PHILADELPHIA—Most people who met proposed clinical criteria meant to identify chronic traumatic encephalopathy (CTE) during life did not show hallmark brain changes of the disease at autopsy. The findings raise concerns that widespread clinical adoption of these criteria could lead to misdiagnosis and unintended mental health consequences for people at higher risk, including athletes and military veterans.
In the study published today in Nature Medicine , researchers from the University of Pennsylvania Perelman School of Medicine found that 75 percent of individuals who would be classified as having traumatic encephalopathy syndrome (TES)—a set of symptoms proposed to reflect underlying CTE—did not have the abnormal buildup of hyperphosphorylated tau (p‑tau) protein that defines CTE when their brains were examined after death.
"It is far more likely that someone who meets the current clinical criteria does not have CTE than that they do," said study lead author John D. Arena, MD, Chief Resident in the Department of Neurosurgery and member of the Center for Brain Injury and Repair at Penn Medicine . "Until we have diagnostic tools that can reliably detect CTE neuropathology in living people, applying these criteria in clinical settings risks doing more harm than good."
A CTE diagnosis cannot be confirmed during life
CTE entered the public spotlight about two decades ago as a neurodegenerative disease thought to be caused by repetitive head impacts and defined by a distinctive pattern of p‑tau deposits in the brain. Because these changes can only be identified after death, linking CTE to specific symptoms in living individuals has proven challenging.
Adding to the complexity, while a diagnosis of CTE can be established by the presence of even sparse characteristic p-tau pathology, this is often found coexisting alongside other more extensive neurodegenerative processes such as Alzheimer's disease or Parkinson's disease. Consequently, the specific contribution of CTE to observed symptoms can be unclear.
Notably, symptoms often associated with CTE—such as problems with memory, decision-making, mood, and behavior—are also common in the general population and in people with other neurological or psychiatric conditions. As awareness of CTE has grown, some former athletes and others with a history of head injury have come to believe they have the disease, sometimes experiencing worsening depression, anxiety, and even suicidality as a result.
Testing proposed clinical criteria against brain pathology
In 2019, the National Institute of Neurological Disorders and Stroke (NINDS) convened a panel of experts to determine how to accurately identify which individuals are likely to have CTE. The panel proposed criteria for traumatic encephalopathy syndrome (TES), or the clinical symptoms in living people associated with CTE. These criteria include substantial exposure to repetitive head impacts, cognitive or behavioral impairment, and the absence of another condition that better explains the symptoms, like Alzheimer's disease. To test how well these criteria perform, Arena and colleagues analyzed data from 1,038 individuals whose brains were donated to the Penn Brain Bank at the Center for Neurodegenerative Disease Research. A multidisciplinary team comprised of clinicians and scientists from the Departments of Neurosurgery, Neurology, and Pathology and Laboratory Medicine compared clinical records from life with detailed neuropathological findings after death.
Of the 1,038 brain donors, 161 had a documented history of repetitive head injury or traumatic brain injury, including 32 linked to contact sports such as football, soccer, or boxing. Only 25 individuals met the proposed TES clinical criteria. Among those 25 cases, just six—24 percent—had evidence of CTE pathology at autopsy.
Seven additional individuals had CTE p-tau deposits but did not fully meet the TES criteria during life, despite having some cognitive or behavioral symptoms and, in most cases, a history of head injury.
Taken together, the results show that the proposed criteria may miss some people with CTE pathology while incorrectly identifying many others who do not have the disease.
Next steps: improving diagnosis and reducing harm
The researchers emphasize that their findings do not dismiss the seriousness of head injuries or the suffering experienced by people with cognitive or mental health symptoms. Instead, they highlight the risk of labeling patients with a diagnosis that cannot yet be accurately confirmed—and the psychological harm that may follow.
"Before we can responsibly diagnose CTE in living patients, we need a much clearer understanding of how the disease develops and which symptoms it truly causes," Arena said. "The necessary next step is prospective longitudinal research that follows people during life, carefully documents head injury exposures and symptoms, and then assesses for neuropathology after death."
The study reflects work from the ongoing TRANSFORM-TBI initiative led by Penn Medicine. Co-authors include TRANSFORM-TBI investigators William Stewart, MBChB, PhD, Andrea L.C. Schneider, MD, PhD, Edward B. Lee, MD, PhD, and Douglas H. Smith, MD. The late Victoria E. Johnson, MBChB, PhD is recognized for her mentorship and valuable contributions to the project. The study was funded in part by the NINDS (U01NS137500, U54NS115322, T32NS043126, K23NS123340); the National Institute on Aging (P30AG072979, P01AG066597, P01AG084497); and the Medical Research Council (MR/Y008502/1).
