE CTE research project is one of the most comprehensive and rigorous studies on CTE to date. It hopes to fill some of the knowledge gaps that exist in this field and to provide valuable information for the scientific community, the public health sector, and the affected individuals. Some of the potential implications of this project are:

To improve the diagnosis and management of people who suffer from TES or are at risk of developing CTE.
To facilitate the development and evaluation of new therapies and interventions for CTE and its related conditions, both conventional and alternative.
To contribute to global efforts to reduce the burden and impact of neurodegenerative diseases.

The DIAGNOSE CTE research project is a collaborative and interdisciplinary endeavor that involves many researchers, institutions, and stakeholders. It is led by Dr. Robert Stern, a professor of neurology, neurosurgery, and anatomy and neurobiology at Boston University School of Medicine, along with other principal investigators: Dr. Jeffrey Cummings, Dr. Eric Reiman, and Dr. Martha Shenton. The project is supported by the NINDS, part of the National Institutes of Health, as well as by other partners and donors.