By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department
of Neurology, Weill Cornell Medical College
Dr. Ishii reports no financial relationships relevant to this field of study.
Former NFL players with symptoms consistent with chronic traumatic encephalopathy had increased tau tracer uptake that was associated with years of playing football but not with cognitive or neuropsychological measures.
Stern RA, Adler CH, Chen K, et al. Tau positron-emission tomography in former National Football League players. N Engl J Med 2019;380:1716-1725.
The National Football League (NFL) is the most popular sports league in the United States, but chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repeated head impacts, is a growing long-term safety concern for its players. Reported symptoms of CTE include cognitive impairment, mood disturbances, and lack of behavioral control. Currently, CTE is defined neuropathologically by the deposition of paired helical filament tau aggregates. These tau aggregates initially form in the frontal, temporal, and parietal cortices before becoming more extensively distributed in a distinct pattern from other tauopathies such as Alzheimer’s disease (AD). However, as CTE can be diagnosed formally only postmortem, this limits our ability to accurately diagnose CTE in patients and to develop effective prevention and treatment trials. Therefore, Stern et al sought to use a recently developed positron-emission tomography (PET) tau tracer 18F-flortaucipir to compare brains of living former NFL players with neuropsychiatric symptoms consistent with CTE to asymptomatic controls without a history of head injuries.
Study participants were 26 former NFL players who reported cognitive, mood, and behavioral control symptoms and 31 asymptomatic control participants. All subjects were males 40 to 69 years of age with no history of traumatic brain injury, other than contact while playing football. The former NFL players were recruited from two separate investigator-initiated CTE studies. Eighteen subjects were from a study conducted in Boston (Boston University and Brigham and Women’s Hospital) with another eight subjects from a separate study conducted in Arizona (Mayo Clinic Scottsdale and Banner Alzheimer’s Institute). Control subjects were from four separate studies, including nine from the CTE study in Boston, one from the CTE study in Arizona, 18 from an earlier Avid-sponsored AD trial, and three from the Alzheimer’s Disease Neuroimaging Initiative. The Mini-Mental Status Examination (MMSE) was administered to all subjects. Former NFL players were also administered tests for executive function, episodic memory, and behavioral regulation. Each participant underwent flortaucipir PET (for the detection of tau), florbetapir PET (for the detection of amyloid-beta), and T1-weighted volumetric MRI of the head. Overall demographic characteristics, including mean ages and years of education, were similar between the two groups, except the group of former NFL players included a higher percentage of black participants and lower MMSE scores (former NFL players: 27.23 ± 1.73; controls: 29.06 ± 0.81; P < 0.001).
An analysis of the age-adjusted flortaucipir standard uptake value ratios (SUVRs) found significantly higher tau tracer uptake in the former NFL players group compared to the control group, primarily in the bilateral superior frontal, bilateral medial temporal, and left parietal regions. Although mean differences in flortaucipir SUVRs were significantly different between the groups, there was significant overlap on an individual level. There also was no significant difference in flortaucipir SUVRs between self-identified black and white former players. Furthermore, flortaucipir SUVRs were not significantly associated with cognitive or neuropsychological test scores. However, years of playing football did correlate with tau tracer uptake. With respect to amyloid PET, there were no significant differences in the florbetapir SUVRs between former NFL players and control subjects. One former NFL player and two controls had positive amyloid PET scans.
COMMENTARY
This important study provides good evidence that non-invasive tau PET imaging can detect tau pathology in vivo in a pattern similar to postmortem neuropathological studies of CTE. However, there are significant concerns and limitations. First, as the authors pointed out, there was significant overlap in tau tracer uptake between the groups. Therefore, it would not be possible to use flortaucipir as is to diagnose individuals with CTE. Second, the overall positive tau uptake was significantly lower than that seen in AD, suggesting that flortaucipir does not bind to the tau aggregates in CTE as well as it does in AD. This could be because of differences in the molecular structures of tau aggregates between CTE and AD or from the difficulty in imaging tau accumulation in the deep sulci as commonly seen in CTE. Also, flortaucipir is a first-generation tau tracer that may have nonspecific binding and other specificity and sensitivity issues.
Additionally, the tau tracer uptake did not correlate with any cognitive or neuropsychological measure. Although this could be from a low sample number resulting in an underpowered study or from the relatively mild cognitive symptoms, it also is possible that tau aggregates in CTE do not necessarily reflect functional outcomes. Furthermore, since these neuropsychological symptoms are relatively common and may be seen in many other conditions, some of the symptomatic subjects may not have CTE. Finally, there are study design considerations. This study was cross-sectional, with subjects accrued from several other studies across different sites, including a majority of control subjects recruited from non-CTE studies. While the investigators did their best to match the groups, there was likely to be variability within the groups due to the differences in the enrollment sites.
Despite limitations, this study significantly advances the field by showing that it is feasible to detect tau pathology in CTE by PET. Replication studies are needed with larger numbers of well-matched subjects using the newer second-generation tau tracers that may be more specific. It would be ideal to conduct longitudinal studies including clinicopathological correlation with the tau PET. While tau PET is not yet ready for prime time, future studies based on this one are likely to help establish whether tau PET can be used as a diagnostic agent in clinical practice and for the development of prevention and treatment trials.
