Clinical presentation of chronic traumatic encephalopathy
Open accessAbstract
OBJECTIVE: The goal of this study was to examine the clinical presentation of chronic traumatic encephalopathy (CTE) in neuropathologically confirmed cases. METHODS: Thirty-six adult male subjects were selected from all cases of neuropathologically confirmed CTE at the Boston University Center for the Study of Traumatic Encephalopathy brain bank. Subjects were all athletes, had no comorbid neurodegenerative or motor neuron disease, and had next-of-kin informants to provide retrospective reports of the subjects' histories and clinical presentations. These interviews were conducted blind to the subjects' neuropathologic findings. RESULTS: A triad of cognitive, behavioral, and mood impairments was common overall, with cognitive deficits reported for almost all subjects. Three subjects were asymptomatic at the time of death. Consistent with earlier case reports of boxers, 2 relatively distinct clinical presentations emerged, with one group whose initial features developed at a younger age and involved behavioral and/or mood disturbance (n = 22), and another group whose initial presentation developed at an older age and involved cognitive impairment (n = 11). CONCLUSIONS: This suggests there are 2 major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.
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TL;DR
In 36 male athletes with neuropathologically confirmed CTE, a triad of cognitive, behavioral, and mood impairments was common, and two clinical presentations emerged: a younger-onset behavior/mood variant (n = 22) and an older-onset cognition variant (n = 11). Three subjects were asymptomatic, and APOE ε4 homozygosity was overrepresented, especially in the cognition group.
Key findings
- Among 33 symptomatic subjects, cognitive deficits were reported in 93.9%, behavioral features in 75.8%, and mood features in 84.8%; 90.9% had a progressive course. Three of 36 subjects (8%) were asymptomatic.
- Initial presentation was behavior/mood in 22 subjects and cognition in 11; mean age at first clinical feature was 34.5 ± 11.6 years for the behavior/mood group vs 58.5 ± 17.7 years for the cognition group. Dementia diagnosis at death was 18.2% vs 54.5%, respectively.
- Ten subjects had dementia, all with stage IV CTE; mean age of symptom onset was 57.7 years (SD 18.3), mean age of dementia diagnosis was 72.6 years (SD 8.5), and mean time from diagnosis to death was 8.0 years (SD 5.5). All 10 had memory and executive impairment, 7 had language deficits, and 2 had visuospatial difficulties.
- APOE genotypes differed from an age-matched normative sample (χ²[2] = 6.63, p < 0.05), driven by more ε4 homozygotes (p < 0.05); the cognition group had proportionally more ε4 homozygotes than expected (χ²[2] = 13.3, p < 0.05). Two of 11 cognition-group subjects and 1 of 22 behavior/mood-group subjects were ε4 homozygous.
Methods
- Retrospective postmortem study of 36 adult male athletes selected from 81 neuropathologically confirmed CTE cases at the Boston University CSTE brain bank; exclusions were nonathletic repetitive brain trauma, no next-of-kin contact, and comorbid neurodegenerative, motor neuron, or other significant neuropathology. Twenty-eight were from a previous report and 8 were new.
- CTE was staged I–IV by p-tau pathology blind to medical history, APOE genotype, and informant interview. History and clinical presentation came from postmortem telephone interviews with next-of-kin by a neuropsychologist blinded to neuropathologic findings and APOE status; medical records were reviewed for 23 cases. APOE genotyping was performed on brain tissue.
- Between-group differences used independent-sample t tests and chi-square analyses; APOE genotype was compared with population norms using χ² goodness-of-fit; p = 0.05 throughout; analyses used SPSS version 19.0.
Limitations
- The paper states the overall sample is small, limiting generalization to the larger athlete population or the overall clinical presentation of CTE; the dementia subsample is also small, limiting generalization of CTE dementia presentation.
- The paper states postmortem brain donation introduces selection bias (families choosing donation may be more likely to have witnessed symptoms, possibly yielding more severe symptom reports and only 3 asymptomatic cases), and excluding comorbid pathology and nonathletes further limits generalizability. Results should not be interpreted as population prevalence or generalized to living athletes with CTE.
- The paper states retrospective informant reports may have reduced reliability and validity, with possibly reduced accuracy for older subjects’ early- or midlife events, and there was no comparison group of former athletes without CTE.
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- Findingown data§ RESULTS
Motor features, including parkinsonism, were not common in our sample.
“It is noteworthy that motor features, including parkinsonism, were not common in our sample.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The proportions of APOE genotypes in the CTE sample were significantly different from those found in an age-matched normative sample.
“The proportions of APOE genotypes (i.e., e4 homozygotes, combined e4 homozygotes and heterozygotes, and e4 noncarriers) in our CTE sample were significantly different from those found in an age-matched normative sample 17 (x 2 [2] 5 6.63, p , 0.05).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] source
Not checked in the free run.
- Findingown data§ RESULTS
Significantly fewer subjects in the cognition group demonstrated behavioral and mood changes during the course of their illness than in the behavior/mood group.
“significantly fewer subjects in the cognition group demonstrated behavioral and mood changes during the course of their illness.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Subjects in the cognition group were significantly more likely to progress to dementia than those in the behavior/mood group.
“Subjects in the cognition group were significantly more likely to progress to dementia than those in the behavior/mood group”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
The behavior/mood group demonstrated symptoms at a significantly younger age than the cognition group.
“The behavior/mood group demonstrated symptoms at a significantly younger age than the cognition group.”
Quote in the paperSubstantial claim
- Study design and conductown data§ RESULTS
The overall sample size is small, limiting generalization of the results to the larger population of athletes or to the overall clinical presentation of CTE.
“First, the overall sample size is small, and caution should be taken when generalizing these results to the larger population of athletes or to the overall clinical presentation of CTE.”
Quote in the paperSubstantial claim
- May combine two claims. 4
May combine two claims.
Findingown data§ RESULTSThe effect of increased e4 homozygosity was largely driven by the cognition group: 2 of 11 subjects in the cognition group and 1 of 22 subjects in the behavior/mood group were homozygous for the e4 allele.
“Furthermore, this effect was largely driven by the cognition group: 2 of 11 subjects in the cognition group and 1 of 22 subjects in the behavior/mood group were homozygous for the e4 allele.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSThe behavior/mood group was significantly more explosive, out of control, physically and verbally violent, and depressed than the cognition group.
“The behavior/mood group was significantly more explosive, out of control, physically and verbally violent, and depressed than the cognition group.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractAmong symptomatic CTE subjects, initial features grouped into a behavior/mood group (n=22) with younger onset behavioral/mood disturbance and a cognition group (n=11) with older onset cognitive impairment.
“one group whose initial features developed at a younger age and involved behavioral and/or mood disturbance (n 5 22), and another group whose initial presentation developed at an older age and involved cognitive impairment (n 5 11)”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractThere are two major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.
“This suggests there are 2 major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.”
Quote in the paperSubstantial claim- Rests on an assumption: The clinical features reported in these subjects are caused by CTE rather than other factors.
The paper relies on this without support.
The clinical features reported in these subjects are caused by CTE rather than other factors.
“This may limit the ability to draw conclusions that the clinical presentation described is specifically due to the effects of CTE.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Two presentations of CTE were found: one consisting of behavioral and mood symptoms usually appearing in the third decade of life (mean age at onset of 35 years) and another consisting of cognitive impairment and memory loss developing in the fifth decade (mean age at onset of 59 years).
“Specifically, two presentations of CTE were found, one that consisted of behavioral and mood symptoms usually appearing in the third decade of life (mean age at onset of 35 years) and another consisting of cognitive impairment and memory loss developing in the fifth decade (mean age at onset of 59 years).”
From The neuropathology of sport (2014) · cites this paper as [175]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Dementia cases assigned to different initial-presentation groups
MajorThe text says 7 of the 10 subjects with dementia initially had cognitive symptoms. Table 2 reports dementia in 54.5% of the 11-person cognition group, which is 6 subjects, leaving 4 in the behavior/mood group rather than the 3 described in the text.
“Of the 10, 7 exhibited cognitive symptoms initially, 2 exhibited mood symptoms initially, and 1 initially presented with behavior changes.”
“| Percent with dementia diagnosis at death | 30.3 | 18.2 b | 54.5 b |”
Verbally violent subgroup percentages do not match the overall percentage
MinorWith 22 subjects in the behavior/mood group and 11 in the cognition group, the subgroup percentages imply approximately 16 and 2 verbally violent subjects, respectively. That is about 18 of 33 subjects (54.5%), not the reported overall 48.5% (16 of 33).
“| Verbally violent | 48.5 | 73.6 b | 18.2 b |”
“| Variable | % (n 5 33) | % (n 5 22) a | % (n 5 11) a |”
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Self-citationA critical review of chronic traumatic encephalopathy
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Current understanding of chronic traumatic encephalopathy
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The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features
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Suicide and chronic traumatic encephalopathy
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Suicide in professional American football players in the past 95 years
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DNA repair deficiency and senescence in concussed professional athletes involved in contact sports
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Chronic Effects of Mild Neurotrauma: Putting the Cart Before the Horse?
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Psychiatric phenotypes in chronic traumatic encephalopathy
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Self-citationConcomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer
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DNA damage as a marker of brain damage in individuals with history of concussions
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Self-citation
- Authors
- Stern, R. A., Daneshvar, D. H., Baugh, C. M., Seichepine, D. R., Montenigro, P. H., Riley, D. O., Fritts, N. G., Stamm, J. M., Robbins, C. A., McHale, L., Simkin, I., Stein, T. D., Alvarez, V. E., Goldstein, L. E., Budson, A. E., Kowall, N. W., Nowinski, C. J., Cantu, R. C., & McKee, A. C.
- Affiliations
- Boston University (US)
- ORCID
- Venue
- Neurology
- Published
- 2013-09-24
- Volume
- 81
- Issue
- 13
- Pages
- 1122-1129
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3795597
- OpenAlex
- W2110282732
- Cited by
- 564
- References
- 45
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 30 · 2023: 29 · 2022: 44 · 2021: 43 · 2020: 67 · 2019: 60 · 2018: 50 · 2017: 51 · 2016: 54 · 2015: 54 · 2014: 38 · 2013: 4 · 2012: 1
- FWCI
- 36.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 CX001038)
- National Institute on Aging (R01AG1649, U01AG010483, U01AG015477, P30AG013846, T32AG036697, NIH P30AG13846)
- National Institute of Mental Health (R01MH080295)
- National Cancer Institute (R01CA129769, U54CA137788, U54CA132378)
- National Institute of Neurological Disorders and Stroke (R01NS078337, F31NS081957)
- Topics
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- chronic traumatic encephalopathy, clinical features, cognitive impairment, athletes, boxing, brain banks, age of onset
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Apolipoproteins E, Behavioral Symptoms, Cognition Disorders, Genotype, Humans, Interview, Psychological, Male, Middle Aged, Single-Blind Method, Disease Progression, Brain Injury, Chronic, Young Adult
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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