The utility of clinical criteria in patients with chronic traumatic encephalopathy

Abstract

BACKGROUND:

Repetitive traumatic brain injury (TBI) is associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by Alzheimer-like changes in the brain. CTE has been defined through neuropathological findings among deceased athletes and others exposed to repetitive TBI, but to date there are no definitive clinical criteria for CTE.

OBJECTIVE:

To evaluate the utility of currently proposed clinical criteria for CTE and suggest improvements.

METHODS:

We describe two well-characterized patients referred for evaluation of CTE and apply the four major proposed criteria for CTE. These criteria were further assessed in a cohort of patients referred to a neurobehavior clinic with or without a history of TBI.

RESULTS:

Without a CTE biomarker, the current criteria were of limited utility when applied to the two patient and the Neurobehavior cohort. Six items were extracted as potentially improving the clinical diagnosis of CTE: length of exposure to head impacts, a progressive course, specific psychiatric symptoms, frontal-executive dysfunction, parkinsonism and tremors, and targeted findings on neuroimaging.

CONCLUSIONS:

The prevention and neurorehabilitation of CTE depends on clinical diagnosis, but, without a biomarker, the clinical diagnosis of CTE remains difficult. This report suggests that clinical criteria for CTE may be greatly improved with emphasis on several critical historical and clinical correlates of CTE.

Keywords

Chronic traumatic encephalopathy traumatic brain injury dementia

1. Introduction

Traumatic brain injury (TBI) is a risk factor for dementia (Nemetz et al., 1999; Shively, Scher, Perl, & Diaz-Arrastia, 2012). Although there are conflicting studies on the risk of a single mild TBI (mTBI) for dementia (Gavett, Stern, Cantu, Nowinski, & McKee, 2010; Godbolt et al., 2014; Lee et al., 2013), epidemiological evidence suggests that repetitive mTBIs can increase the risk for dementia (Graves et al., 1990; Schofield et al., 1997). For example, a Taiwanese study of one million people with a three-year follow-up found a three-fold increased risk for dementia in those with a history of mild TBIs (Lee, et al., 2013), and a California statewide health database study found an increased risk of dementia from mild TBIs among elderly individuals (Gardner et al., 2014). Repetitive mTBIs are particularly common from participation in contact sports and from military deployment (Hoge, Goldberg, & Castro, 2009; MacGregor, Dougherty, & Galarneau, 2011; Terrio et al., 2009), putting athletes and veterans at increased for the development of dementia.

Several studies suggest that the association of repetitive mTBI with dementia is due to chronic traumatic encephalopathy (CTE), a neurodegenerative disorder characterized by progressive deposition of abnormal tau and other neurodegenerative proteins in the brain (Affairs, 2013; DeKosky, Blennow, Ikonomovic, & Gandy, 2013; Goldstein et al., 2012; Johnson, Stewart, & Smith, 2012; Lakis, Corona, Toshkezi, & Chin, 2013; McCrory, Meeuwisse, Kutcher, Jordan, & Gardner, 2013; McKee et al., 2009; McKee et al., 2013; Schmidt, Zhukareva, Newell, Lee, & Trojanowski, 2001; Smith, Johnson, & Stewart, 2013; Sponheim et al., 2011; Yoshiyama et al., 2005). In CTE, neurofibrillary tangles containing hyperphosphorylated tau are irregularly located in perivascular neurons and glia in the depth of sulci in frontal lobes and surrounding (Goldstein, et al., 2012; McKee et al., 2016; McKee, et al., 2013; Smith, et al., 2013; Sponheim, et al., 2011). These tau deposits have a 3-Repeat/4-Repeat tau isoform ratio similar to the isoform ratio in AD (McKee, Daneshvar, Alvarez, & Stein, 2014). Furthermore, among neuropathologically diagnosed cases of CTE (McKee, et al., 2016), over half have amyloid-β deposition, which is also characteristic of AD (McKee, et al., 2013; Stein et al., 2015). These neuropathological aspects of CTE have occurred in both athletes involved in collision sports and military veterans exposed to repetitive mTBI (Goldstein, et al., 2012; Lakis, et al., 2013; McCrory, et al., 2013; McKee, et al., 2009; McKee, et al., 2013; Omalu et al., 2011). Some estimates suggest that as many as 30% of individuals with a history of repetitive mTBIs have underlying CTE neuropathology(Asken, Sullan, DeKosky, Jaffee, & Bauer, 2017).

Clinically, CTE may manifest with executive deficits, memory problems, and behavioral changes such as depression, mood swings, explosiveness, irritability, impulsivity, and suicidal behavior (Barnes et al., 2014; Gardner & Yaffe, 2014; Goldstein, et al., 2012; Lee, et al., 2013; Nordstrom, Michaelsson, Gustafson, & Nordstrom, 2014; Stern et al., 2013). Symptoms of CTE may occur after a delay of 8–10 years and may progress in stages from mild cognitive or behavioral changes to severe dementia (McKee, et al., 2013; Mendez, 1995). These findings suggest that clinical evidence of CTE could be detected through select frontal cognitive and mood-behavior measures long before the emergence of frank dementia. McKee et al. (2013) proposed classifying clinical CTE into four successive stages (See Table 1). In Stage I, there may be attentional deficits, dizziness, and headaches, while in Stage II there may increased prominence of mood or emotional changes, impulsive behavior or poor judgment, and memory loss (McKee, et al., 2013). Stage II may also include explosive behavior, pathological intoxication, and morbid or paranoid jealousy(Mendez, 1995). By Stage III, there is more pronounced memory and cognitive impairment, including executive dysfunction. Finally, Stage IV manifests as a progressive AD-like dementia with motor symptoms such as trremors, parkinsonism or lack of coordination, hypomimia and speech abnormalities. These clinical symptoms may correspond with progressive neuropathological changes, including broad atrophy in the cerebral cortex, enlarged ventricles, the presence of a cavum septum pellucidum, and characteristic tau deposition described above (McKee, et al., 2013).

Table 1
Early Clinical Symptoms of Chronic Traumatic Encephalopathy (McKee et al., 2013)

Cognitive Emotional Behavioral

Memory impairment Suicidality Substance Abuse, Other Addictions

Executive dysfunction (e.g., problems with planning, organization, multi-tasking, judgment) Depression Disinhibition

Irritability Impulse Control Problems (eg, “short fuse”)

Apathy Aggression and Increased Violence

Cognitive	Emotional	Behavioral
Memory impairment	Suicidality	Substance Abuse, Other Addictions
Executive dysfunction (e.g., problems with planning, organization, multi-tasking, judgment)	Depression	Disinhibition
	Irritability	Impulse Control Problems (eg, “short fuse”)
	Apathy	Aggression and Increased Violence

Despite this clinicopathological elucidation of CTE, the clinical diagnosis of CTE in living individuals remains challenging. Currently, CTE can only be confirmed upon autopsy(Jordan, 2013), and there are no reliable antemortem CTE biomarkers. Therefore, in order to study this condition and its causes and effects, we need to establish a uniform method of diagnosing CTE in patients through the use of clinical criteria. Investigators have proposed several provisional criteria for clinical CTE (Jordan, 2013; Montenigro et al., 2014; Reams et al., 2016; Victoroff, 2013), but their utility remains uncertain in the absence of a definitive diagnostic biomarker. We seek to add clarity to the diagnosis of clinical CTE by reviewing two patients diagnosed with probable CTE during their lifetime, and reviewing current proposed CTE criteria as it applies to a larger neurobehavior clinic cohort with and without a prior history of TBI. Finally, we such an approach to further optimizing the proposed diagnostic criteria for clinical CTE.

2. Methods

2.1. Part A: Case reports

Patient No. 1: A 59-year-old right-handed man with memory and cognitive deficits was referred because of “clinical CTE.” The patient was an ex-professional soccer player with 12 years of formal education who presented with a two-year history of progressive memory and word-finding difficulties as well as trouble with multi-tasking and completing complex tasks. He also had difficulty keeping track of current events, remembering appointments, shopping for household necessities, and performing his job as a house painter. His wife described him as becoming quieter with decreased initiative but without emotional problems or lability. His brother further described him as having slowed motor movements with a tendency to “walk like an old man.” There was no history of alcohol, tobacco, or drug use or any family history of neurologic disease or dementia.

The patient played professional soccer for over twenty years, and although he denied any major head injury or loss of consciousness, he did report heading the ball many times over the course of his career. He also had a bicycle accident 10 years previously in which he was wearing a helmet, but landed on his head without loss of consciousness. He was taken to a hospital where a head computerized tomography (CT) scan showed no acute changes but spine magnetic resonance imaging (MRI) revealed an acute compression fracture of the T4 and T5 vertebral bodies. The patient apparently recovered without evident sequelae.

During the examination, the patient was cooperative with appropriate affect but decreased spontaneous speech and facial expressivity. His Mini-Mental State Examination (MMSE) score was 17/30 due to difficulty with orientation (date, year, place), inability to spell “world” backward, and impaired delayed recall (Folstein, Folstein, & McHugh, 1975). He only generated 4 animals/minute and 2 “F” words/minute, and his score on an extended mini-Boston Naming Test (mBNT) was 10/20. On a verbal learning test, his delayed recall was 0/10. Visuospatial constructions were within normal limits. On the Frontal Assessment Battery (FAB) (Dubois, Slachevsky, Litvan, & Pillon, 2000), the patient scored 14/18, and he his proverb interpretations were concrete. Neurologic examination revealed rigidity with increased tone with augmentation and postural tremors in the bilateral upper extremities. Coordination was intact without dysmetria, and the remainder of his neurological exam was unremarkable.

Diagnostic evaluations included structural MRIs, diffusion tensor imaging (DTI), and amyloid positron emission tomography (PET). MRI indicated a cavum septum pellucidum (see Fig. 1A), an abnormal amount of atrophy with large ventricles with frontal horns greater than occipital horns (see Fig. 1B) and a thinned corpus callosum (see Fig. 1C). Atrophy was also seen in the hippocampi (left worse than right) and in the anterior commissure. DTI indicated diminished fractional anisotropy levels associated with damaged white matter tracts particularly in the frontal region (see Fig. 1D). No abnormal amount of amyloid was present on PET imaging (see Fig. 1E).

Fig. 1.

Imaging for Patient 1 referred for CTE evaluation. A and B: Magnetic resonance imaging (MRI) flair imaging showing cavum septum pellucidum and enlarged ventricles, particularly frontal horns (B). C: Midsaggital T1 MRI showing decreased size of corpus callosum. D: MRI diffusion tensor imaging (DTI) indicating loss of radiations across and from frontal callosum (red). E: Amyloid (florbetapir) positron emission tomography (PET) showing normal white matter (black) and neocortical (white) boundaries indicating a normal scan.

Follow-up clinic visits over the subsequent six months revealed progression of his neurological disorder, possibly exacerbated by another TBI from a bike accident. His wife described an increased delay in his responses and further decreased motivation and engagement. Most notably, the patient had developed several compulsions, such as making tea with “lots of tea bags” and constantly eating chocolate. He also become dependent in his ADLs and incontinent of urine. Serial cognitive evaluations demonstrated deficits in reverse digit span, verbal fluency, confrontation naming, delayed recall learning, proverb interpretation, and clock drawing. On neurological examinations, he continued to exhibit bilateral postural tremors, with increasing difficulty with manual dexterity and bradykinesia, where were both predominantly on the right side. His posture had become stiff and mildly stooped.

Patient No. 2. A 54-year-old right handed man presented for the consideration of clinical CTE. He was a former professional boxer, active in the sport for 17 years (four losses by knock-outs), with an additional 7 years of sparring thereafter. He presented with a three-year history of memory deficits, increased irritability/impulsivity, tremor and changes in gait, and the development of new drinking and cigar smoking habits. His wife reported that he was having difficulty with transportation, remembering appointments or medications, keeping track of current events, and understanding television or reading material. The patient additionally reported a rare, poorly formed visual hallucination of a squirrel or rodent. He had developed bilateral upper extremity tremors most notable in the right hand and leg, which was usually present at rest, but worse with anxiety or stress. His mother committed suicide at age 56 from possible bipolar disease and his maternal grandmother died in her late 60 s from an unknown psychiatric illness.

His wife elaborated on a “personality change” in her husband. He had become irritable and “mean”, losing his sense of humor, and exhibiting inappropriate behaviors, such as drinking other people’s drinks without asking or eating off of a stranger’s plates in restaurants. The patient displayed paranoid jealousy towards his wife, accusing her of cheating on him and having had prior undisclosed sexual relationships. His irritability and jealousy had worsened after he began drinking alcohol five years previously.

Fig. 2.

Imaging for Patient 1 referred for CTE evaluation. A: MRI axial flair with small cavum septum pellucidum. B: Patient 2 fluorodeoxyglucose PET with normal brain metabolism.

On examination, the patient displayed appropriate affect and good quality and intonation of speech. The patient’s initial MMSE was 24/30 due to deficits in orientation (could not identify the name of hospital or identify the floor he was on) and verbal recall. Attention was within normal limits, as was verbal fluency (14 animals/minute and 14 “F” words/minute), naming (extended mBNT 17/20), and visuospatial constructions. However, his delayed recall score on a verbal list learning task was only 4/10, and his FAB score was 15/18, including problems on the GoNoGo task and abstractions. On neurological examination, his cranial nerves were intact other than mildly poor smooth pursuit. Bilateral resting tremors and mild cogwheel rigidity were noted, both more prominent on the right side. Sensation and cerebellar testing were intact, but his gait was notable for mildly decreased arm swing on the right.

After the initial assessment, he underwent MRI and fluorodeoxyglucose (FDG) PET imaging. The MRI showed a small cavum septum and a mild degree of white matter hyperintensity capping the latter ventricles (See Fig. 2A). His hippocampi appeared disproportionately small compared to the rest of his brain. The FDG PET showed essentially normal regional metabolism (see Fig. 2B).

The patient was followed over the course of the next year. Buproprion improved his mood and diminished his irritability, lability, and episodes of jealousy. He also stopped drinking and smoking cigars. Nevertheless, he continued to report memory deficits and difficulty figuring out logical sequences, such as what to do if, for example, if he must get money or solve everyday household problems. Subsequent examinations revealed continued memory impairment, progressive difficulties with abstract thinking, and new deficits in visuospatial constructions. Neurologic examination continued to demonstrate upper extremity tremors, now accompanied by hypomimia and hypophonia. Motor examination demonstrated clear bradykinesia and increased tone in the upper extremities, with slow and decreased associative movements on ambulation.

2.2. Part B: Application of clinical diagnostic criteria

We retrospectively applied the proposed four diagnostic criteria for CTE or traumatic encephalopathy syndrome (TES; clinical analogue of CTE) to these two patients and to a larger cohort of neurobehavior patients. In order to determine the applicability of these criteria in a broader population, we performed a chart review of 140 patients seen in the West Los Angeles Veteran’s Administration Neurobehavior clinic for cognitive complaints of unclear etiology between 1/1/2016 and 6/30/2016. The patients were divided into those with and without a history of prior TBI (see Table 2), and we retrospectively applied the four diagnostic criteria for CTE or traumatic encephalopathy syndrome (TES; clinical analogue of CTE) to these patients. The patients with a prior history of clinically significant TBI presented at younger ages and reported a longer duration of cognitive and/or behavioral symptoms than patients without a prior history of TBI. Two independent raters then determined whether they fulfilled each of the four diagnostic clinical criteria for CTE or traumatic encephalopathy syndrome (TES; clinical analogue of CTE) (Jordan, 2013; Montenigro, et al., 2014; Reams, et al., 2016; Victoroff, 2013). A third rater then adjudicated cases for whom the first two raters differed (see Table 3).

Table 2
Demographic data on 140 patients seen in VA Neurobehavior Clinics

TBI (n = 62) No TBI (n = 78) t/χ2n p

% Male 96.8 96.2 0.04 0.84

% Caucasian 50 56.4 0.57 0.45

M SD M SD

MoCA 20.7 20.7 19.4 5.1 0.01 0.79

Age 56.6 11.7 65.0 10.5 4.48 <0.01

Education (y) 13.5 1.9 13.4 2.2 –0.14 0.89

S. Duration (y) 8.6 11.2 2.8 3.6 –4.04 <0.01

	TBI (n = 62)	No TBI (n = 78)	t/χ2n	p
% Male	96.8	96.2	0.04	0.84
% Caucasian	50	56.4	0.57	0.45
	M	SD	M	SD
MoCA	20.7	20.7	19.4	5.1	0.01	0.79
Age	56.6	11.7	65.0	10.5	4.48	<0.01
Education (y)	13.5	1.9	13.4	2.2	–0.14	0.89
S. Duration (y)	8.6	11.2	2.8	3.6	–4.04	<0.01

MocA=Montreal Cognitive Assessment; y = years; sx = symptoms; M = mean; SD = standard deviation.

Table 3

Summary of CTE/TES diagnostic criteria

	Reams	Montenigro	Victoroff	Jordan	Patient	Patient
	(2016)³⁷	(2014)³⁵	(2013)³⁶	(2013)³⁴	1	2
Multiple or severe TBI	–	++	–	–	X	X
Progressive course	++	+	–	–	X	X
Behavioral symptoms	+	++	+	++	–	X
Mood symptoms	+	++	+	–	–	X
Cognitive Symptoms	++	++	+	++	X	X
Motor Symptoms	+	+	+	++	X	X
Post-TBI symptoms > 1 year	++	++	++	++	X	X
Delayed symptom onset	++	+	–	++	X	X
Persistent headaches	–	+	+	–	–	–

++Required; +Supportive; X symptom present, – symptom not present.

3. Results

3.1 Results for Patients Nos. 1 and 2

Both patients would meet all four proposed diagnostic criteria for CTE (See Table 3), but raise several concerns. First, in considering the Montenigro et al. (Montenigro, et al., 2014), Reams et al. (Reams, et al., 2016), and Victoroff criteria (Victoroff, 2013), although both patients would qualify for a diagnosis of clinical CTE, a major drawback to these three set of criteria is that the base rate for the suggested supportive features are relatively high, which could lead to false positives. These sets of criteria are not specific enough to rule out other psychiatric and neurological conditions, and both patients would qualify for a diagnosis of CTE due to the presence of mood, cognitive, and motor symptoms presenting more than a year after initial head injury. Whereas the Montenigro et al, Reams et al, and Victoroff criteria lack specificity, the Jordan (Jordan, 2013) criteria lack sensitivity, particularly because they do not mandate mood symptoms, which are often the earliest sign of CTE.

3.2 Results for neurobehavior cohort

Most of the TBI-exposed patients (79%) could be diagnosed with possible/probable CTE/TES using at least one of the published provisional criteria by at least one rater (see Fig. 3). The prevalence of CTE/TES was lowest with Jordan criteria, intermediate with Montenigro et al. or Reams et al. criteria, and highest with Victoroff criteria. Inter-rater reliabilities ranged from fair to substantial and were best for Montenigro et al. and Jordan criteria (see Table 4A). Per Landis & Koch (Landis & Koch, 1977), concordances between criteria were only poor to fair though (4B).

Fig. 3.

Prevalence of possible or probable chronic traumatic encephalopathy (CTE) using four sets of proposed clinical diagnostic criteria.

Table 4

Reliability and Concordance of Four Clinical Criteria for CTE

A: Inter-rater reliability
	k	SE	t	p
Montenigro et al.	0.642	0.109	5.06	<0.001
Reams et al.	0.331	0.135	2.67	0.008
Victoroff	0.292	0.115	2.54	0.011
Jordan	0.708	0.111	5.58	<0.001
B: Concordance (k) between criteria
	Montenigro et al.	Reams et al.	Victoroff	Jordan
Montenigro et al.	–	0.280	0.000	–2.013
Reams et al.	–	–	0.316	–0.132
Victoroff	–	–	–	–0.365

4. Discussion

We present two patients with a history of repetitive mild TBIs from contact sports and an evaluation consistent with clinical CTE, and we review the applicability of four sets of proposed clinical criteria for CTE (Jordan, 2013; Montenigro, et al., 2014; Reams, et al., 2016; Victoroff, 2013). Both patients had cognitive, behavioral, neurological, and neuroimaging findings consistent with CTE. These patients, and a comparison group of patients with cognitive complaints and a history of TBI, help clarify the current state of clinical criteria for this condition.

Not only are the currently proposed clinical criteria greatly limited because of the absence of a reliable biomarker for clinical CTE (Jordan, 2013; Montenigro, et al., 2014; Reams, et al., 2016; Victoroff, 2013), but they also have a number of deficiencies. Most notably, with the exception of the Montenigro et al. criteria, the proposed sets of diagnostic criteria fail to assess for exposure to head impacts, subconcussive brain injuries, and/or multiple TBIs (Jordan, 2013; Montenigro, et al., 2014; Reams, et al., 2016; Victoroff, 2013). While the majority of research and clinical attention has focused on TBIs of greater severity and sought to correlate the degree of injury with magnitude of cognitive and behavioral sequelae, less attention has been given to smaller but more frequent injuries or exposure to non-concussive head impacts (Tagge et al., 2018). Some of these criteria also omit the need for a progressive course of the disease (Jordan, 2013; Victoroff, 2013). Additionally, there is varying emphasis on the importance of behavioral and mood symptoms for diagnosis. For example, the Reams et al. criteria (Reams, et al., 2016) only require cognitive symptoms, as documented by neuropsychological testing, and Victoroff criteria (Victoroff, 2013) do not necessitate the presence of behavioral symptoms or mood dysregulation. The Montenigro et al. criteria (Montenigro, et al., 2014) are an advancement as they add the identification of neuroimaging findings, such as the presence of a cavum septum pellucidum or cortical thinning or atrophy, as well as negative cerebrospinal fluid (CSF) and amyloid imaging to rule-out AD. However, these criteria are less focused on the motor symptoms, which could also help in differentiating CTE from other neurodegenerative diseases, such as AD (Montenigro, et al., 2014). Overall, these four sets of criteria fail to fully capture the clinical picture of CTE and, in their current form, are insufficient for the diagnosis of the disorder in living patients. Additionally, like any other criteria established for research purposes, these criteria mostly favor sensitivity over specificity, and can therefore result in false positives when used in a clinical setting. Finally, when comparing the proposed clinical diagnostic criteria for CTE to one another, they demonstrate limited consistency and concordance (see Table 4).

Based on our application of the current criteria to two patients with probable CTE and a cohort of neurobehavior clinic patients, we suggest several revisions to the diagnostic criteria for CTE (see Table 5). These changes include some of the features of the existing proposed criteria while also building off older criteria used to evaluate the neurological sequelae of boxing (Mendez, 1995). First, the criteria should specify length of exposure to activities such as collision sports that predispose to head impacts. The presence of head impacts without actual concussions can be associated with CTE on neuropathology (Tagge, et al., 2018). Second, there should be an explicit requirement for an insidiously progressive course. CTE is a progressive neurodegenerative disorder. Third, the criteria can include a number of psychiatric symptoms. Focusing on mood and behavioral symptoms could enable greater sensitivity for the diagnosis of CTE early in its course and should include some of the less common behavioral symptoms, such as morbid jealousy and newly emergent substance abuse. Fourth, the neuropsychological features of CTE can be specified as predominantly frontal-executive. These include psychomotor slowing, abulia, dysexecutive impairment, and poor impulse control. Fifth, these patients have movement disorders. The most common are parkinsonism, particularly axial, and tremor, both postural and resting. Finally, clinical criteria for CTE must emphasize specific findings on neuroimaging. CT scans in professional boxers show atrophy of the cerebrum, especially the frontal lobes, with ventricular enlargement in 50–60% and a cavum septum pellucidum in up to 2/3rds of cases (Cabanis et al., 1986; Jordan & Zimmerman, 1990; Kaste et al., 1982; Levin et al., 1987). In addition, both CT and MRI scans may show evidence of previous perivascular hemorrhage, contusions, porencephalic cysts, and chronic subdural hematomas. MRI is superior to CT in the long-term evaluation of professional boxers and can detect abnormalities not seen on CT scans (Bogdanoff & Natter, 1989). For example, Cabanis et al. (1986) noted greater cerebral atrophy on the MRI scans of boxers who could “stand punishment” relative to those who avoided punches (Macpherson & Teasdale, 1988). In recent years, neuroimaging for CTE has been greatly improved with increasing clinical availability of diffusion tensor imaging for the detection of diffuse axonal injury (as in Patient No. 1). Finally, the increased clinical application of amyloid and tau PET imaging holds great promise for showing lack of significant amyloid deposition early in CTE (as in Patient No. 1), and the presence of abnormal tau deposition in CTE using ligands such as [¹⁸F]T807/AV1451(Dickstein et al., 2016).

Table 5

Proposed Modified CTE Clinical Criteria for Further Research 4 Criteria must be Present: 1, 2, and 2 from the remaining 4

1. Prolonged exposure to head impacts

2. A progressive course

3. Specific psychiatric symptoms (1 or more)

Emotional lability, including suicidality

Exaggeration of personality traits

Explosive behavior or aggressiveness

Inappropriate sexual or other behavior

Irritability, restlessness

Mood difficulties such as euphoria or hypomania, talkativeness, depression

Morbid jealousy and concern for spousal infidelity

Pathological intoxication or new substance abuse

Puerile/childishness, cheerful or silly affect

Suspiciousness or paranoia

4. Frontal-executive and related cognitive dysfunction (1 or more)

Abulia/apathy or decreased behavioral initiation, spontaneity, engagement

Associated memory difficulties

Decreased complex attention

Executive deficits in planning, organizing, sequencing, abstraction, judgment

Impaired insight

Poor impulse control and disinhibition

Slowed psychomotor speed

5. Movement disorders (1 or more)

Decreased fine motor coordination especially in non-dominant hand

Dysarthria, scanning and/or slurred

Parkinsonism with rigidity, bradykinesia

Tremors, postural or resting

6. Targeted findings on neuroimaging (1 or more)

Cavum septum pellucidum

Chronic subdural hematomas

Diffusion tensor imaging for diffuse axonal injury

Frontal and diffuse cerebral atrophy

Prior perivascular hemorrhages

Regional, especially frontotemporal, contusions or encephalomalacia

Tau positron emission tomography for abnormal tau deposition

Thinning of corpus callosum

White matter changes

In conclusion, in order to improve the clinical diagnosis of CTE, we propose modifying the proposed criteria based on current knowledge and the prior experience with professional boxers (Mendez, 1995). They would include an emphasis on length of exposure, a progressive course, behavioral changes, frontal-executive dysfunction, movement disorders, and neuroimaging findings. Investigators need to test these proposed, modified criteria in a large, longitudinal study with neuropathological verification of CTE. More definitive clinical diagnostic criteria for this syndrome may depend on further development of tau-specific neuroimaging and/or other biomarker technologies.

Conflict of interest

The authors listed do not have affiliations that would cause a conflict of interest, financial or otherwise, regarding the material presented here.

Funding

NIA R01AG050967.

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