Chronic traumatic encephalopathy can only be formally diagnosed by examining the brain after death, but researchers are inching closer to spotting the neuropathological hallmarks of disease during life. A study published April 10 in the New England Journal of Medicine described the results of PET scans in 26 former National Football League players with mild cognitive symptoms. Researchers led by Robert Stern at Boston University School of Medicine and Eric Reiman of the Banner Alzheimer’s Institute in Phoenix reported that compared with controls, the players had a higher average uptake of flortaucipir, a tau tracer, in three regions of the brain typically affected in people with CTE. However, the players’ flortaucipir uptake was modest compared with that observed in people with AD, and substantial overlap existed between cases and controls. Only one of the former players had evidence of Aβ accumulation.
- Former NFL players with cognitive complaints had higher flortaucipir uptake in three brain regions than controls.
- Tracer uptake did not correlate with cognitive or neuropsychological test scores.
- Years of playing football did correlate with uptake.
“This is a welcome and carefully written paper,” commented Christopher Rowe of the University of Melbourne in Australia. “It is the first good evidence that tau imaging can detect a signal in chronic traumatic encephalopathy, but the authors make very clear that this is a long way off from being a useful diagnostic test for individuals suspected of having the disease.”
To investigate whether PET scans could detect tau pathology in people with a history of repeated head trauma, the researchers scanned 26 former NFL players, aged 40–69, who reported cognitive, mood, or other behavioral symptoms. The retired athletes had played in the NFL for at least two years, and had played tackle football for a minimum of 12 years. The investigators also scanned 31 controls without a history of repeated head injury. Compared with controls, former players had modestly elevated tau tracer standardized uptake value ratios (SUVRs) in the bilateral superior frontal, bilateral medial frontal, and left parietal cortex—all regions previously identified as tau pathology hot spots in people with CTE. Only one former player had evidence of Aβ accumulation, as measured separately using florbetapir-PET scans.
Though former players had a higher average tau tracer uptake than controls, individual measurements overlapped extensively between the groups, indicating that this form of tau PET imaging could not be used for individual diagnosis.
The participants took a series of cognitive and neuropsychological tests, on which many players scored in the impaired range. Notably, 81 percent were considered depressed, and 35 percent had deficits in delayed recall. However, the extent of tau tracer uptake in any of the three affected brain regions did not correlate with test scores. In a post hoc analysis, the researchers found that tracer uptake correlated with the former players’ total number of years playing tackle football.
Reiman told Alzforum he was disappointed that flortaucipir uptake could not distinguish between former players and controls at the individual level. He and other commentators offered several potential explanations for the weak tau signals. For one, it is possible that in response to repeated head injuries, tau accumulates in a highly localized pattern, for example around the deep sulci as they warp under impact. This spotty pattern would preclude a strong tau tracer signal, Reiman said. Bill Jagust of the University of California, Berkeley, added that patchy, inconsistent deposition patterns make tau difficult to quantify, especially when averaging across subjects.
Another possibility is that flortaucipir simply does not bind CTE-tau filaments as strongly as it binds AD-tau, Reiman and Jagust said. Tau filaments in AD and CTE both consist of three-repeat and four-repeat isoforms, but recent structural studies of the two types of filament visualized distinct core structures (Jul 2017 news; Mar 2019 news). Michel Goedert, who co-led both structural studies with Sjors Scheres at the MRC Laboratory of Molecular Biology in Cambridge, U.K., said that future work will identify the binding sites of flortaucipir to AD-tau and CTE-tau filaments, which could clarify this issue.
“It will be interesting to see how second-generation tau tracers, such as MK6240, perform in this population,” wrote Gil Rabinovici at the University of California, San Francisco. “Overall, this [study] is an encouraging first step, but I agree with the authors that tau PET is not yet ready for ‘prime time’ as a diagnostic agent in CTE,” he added.
What to make of the finding that flortaucipir-PET did not correlate with cognitive or neuropsychological test scores? Reiman said he was unsurprised by that, given the small number of participants and their mild symptoms. Rowe raised the possibility that some of these former players do not have CTE at all. “This is highly likely given the nonspecific nature of the mood, cognition, and behavioral features used for clinical diagnosis of CTE,” he wrote.
Reiman thinks larger studies, of people with a wide range of symptom severity, might detect a connection between tau pathology and clinical symptoms. To that end, he is collaborating with Stern and other investigators to recruit participants to the DIAGNOSE-CTE study (see clinicaltrials.gov). This longitudinal study will enroll 120 former NFL players, 60 former college football players, and 60 controls. It will track tau, Aβ, and neurodegeneration via various neuroimaging techniques, search for potential biomarkers in cerebrospinal fluid and blood, and monitor cognition and behavior.
Kaj Blennow of the University of Gothenburg in Sweden stressed the importance of such multimodal, longitudinal studies. “It will be interesting to learn whether regional cortical tau deposition also is associated with biomarker evidence of neurodegeneration in the same areas (evaluated by volumetric MRI), or by increases in fluid biomarkers reflecting neurodegeneration, such as plasma levels of tau or neurofilament light (NFL) protein, especially in longitudinal studies employing such measures.”—Jessica Shugart
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- Traumatic Tau: Filaments from CTE Share Distinct Structure
- Stern RA, Adler CH, Chen K, Navitsky M, Luo J, Dodick DW, Alosco ML, Tripodis Y, Goradia DD, Martin B, Mastroeni D, Fritts NG, Jarnagin J, Devous MD Sr, Mintun MA, Pontecorvo MJ, Shenton ME, Reiman EM. Tau Positron-Emission Tomography in Former National Football League Players. N Engl J Med. 2019 May 2;380(18):1716-1725. Epub 2019 Apr 10 PubMed.