Tau and Amyloid Deposition in Living Former NFL Players

In recent weeks, there has been a surge in media accounts of athletes with confirmed or suspected chronic traumatic encephalopathy (CTE). In May 2019, for example, the Los Angeles Times reported a lawsuit filed against UCLA by former student athletes who allege that injuries they suffered while playing football there were mishandled.¹ Two of the players claim to have sustained multiple concussions and now suffer from symptoms associated with CTE.

While the disorder first gained widespread attention due to its high prevalence in National Football League (NFL) players, CTE has also been identified in soccer and ice hockey players, as well as athletes from other contact sports that involve repetitive head impacts.^2-4 The neuropathology of CTE involves the “deposition of paired helical filament tau aggregates in neurons, astrocytes, and cell processes in an irregular pattern around small blood vessels at the depths of cortical sulci,” explained RA Stern, PhD, professor of neurology, neurosurgery and anatomy & neurobiology, Boston University Research CTE Center, Massachusetts, et al, in a study published in the New England Journal of Medicine (NEJM).⁵

In the early stages of CTE, tau aggregates are detected in the frontal, temporal, and parietal cortices, while more extensive distribution throughout the cerebral cortex, medial temporal lobe, diencephalon, and brain stem are observed in the later stages. “This pattern distinguishes CTE from other neurodegenerative diseases, including other tauopathies, such as Alzheimer’s disease and certain forms of frontotemporal neurodegeneration,” the researchers wrote.⁵ “Unlike Alzheimer’s disease, CTE typically involves neuritic amyloid-beta plaque deposition only in advanced stages of disease.”

Currenty, a diagnosis of CTE can only be determined via postmortem examination. Stern and colleagues noted that the ability to detect CTE in the brains of living individuals could improve our understanding of the disease and inform research regarding prevention and treatment. To that end, they evaluated patterns of tau and amyloid-beta deposition in the brains of 26 former NFL players and 31 healthy controls, using flortaucipir positron-emission tomography (PET) and florbetapir PET.

For inclusion in the study, the former players were required to have played in the NFL for at least 2 years, with a minimum of 12 years of overall experience with tackle football. In addition, they had to demonstrate cognitive, behavioral, and mood-related symptoms as assessed with the Mini-Mental State Examination (MMSE) and various neuropsychologic tests.

The researchers then used automated image-analysis algorithms to “compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the 2 groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group,” as described in the paper.

The results showed a higher mean flortaucipir SUVR in former players vs controls in the following brain regions: bilateral superior frontal (1.09 vs 0.98; adjusted mean difference, 0.13; 95% CI, 0.06-0.20; P <.001), bilateral medial temporal (1.23 vs 1.12; adjusted mean difference, 0.13; 95% CI, 0.05-0.21; P <.001), and left parietal (1.12 vs 1.01; adjusted mean difference, 0.12; 95% CI, 0.05-0.20; P =.002).

Exploratory analyses revealed correlation coefficients between these SUVRs and years of play as follows: 0.58 (95% CI, 0.25-0.79), 0.45 (95% CI, 0.07-0.71), and 0.50 (95% CI, 0.14-0.74), respective in each of the 3 brain regions. No association was found between tau deposition and neuropsychiatric and cognitive test scores. The investigators further reported that amyloid-beta deposition levels congruent with Alzheimer’s disease were observed in only one of the former players.

Although “these techniques cannot yet be used to diagnose CTE in an individual player… [the new study] certainly does strengthen the case that tau is the offender early in CTE, but other links remain to be clarified” Allan H. Ropper, MD, executive vice chair of neurology and professor, Harvard Medical School, Cambridge, Massachusetts, stated in a related editorial published in the same issue of NEJM.⁶ “The techniques for studying living biology, such as this use of tau-ligand PET, are making a difference,” he concluded.

Neurology Advisor interviewed Jennifer M. Coughlin MD, associate professor in the department of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, Baltimore, Maryland, for additional insights regarding CTE and the results of Stern, et al.

Neurology Advisor: What are your thoughts about these recent findings, and what is their broader significance from your perspective?

Jennifer M. Coughlin, MD: The study reports high levels of paired helical filament tau deposits, measured with ¹⁸F-flortaucipir PET in 3 brain regions of former NFL players, relative to measures detected in control individuals. As of now, the diagnosis of CTE is made at autopsy. Thankfully, several radiotracers to detect tau with PET in the living human brain have recently emerged. The findings by Stern and colleages not only demonstrate the promise of ¹⁸F-flortaucipir PET as a clinical research tool, but also suggest that early detection of CTE may be possible — an essential step toward the ultimate goal of early intervention to halt or even reverse the condition.

It is puzzling that the high tau burden detected in the brains of the former players was not associated with proposed symptoms of CTE such as memory deficits. As the investigators suggest, it may take a much larger study to best understand the links between regional tau burden and clinical symptoms.

Neurology Advisor: What are the potential implications of these results for clinicians?

Dr Coughlin: Techniques for imaging tau in the living brain such as ¹⁸F-flortaucipir PET are showing early promise in research endeavors. The use of tau imaging can be combined with that of imaging amyloid-beta protein to better understand the pattern of pathologic proteins in various neurologic conditions such as Alzheimer’s disease and now CTE. One advantage of imaging living individuals is that we can then study the relationship between these molecular markers and clinical symptoms, which may one day guide treatment.

Neurology Advisor: What should be the focus of future research and other efforts in this area?

Dr Coughlin: Our ultimate goal is to help patients who suffer from clinical symptoms incurred from repeated hits to the head. These findings suggest that we need to keep pursuing this line of research from many angles.

• PET researchers, including our team at Johns Hopkins, are working hard to improve PET imaging techniques.

• Clinicians must continue to disseminate their observations when treating patients with a history of collision sports.

• Data-sharing initiatives must grow in order to promote the study of larger PET imaging datasets.

• We need to better facilitate the participation of busy former players in this line of research.

• Our PET imaging lab at Johns Hopkins is also imaging the brain’s immune response and studying markers that reflect inflammatory pathways to elucidate the mechanisms that drive and/or promote tau pathology in vivo.

In other words, in order to have an impact on clinical care, we will need the continued efforts of researchers, physicians, and research volunteers. The good news is that, with the help of evolving PET technology, we are moving closer to clinically meaningful findings.      

References

1. Bolch B. Three former UCLA football players sue school and coach Jim Mora over alleged mishandling of injuries. Los Angeles Times. May 30, 2019. https://www.latimes.com/sports/ucla/la-sp-ucla-football-lawsuit-jim-mora-20190530-story.html. Accessed June 7, 2019.
2. Ling H, Morris HR, Neal JW, et al. Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players. Acta Neuropathol. 2017;133(3):337-352.
3. Pollock N. The Tragic Post-Hockey Life of an NHL ‘Enforcer’. The Atlantic. April 25, 2019.  https://www.theatlantic.com/health/archive/2019/04/hockey-cte-todd-ewen-brain-injury/587818/. Accessed June 7, 2019.
4. Trammell K, Riess R. Ex-WWE star Ashley Massaro’s brain could be donated to research. CNN. May 21, 2019.
5. Stern RA, Adler CH, Chen K, et al. Tau positron-emission tomography in former National Football League players. N Engl J Med. 2019;380(18):1716-1725.
6. Ropper AH. Links in the chain of chronic traumatic encephalopathy. N Engl J Med. 2019;380(18):1771-1772.