Examining the New Consensus Criteria for Traumatic Encephalopathy Syndrome in Community-Dwelling Older Adults

Abstract

In 2021, an expert panel of clinician-scientists published the first consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), a clinical condition thought to be associated with chronic traumatic encephalopathy neuropathological change. This study evaluated the TES criteria in older adults and assessed associations between TES criteria and a history of repetitive head impacts. This cross-sectional, survey-based study examined the symptoms of TES, previous repetitive head impacts, and a variety of current health difficulties. To meet symptom criteria for TES, participants had to report progressive changes with memory, executive functioning, and/or neurobehavioral dysregulation. To meet the criterion for substantial exposure to repetitive head impacts via contact sports, participants reported at least 5 years of contact sport exposure (with 2+ years in high school or beyond). A sample of 507 older adults (mean age = 70.0 years, 65% women) completed the survey and 26.2% endorsed having one or more of the progressive core clinical features of TES. Those who had a significant history of contact sport exposure were not significantly more likely to meet TES criteria compared with those who did not (31.3% vs. 25.3%, p = 0.46). In a binary logistic regression predicting TES status, current depression or anxiety (odds ratio [OR] = 12.55; 95% confidence interval [CI] = 4.43-35.51), history of psychiatric disorders (OR = 2.07, 95% CI = 1.22–3.49), male sex (OR = 1.87), and sleep problems (OR = 1.71, 95% CI = 1.01-2.91) were associated with meeting TES criteria. The sport exposure criterion, age, and current pain were not significantly associated with TES status (ps > 0.05). A significant minority of participants with no history of neurotrauma endorsed symptoms consistent with TES (22.0% of men and 19.8% of women). Nearly 80% of neurotrauma naïve participants with clinically significant anxiety/depression met criteria for TES. In summary, approximately one in four older adults met the symptom criteria for TES, many of whom had no history of repetitive neurotrauma. Mental health problems and sleep issues were associated with TES, whereas having a history of repetitive head impacts in contact sports was not. These data suggest that the new consensus diagnostic criteria for TES may have low specificity and may carry a higher risk of misdiagnosing those with other physical and mental health conditions as having TES.

Introduction

Neurological problems, such as cognitive impairment, dysarthric speech, and movement abnormalities, have been described in current and former boxers throughout the 20th century.^1
–3 These neurological problems have been known historically by a variety of terms, including chronic traumatic encephalopathy (CTE)^1,2 and traumatic encephalopathy syndrome (TES).³ In recent years, the term CTE has been used interchangeably to represent both a diverse range of psychiatric and neurological problems^4,5 and a post-mortem neuropathological entity.^5
–7 To avoid conceptual confusion, we refer to the post-mortem neuropathological entity as CTE neuropathological change (CTE-NC)⁸ or CTE neuropathology^9,10 and we refer to the possible in vivo clinical syndrome as TES.^3,11

There are no validated diagnostic criteria for TES, although several definitions and sets of criteria have been proposed in the past decade.^11

–15 Studies have shown that the clinical criteria for these proposed definitions can also be met by persons in the general population^16,17 as well as persons with primary psychiatric conditions.^18,19 The non-specific nature of symptoms and problems associated with TES can overlap with symptoms reported by men with intermittent explosive disorder¹⁸ or depression.¹⁹ Moreover, in one study, approximately 45% of men from the general population met symptom-based criteria for TES (regardless of their neurotrauma history), and men who participated in several years of contact sports were not more likely to meet criteria for TES than men who did not participate in contact sports.¹⁷

In an effort to refine the clinical symptoms of TES, a panel of expert clinician-scientists participated in a modified Delphi process to create the first consensus diagnostic criteria for TES, for research purposes.²⁰ There has been limited research on these new criteria to date. In a sample of professional active/retired professional fighters, 41% met the consensus TES criteria based on their symptoms and cognitive testing.²¹ When the consensus criteria were applied retrospectively to samples of retired athletes (American football players and boxers), the prevalence of TES was 21.3%.²²

To our knowledge, no study to date has examined the prevalence TES symptoms and problems in the general population using the new criteria. The purpose of this study was to examine the consensus criteria in a cohort of community-dwelling older adults and determine the association between TES criteria and a history of repetitive head impacts (RHIs).

Methods

Standard protocol approvals, registrations, and patient consents

The study was approved by the Vanderbilt Institutional Review Board (VUMC IRB #220132). Written informed consent was obtained from all participants in the study.

Participants and procedures

A cross-sectional survey study was conducted. All participants were at least 45 years of age. Participants were members of the Vanderbilt Memory and Alzheimer's Center (VMAC) Participant Registry, a clinical-research database that has been built over several years from individuals who have participated in one of the center's studies and agreed to be contacted about future research opportunities.

To participate in the Registry, participants had to be at least 40 years of age and free of any major psychiatric disorders (e.g., bipolar disorder, schizophrenia), neurological conditions (including brain surgery and tumors), and dementia/ neurodegenerative disorders (e.g., Alzheimer disease) at the time of enrollment. There are approximately 3500 members of this Registry. At the time of the analyses for the current study, all individuals who endorsed any of the aforementioned major psychiatric disorders, neurological conditions, or dementia/neurodegenerative disorders at the time of the survey were removed.

All members of the Registry were sent information about the current study, titled “Brain Health in Older Adults,” via email or traditional mail. Participants were given the option to complete the survey on a secure online platform or on paper. More than 99% of respondents completed the survey online. The survey took approximately 30 min to complete. No financial compensation was associated with this study.

Survey

Participants completed a series of questions specifically designed to assess for the features of TES, according to the consensus operational diagnostic criteria.²⁰ Participants also completed questions about their demographics, health history, previous athletic participation, concussion history, and current symptoms in a variety of areas.

RHIs

Participants were asked about their history of RHIs related to sports, military/law-enforcement, and domestic violence. For each sport they endorsed playing, participants were asked to provide an estimation (in years) they engaged in each competition level (i.e., before high school, during high school, college, semi-professionally, professionally). They also reported their age of first exposure to each sport.

Further, participants were asked about other sources of RHIs, such as military/law-enforcement service, as well as whether they ever experienced domestic violence. If participants endorsed either of these, follow-up questions included amount of exposure (in days) to combative training, number of explosive breaches they experienced, number of blasts/explosions during which they felt overpressure, number of rounds of heavy weapons systems, number of controlled detonations, number of improvised explosive devices (IEDs), and number of times they experienced domestic violence where they were hit in the head.

Concussion history

Although a history of concussion is no longer a part of the operational diagnostic criteria for TES, we thought it was important to assess. In the survey, a definition of concussion was provided: “We define a concussion as a blow to the head or whiplash that caused any one or more of the following: (1) witnessed loss of consciousness (being “knocked out” and someone seeing it), (2) loss of memory for events immediately before and/or after the injury, or (3) feeling dazed and confused for at least 30 seconds.”

While not a validated definition for concussion, it conforms with most mainstream definitions of concussion and mild traumatic brain injury and does not include milder forms of injury that might not represent a concussion. Moreover, concussion history is not part of the consensus criteria for TES. Based on this definition, participants were asked the number of lifetime concussions they have sustained, as well as when the most recent concussion had occurred.

Core clinical features of TES

We assessed whether respondents thought they had progressive cognitive impairment and/or neurobehavioral dysregulation. Table 1 summarizes TES features as defined by Katz and coworkers²⁰ and the manner in which the core clinical features of TES were queried in this study.

Table 1.

Consensus Core Clinical Features of Traumatic Encephalopathy Syndrome and Survey Questions Assessing Core Clinical Features

Core Clinical Features per Katz et al.²⁰	Survey Questions Assessing Core Clinical Features
“Cognitive impairment or neurobehavioral dysregulation, or both, is required to meet TES criteria. A progressive course is also required to meet TES criteria.”	1. Memory: For a period of one or more years during my lifetime I have experienced a significant problem with memory.
Cognitive impairment (all 4 are required)	- For example, significant problems with my memory for specific events that I have experienced, such as recent conversations or important things I have done in the past two weeks.
As reported by self or informant, or by clinician's report.
Representing a significant decline from baseline functioning. The determination of baseline level of functioning may be challenging and require clinical judgment in cases where decline may have begun during the period of RHI exposure.
	- Do not say yes if you, or most people, would consider this to be a mild or normal problem with memory.
With deficits in episodic memory and/or executive functioning (additional domains may be impaired in addition to these).	□ No □ Yes, to some degree □ Yes, definitely
	(If yes) My problem with memory has gotten worse in the past year. □ No □ Yes, to some degree □ Yes, definitely
Substantiated by impaired performance on formal neuropsychological testing (if available), as defined by performance at a level of at least 1.5 SDs below appropriate norms, accounting for the individual's estimated premorbid functioning. If formal neuropsychological testing is not available, there should be substantial evidence of impairment below expected norms and/or a person's estimated baseline in episodic memory and/or executive functioning on a standardized mental status examination (e.g., Montreal Cognitive Assessment and Mini-Mental State Examination) by a clinician experienced in the evaluation of cognition. Neurobehavioral dysregulation (all 3 are required) As reported by self or informant, or by clinician's report. Representing a significant change from baseline functioning. The determination of baseline level of functioning may require clinical judgment in cases where change may have begun during the period of RHI exposure.	2. Executive Functioning: For a period of one or more years during my lifetime I have experienced a significant problem with my executive functioning. - Executive functioning includes several cognitive skills and functions, including planning things in my daily life, organizing my daily schedule, flexible thinking, inhibiting my impulses, shifting between tasks, multitasking, and problem solving. - Do not say yes if you, or most people, would consider this to be a mild or normal problem with executive functioning. □ No □ Yes, to some degree □ Yes, definitely (If yes) My problem with executive functioning has gotten worse in the past year. □ No □ Yes, to some degree □ Yes, definitely
With symptoms and/or observed behaviors representing poor regulation or control of emotions and/or behavior, including (but not limited to) explosiveness, impulsivity, rage, violent outbursts, having a short fuse (exceeding what might be described as periodic episodes of minor irritability), or emotional lability (often reported as mood swings), preferably substantiated by standardized measures that demonstrate clinical impairment in these domains. In most cases, standardized measures of neurobehavioral dysregulation will not be available, but there should be substantial evidence of change from a person's baseline. These symptoms and/or observed behaviors do not appear to represent a transient response to life events, e.g., divorce, death of loved one, and financial problems.	3. Emotional and Behavioral Control Problems: For a period of one or more years during my lifetime I have experienced a significant problem controlling my emotions and behavior? - Examples would be a significant problem with one or more of the following: explosiveness, impulsivity, rage, violent outbursts, having a “short fuse,” and mood swings. - Do not say yes if you, or most people, would consider this to be a mild or normal problem with anger or mood swings. □ No □ Yes, to some degree □ Yes, definitely (If yes) My problem with controlling my emotions and behavior has gotten worse in the past year. □ No □ Yes, to some degree □ Yes, definitely
Progressive course There is evidence of progressive worsening of these clinical features over a period of at least 1 y in the absence of continued exposure to RHIs or TBI. The evidence should be supported by serial standardized testing (if available) or clear history supporting a change in functioning over time (e.g., clinician reports, job performance evaluations, or self- or informant report).”
Katz DI, Bernick C, Dodick DW, et al. National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome. Neurology. 2021;96(18):848-863. doi:10.1212/WNL.0000000000011850

RHI, repetitive head impact; TBI, traumatic brain injury; TES, traumatic encephalopathy syndrome; y, year(s).

Participants reported whether they perceived that they had significant problems with (1) episodic memory (i.e., “significant problems with my memory for specific events that I have experienced, such as recent conversations or important things I have done in the past two weeks,” (2) executive functioning (problems “planning things in my daily life; organizing my daily schedule; flexible thinking; inhibiting my impulses; shifting between tasks; multi-tasking; problem solving,” and (3) neurobehavioral dysregulation (“significant problem controlling my emotions and behavior” such as issues with explosiveness, impulsivity, rage, violent outbursts, having a “short fuse;” “mood swings”) for at least one year.

For each core feature, participants were given three choices (0 = No, 1 = Yes, to some degree, 2 = Yes, definitely). For each core feature that the participant endorsed having problems with, the progressive nature of the feature was assessed by asking whether the specific problem has gotten worse over the past year.

Other current symptoms

Several of the supportive features of TES were assessed. Participants rated the frequency of dysarthria, ataxia, imbalance, and tremor over the past year in a self-report manner (response options: never, rarely, sometimes, often, always). Participants also reported whether they had ever been told by a doctor/health care provider they had depression (yes/no) or anxiety (yes/no). The Patient Health Questionnaire-9 (PHQ-9)²³ and the General Anxiety Disorder-7 (GAD-7)²⁴ self-report questionnaires were administered to assess symptoms of depression and anxiety over the previous two weeks.

We also asked participants to self-report their current functional status consistent with the consensus criteria.²⁰ Participants were given brief definitions designed to correspond to the five levels of functional status discussed in the consensus criteria²⁰—i.e., (i) independent; (ii) subtle/mild functional limitations; (iii) mild dementia [i.e., impairment in instrumental activities of daily living]; (iv) moderate dementia [i.e., not independent and needs assistance with basic activities of daily living]; and (v) severe dementia [i.e., cannot participate in functions outside the home—and chose the one they thought was most appropriate. Additional questions were asked regarding other health problems not directly related to TES, including sleep problems (i.e., I have had trouble falling or staying asleep), chronic pain (i.e., I have had pain in one or more parts of my body) and migraines (i.e., I have had migraine headaches) in the past year.

Sport exposure criterion and other RHIs

The Sport Exposure Criterion was treated as a binary variable. To meet the Sport Exposure Criterion (coded “1”), participants had to have had ≥2 years of contact sport participation during high school (or beyond) and ≥5 years of contact, collision, or combat sport participation during their lifetime consistent with the TES criteria.²⁰ Football, soccer, hockey, rugby, lacrosse, martial arts, boxing, and wrestling were considered contact, collision, or combat sports.

Participants in this study also reported whether they had exposures to repeated head blows, breaching, blasts, heavy weapons, controlled detonations, IEDs, or domestic violence involving head blows that met the RHI criterion. It is understood that the criteria for exposure to low-level blasts and interpersonal violence are not well-defined and in need of future refinement—as noted by the authors of the consensus criteria.²⁰

Therefore, participants who did not meet the Sport Exposure Criterion but reported head impacts from the aforementioned non-sport etiologies were excluded from analyses comparing those who met the Sport Exposure Criterion versus those who did not. Participants who did not meet the Sport Exposure Criterion and denied other forms of RHI were used as a comparison group (coded “0”) for those who met the Sport Exposure Criterion.

Statistical analyses

All analyses were completed using SPSS 28.0. Descriptive statistics were performed to present both the proportions of the sample who met the (1) Sport Exposure Criterion (as defined above), (2) those who did not meet the Sport Exposure Criterion and denied other RHIs. The proportions of the sample who reported each core clinical feature of TES are presented, as well as the proportions of those who reported other health problems not related to TES.

Chi-square analysis was used to compare the proportions of those who met the core clinical feature of TES stratified by those who met the Sport Exposure Criterion and those who did not. Similarly, a chi-square analysis was used to compare the proportions of those who exhibited other health problems not related to TES stratified by those who met the Sport Exposure Criterion and those who did not.

We conducted two binary logistic regressions predicting TES Status (i.e., having one or more progressive core clinical features of TES) with a variety of independent variables. Our primary independent variable of interest in both regressions was the Sport Exposure Criterion. Covariates in the first regression only included clinical variables independent of the consensus TES criteria (e.g., age, gender, chronic pain, sleep problems).

The second model used the variables from the first model as well as psychiatric features, which are included as supportive features in the consensus TES criteria but would need to be deemed as not fully accounting for the TES core criteria. These psychiatric features were operationalized as a history of psychiatric disorders (i.e., depression, anxiety, post-traumatic stress disorder, substance abuse) and current depression or anxiety (i.e., PHQ-9 ≥ 10 or GAD-7 ≥ 10).

In a subanalysis including only those with no history of head impacts (i.e., those with no previous concussion history, sports exposure, military exposure, or history of head trauma from domestic violence), we present proportions of those who endorse TES symptoms, stratified by the significant covariates included in our second multi-variable model.

Data availability

The statistical analyses and underlying data supporting the conclusions of this article will be made available by the authors to qualified researchers, without undue reservation.

Results

Sample characteristics

Of 535 unique participants who consented to participate in the study, several were excluded. Some (n = 21) completed less than 70% of the survey and were excluded from all analyses. In addition, quality control analyses revealed a participant (n = 1) who appeared to respond in an invalid manner (i.e., endorsed having multiple conditions, such as encephalocele, Rett disorder, multiple sclerosis, amyotrophic lateral sclerosis, and several others) and was subsequently excluded. Further, two individuals (n = 2) reported having a concussion over the past six months and four individuals had neurological conditions (n = 2 Parkinson disease, n = 1 Alzheimer disease, n = 1 epilepsy). Given that symptoms of concussion and these neurological conditions can be associated with a variety of cognitive and psychological symptoms, we chose to exclude these individuals in an effort not to overrepresent the proportion of persons who experience TES-like symptoms.

The final sample included 507 participants. The mean age was 70.0 years (standard deviation [SD] = 9.0, range = 47.0–94.0). The sample was predominantly female (65.3%; male = 34.7%), white (93.9%, Black/African American = 5.3%, Asian = 0.2%, Other = 0.6%), and not Hispanic or Latino/a (99.2%; Hispanic or Latino/a = 0.8%). Approximately two thirds were currently married (65.5%, separated/divorced = 18.5%, widowed = 9.3%, never married = 4.9%, living with partner = 1.8%).

Regarding concussion history, 58.2% had no previous history of concussions, 17.2% reported 1 previous concussion, 7.1% reported two concussions, and 6.1% reported three or more concussions. Regarding RHIs, 6.3% (n = 32) met the Sport Exposure Criterion and 85.0% (n = 431) did not meet the Sport Exposure Criterion and denied other forms of repetitive head impacts. A small minority (6.7%, n = 34) reported other forms of repetitive head impacts and was thus excluded from analyses directly comparing those who met the Sport Exposure Criterion and those who did not (Table 2).

Table 2.

Sample Demographics and Head Impact Exposures

Demographics	N = 507
Age	M = 70.0, Md = 71.0, SD = 9.0,
	IQR = 64.0-76.0,
	Range = 47.0-94.0
Gender
Men	n = 176, 34.7%
Women	n = 331, 65.3%
Race
Black/African American	n = 27, 5.3%
White	n = 476, 93.9%
Asian	n = 1, 0.2%
Other	n = 3, 0.6%
Ethnicity
Hispanic or Latino/a,	n = 4, 0.8%
Not Hispanic or Latino/a,	n = 503, 99.2%
Marital Status
Married	n = 332, 65.5%
Living with Partner	n = 9, 1.8%
Separated/Divorced	n = 94, 18.5%
Widowed	n = 47, 9.3%
Never Married	n = 25, 4.9%
Education
8^th Grade	n = 1, 0.2%
High School/GED	n = 19, 3.7%
Some College/Technical degree/Associate's degree	n = 89, 17.6%
College Degree	n = 186, 36.7%
Advanced Degree (MS, PhD, MD)	n = 211, 41.6%
missing	n = 1, 0.2%
Concussion History
0	n = 295, 58.2%
1	n = 87, 17.2%
2	n = 36, 7.1%
3+	n = 31, 6.1%
missing	n = 58, 11.4%
Most Recent Concussion	N = 154 with concussion history
6-12 months ago,	n = 2, 1.3%
1 or more years ago	n = 145, 94.2%
missing	n = 7, 4.5%
Repetitive Head Impacts
Police with Combative Training	n = 0, 0.0%
Police with Breaching	n = 0, 0.0%
Military/Veterans with Blast Exposure	n = 20, 3.9%
Military/Veterans with Heavy Weapon Exposure	n = 19, 3.7%
Military/Veterans with Controlled Detonation Exposure	n = 16, 3.2%
Military/Veterans with Improvised Explosive Devices (IEDs)	n = 5, 1.0%
Domestic Violence with Head Blows	n = 16, 3.2%
Total with Other Repetitive Head Impacts (positive for any of the above)	n = 34, 6.7%
Sports Exposure Criterion (i.e., a total of 5+ years of contact sport exposure, with at least 2 years in high school or above)	n = 32, 6.3%

GED, General Educational Development; IQR, interquartile range; M, mean; Md, median; n, sample size; SD, standard deviation.

Symptom reporting consistent with TES

A total of 26.2% of participants endorsed having one or more progressive core clinical features of TES (Table 3). The proportions of the sample that met core clinical features of TES were the following: memory = 22.7%, progressive memory problem = 22.1%, executive functioning = 12.7%, progressive executive functioning problem = 12.1%, neurobehavioral dysregulation = 11.1%, and progressive neurobehavioral dysregulation = 6.2%. Motor problems, which are discussed in the TES criteria as supportive features, were reported in 22.0% of the sample (balance = 15.7%, tremor = 6.7%, falls = 5.9%, and dysarthria = 2.9%).

Table 3.

Endorsement of Each Survey Question Used to Assess Traumatic Encephalopathy Syndrome Features, Consistent With the Consensus Criteria for Traumatic Encephalopathy Syndrome²⁰

Question	Total sample (N = 497)	Men (n = 173)	Women (n = 324)	Did not meet Sport Exposure Criterion or report other repetitive head impacts (n = 431)	Met Sports Exposure Criterion (n = 32)	X²	p
Core Clinical Features of TES
Memory“Significant problems with my memory for specific events that I have experienced, such as recent conversations or important things I have done in the past two weeks.”	22.7%	24.9%	21.6%	22.5%	28.1%	0.53	0.465
Progressive memory problem	22.1%	24.3%	21.0%	21.8%	28.1%	0.69	0.407
Executive Functioning“Significant problems with executive functioning, which includes several cognitive skills and functions, including: planning things in my daily life, organizing my daily schedule, flexible thinking, inhibiting my impulses, shifting between tasks multitasking, problem solving.”	12.7%	17.3%	10.2%	11.8%	18.8%	1.32	0.251
Progressive executive functioning problem	12.1%	16.8%	9.6%	11.4%	18.8%	1.55	0.213
Neurobehavioral Dysregulation“Significant problem controlling my emotions and behavior. Examples would be a significant problem with one or more of the following: explosiveness, impulsivity, rage, violent outbursts, having a “short fuse,” mood swings.”	11.1%	12.1%	10.5%	10.4%	9.4%	0.04	0.849
Progressive neurobehavioral dysregulation	6.2%	6.9%	5.9%	6.0%	3.1%	0.46	0.491
One or more progressive core features	26.2%	30.1%	24.1%	25.3%	31.3%	0.55	0.457

TES, traumatic encephalopathy syndrome.

The above questions were presented to study participants verbatim and were based on common definitions of the terms used in the consensus definition.

Regarding other health problems, 60.7% endorsed having chronic pain, 48.3% reported sleep problems, and 8.9% reported having migraines. A total of 37.1% reported having a past history of psychiatric disorders (i.e., depression, anxiety, post-traumatic stress disorder, substance abuse), and 7.8% screened positively for current depression or anxiety (i.e., PHQ-9 ≥ 10 or GAD-7 10). The majority of the sample reported being functionally independent (86.8%), while some reported subtle or mild functional limitations (10.9%) and the remainder reported more significant functional impairment (Table 4).

Table 4.

Endorsement of Supportive Traumatic Encephalopathy Syndrome Symptoms and Other Health Problems

Other Health Problems Not Related to TES	Total Sample	Men	Women	Did not meet Sport Exposure Criterion or report other repetitive head impacts (n = 431)	Met Sports Exposure Criterion (n = 32)
	N = 484	n = 168	n = 316	n = 418	n = 2	X²	p
Sleep Problems I have had trouble falling or staying asleep.	48.3%	38.1%	53.8%	50.5%	31.3%	4.40	0.036
Chronic Pain I have had pain in one or more parts of my body.	60.7%	54.8%	63.9%	60.8%	65.6%	0.30	0.587
Migraines I have had migraine headaches.	8.9%	3.0%	11.9%	9.6%	6.3%	0.39	0.534
Supportive TES Symptoms	n = 477	n = 162	n = 315	n = 411	n = 32
Dysarthria I have had difficulty with my speech, such as slurred or slow speech.	2.9%	3.1%	2.9%	2.4%	3.1%	0.06	0.809
Balance I have noticed difficulties or problems with my balance and my ability to walk.	15.7%	16.0%	15.6%	15.8%	18.8%	0.19	0.663
Falls I have lost my balance and fallen.	5.9%	5.6%	6.0%	5.4%	12.5%	2.75	0.100
Tremor I have a tremor (such as hand shaking).	6.7%	6.2%	7.0%	7.1%	6.3%	0.03	0.863
Any Motor Problem	22.0%	19.8%	23.2%	22.1%	21.9%	0.00	0.972
	n = 464	n = 156	n = 308	n = 398	n = 32
History of Depression	28.4%	17.9%	33.8%	29.4%	12.5%	4.18	0.041
History of Anxiety	25.0%	14.1%	30.5%	25.4%	12.5%	2.66	0.103
History of Psychiatric Disorders (i.e., Depression, Anxiety, PTSD, Substance Abuse)	37.1%	23.7%	43.8%	38.7%	18.8%	5.04	0.025
	n = 491	n = 170	n = 321	n = 425	n = 32
PHQ-9 ≥ 10	6.5%	6.5%	6.5%	6.6%	3.1%	0.60	0.438
GAD-7 ≥ 10	2.9%	3.5%	2.5%	2.8%	0.0%	0.93	.335
Current Depression or Anxiety(i.e., PHQ-9 ≥ 10 or GAD-7 ≥ 10)	7.8%	7.6%	7.8%	7.8%	3.1%	0.94	0.333
Functional Status	n = 470	n = 158	n = 312	n = 404	n = 32
Independent	86.8%	85.4%	87.5%	87.6%	90.6%	1.54	0.819
Slightly Reduced Performance/ Functioning	10.9%	12.0%	10.3%	10.4%	6.3%
Definite Impairment	1.7%	1.3%	1.9%	1.2%	3.1%
Not Independent	0.2%	0.6%	0.0%	0.2%	0.0%
Cannot Participate	0.4%	0.6%	0.3%	0.5%	0.0%

TES, traumatic encephalopathy syndrome; PHQ9, Patient Health Questionnaire-9; GAD7, General Anxiety Disorder-7.

Sleep problems, chronic pain, and motor symptoms were considered to be present if the participant rated them “sometimes,” “often,” or “always” over the past year. Regarding Functional Status, participants were given brief definitions designed to correspond to the five levels of functional status discussed in the consensus criteria²⁰ [i.e., (i) independent; (ii) subtle/mild functional limitations; (iii) mild dementia (i.e., impairment in instrumental activities of daily living); (iv) moderate dementia (i.e., not independent and needs assistance with basic activities of daily living); and (v) severe dementia (i.e., cannot participate in functions outside the home)] and chose the one they thought was most appropriate.

Between those who met the Sport Exposure Criterion (n = 32) and those who did not meet the Sport Exposure Criterion and denied other forms of repetitive neurotrauma (n = 431), those who met the Sport Exposure Criterion were less likely to have sleep problems than those who did not (31.3% vs. 50.5%, χ² = 4.40, p = 0.036). Similarly, the Sport Exposure Criterion group was less likely to endorse a previous history of depression (12.5% vs. 29.4%, χ² = 4.18, p = 0.041) and previous history of psychiatric disorders (18.8% vs. 38.7%, χ² = 5.04, p = 0.025) than those who did not meet the Sport Exposure Criterion and denied other forms of repetitive neurotrauma.

The proportions across all other features assessed (including core clinical features of TES, supportive TES symptoms, and other health problems not related to TES) were not significantly different between the two groups (p > .05) (Table 4).

Predictors of progressive core clinical features of TES

In a series of separate univariable logistic regressions predicting TES status, significant predictors (listed in order of magnitude from largest to smallest) were: current psychiatric symptoms (Odds ratio [OR] = 16.38), any motor problems (OR = 4.23), history of psychiatric disorders (OR = 3.17), sleep problems (OR = 2.55), chronic pain (OR = 1.83), and number of previous concussions (OR = 1.19; Table 5). Age, gender, and the Sport Exposure Criterion were not significant predictors in the unadjusted, univariable analyses (Table 5).

Table 5.

Univariable Logistic Regressions Predicting Having One or More Progressive Core Clinical Features of Traumatic Encephalopathy Syndrome

	Univariable
	B	SE	Wald	df	p	OR	95% CI for OR
Age	-0.01	0.01	0.34	1	.559	0.99	0.97-1.02
Gender (reference = women)	0.33	0.21	2.43	1	.119	1.39	0.92-2.10
Sports Exposure Criterion	0.30	0.40	0.55	1	.458	1.34	0.62-2.93
Chronic Pain (Sometimes or Greater)	0.60	0.23	7.20	1	.007	1.83	1.18-2.84
Sleep Problems (Sometimes or Greater)	0.94	0.22	18.63	1	<.001	2.55	1.67-3.90
Number of Prior Concussions	0.17	0.08	4.39	1	.036	1.19	1.01-1.40
Migraine Headaches (Sometimes or Greater)	0.37	0.34	1.18	1	.227	1.45	0.74-2.85
Any Motor Problem (Sometimes or Greater)	1.44	0.24	37.38	1	<.001	4.23	2.67-6.72
History of Psychiatric Disorders	1.15	0.22	26.81	1	<.001	3.17	2.05-4.90
Current Depression or Anxiety	2.80	0.43	41.50	1	<.001	16.38	7.00-38.34

SE, standard error; OR, odds ratio; CI, confidence interval.

All clinical variables are coded as binary: no/absent or yes/present. Current Depression or Anxiety refers to a score of 10 or more on the Patient Health Questionnaire-9 or Generalized Anxiety Disorder-7.

The first multi-variable logistic regression model was significant in predicting TES status, χ²(5) = 2 3.97, p < 0.001. The model only explained 8% of the variance (Nagelkerke R² = 0.08). The significant predictors were sleep problems (OR = 2.55) and male sex (OR = 1.65); age, the Sport Exposure Criterion, and pain were not significant predictors of TES status (Table 6).

Table 6.

Multivariable Logistic Regression Predicting Meeting Criteria for Traumatic Encephalopathy Syndrome

	Multi-variable Model 1							Multi-variable Model 2
	B	SE	Wald	df	p	OR	95% CI for OR	B	SE	Wald	df	p	OR	95% CI for OR
Age	0.01	0.01	0.21	1	.645	1.01	0.98-1.03	0.02	0.02	1.06	1	.303	1.02	0.99-1.05
Gender (ref = women)	0.50	0.25	3.93	1	.047	1.65	1.01-2.72	0.62	0.29	4.61	1	.032	1.87	1.06-3.30
Sports Exposure Criterion	0.21	0.44	0.22	1	.637	1.23	0.52-2.91	0.44	0.46	0.89	1	.344	1.55	0.63-3.82
Chronic Pain (Sometimes or Greater)	0.36	0.25	2.03	1	.154	1.43	0.87-2.34	0.27	0.28	0.90	1	.344	1.30	0.75-2.26
Sleep Problems (Sometimes or Greater)	0.90	0.24	13.55	1	<.001	2.45	1.52-4.00	0.54	0.27	3.96	1	.047	1.71	1.01-2.91
History of Psychiatric Disorders	-	-	-	-	-	-	-	0.73	0.27	7.36	1	.007	2.07	1.22-3.49
Current Depression or Anxiety	-	-	-	-	-	-	-	2.53	0.53	22.66	1	<.001	12.55	4.43-35.51

SE, standard error; OR, odds ratio; CI, confidence interval.

The second model, which added psychological factors, was also significant, χ²(7) = 68.45, p < 0.001, and explained 22% of the variance (Nagelkerke R² = 0.22). Significant predictors for the second model (listed in order of magnitude from largest to smallest) included: current depression or anxiety (OR = 12.55), history of psychiatric disorders (OR = 2.07), male sex (OR = 1.87), and sleep problems (OR = 1.71). The Sport Exposure Criterion, age, and pain were not significantly associated with TES status (Table 6).

Subanalysis of those with no history of RHIs

A post hoc analysis showed that 247 participants denied a lifetime history of head impacts (i.e., those with no previous concussion history, no contact sports exposure/military exposure, and no history of head trauma from domestic violence). Approximately 20% of this neurotrauma naïve sample endorsed one or more core features of TES (men = 22.0%, women = 19.8%; Table 7). There were no gender differences in the endorsement of TES core criteria.

Table 7.

Subanalysis of Those With No History of Head Impacts^*

	Gender (N = 247)				Any Motor Problem (N = 247)				History of Psychiatric Disorders (N = 247)				Current Depression or Anxiety (N = 247)
Core Clinical Features of TES	Men (n = 50)	Women (n = 197)	X²	p	No (n = 189)	Yes (n = 58)	X²	p	No (n = 151)	Yes (n = 96)	X²	p	No (n = 228)	Yes (n = 19)	X²	p
Memory	16.0%	19.8%	0.37	0.541	14.3%	34.5%	11.75	<0.001	11.9%	30.2%	12.74	<0.001	14.9%	68.4%	32.59	<0.001
Progressive memory problem	16.0%	18.8%	0.21	0.649	13.2%	34.5%	13.46	<0.001	11.9%	28.1%	10.34	0.001	14.0%	68.4%	34.82	<0.001
Executive Functioning	6.0%	7.1%	0.08	0.783	5.8%	10.3%	1.42	0.234	4.6%	10.4%	3.06	0.080	3.5%	47.4%	52.64	<0.001
Progressive executive functioning problem	6.0%	6.6%	0.02	0.878	5.3%	10.3%	1.87	0.171	4.6%	9.4%	2.18	0.140	3.1%	47.4%	56.81	<0.001
Neurobehavioral Dysregulation	10.0%	8.1%	0.18	0.671	7.4%	12.1%	1.24	0.226	4.0%	15.6%	10.24	0.001	5.7%	42.1%	29.88	<0.001
Progressive neurobehavioral dysregulation	8.0%	4.6%	0.94	0.332	4.2%	8.6%	1.71	0.191	1.3%	11.5%	12.09	<0.001	2.2%	42.1%	56.03	<0.001
One or more progressive core features	22.0%	19.8%	0.12	0.729	14.8%	37.9%	14.69	<0.001	12.6%	32.3%	14.12	<0.001	15.4%	78.9%	43.94	<0.001

Those with no prior concussion history, sports exposure, military exposure, or history of head trauma from domestic violence.

Participants who reported having motor problems were more likely to report memory difficulties (34.5% vs. 14.3%, χ² = 11.75, p = < 0.001), progressive memory problems (34.5% vs. 13.2%, χ² = 13.46, p = < 0.001), and one or more progressive core features (37.9% vs. 14.8%, χ² = 14.69, p = < 0.001) compared with those without motor problems.

Participants who endorsed a history of a psychiatric disorder were more likely to report memory difficulties (30.2% vs. 11.9%, χ² = 12.74, p = < 0.001), progressive memory problems (28.1% vs. 11.9%, χ² = 10.34, p = 0.001), neurobehavioral dysregulation (15.6% vs. 4.0%, χ² = 10.24, p = 0.001), progressive neurobehavioral dysregulation (11.5% vs. 1.3%, χ² = 12.09, p = < 0.001), and one or more progressive core features (32.3% vs. 12.6%, χ² = 14.12, p = < 0.001) than those without.

Finally, those with current depression or anxiety were more likely to endorse each of the core clinical features of TES compared with those who did not endorse current depression/anxiety (i.e., memory, executive functioning, and neurobehavioral dysregulation; all ps < 0.001). About four in five neurotrauma naïve participants with current anxiety or depression reported at least one core progressive feature of TES (78.9%).

Discussion

We investigated the new consensus criteria for TES²⁰ in a sample of community dwelling older adults. Approximately one in four participants endorsed one or more progressive core clinical features of TES. Those who met the Sport Exposure criterion for having a significant lifetime history of contact or collision sport exposure were not significantly more likely to meet the criteria for TES, nor did they have high rates of endorsing any of the core or supportive criteria of TES that were included in this study. Similarly, in a multi-variable logistic regression model, a history of significant contact or collision sport exposure was not predictive of TES status.

The significant predictors of meeting the symptom-based TES criteria included screening positively for current depression or anxiety, a history of psychiatric disorders, and current sleep problems. In addition, men were more likely to meet TES criteria than women. Last, a significant minority of neurotrauma naïve participants endorsed symptoms consistent with TES (22.0% of men and 19.8% of women). In a sub-analysis that only examined participants with no history of repetitive neurotrauma who reported clinically significant anxiety or depression, nearly 80% met criteria for TES.

Our findings suggest that older adults who participated in contact or collision sports early in life—and who currently have mental health problems —may be at higher risk for being misdiagnosed as having TES given that most older adults without a neurotrauma history but who have mental health problems would likely meet criteria for TES.

Importantly, this was a survey study—and as such, all data were self-reported. We only simulated the new diagnostic criteria for TES; we did not apply them as designed during an in-person clinical evaluation. The consensus criteria require objective cognitive testing and are likely best applied when an experienced clinician gathers information from both the participant and an informant.

Therefore, the current study should not be considered a diagnostic accuracy study, nor should it be considered a study designed to “validate” the consensus criteria for TES. Objectively measuring cognition is important, as evidenced by a study that applied the 2014 criteria for TES to a sample of former professional American-style football players and found that a substantial percentage of those meeting symptom criteria TES did not have objectively measured cognitive impairment.²⁵ We would anticipate something similar—that many persons who were classified as having cognitive impairment based on self-report would not be classified as having cognitive impairment based on neuropsychological testing. Future studies that apply these new criteria to data collected during in-person clinical evaluations are needed.

In addition, 37.1% of our sample endorsed a history of psychiatric disorders, which encompassed depression, anxiety, PTSD, and substance abuse. When only examining depression and anxiety, 28.4% endorsed a history of depression and 25.0% endorsed a history of anxiety. While this is a large proportion of our sample, this appears to be consistent with previous literature. A large, systematic review and meta-analysis²⁶ of 42 studies across 57,486 elderly populations worldwide showed a pooled expected prevalence of depression as high as 31.74% (95% CI = 2 7.90–35.59). In the United States, the most recent data from the Centers for Disease Control²⁷ showed that 31.8% of adults aged 50–59 years, 24.9% of adults aged 60–69 years, 18.6% of adults aged 70–79 years, and 20.1% of adults 80 years or older endorsed symptoms of an anxiety or depressive disorder. Women had higher prevalence of those with these symptoms compared with men,²⁷ potentially explaining the high endorsement of these symptoms in our sample, which was predominantly women.

Previously published studies using the 2014 criteria for TES revealed serious limitations for their clinical and research usefulness. First, persons in the general population who had a mood disorder or intermittent explosive disorder were deemed at risk for having a misdiagnosis of TES.^18,19 Second, in a survey study of men from the general population, men with a history of participating in several years of contact or collisions sports were not significantly more likely to meet criteria for TES than men who did not participate in contact or collision sports.¹⁷ Finally, they were not useful for drawing conclusions about whether or not a person had CTE-NC in a major clinicopathological validation study.²⁸ Of the 336 brain donors who had exposure to RHIs, 309 met the 2014 criteria for TES (92.0% of the sample), including 236/244 who had CTE-NC (96.7%) and 73/92 (79.3%) who did not have CTE-NC (sensitivity = 0.97, specificity = 0.21).²⁸ The authors reported that the anger dyscontrol and depression criteria for TES were not significantly associated with the presence of CTE-NC—but the cognitive impairment criterion was significantly associated with having CTE-NC.²⁸ The present study, combined with other studies published to date, suggests that depression and anxiety need to be carefully disentangled from TES and assumptions relating to CTE-NC.

The current study has clinical implications. It is evident from our results that a large proportion of older adults with current psychiatric symptoms, a history of psychiatric conditions, and current sleep problems report progressive symptoms suggestive of TES, regardless of their previous history of exposure to RHIs in sports. Therefore, the risk of misdiagnosing TES in older adults with mental health problems may be increased. The condition TES, albeit used primarily for research purposes at present, is purported to be the in vivo manifestation of CTE neuropathological change (although studies establishing a strong clinicopathological correlation are lacking to date).²⁸ Misdiagnosing a more treatable condition, such as depression, anxiety, and sleep problems as TES may have grave ramifications for the patient.^16,17,29,30

It is important to mention that the current TES criteria state that TES features must not be “fully accounted for” by other disorders to ensure that TES is not diagnosed based on symptomatology related to other conditions. The terminology “not fully accounted for” is problematic in that it is extreme compared with terminology used in psychiatry, for example, such as “not better accounted for” or “not better explained.” Research is needed to help illustrate how to accurately apply this criterion in TES research.

At present, there is not adequate scientific evidence supporting the validity or accuracy of the diagnostic criteria for TES, and it has not been established that CTE-NC is an underlying cause for symptoms and problems believed to comprise TES—especially psychiatric symptoms. In a large study of brain donors, all who had exposure to RHIs, there was no difference between those with and without CTE-NC in depressive symptoms, hopelessness, suicidality, anxiety, impulsivity, paranoia, explosivity, physical violence, or verbal violence (see Mez and associates²⁸ online supplement eTable 5).

Therefore, researchers and clinicians are encouraged to be extraordinarily cautious when working with patients and research subjects with a history of head impacts who may meet the current consensus criteria of TES, in discussing their presentation, etiology, symptomatology, and diagnosis.^29,30

The current study has several important limitations. First, data were collected via a self-report survey, and therefore, are subject to recall bias. There are inherent limitations associated with this study being a questionnaire-based study without an in-person evaluation (i.e., neuropsychological assessment, medical examination), informant assessment from the participant's spouse/family, or examination of official healthcare records. It will be helpful for future efforts to incorporate clinical examinations by healthcare professionals, family report, and objective cognitive testing. Second, a relatively small number of persons in our cohort met the Sport Exposure Criterion (n = 32); larger samples may be necessary to better understand the potential associations with repetitive sports head impacts.

Third, we included wrestling as a contact sport with risk of RHIs, similar to past studies,³¹ whereas the consensus TES criteria does not specifically include wrestling (although it does include “professional wrestling”). We do not think this would affect our findings because a minority of the sample (n = 8, 25%) reported having engaged in wrestling, all of whom participated in additional contact sports (with n = 4 who would have met the Sport Exposure Criteria without any wrestling participation).

Fourth, when assessing history of military exposure and domestic violence, there are no published cutoffs regarding the exposure risk thresholds necessary to meet the TES definition. We included these individuals in the overall sample to increase the generalizability and external validity of this study, but did not include them in analyses related to substantial RHIs because it is possible (if not likely) that these participants may not have the necessary exposure to head impacts to be at risk for TES or CTE-NC.

It is important for other studies to analyze larger samples of persons in these groups related to their cumulative head impact exposures and their risk of TES and CTE-NC. Future efforts should investigate the specificity of the new consensus criteria in other populations, including younger cohorts and those with confirmed diagnoses of psychological conditions, to assess the generalizability of our findings.

Further, it may be interesting to investigate other relevant variables (i.e., number of concussions, age of first exposure, and length of RHI exposures) as a predictor for TES core features and overall long-term neurological, psychiatric, and behavioral outcomes.

Finally, while the majority of studies in the literature on RHI and TES use a sample that is primarily men, our study population had a predominance of women (65.3%). While this may broaden generalizability of our findings, it is important to note possible intrinsic differences in gender—in severity and mechanism of RHI secondary to differences in type/level of contact sport participation—that may have affected our results. In addition, differences in physiological, cultural, and sociodemographic factors between gender in the context of RHI and TES were beyond the scope of our study.

The 2021 consensus criteria for TES were designed for research use, and the consensus authors did not recommend their use in clinical care. It seems likely, however, that some clinicians will use the criteria and diagnose TES in patients. Clinicians are encouraged to consider that cognitive impairment in former athletes can have many causes. Moreover, clinicians should know that there is not an established correlation between CTE neuropathology and neurobehavioral dysregulation or psychiatric problems.²⁸ Clinicians working with former athletes who have psychiatric problems, neurological conditions, or cognitive impairment are encouraged to approach these cases similarly to any other patient with these problems, seeking to define the nature and severity of the problem and determine whether there are treatments that could reduce symptoms and improve functioning.

Conclusion

The current study evaluated the TES criteria in older adults and assessed associations between TES criteria and a history of RHIs. Approximately one in four older adults endorsed one or more progressive core clinical features of TES. A significant history of contact sport exposure was not associated with TES status, but psychological symptoms and sleep problems were significant predictors of TES. This study suggests that the new consensus diagnostic criteria for TES may have problematic specificity and carry an increased risk of misdiagnosing older adults with mental health problems and a history of contact sports as having a presumptive progressive neurological disease. Better designed studies are needed, however, to draw conclusions about the validity of the new criteria for TES.

Transparency, Rigor, and Reproducibility Summary

The study was not formally pre-registered. Data was labeled using a subject ID to ensure participant de-identification. Analyses were performed using SPSS 28 (IBM, Armonk, NY). Data from this study are not publicly available but may be made available (per institutional IRB standards) by emailing the corresponding author. Additionally, analytic code for analysis may be available by emailing the corresponding author.

Footnotes

Acknowledgments

We would like to thank Angela Jefferson, PhD, Katherine Gifford, Psy.D., and others in the Vanderbilt Memory & Alzheimer's Center for their assistance in data collection.

Authors' Contributions

Author 1: Conceptualization, methodology, investigation, supervision (lead), validation, writing – review and editing; Author 2: Conceptualization, methodology, investigation, data curation, formal analysis, writing- original draft, writing – review and editing; Author 3: writing- review and editing; Author 4: writing- review and editing; Author 5: Funding acquisition, conceptualization, methodology, writing – review & editing; Author 6: Investigation, supervision, validation, writing – review and editing.

Funding Information

The study had no direct sponsored funding. Grant Iverson, PhD is supported in part by research funding from the Wounded Warrior Project™ to conduct research relating to traumatic encephalopathy syndrome.

Author Disclosure Statement

Douglas Terry, PhD, serves as a scientific advisor for HitIQ. He previously consulted for REACT Neuro, Inc. He has a consulting practice in forensic neuropsychology, including expert testimony, involving individuals who have sustained mild TBIs (including former athletes). He receives research funding from Amgen, Inc., and Football Research, Inc.

Grant Iverson serves as a scientific advisor for NanoDX^®, Sway Operations, LLC, and Highmark, Inc. He has a clinical and consulting practice in forensic neuropsychology, including expert testimony, involving individuals who have sustained mild TBIs (including former athletes). He has received past research support or funding from several test publishing companies, including ImPACT Applications, Inc., CNS Vital Signs, and Psychological Assessment Resources (PAR, Inc.). He receives royalties from the sales of one neuropsychological test (WCST-64). He has received travel support and honorariums for presentations at conferences and meetings. He has received research funding as a principal investigator from the National Football League, and subcontract grant funding as a collaborator from the Harvard Integrated Program to Protect and Improve the Health of National Football League Players Association Members. He has received research funding from the Wounded Warrior Project™. He acknowledges unrestricted philanthropic support from ImPACT Applications, Inc., the Mooney-Reed Charitable Foundation, the National Rugby League, Boston Bolts, and the Schoen Adams Research Institute at Spaulding Rehabilitation.

Scott Zuckerman, MD, MPH, is a member of the NFL Head, Neck, and Spine Committee.

For the remaining authors, no competing financial interests exist.

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