Research Spotlight: New Research Suggests PET Test for Chronic Traumatic Encephalopathy Has Limited Value

Aaron Baggish, MD, founder of the Cardiovascular Performance Program at Massachusetts General Hospital and an associate professor of Medicine at Harvard Medical School, is co-senior author of a recent paper published in the Journal of Neurotrauma, Tau Positron Emission Tomography and Neurocognitive Function Among Former Professional American-Style Football Players. 

Summary:

Professional football has been tied to a neurodegenerative condition called chronic traumatic encephalopathy (CTE), which can only be diagnosed by conducting an autopsy of deceased players. However, there has been considerable interest in discovering a way to diagnose CTE in living players.  A 2019 study of former NFL football players found that when researchers injected a PET tracer (which is absorbed by the body’s tissues, allowing clinicians to observe disease in the brain) into former NFL players exposed to head injury, the tracer “lit up” the same areas of the brain that were identified in previous autopsy studies. This finding suggested that clinicians and researchers could diagnose CTE in living players.

Accurately diagnosing brain disease in former living players is of paramount importance. However, when we replicated this study by scanning those same brain areas, we found no differences in PET tracer absorption between former NFL players and people in a control group.

Our results call into question whether this PET tracer can be used to diagnose or study CTE in living players and may spare many men from undergoing a test that appears to be of limited value. This critical finding emphasizes the importance of validation studies before any medical test can be broadly used for clinical decision making.

Q&A

What Question Were You Investigating?

Chronic traumatic encephalopathy (CTE) is a brain condition thought to be linked to repeated injuries to the head.

This study was performed to examine patterns of tau-protein (tau) deposition, the proposed hallmark of CTE, using positron emission tomography (PET) among former professional football players.

We undertook this study to replicate findings from a landmark study (Stern et al. NEJM, 2019) that used PET and showed increased tau in the brains of former professional football players when compared to controls.

The Stern et al. results suggested that PET, using the radio tracer Flortaucipir (FTP), which has been FDA-approved for the evaluation of adults undergoing evaluation for suspected Alzheimer’s disease, could be used to diagnose CTE in living players.

This provocative finding challenged the notion that CTE could only be diagnosed postmortem by autopsy. Stern et al. reported that increased tau was related to the length of football exposure, but found no association between tau and the correlated clinical symptoms that are currently attributed to underlying CTE.

Specifically, players with brain PET scans that were most suggestive of CTE performed similarly on cognitive and mood tests compared to non-football controls.  We undertook the present validation study to further clarify the potential role of PET in diagnosing CTE in living players.

What Methods or Approach Did You Use?

We used PET scans on former NFL players and non-football controls. We also performed detailed cognitive testing on study participants.

What Were Your Findings?

In conducting this study, we anticipated validating the prior findings of Stern et al, which would further support the use of the PET scan in clinical practice. However, our work failed to validate their findings.

Specifically, we found no significant increase in tau tracer binding in the brains of former players compared to non-football playing controls. In addition, the overall magnitude of tau tracer binding in former players and controls was one tenth of the magnitude previously reported.

We did however see increased non-specific tracer binding to brain areas high in neuromelanin, a protein found in the brains of Black players. This finding suggests that a possible “contamination effect,” which could lead to over-diagnosis of true tau deposition in certain populations of players.

Like Stern et al., we found no associations between cognitive function and tau, thereby challenging the clinical relevance of PET scan results.

What Are the Clinical Implications?

These results call into question the use of FTP-PET to identify premortem CTE. It also casts doubt on whether this tracer is appropriate to use in anyone expressing neuromelanin. Our results suggest that clinicians working with former football players should question the role and perhaps avoid using FTP-PET scanning for the diagnostic evaluation of CTE. 

What Are the Next Steps?

The development of more accurate tools to confirm CTE represents an important area of future work. Our next steps include using second-generation tracers with more specific binding profiles for the tau proteins that are believed to aggregate in the brain areas affected by CTE. We are also evaluating other imaging techniques (e.g., MR) in the search for CTE and other forms of brain-based pathology that results from repetitive head injury. We also recommend future studies examine entorhinal cortex tau deposition, a novel preliminary finding in the current study, among people exposed to repetitive head injuries.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.