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The PET tracer ¹⁸F-flortaucipir (FTP) may have limited utility as a tau pathology biomarker in chronic traumatic encephalopathy (CTE), findings from a case report suggested.

In a former National Football League (NFL) player with pathologically confirmed CTE, flortaucipir PET findings during life showed only a modest correspondence with postmortem CTE pathology, reported William Mantyh, MD, of the University of California San Francisco (UCSF), and colleagues, in .

This is the first report to describe a PET-to-autopsy correlation in a patient with CTE, Mantyh noted.

Currently, CTE can be diagnosed only after death. Last year, Boston University researchers reported that FTP PET scans showed elevated tau levels in brain regions affected by CTE in living former NFL players, suggesting FTP could detect CTE pathology in life.

While the UCSF researchers found a similar FTP pattern to what was seen in the Boston University study and , "when we compared this signal to the amount of tau pathology, there was only a modest correlation," Mantyh told 番茄社区.

"Our case suggests this tracer may not be a home run for detecting CTE," said co-author Gil Rabinovici, MD, also of UCSF. "Unfortunately, it tempers some of the enthusiasm about the ability to use this tracer to detect CTE in living people because the correlations were quite modest and lower than what's been reported in Alzheimer's disease," he told 番茄社区.

Flortaucipir was developed to detect Alzheimer's tangles and was validated against post-mortem tissue from Alzheimer's patients, he added. "It seems it doesn't bind quite as well to tau in CTE," he said.

"Biochemically, the composition of tangles in CTE and Alzheimer's is very similar, and some aspects of the filaments are similar," Rabinovici explained. "But what's been found is that there are actually differences in the folding of the filaments in these two disorders. Those kinds of differences could certainly impact the ability of a PET tracer to bind to the aggregates."

The case report involved a white former NFL player who played football for 17 years starting in high school, and who had been clinically diagnosed with traumatic encephalopathy syndrome. After retiring from football, he worked as a professional stuntman.

At age 57, he had depression, social withdrawal, episodic rage, anxiety, and a reduced ability to multitask. At 63, he developed postural tremor, stooped posture, and a shuffling gait; exams at ages 65 and 68 showed mild parkinsonism. He was clinically diagnosed with traumatic encephalopathy syndrome with behavioral, cognitive, mood, and motor features. At age 72, he developed recurrent seizures, was hospitalized, and died. About 52 months before his death, he underwent imaging, including FTP PET. His autopsy was performed using a neurodegenerative research protocol.

Pathology results showed he had stage 4 CTE, plus neurofibrillary tangles typical of Alzheimer's disease (Braak stage 3) and findings consistent with limbic argyrophilic grain disease and stage 2 limbic-predominant, age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy. Immunohistochemical analyses for alpha-synuclein and beta-amyloid were negative.

When the researchers compared FTP standardized uptake value ratios (SUVRs) in pathologically sampled regions with tau area fraction, they saw a modest correlation (ρ=0.35), which did not reach statistical significance (P=0.17). Regions with the highest pathological tau burden measured by area fraction had the highest SUVR values, although similar average SUVR values were found in regions with low pathological tau area fraction.

A major limitation of the study is that 4 years elapsed between PET scanning and death, and tau pathology may have progressed during that period, Rabinovici noted. "There also may have been idiosyncratic features that could have affected results in this case. That said, the pattern of binding we observed was pretty typical of what we reported in other studies of football players," he said. "At face value, this appears to be quite representative of the in vivo findings that we've seen in CTE and doesn't appear to be an outlier in any clear way."

Additional PET-to-autopsy reports are needed to validate or extend these findings, he added. The study also points to the need to explore other tracers in CTE. "It may be that some of the second-generation tracers will hold greater promise," Rabinovici said. "We don't know."

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