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Most people who meet the proposed clinical criteria for chronic traumatic encephalopathy (CTE) during life do not have hallmark disease pathology at autopsy.

A retrospective autopsy validation study showed that only six of 25 individuals (24%) who met criteria for traumatic encephalopathy syndrome (TES) — the proposed clinical syndrome associated with CTE — had CTE neuropathology at autopsy.

“It is far more likely that someone who meets the current clinical criteria does not have CTE than that they do,” lead author John D. Arena, MD, of the Center for Brain Injury and Repair at Perelman School of Medicine, University of Pennsylvania in Philadelphia, said in a news release.

“The low validity of TES criteria raises considerable concern for its potential negative impact on the psychological health of current and former athletes,” the investigators noted.

However, a member of the panel that drafted the criteria told Medscape Medical News that while independent validation of the criteria is important, this study has methodological issues.

The paper was published online on May 14 in Nature Medicine.

Some Cases Missed, Others Misidentified

CTE is a neurodegenerative disease associated with repetitive blows to the head. At present, the disease can only be definitively diagnosed postmortem through the examination of brain tissue for characteristic abnormal tau protein deposits.

In 2019, the National Institute of Neurological Disorders and Stroke (NINDS) convened an expert panel that drafted consensus criteria for TES, the proposed clinical correlate of CTE.

The panel reached consensus that diagnosis of TES requires a history of repetitive hits to the head from contact sports, military service, or other causes; core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; and that the clinical features are not fully explained by any other neurologic, psychiatric or medical conditions.

To evaluate how accurately the TES criteria predict underlying CTE pathology, Arena and colleagues reviewed medical records and brain tissue from 1038 individuals whose brains were donated to the Penn Brain Bank at the Center for Neurodegenerative Disease Research, University of Pennsylvania. All participants had undergone detailed neurologic evaluations during life and comprehensive neuropathologic assessment after death.

Among all cases, 161 had a documented history of repetitive head impacts or traumatic brain injury (TBI), including 32 exposed through contact sports such as football, soccer, and boxing.

Overall, CTE neuropathologic change was identified in 13 cases, representing about 1.3% of the study population. Seven of those individuals had participated in contact sports, four had a history of non-sport TBI, and two had no documented head injury history.

Among the 25 individuals who met TES clinical criteria, only six had confirmed CTE pathology at autopsy, yielding a positive predictive value of 24%. Seven additional individuals had the characteristic abnormal tau protein deposits but did not fully meet TES criteria during life, despite having cognitive or behavioral symptoms and, in most cases, a history of head injury.

The predictive ability of the TES criteria was driven largely by exposure history rather than the proposed clinical symptoms themselves, the researchers found. They detected no significant differences in core or supportive TES clinical features between cases with CTE neuropathologic change and matched controls.

Taken together, the results suggest that the proposed criteria may miss some people with CTE pathology while incorrectly identifying others who do not have CTE, the researchers said.

Methodological Concerns

However, Jesse Mez, MD, co-director of clinical research at the Boston University CTE Center in Boston, a member of the panel that drafted the criteria, told Medscape Medical News that he has “significant” methodological concerns about the study and cautioned against drawing any firm conclusions pending further validation research.

Mez noted that the study focuses on the positive predictive value, which depends heavily on disease prevalence. In this study, he explained, the prevalence of CTE pathology in the sample was “incredibly low” at around 1% “and the positive predictive value gets lower as the prevalence gets lower.”

He added that the “most important” measure to focus on is the positive likelihood ratio, which is independent of prevalence. “When you calculate that value, which isn’t included in the paper, the criteria perform well by standard clinical thresholds,” he noted.

He also emphasized that currently the criteria are intended only for research purposes, not routine clinical use pending further validation.

Multiple validation studies are underway, including by his Mez’s own group. The National Institutes of Health (NIH) plans to sponsor a summit in early next year to evaluate the performance of the criteria, address issues around diagnosis of CTE during life, and make recommendations, he said.

The study was supported by awards and grants from the NIH-NINDS, the Institute on Aging, and the Medical Research Council. Disclosures for the authors are available with the original study publication. Mez had no conflicts of interest.