A study of deceased former NFL players estimated that nearly 75% had CTE neuropathology, while a phase 3 trial is evaluating whether F-18 FNT-PET imaging could help identify disease-associated patterns in living patients.
Chronic traumatic encephalopathy (CTE) remains one of the most challenging conditions to study in neurology. Associated with repetitive head impacts in contact sports and military settings, the neurodegenerative disease can currently be definitively diagnosed only through postmortem examination of brain tissue. This limitation has made it difficult to determine how frequently CTE occurs, how its neuropathology relates to symptoms during life, and how the disease might ultimately be identified and treated.
A study published in JAMA Network Open in October 2026 offered a new estimate of CTE neuropathology prevalence among deceased former National Football League (NFL) players, using an approach designed to account for selection bias that has complicated previous research. Among 2362 former NFL players who died between 2008 and 2023, investigators found that 362 of 387 brain donors with known CTE status (93.5%) had CTE neuropathology. After adjusting for differences in the likelihood of brain donation, the researchers estimated that 74.5% (95% CI, 69.6%-78.3%) of the full cohort had CTE neuropathology at death.¹
Previous studies have reported high rates of CTE among donated brains, but those findings have been difficult to interpret because brain donors may not be representative of the broader population of former players. Individuals who experienced cognitive, behavioral, or other symptoms may have been more likely to donate their brains, potentially inflating prevalence estimates. To address this concern, the investigators used mortality records and information from brain donors to model the likelihood of donation and adjust their estimate accordingly.
The resulting estimate suggests that selection bias materially affects the prevalence figures derived from brain donors, but does not fully account for the high burden of CTE neuropathology in this population. In a more conservative sensitivity analysis, the investigators estimated a prevalence of 63.7% (95% CI, 57.2%-68.9%), further suggesting that the findings were not solely explained by the overrepresentation of symptomatic individuals among brain donors.¹
For Rory Siegel, DO, a brain injury medicine physician at Burke Rehabilitation Hospital, the study represents an important step toward better understanding the prevalence of CTE among former NFL players.
“Previous studies have found a high prevalence of CTE among brain donors, raising questions about potential selection bias,” Siegel told NeurologyLive. “Some players who experienced symptoms may have been more likely to donate their brains, while others may not have known that brain donation was an option.”
Although the study provides a new estimate of CTE neuropathology among deceased former NFL players, the findings do not establish how frequently that pathology produces clinical symptoms. This distinction is important because cognitive and behavioral changes can have several potential causes, particularly among older adults.
“One potential limitation of this study is that researchers linked the prevalence of dementia or cognitive impairment to a potential clinical suspicion of CTE,” Siegel told NeurologyLive. “While that approach is helpful, it may not fully account for the wide range of conditions that can contribute to cognitive decline in an aging population, including Alzheimer's disease, vascular dementia, and frontotemporal dementia. While I appreciate that the researchers highlighted dementia as a potential symptom of CTE, it is important to recognize that other conditions and factors may also contribute.”
Julien Bailes, MD, chief medical officer of CereMark Pharma, told NeurologyLive the importance of better understanding the clinical significance of the different stages of CTE neuropathology, particularly among older individuals. Although the study identified CTE pathology across its various stages, Bailes, who is also the system executive physician for neurosurgery at Endeavor Health in Chicago, noted that the relationship between lower-stage pathology and dementia remains unclear.
“I applaud the investigators and the authors of that study,” Bailes told NeurologyLive. “But there's a lot of things that have to be further understood. For instance, they have 75% of the people that have all stages of CTE. The low stages of CTE really are not associated with dementia. The clinical significance of their prevalence therefore remains undetermined.”
Bailes also raised questions about the potential influence of aging on the findings, noting that some of the observed neuropathological changes may be associated with age-related processes. He pointed out that many of the former players included in the study competed decades ago, before changes to football rules and equipment.
“I think it was a good study, an important study, provocative,” Bailes said. “But I think there's a lot more that needs to be understood concerning what they're seeing and how this relates to the symptoms, and is it correlated with CTE or is it other forms of dementia?”
These challenges are not limited to former professional football players. Repetitive head impacts occur across multiple contact sports, including rugby, hockey, and soccer, while military personnel may experience repeated blast exposure. Better understanding who develops CTE pathology, how it progresses, and how it relates to clinical symptoms remains essential to advancing research in the field.
The inability to diagnose CTE during life has consequences beyond estimating its prevalence. Without a reliable way to identify the disease in living individuals, researchers have limited opportunities to follow its progression, establish how pathology relates to symptoms over time, or evaluate whether an investigational treatment is having an effect on the underlying disease.
One ongoing effort to address this diagnostic challenge is the phase 3 CMK-0301 trial (NCT06254469), which is evaluating [F-18]flornaptitril positron emission tomography (PET) in individuals with mild cognitive impairment (MCI) attributed to suspected CTE or Alzheimer disease (AD). Sponsored by CereMark Pharma, the study is investigating whether the imaging approach can help predict clinical progression and distinguish suspected CTE from AD.²
The trial is designed to enroll approximately 230 participants, including individuals with MCI attributed to suspected CTE or AD, as well as a smaller group of age-matched healthy volunteers. Participants undergo imaging with a single dose of [F-18]flornaptitril, with investigators assessing the relationship between PET findings and subsequent clinical changes. One of the study's primary objectives is to evaluate the correlation between predicted neurodegeneration based on imaging and changes in Clinical Dementia Rating Scale–Sum of Boxes scores over 2 years.
The study also includes assessments of whether trained readers can distinguish suspected CTE from AD based on imaging patterns. Additional objectives include evaluating safety and tolerability and examining relationships between imaging findings and other clinical measures. The trial is also designed to assess correlations between [F-18]flornaptitril binding and neuropathological findings, including tau tangles and amyloid-beta plaques, when autopsy data are available.²
Bailes described the investigational approach as a way to assess abnormal protein deposits through PET imaging. The proposed approach involves using a radioactive tracer to identify protein-binding patterns that may help distinguish CTE-associated changes from those seen in AD and other dementias. However, whether those patterns can reliably differentiate the conditions in living patients remains to be established.
“That's the purpose of the phase 3 trial. We're not there yet, but that's the purpose of it: to try to see if we can identify CTE in imaging and distinguish it in particular from Alzheimer's disease,” Bailes said.
The distinction between the rationale for the imaging approach and its demonstrated performance is important. CMK-0301 is an ongoing investigational study, and its results have not yet established whether [F-18]flornaptitril PET can identify CTE or reliably differentiate it from other neurodegenerative conditions. The trial is therefore a step in evaluating the approach, rather than evidence that a diagnostic method is already available.
A reliable method of identifying CTE-associated pathology during life could address several limitations that currently affect the field. Beyond providing a potential diagnostic tool, imaging could allow researchers to follow individuals over time and investigate how changes in protein deposition relate to cognitive, behavioral, and other neurologic symptoms.
For clinicians and researchers, establishing that relationship will be important in determining whether imaging findings can help characterize disease progression and identify meaningful clinical differences between individuals. It could also help distinguish symptoms associated with CTE from those arising from other neurodegenerative conditions, an issue that remains particularly relevant when studying older patients with cognitive impairment.
Bailes said that improved identification of CTE could also have implications for treatment development. At present, there are no established disease-specific treatments for CTE. A diagnostic approach that can identify individuals with the disease during life could help researchers develop clinical trials targeting CTE and evaluate potential treatments in appropriately characterized patient populations.He also discussed the possibility of using imaging to monitor changes over time, including whether changes in PET findings correspond with clinical responses during treatment. Such applications would depend on first establishing the accuracy and reliability of the imaging method and determining how its findings relate to meaningful clinical outcomes.
For now, the prevalence study and the ongoing imaging trial address different but complementary challenges in CTE research. The JAMA Network Open study provides a new estimate of neuropathology among deceased former NFL players, while CMK-0301 is investigating whether a potential imaging approach could help identify disease-associated changes during life. Neither effort alone resolves the relationship between CTE pathology and clinical symptoms, but together they highlight the need for research that moves beyond postmortem findings.
Ultimately, a clearer understanding of how CTE neuropathology develops, how it relates to symptoms, and whether it can be identified in living patients will be necessary to advance both clinical research and future treatment development.
