Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative tauopathy¹ associated with repetitive head impacts (RHIs).² By definition, CTE is a neuropathological diagnosis,^1,3 and it has been frequently diagnosed in deceased American football players. Traumatic encephalopathy syndrome (TES) represents research diagnostic criteria for the clinical syndrome of CTE neuropathology.⁴ Initial TES criteria, published in 2014, were highly sensitive and poorly specific.⁵ A 2021 revision of TES attempted to improve specificity⁴; however, its validity is being evaluated and is not currently recommended for clinical practice. Core clinical features include cognitive impairment and/or neurobehavioral dysregulation while supportive features include various psychiatric symptoms. Suicidality was a supportive feature of the 2014 TES criteria. Due to the absence of evidence directly linking CTE neuropathology and suicidality, it was not included in the 2021 criteria. Brain bank studies investigating CTE neuropathology have shown suicide to be a common cause of death,⁶ raising the question of whether suicidality is a symptom and/or a function of selection bias as autopsies are often performed after suicide. There have been several public-facing cases of high-profile football players who have died by suicide. Overall, some contend there is a public perception that an association between CTE neuropathology and suicide/suicidality exists. There is concern that people who play or played American football and develop psychiatric symptoms might attribute them to CTE neuropathology when in fact it may or may not be related and there is opportunity for treatment and hope.

In this issue of JAMA Neurology, Grashow et al⁷ examined the association between perceived CTE and various clinical correlates including suicidality among 1980 former professional American football players. The participants are from the Football Players Health Study (FBHS), which enrolled 4180 football players who played in a professional league between 1960 and 2020 (n鈥�=鈥�15鈥�011). For the current study, 1980 (about 47% of eligible participants) had follow-up surveys and were asked, 鈥淒o you believe you have chronic traumatic encephalopathy (CTE)?鈥� with those responding yes classified as having perceived CTE. While we use perceived CTE in this Editorial to align with the study, we do not encourage continued use of this terminology until validation is conducted. Of the participants who responded, 681 (34.4%) were classified as having perceived CTE with the strongest predictors of perceived CTE being subjective cognitive difficulties, followed by low testosterone, greater concussion burden from football, symptoms of depression, emotional and behavioral dyscontrol symptoms, and pain intensity. The participants with perceived CTE were more likely to endorse suicidality over the past 2 weeks (assessed by 1 question from the Patient Health Questionniare-9) compared to those who did not believe they had CTE (25.4% vs 5.0%). This study provides insights into former professional football players beliefs about having CTE and the accompanying clinical correlates.

Findings are limited by lack of autopsy confirmation of CTE neuropathology and collection of data by self-report measures. We highlight the crude assessment of suicidality and psychiatric symptoms. These symptoms, and most of the data collected, were assessed using brief screening measures in the absence of clinician assessment and judgement and there is a high likelihood for misclassification. The authors tried to account for responder bias using inverse probability weighting for dropout but this remains a concern.

We underscore the following: (1) there are no data that directly link CTE neuropathology and suicidality or suicide, and (2) findings from the current study should not be construed to mean that one鈥檚 perception of having CTE will independently lead to suicidality. It is noteworthy that 65.6% of the sample did not believe they had CTE despite this being a population where CTE is most discussed in scientific and public communities. Of those with perceived CTE, 91.8% had no (74.6% said 鈥渘ot at all鈥�) or less frequent suicidality (17.2% said 鈥渟everal days鈥�), resulting in 8.1% (n鈥�=鈥�55) who endorsed more severe suicidality over the past 2 weeks. Existing mortality studies show lower rates of suicide mortality in former National Football League players compared with the general population,⁸ and no difference compared with Major League Baseball players.⁹ The elevated rate of suicidality in the perceived CTE group is best attributable to this group having several risk factors for suicidality, including younger age, more psychiatric symptoms, greater concussion burden from football, and increased likelihood of having reported dementia diagnoses. Sample populations in TES and CTE neuropathology investigations are at elevated risk for suicidality irrespective of CTE neuropathology as they tend to be males with a history of repetitive concussions who have higher rates of cognitive impairment.^10,11 While the authors controlled for suicidality risk factors, we caution not to make inferences that perceived CTE in and of itself confers risk for suicidality. Suicidality is complex with multifactorial biological and nonbiological causes.

The directionality of associations from the study is unclear. The perceived CTE group might include participants who have been historically symptomatic (including suicidality), have been unresponsive to treatments, and are trying to explain their symptoms. That is, symptoms may have preceded their belief about having CTE. In addition, the perceived CTE group had overall poorer health and greater subjective cognitive concerns, a marker of early neurodegenerative disease. It is possible that perceived CTE represents the subgroup of individuals at greatest risk for having CTE neuropathology. Interestingly, a previous report among the FBHS cohort showed an association between greater number of seasons played professionally and long-term cognitive and neuropsychiatric symptoms.¹² Postmortem brain examination will be needed to determine the presence of CTE neuropathology in the FBHS sample.

The study raises big-picture questions regarding communication of TES and CTE neuropathology with patients and the public moving forward. An accurate diagnosis of CTE during life is not currently possible due to the need to clarify its symptom and biomarker profiles. However, do we need to wait 20 to 30 years when current prospective clinical-pathological correlation studies are complete to convey public health messages? Until relatively recent advances in biomarkers for Alzheimer disease (AD), there was substantial uncertainty about its presence especially in preclinical or early stages, but this did not prevent in vivo diagnoses and treatment trials. There is robust evidence that CTE (1) is a unique neurodegenerative tauopathy,^1,3,13 (2) is associated with cognitive symptoms,¹⁴ and (3) has a dose-response relationship with exposure to RHI.^2,15 There are clinical scenarios in which confidence for underlying CTE neuropathology can be high, ie, older cognitively impaired former elite football players who have evidence of frontotemporal neurodegeneration and other causes of dementia (eg, AD) have been ruled out. Conversely, there are clinical scenarios where confidence is low, ie, younger-aged cognitively normal individuals exposed to RHI who have a predominant psychiatric manifestation. This is partially because CTE neuropathology is strongly associated with older age and cognitive symptoms whereas there is a weaker association with psychiatric symptoms.¹⁴

While uncertainty exists (common to neurodegenerative diseases), it is a disservice to concerned patients and the public to be dismissive of CTE. This does not mean that we should currently be informing individuals that they have underlying CTE neuropathology during life. It is our duty as scientists and clinicians to provide balanced, transparent, and unbiased counsel and education on what we do and do not know about TES and CTE neuropathology. Regarding suicidality and psychiatric symptoms like depression and anxiety, the multifactorial and often treatable causes of these symptoms along with the unknown association to CTE neuropathology needs to be emphasized. There could be situations when it might be appropriate to limit discussion of CTE neuropathology to avoid misattribution of symptoms, particularly if the clinician believes that individuals鈥� symptoms are better explained by another condition. This is especially true for younger-aged individuals. In a recent study in JAMA Neurology of 152 deceased contact sport participants younger than age 30 years, 63 (41.4%) had autopsy-confirmed low-stage CTE neuropathology.⁶ There were no differences between those with and without CTE neuropathology in suicide as a cause of death or clinical symptoms as all were symptomatic. Football players often have a host of health conditions and diseases, including psychiatric symptoms, that can be treated with beneficial results. One of these modifiable factors might in fact be beliefs about CTE neuropathology and TES.

Attribution (and misattribution) of symptoms to disease is common and not unique to CTE. An analogy is cognitive aging in which older adults often misattribute normal age-related memory failures (eg, misplacing the keys) to the start of AD. These 鈥渕isperceptions鈥� can in some ways reflect awareness and motivate treatment engagement. Misperceptions might also contribute to emotional distress, representing an opportunity for psychoeducation. Grashow et al examined former professional football players鈥� beliefs about having CTE and the related clinical correlates including suicidality. Suicidality is complex with multifactorial causes, rarely driven by a singular factor including personal beliefs about CTE status or CTE neuropathology. The study is a reminder that many symptoms and health conditions in former football players, including psychiatric symptoms, can be managed and treated regardless of their relationship to CTE neuropathology. Yet, the presence of modifiable factors does not mean absence of an underlying neurodegenerative disease. Through balanced education on CTE provided by experts in neurodegenerative disease along with critical ongoing research, patient care will be optimized and misinformation to the public will be minimized.

Corresponding Author: Michael L. Alosco, PhD, Boston University Alzheimer鈥檚 Disease Research Center and Boston University CTE Center, Boston University Chobanian & Avedisian School of Medicine, Department of Neurology, 72 E Concord St, Instructional Building, L5, Boston, MA 02118 (malosco@bu.edu).

Published Online: September 23, 2024. doi:10.1001/jamaneurol.2024.3078

Conflict of Interest Disclosures: Dr Alosco reported grants from the National Institutes of Health, Life Molecular Imaging Inc, and Rainwater Charitable Foundation Inc, honorarium for consulting services from the Michael J Fox Foundation, and royalties from Oxford University Press, Inc. Dr Yaffe reported personal fees from Alector for being a board member and service on the data safety monitoring board for DIAN and grants from the National Institutes of Health, the Department of Defense, and the Veterans Health Administration.