Standalone Traumatic Brain Injuries Rarely Lead to Chronic Traumatic Encephalopathy Development

Chronic Traumatic Encephalopathy (CTE) is an irreversible neurodegenerative disease associated with repeated head trauma. CTE is defined by an abnormal accumulation of hyperphosphorylated tau protein (p-tau) in a distinct pattern around small blood vessels, particularly at the depths of the brain’s cortical sulci. The disease is most commonly observed in those with high exposure to repetitive head impacts (RHIs), including athletes who compete in contact sports such as American football, boxing, and hockey, as well as military personnel.

At the moment, CTE can only be definitively diagnosed through a postmortem autopsy. This is because current imaging techniques, tau – PET scans and MRIs, cannot reliably detect the buildup of p-tau in a living brain. There are no disease modifying therapies for CTE, so clinicians emphasize prevention as the most effective strategy to avoid diagnosis. In addition to repetitive head trauma, risk factors in developing CTE include exposure at a young age and the cumulative duration of repeated cranial impacts over several years.

To better understand the risk of CTE, researchers from the Brain Injury Research Center of Mount Sinai conducted a study on individuals with isolated traumatic brain injuries (iTBIs) or less extensive impacts. Led by Enna Selmanovic, a PhD candidate at Mount Sinai, the study analyzed the neuropathology of postmortem brain tissue of 47 donors enrolled in the Late Effects of Traumatic Brain Injury Project. Published in the Journal of Neuropathology & Experimental Neurology, findings indicated that individuals with one-off TBIs or less extensive impacts were less likely to develop the CTE than those with RHI.

In an exclusive interview with NeurologyLive®, Selmanovic discussed the key findings of the study and their clinical significance. In addition, she addressed common misconceptions clinicians face when treating patients at risk for CTE and the recent research that could potentially enable diagnosis in living individuals.

NeurologyLive: Discuss the reasoning behind this study – why was this something you wanted to pursue?

Enna Selmanovic: It’s important to understand that studying brain tissue allows us to examine the cumulative impact of exposures across a person’s life course—the final biological record of injuries, diseases, and repair processes that shape the brain over time. Clinically, symptoms of different neurodegenerative diseases often overlap, so we can’t always distinguish between conditions like Alzheimer disease, vascular injury, or trauma-related degeneration based on symptoms alone in life. The gross and microscopic examination of brain tissue is what helps us ultimately clarifies those diagnoses.

In this study, we used established consensus criteria for CTE—which define a very specific pattern of phosphorylated tau around small blood vessels at the depths of cortical sulci—to determine how often CTE appears in a real-world TBI brain bank cohort. Most prior studies have focused on highly selected groups, like former athletes who have high levels of head trauma exposure and/or concerns about clinical symptoms. This can overestimate prevalence, meaning how common the condition may be, in less selected samples. By studying a TBI brain bank sample that includes decedents with a wide range of head trauma exposures, we aimed to learn more about the prevalence of CTE across different types and patterns of head trauma, while setting the stage for future work that links these tissue findings back to clinical symptoms and head trauma exposure data.

What were the biggest takeaways or highlights from this study?

One of the main takeaways from this study is that CTE was relatively uncommon in a cohort of individuals with head trauma, even among people with a history of isolated traumatic brain injury. Out of 47 consecutive brain donors, only 7 showed pathology consistent with CTE, and most of those cases were mild (also called low-stage CTE). Nearly all individuals with CTE had substantial exposure to repetitive head impacts—through contact sports, military service, or interpersonal violence. Only one case had no known repetitive head impact exposure; this case had two isolated, single-event TBIs.

These results reinforce that repetitive head impact exposure appears to be a key driver of CTE-type changes, but also that exposure is not destiny. Many individuals with substantial lifetime head-impact histories did not develop CTE, suggesting that other biological, genetic, and vascular factors shape vulnerability. CTE is rare in individuals in this cohort with isolated TBI. In short, CTE exists, but in the general population it seems far less common—and far more variable—than what we see in highly selected athlete cohorts.

Why do you think CTE is more common in those with repeated head trauma than those who have had one or two isolated traumatic brain injuries?

While we don’t have all the answers, biomechanically, we believe CTE is more common after repetitive head impacts because of how the brain responds to cumulative mechanical stress. Each impact, even if it does not result in clinical symptoms, can stretch and strain the small blood vessels and nerve fibers at the depths of the brain’s grooves – the same regions where CTE lesions are found. Over time, that repeated stress may lead to abnormal buildup of proteins, specifically tau, around small vessels, producing the characteristic pattern that defines CTE.

In contrast, one or two isolated TBIs may cause different types of damage – such as injury to axons, vascular disruption or interruption of blood flow, or aggregation of other neurodegenerative pathologies, but they don’t typically trigger the same chronic, sulcal-focused tauopathy.

What are some common misconceptions regarding CTE, TBI, or repetitive head impacts?

One major misconception is that concussion or brain injury commonly leads to CTE. In reality, CTE develops only in a subset of individuals with repetitive head-impact exposure, and many people with very high levels of repetitive head impact exposure never develop it at all. Another misconception is that CTE can be diagnosed in life. At present, it remains a pathological diagnosis requiring confirmation under the microscope. It’s also often assumed that CTE is uniformly progressive and inevitably fatal, but pathology can range from very mild to more advanced, and the relationship between pathological progression and clinical course is not yet well understood.

With that in mind, we also cannot confirm that the signs and symptoms often associated with CTE – like aggression, mood changes or cognitive decline – are directly caused by the pathology. In some individuals, these symptoms may have predated brain changes, and/or the symptoms may be exacerbated by brain changes. Some of these symptoms may even stem from other co-morbidities unrelated to brain trauma. Finally, it’s essential to remember that many of the symptoms associated with CTE like sleep, mood changes, memory problems, or substance use, can be treated and managed. Understanding that evidence-based treatments exist can help replace fear with informed action.

What are your thoughts on the recent findings in Brain Communications suggesting early trauma-related brain changes in at-risk patients, and on the broader field of CTE and TBI research in living individuals?

The Brain Communications study completed by colleagues at NYU is an exciting step toward understanding how repeated head impacts might leave early structural footprints in the living brain. They found subtle differences in the left superior frontal sulcus of former football players—an area that aligns with where CTE lesions tend to cluster in postmortem studies. However, to be clear, these kinds of MRI-based findings don’t “diagnose” CTE, but they may reflect early or cumulative effects of repetitive impacts, offering potential clues to track risk before disease develops.

More broadly, this type of research brings us closer to connecting what we see under the microscope with what we can detect in life. The goal isn’t to use imaging to predict a diagnosis, but to identify biological markers of exposure and vulnerability. If we can link those markers to outcomes that matter to people— such as cognition, behavior, resilience—it could transform how we monitor, prevent, and ultimately protect brain health across high-risk populations.

Looking ahead at CTE research, what other studies do you think have to be done to advance CTE diagnosis prior to autopsies? Where do you see this kind of research heading in the next 5 years?

Looking ahead, the next phase of CTE research has to focus on understanding how different types of head trauma relate to CTE neuropathology and identifying reliable in-life markers of trauma-related brain change. That means integrating advanced imaging, blood-based biomarkers, genetics, and detailed exposure histories to detect subtle patterns that correspond to what we later confirm at autopsy. We need large, longitudinal studies—like the Late Effects of Traumatic Brain Injury (LETBI) study at Mount Sinai, Massachusetts General Hospital, and the University of Washington —that follow people over time across sports, military, and community settings to better understand who develops CTE and other brain pathologies and why.

Equally important is understanding resilience—why some individuals with extensive head-impact histories never develop CTE. Studying those protective factors will be just as valuable as identifying risks, and doing so will require broader representation in brain donation and research participation of people with a range of head trauma histories and a range of clinical symptoms – including those who are functioning well. Within the next five years, the field is moving toward datasets that combine life-course information with tissue confirmation. That’s the bridge we need to make accurate living diagnosis possible and to shift the focus from postmortem detection to prevention and treatment in life. With that in mind, we encourage everyone to consider brain donation to help advance scientific understanding of the brain. A single donated brain fuels hundreds of scientific discoveries.

Transcript edited for clarity.