Updates and Future Directions
Dr Alosco is Assistant Professor of Neurology, Dr Stern is Professor of Neurology, Neurosurgery, and Anatomy and Neurobiology, Boston University Alzheimer Disease Center and BU CTE Center, Boston University School of Medicine, Boston, MA.
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is believed to be a consequence of exposure to repetitive head impacts, including concussions and subconcussive injuries, such as those incurred during participation in contact sports (eg, tackle football, boxing) or blast exposures from military combat.1-4 CTE can only be diagnosed through neuropathological examination that initially shows the deposition of hyperphosphorylated tau (p-tau) in neurons and astroglia around small blood vessels in an irregular pattern at the depths of the cortical sulci. As the disease progresses, the p-tau spreads, eventually causing widespread neurodeneration.3,5 CTE is thought to present with a constellation of progressively worsening cognitive impairments (eg, episodic memory and executive dysfunction), and behavioral (eg, aggression and impulsivity) and mood disturbances (eg, depression).5-7
Critical gaps in our knowledge of CTE remain, including its incidence and prevalence, and specific repetitive head impacts exposure and genetic risk factors. In vivo biomarkers that can accurately detect underlying CTE neuropathology are necessary to conduct research to fill these gaps; however, they do not exist.
In other neurodegenerative diseases (eg, Alzheimer disease [AD]), in vivo biomarkers facilitate disease detection and diagnosis, are used to monitor disease progression, and serve as endpoints for prevention and treatment clinical trials. Identification of in vivo biomarkers for CTE is thus a high priority and essential for the accurate diagnosis of CTE. In this article, we provide a brief update on promising candidate biomarkers for CTE.
Candidate CTE biomarkers
Biomarkers can be classified as either specific or non-specific to the target neurodegenerative disease. Specific biomarkers are usually diagnostic, for example, cerebrospinal fluid (CSF) concentrations of beta-amyloid and p-tau in the setting of AD. Non-specific biomarkers (also referred to as “supportive” or “downstream” biomarkers) include general markers of neurodegeneration that are valuable for the detection and monitoring of disease progression (eg, hippocampal atrophy on structural magnetic resonance imaging [MRI]).
Positron emission tomography. One of the most promising in vivo methods for the specific detection of underlying CTE neuropathology (ie, p-tau) is positron emission tomography (PET) tau imaging. Although not yet approved by the FDA, several PET ligands that specifically bind to p-tau exist, such as flortaucipir (also known as AV-1451 and T807). Although flortaucipir has been shown to bind to p-tau in AD, whether it binds to specific paired helical filament tau isoforms that are seen in CTE remains unclear.
The use of flortaucipir or another tau ligand, in combination with PET amyloid imaging will be particularly powerful for differentiating between CTE and AD. PET ligands that bind to fibrillar amyloid (eg, florbetapir) are approved by the FDA and are used to detect amyloid uptake in AD.
Unlike AD, beta-amyloid is not a consistent pathological feature in CTE and, if present, beta-amyloid presents as diffuse core plaques more than it does as the neuritic plaques observed in AD. Therefore, among individuals with extensive exposure to repetitive head impacts and who meet provisional clinical diagnostic criteria for CTE, a “positive” flortaucipir (ie, uptake at the depths of the cortical sulci in frontal, temporal, and parietal regions, in additional to medial temporal uptake in more advanced cases) combined with a negative amyloid PET would be highly suggestive of CTE and argue against AD as the underlying neurodegenerative disease.6
Cerebrospinal fluid. CSF extraction by lumbar puncture is more time- and cost-efficient than PET imaging and still provides a window into the environment of the CNS. Similar to AD, analysis of concentrations of total tau (t-tau; a marker of neurodegeneration), p-tau, and beta-amyloid in the CSF may play a role in the diagnosis of CTE.
Our team is currently examining the utility of these and other CSF analytes in participants at high risk for CTE (ie, symptomatic former National Football League [NFL]) players. There are now ultrasensitive immunoassay platforms that can detect low abundant proteins in blood, including t-total tau and, more recently, p-tau. Although it remains unclear whether protein concentrations in the blood accurately reflect the CNS environment, blood tests are a less invasive alternative to lumbar puncture.
Based on recent research in symptomatic former NFL players, plasma t-tau and exosomal tau may represent candidate biomarkers for CTE and/or other long-term neurological consequences associated with exposure to repetitive head impacts.8,9 Investigations of plasma p-tau in the setting of possible CTE are underway. Although current candidate fluid biomarkers for CTE cannot be as diagnostically clear as tau PET imaging (because of the lack of detection of the specific pathognomonic locations of tau deposition in CTE), future fluid biomarkers based on proteomic signatures of CTE tau hold great promise.
Magnetic resonance imaging. Structural MRI is an integral component of the clinical evaluation of neurodegenerative diseases. Structural MRI patterns in CTE are not well understood but can be hypothesized based on the gross neuropathological features of CTE. In addition, compared to controls, former tackle football players have been shown to exhibit reduced volume and/or thinning of the frontal lobe and medial temporal lobe, greater burden of white matter signal abnormalities, and greater rates of a cavum septum pellicidum.10-14
Although a cavum septum pellicidum can be found in the general population, it is a common neuropathological finding in CTE and it is hypothesized that rates of a cavum septum pellicidum may be higher in the setting of head trauma. Magnetic resonance spectroscopy and diffusion tensor imaging are other MR modalities that may be able to detect non-specific pathologies that often accompany CTE, such as neuroinflammation and axonal and white matter injury. With the increasing awareness of CTE, numerous studies have examined various MR-based modalities in individuals exposed to repetitive head impacts. Importantly, many of these imaging tools evaluate “proxy” markers of CTE neuropathological changes and not p-tau deposition.
CTE may be a major public health concern given the millions of individuals who are actively exposed to or have a history of repetitive head impacts from contact sport participation, military service, or other settings (eg, domestic violence). Continued neuropathological research on CTE is essential to clarify disease mechanisms and to identify potential biomarker targets. Prospective clinicopathological correlation studies are also needed, as they are the gold standard for the development of in vivo biomarkers.
There is currently an ongoing NINDS-funded, 7-year multicenter study, known as the DIAGNOSE CTE Research Project (PIs: Robert A. Stern [Contact PI], Jeffrey Cummings, Eric Reiman, Martha Shenton). DIAGNOSE CTE is a longitudinal examination of former NFL players (with and without symptoms), former college football players (with and without symptoms), and a control group without a history of head trauma. At baseline and at 3-year followup, participants complete clinical exams (neurological, neuropsychological, psychiatric), neuroimaging (PET tau and amyloid, MRI, functional MRI, diffusion tensor imaging, magnetic resonance spectroscopy), lumbar puncture, and blood draw.
A primary endpoint of DIAGNOSE CTE is the development and validation of in vivo biomarkers for CTE. The in vivo diagnosis of CTE is the critical next step in order to initiate clinical research studies on disease risk factors, epidemiology, treatment, and prevention.
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