Abstract
Repetitive head impacts (RHIs) from football are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). It is unclear whether a history of traumatic brain injury (TBI) is sufficient to precipitate CTE neuropathology. We examined the association between TBI and CTE neuropathology in 580 deceased individuals exposed to RHIs from football. TBI history was assessed using a modified version of the Ohio State University TBI Identification Method Short Form administered to informants. There were 22 donors who had no TBI, 213 who had at least one TBI without loss of consciousness (LOC), 345 who had TBI with LOC, and, of those with a history of TBI with LOC, 36 who had at least one moderate-to-severe TBI (msTBI, LOC >30 min). CTE neuropathology was diagnosed in 405. There was no association between CTE neuropathology status or severity and TBI with LOC (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.64–1.41; OR = 1.22, 95% CI = 0.71–2.09) or msTBI (OR = 0.70, 95% CI = 0.33–1.50; OR = 1.01, 95% CI = 0.30–3.41). There were no associations with other neurodegenerative or cerebrovascular pathologies examined. TBI with LOC and msTBI were not associated with CTE neuropathology in this sample of brain donors exposed to RHIs from American football.
Keywords: Alzheimer's disease, chronic traumatic encephalopathy, concussion, repetitive head impacts, traumatic brain injury
Introduction
Participation in contact and collision sports (CCS), particularly American football, can result in exposure to repetitive head impacts (RHIs).1–4 RHIs, defined as recurrent blows to the head that may or may not result in symptoms, is differentiated from traumatic brain injury (TBI), which refers to discrete events leading to alterations in brain functioning resulting in symptom expression at the time of injury.
A history of RHI is a primary risk factor for the neurodegenerative tauopathy, chronic traumatic encephalopathy (CTE).5–8 CTE is a neuropathological entity that can only be diagnosed post-mortem, and our use of the term CTE throughout this study is in reference to neuropathological changes in the brain. Duration of football play, a proxy of RHI, has been tied to CTE neuropathology8 and binding on tau PET imaging.9 These studies and others support CTE neuropathology as a consequence of football play.5,6,10–12 Less is known about the long-term sequelae of a single TBI, particularly as it pertains to CTE.
A history of TBI, specifically moderate-to-severe TBI (msTBI), has been identified as a risk factor for all-cause dementia.13–16 TBI with and without loss of consciousness (LOC) has been viewed as a risk factor for Alzheimer's disease (AD)16–18; this conclusion has been based primarily on studies that used clinical diagnoses.13–15,19 Recent biomarker and autopsy studies suggest that TBI may not confer risk for traditional AD neuropathological changes,19–23 although findings are mixed.24 Multiple studies have identified an association between TBI and non-AD neuropathologies.17,24
Prior examination of the relationship between TBI and CTE neuropathology has been limited. While there has been evidence that msTBI may lead to neuropathological changes consistent with CTE,25 large post-mortem studies examining the association between a history of TBI and CTE neuropathological outcomes, particularly in the context of a well-characterized history of exposure to RHI, are lacking.5 Most studies examining the relationship between TBI and AD and non-AD pathologies have failed to comprehensively assess and characterize RHI, which may account for prior inconsistencies in the literature. Given the epidemiological concerns surrounding RHI, TBI, and neuropathological changes associated with CTE, it is imperative that we better understand the contributions of these risk factors to the development of neuropathological disease.
The current study investigated the association between history of TBI and autopsy confirmed CTE neuropathology among brain donors exposed to football play. A TBI history was evaluated as a potential effect modifier of the association between years of football play and CTE neuropathological outcomes. Secondary analyses investigated the relationship between TBI and other neurodegenerative and cerebrovascular pathologies. Based on existing literature,5,25 we did not expect that TBI with LOC of any duration or msTBI (LOC >30 min) would be associated with CTE neuropathology. We hypothesized that msTBI would moderate the relationship between RHI exposure and CTE pathology.
Methods
Brain donors and study design
Brain donors were from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study.26 Brain donations were facilitated by next of kin who contacted the brain bank before death, referrals from medical examiners, outreach and recruitment by the Concussion Legacy Foundation, and/or participation in the Brain Donation Registry during life. Brain donors were required to have RHI from CCS (e.g., from football, soccer, hockey), military service, physical violence, and/or other sources; however, symptomatic status was not an eligibility requirement. Brain donors with poor tissue quality were excluded. Institutional Review Board approvals were obtained through the Boston University Medical Campus Institutional Review Board.
Sample size
The UNITE study included 710 brain donors at the time of this data freeze (August 2021). The final analytic sample was reduced to 580 after exclusions. First, the sample was restricted to brain donors who played football (n = 125 excluded) because this subgroup offers homogeneity in their demographic and RHI exposure characteristics to facilitate inferences and interpretation of associations. Five donors were excluded because of missing data on primary study variables—namely, CTE neuropathology status and TBI.
Lifetime history of TBI
Lifetime history of TBI was assessed by telephone with informants of brain donors using a modified version of the Ohio State University Traumatic Brain Injury Identification Method Short Form (OSU-TBI-ID).27 While there is preference to interview the person who experienced TBI, there is precedence for interviewing proxies in the TBI Model Systems National Data Set.28
Informants were blinded to the neuropathology of the donor. There could have been multiple informants, and the most frequent type of informant included spouse/partner (n = 265, 45.8%), followed by child (n = 117, 20.2%), parent (n = 113, 19.6%), and then sibling (n = 61, 10.6%). Other types of informants were rare and included other relative, friend, or teammate. There were 263 (45.6%) informants who lived with the donor at the time of death. The mean (standard deviation [SD]) duration of relationship for informants that knew the donor the longest was 41.03 (15.98) years.
The OSU-TBI-ID is a brief, structured interview to elicit history of TBI using five yes or no questions, with querying intended to identify LOC. If TBI with LOC was endorsed, additional characterization of TBI was pursued, including LOC duration and age at time of TBI with LOC. The five most severe TBIs with LOC were queried. The TBI variables examined in this study included no TBI, TBI without LOC, TBI with LOC, and msTBI (TBI with LOC >30 min).29 The TBI with LOC group was inclusive of those with msTBI.
Neuropathological examinations
Brain donations were processed using published protocols.26,30,31 Neuropathologists blinded to brain donor clinical, athletic, and medical histories diagnosed and staged neurodegenerative diseases using established criteria and scales. Neuropathological diagnosis of CTE was made using criteria defined by the NINDS-NIBIB Consensus Conference; the pathognomonic lesion of CTE required an accumulation of abnormal p-tau within neurons around blood vessels and concentrated at the depths of the cortical sulci.32,33 CTE p-tau pathology was classified into four stages using the McKee staging criteria.34,35
The Ischemic Injury Scale (IIS) was used as a global index of cerebrovascular disease. The IIS is a summary composite of the following pathologies: hippocampal sclerosis, infarcts, microinfarcts, microbleeds, laminar necrosis, arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy (CAA), white matter rarefaction, and cribriform state.36 Arteriolosclerosis, atherosclerosis, CAA, white matter rarefaction, and cribriform state were rated on a four-point semiquantitative scale (0 = none, 3 = severe).37 Remaining pathologies were rated if they were present or absent.
Sample characteristics
Online surveys and/or telephone interviews with informants of brain donors, as well as review of medical records, were used to retrospectively obtain clinical data.26 Interviewers and informants were blinded to the neuropathological results. Demographics, educational attainment, and athletic history (type of sports played, level, position, age of first exposure, and duration) were queried during a telephone interview prior to 2014; after 2014, these variables were assessed via telephone interview and/or online surveys. Clinicians conducted semi-structured interviews and research assistants conducted structured interviews to acquire detailed medical, psychiatric, and clinical histories.
The data gathered through surveys and interviews were summarized and presented to an expert consensus panel to adjudicate antemortem dementia diagnosis using adapted Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria.
Statistical analyses
Only 22 brain donors had no TBI, and thus there was an insufficient sample to examine them separately; they were combined with the TBI without LOC group. The TBI predictor variables included: TBI with LOC (referent: no TBI + TBI without LOC) and msTBI (referent: no TBI + TBI without LOC + TBI with LOC <30 min). Primary outcomes included CTE neuropathology status (absent/present) and CTE neuropathology severity (low [stage I-II], high [stage III-IV]).
We used multi-variable binary logistic regressions to test the association between each TBI predictor and each pathological outcome in separate models. Models controlled for age at death and years of football play.8 Years of football play was included in models because of its documented association with CTE neuropathology and other neurodegenerative and non-neurodegenerative disease pathologies.10,13,20,38–41 To test whether TBI moderated the effects of exposure to RHI, using years of football play as a proxy, on CTE neuropathology, we repeated the models examining CTE neuropathology outcomes (i.e., status, severity) with the inclusion of an interaction term (years of football play × TBI) for each TBI predictor variable (separate models).
Sensitivity analyses were conducted by stratifying the sample by median age of death (i.e., 60). We conducted binary, ordinal, or linear regression models for other neurodegenerative and cerebrovascular pathologies, including AD status (absent/present), frontotemporal lobar degeneration status (absent/present), Lewy body dementia status (absent/present), transactive response deoxyribonucleic acid (TAR DNA)-binding protein 43 (TDP-43) inclusions (absent/present), Braak stage (0, I/II, III/IV, V/VI), CERAD neuritic plaque score (none, sparse, moderate, frequent), and the IIS. Age at death and years of football play were included as covariates.
Analyses were performed in SPSS version 27. A false discovery rate (FDR) adjusted p value less than or equal to 0.05 defined statistical significance for primary models. For TBI and CTE neuropathology outcomes, adjustment was based on four analyses (two predictors, two outcomes), as were the p values from the interaction analyses that also had two predictors and two outcomes. The p values from sensitivity analyses were unadjusted.
Consent statement
Informed consent for brain donation and study enrollment was obtained from the brain donor's next of kin.
Results
Twenty-two donors had no TBI, 213 had a TBI without LOC, and 345 had a TBI with LOC (111 with 2+ and 26 with at least five TBIs with LOC). Thirty-six donors were reported as having a history of msTBI (31 reported only one msTBI). Years since most recent TBI with LOC was 32.58 (SD = 21.52, median = 35, interquartile range [IQR] = 40), on average. Donors in this sample participated in an average of 12.44 (SD 5.85) years of football, with most having their highest level of play at the college (n = 188, 32.5%) or professional (n = 258, 44.6%) level.
The sample was predominantly male; three donors were identified as females at birth. The sample was 16.6% Black or African American and well educated. Neurodegenerative disease was the most common cause of death (Table 1). A summary of responses to individual items on the OSU-TBI-ID is provided (Table 2).
Table 1.
Sample Characteristics of 580 Deceased American Football Players
| Total sample (N = 580) | No TBI/TBI w/o LOC (n = 235) | TBI with LOC (n = 345) | p * | msTBI (n = 36) | p * | |
|---|---|---|---|---|---|---|
| Demographics | ||||||
| Age at death, mean (SD) years, range | 60.22 (19.75), 13-97 | 58.32 (20.58), 13-90 | 61.51 (19.01), 14-97 | 0.06 | 61.19 (16.77), 26-87 | 0.76 |
| Sex, n (%) Male | 577 (99.5) | 234 (99.6) | 343 (99.4) | – | 35 (97.2) | – |
| Racial identity, n (%) Black | 96 (16.6) | 45 (9.1) | 51 (14.8) | 0.17 | 3 (8.3) | 0.25 |
| Education level, n (%) | ||||||
| No high school | 1 (0.2) | 0 (0.0) | 1 (0.3) | 0.59 | 0 | 0.43 |
| Some high school | 9 (1.6) | 5 (2.1) | 4 (1.2) | 0 | ||
| High school diploma/GED | 22 (3.8) | 8 (3.4) | 14 (4.1) | 2 (5.6) | ||
| Some college | 128 (22.1) | 49 (20.9) | 79 (22.9) | 10 (27.8) | ||
| College degree | 273 (47.1) | 111 (47.2) | 162 (47.0) | 15 (41.7) | ||
| More than college | 26 (4.5) | 8 (3.4) | 18 (5.2) | 2 (5.6) | ||
| Graduate degree | 121 (20.9) | 54 (23.0) | 67 (19.4) | 7 (19.4) | ||
| RHI/TBI characteristics | ||||||
| Years of football play, mean (SD) | 12.44 (5.85) | 12.48 (5.45) | 12.39 (6.06) | 0.82 | 9.58 (5.63) | < 0.01 |
| Age of first exposure to football, mean (SD) | 11.49 (3.31) | 12.50 (5.54) | 11.46 (3.38) | 0.78 | 12.08 (4.48) | 0.27 |
| Highest level of play, n (%) | ||||||
| Youth | 18 (3.1) | 9 (3.8) | 9 (2.6) | 0.83 | 2 (5.6) | 0.04 |
| High school | 91 (15.7) | 37 (15.7) | 54 (15.7) | 10 (27.8) | ||
| College | 188 (32.5) | 76 (32.3) | 112 (32.5) | 12 (33.3) | ||
| Semi-professional | 24 (4.1) | 7 (3.0) | 17 (4.9) | 2 (5.6) | ||
| Professional | 258 (44.6) | 106 (45.1) | 152 (44.1) | 10 (27.8) | ||
| Years since last TBI w LOC, mean (SD) | 32.58 (21.52) | – | 32.49 (21.50) | – | 29.86 (20.96) | 0.42 |
| Age of most recent TBI w LOC, mean (SD) | 27.69 (14.91) | – | 27.72 (14.93) | – | 31.33 (17.54) | 0.12 |
| Youngest age of TBI w LOC, mean (SD) | 21.51 (11.58) | – | 21.52 (11.60) | – | 24.45 (16.78) | 0.27 |
| Clinical characteristics, n (%) | ||||||
| Coronary artery disease | 117 (79.6) | 52 (22.3) | 65 (19.1) | 0.34 | 9 (25.0) | 0.52 |
| Hypertension | 296 (51.7) | 113 (48.9) | 183 (53.5) | 0.28 | 23 (63.9) | 0.13 |
| Hypercholesterolemia | 209 (37.1) | 88 (38.8) | 121 (35.9) | 0.49 | 11 (32.4) | 0.56 |
| Diabetes | 95 (16.5) | 42 (18.2) | 53 (15.4) | 0.37 | 6 (16.7) | 0.98 |
| History of substance use treatment | 139 (24.3) | 47 (20.3) | 92 (27.1) | 0.07 | 7 (20.0) | 0.54 |
| Dementia status, n (%) | ||||||
| Yes | 304 (54.4) | 118 (52.7) | 186 (55.5) | 0.51 | 18 (52.9) | 0.86 |
| Cause of death, n (%) | ||||||
| Suicide | 99 (17.1) | 44 (19.0) | 55 (15.9) | 0.46 | 7 (19.4) | 0.36 |
| Accidental overdose | 30 (5.2) | 14 (6.0) | 16 (4.6) | 0 | ||
| Cardiovascular disease | 98 (17.0) | 41 (17.7) | 57 (16.5) | 6 (16.7) | ||
| Neurodegenerative | 191 (33.2) | 73 (31.5) | 118 (34.2) | 9 (25.0) | ||
| Motor neuron disease | 11 (1.9) | 6 (2.6) | 5 (1.4) | 1 (2.8) | ||
| Cancer | 40 (7.0) | 12 (5.2) | 28 (8.1) | 2 (5.6) | ||
| **Other | 106 (18.4) | 42 (18.1) | 64 (18.6) | 11 (30.6) | ||
TBI, traumatic brain injury; LOC, loss of consciousness; msTBI, moderate to severe TBI; SD, standard deviation; GED, General Education Diploma; RHI, repetitive head impacts.
Chi-square or Fisher exact test (for binary outcomes) and independent sample t tests (for continuous outcomes) compared TBI with LOC with those without TBI (n = 22) + those with TBI without LOC (n = 213) (first p value) as well as msTBI with no TBI/TBI without LOC + TBI with LOC <30 min (second p value). msTBI was defined as a TBI with LOC for 30 or more minutes. The TBI with LOC group is inclusive of those who had msTBI. For analyses, race was recoded as Black versus other, education level as college degree or more versus other, highest level of play as amateur versus professional, and cause of death as neurodegenerative versus other.
Sample sizes because of missing data: n = 579 for highest level played, n = 298 for years since last TBI with LOC and age of most recent TBI with LOC (of 345 who had TBI with LOC), n = 274 for youngest age of TBI with LOC, n = 574 for coronary artery disease, n = 573 for hypertension, n = 564 hypercholesterolemia, n = 576 for diabetes, n = 571 for history of substance use treatment, n = 559 for dementia status, n = 575 for primary cause of death.
Other causes of death include but are not limited to injury, cerebrovascular disease, infection, sepsis, renal disease, cirrhosis, chronic lower respiratory disease, and liver disease.
Table 2.
Traumatic Brain Injury Characteristics
| Question from OSU-TBI-ID Short Form, n (%) | Total sample (N = 580) | No TBI/TBI w/o LOC (n = 235) | TBI with LOC (n = 345) | p * | msTBI (n = 36) | p * |
|---|---|---|---|---|---|---|
| Hospitalized or treated in ER | 294 (50.9) | 73 (31.2) | 221 (64.2) | < 0.001 | 34 (94.4) | < 0.001 |
| Head or neck injury from motor vehicle accident | 143 (24.7) | 40 (17.0) | 103 (29.9) | < 0.001 | 15 (41.7) | 0.01 |
| Head or neck injury from fall, being hit by something, injured playing sports or on the playground | 515 (88.8) | 188 (80.0) | 327 (94.8) | < 0.001 | 34 (94.4) | 0.41 |
| Head or neck injury from fight, being hit by someone, being shaken violently | 156 (26.9) | 44 (18.7) | 112 (32.5) | < 0.001 | 14 (38.9) | 0.09 |
| Nearby when an explosion or blast occurred, combat-related incidents | 31 (5.4) | 8 (3.4) | 23 (6.7) | 0.09 | 4 (11.4) | 0.11 |
Lifetime history of TBI was assessed by telephone with informants of brain donors using a modified version of the Ohio State University Traumatic Brain Injury Identification Method Short Form (OSU-TBI-ID).29 The OSU-TBI-ID is a brief, structured interview to elicit history of TBI using a series of yes or no questions that are presented in this Table. Responses are not mutually exclusive.
TBI; traumatic brain injury; LOC, loss of consciousness; msTBI, moderate to severe TBI; ER, emergency room.
Chi-square or Fisher exact test (for binary outcomes) compared TBI with LOC with those without TBI (n = 22) + those with TBI without LOC (n = 213) (first p value) as well as msTBI with no TBI/TBI without LOC + TBI with LOC <30 min (second p value). msTBI was defined as a TBI with LOC for 30 or more minutes.
Sample sizes because of missing data: n = 578 for hospitalized or treated in ER and n = 579 for nearby when an explosion or blast occurred, combat related incidents.
TBI with LOC and CTE neuropathology
There were no significant differences between donors with and without a history of TBI with LOC (Table 1). The rate of CTE neuropathology was nearly equivalent between those who had a TBI with LOC (n = 240, 69.6%) and the reference group (no TBI/TBI without LOC) (n = 165, 70.2%; Table 3). CTE neuropathology severity was nearly identical as well (Table 3). Brain donors with a history of TBI with LOC were not more likely to have CTE neuropathology compared with brain donors with no TBI/TBI without LOC (p = 0.99), nor were there significant differences in CTE neuropathology severity (Table 4).
Table 3.
Sample Neuropathology Characteristics of 580 Deceased American Football Players
| Total sample (N = 580) | No TBI/TBI w/o LOC (n = 235) | TBI with LOC (n = 345) | p * | msTBI (n = 36) | p * | |
|---|---|---|---|---|---|---|
| CTE, n (%) | ||||||
| Stage 0 | 175 (30.2) | 70 (29.8) | 10 (30.4) | 0.87 | 16 (44.4) | 0.07 |
| Stage I | 77 (13.3) | 29 (12.3) | 48 (13.9) | 0.25 | 5 (13.9) | 0.81 |
| Stage II | 71 (12.2) | 36 (15.3) | 35 (10.1) | 3 (8.3) | ||
| Stage III | 147 (25.3) | 60 (25.5) | 87 (25.2) | 8 (22.2) | ||
| Stage IV | 110 (19.0) | 40 (17.0) | 70 (20.3) | 4 (11.1) | ||
| Alzheimer's disease, n (%) | 103 (17.8) | 41 (17.4) | 62 (18.0) | 0.86 | 6 (17.1) | 1.00 |
| Lewy body disease, n (%) | 99 (17.1) | 38 (16.2) | 61 (17.8) | 0.61 | 6 (17.1) | 1.00 |
| Frontotemporal lobar degeneration, n (%) | 43 (7.4) | 17 (7.3) | 26 (7.5) | 0.90 | 1 (2.8) | 0.51 |
| TDP-43 inclusions, n (%) | 139 (25.1) | 50 (22.4) | 89 (26.9) | 0.23 | 9 (27.3) | 0.84 |
| Braak stage, n (%) | ||||||
| 0 | 173 (30.2) | 73 (3.6) | 100 (29.3) | 0.90 | 13 (37.1) | 0.76 |
| I/II | 123 (21.5) | 51 (22.1) | 72 (21.1) | 8 (22.9) | ||
| III/IV | 174 (30.4) | 67 (29.0) | 107 (31.4) | 9 (25.7) | ||
| V/VI | 102 (17.8) | 40 (17.3) | 62 (18.2) | 5 (14.3) | ||
| CERAD neuritic plaque score, n (%) | ||||||
| None | 391 (67.5) | 160 (68.1) | 231 (67.2) | 0.82 | 24 (68.6) | 0.94 |
| Sparse | 105 (18.1) | 39 (16.6) | 66 (19.2) | 7 (20.0) | ||
| Moderate | 56 (9.7) | 25 (10.6) | 31 (9.0) | 3 (8.6) | ||
| Frequent | 27 (4.7) | 11 (4.7) | 16 (4.7) | 1 (2.9) | ||
| Ischemic Injury Scale score, mean (SD) | 5.56 (3.72) | 5.47 (3.79) | 5.61 (3.68) | 0.66 | 6.26 (3.76) | 0.28 |
TBI; traumatic brain injury; LOC, loss of consciousness; msTBI, moderate to severe TBI; CTE, chronic traumatic encephalopathy; TDP, transactive response deoxyribonucleic acid-binding protein; SD, standard deviation.
Chi-square or Fisher exact test (for binary outcomes) and independent sample t tests (for continuous outcomes) compared TBI with LOC to those without TBI (n = 22) + those with TBI without LOC (n = 213) (first p value) as well as msTBI with no TBI/TBI without LOC + TBI with LOC <30 min (second p value). msTBI was defined as a TBI with LOC for 30 or more minutes. The Ischemic Injury Scale score is a composite of presence of hippocampal sclerosis, infarcts, microinfarcts, microhemorrhages, laminar necrosis, arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy, white matter rarefaction, and cribriform state.
Sample sizes because of missing data: Alzheimer's disease, frontotemporal lobar degeneration, and CERAD neuritic plaque score: 579; Lewy body disease: 578; TDP-43 inclusions: 554; Braak stage: 572; ischemic injury scale score: 524.
Table 4.
Association Between Traumatic Brain Injury and Chronic Traumatic Encephalopathy Neuropathology
| |
TBI w/ LOC |
Years of play * TBI w/LOC |
||||
|---|---|---|---|---|---|---|
| Outcome | OR | 95% CI | p | OR | 95% CI | p |
| CTE status | 0.95 | 0.64-1.41 | 0.99 | 0.96 | 0.88-1.05 | 0.37 |
| CTE severity | 1.22 | 0.71-2.09 | 0.94 | 1.12 | 1.00-1.25 | 0.20 |
| |
msTBI |
Years of play * msTBI |
||||
|---|---|---|---|---|---|---|
| Outcome | OR | 95% CI | p | OR | 95% CI | p |
| CTE status |
0.70 |
0.33-1.50 |
0.94 |
0.92 |
0.81-1.06 |
0.33 |
| CTE severity | 1.01 | 0.30-3.41 | 0.94 | 1.41 | 0.91-2.18 | 0.24 |
Interaction analyses.
TBI, traumatic brain injury; LOC, loss of consciousness; OR, odds ratio; CI, confidence interval; CTE, chronic traumatic encephalopathy; msTBI,
Binary logistic regression tested the associations for CTE status and severity (low versus high). Models controlled for age at death and years of football play. The p values are FDR-adjusted using the Bejamini-Hochberg procedure.
msTBI and CTE neuropathology
Compared with the referent group (no TBI + TBI without LOC + TBI with LOC <30 min), donors with a history of msTBI played fewer years of football and were more likely to play only at the amateur level (Table 1). There were otherwise no group differences. The rate of CTE for donors with a history of msTBI was 55.6% (n = 20 of 36) compared with 70.8% (385 of 544) in the group with no TBI + TBI without LOC + TBI with LOC <30 min (Table 3). Relative to the referent group, donors with a history of msTBI were not statistically more likely to have CTE neuropathology (p = 0.94), nor were there identified differences in CTE neuropathology severity (p = 0.94; Table 4).
As mentioned above, the referent group played more years of football compared with individuals with msTBI. When the logistic regression just included age (and did not include years of football play) in the model, there was an association between msTBI and CTE neuropathology status (OR = 0.48, 95% CI = 0.24–0.97, p (unadjusted) = 0.04); having no history of msTBI was associated with greater odds for having CTE neuropathology compared with having a msTBI.
Years of football play by TBI interaction
In the models that included age of death and TBI, more years of American football play was associated with higher odds for having CTE neuropathology (OR = 1.17 per year played, 95% CI = 1.12–1.22, p < 0.001) and greater CTE severity (OR = 1.15 per year played, 95% CI = 1.09–1.22, p < 0.01). The years of play by TBI (with LOC and msTBI) interaction terms were not significantly associated with CTE neuropathology status or CTE neuropathology severity.
Sensitivity analyses
Age stratification
Among those 60+ years, donors with TBI with LOC (n = 185) were not more likely to have CTE neuropathology than the no TBI/TBI without LOC group (OR = 0.76, 95% CI = 0.44–1.33, p = 0.34), nor were they more likely to have severe CTE neuropathology (OR = 1.07, 95% CI = 0.55–2.09, p = 0.84). Among those younger than 60, donors with TBI with LOC were not more likely to have CTE compared with the no TBI/TBI without LOC (OR = 1.25, 95% CI = 0.69–2.23, p = 0.46), nor were they more likely to have severe CTE neuropathology (OR = 1.88, 95% CI = 0.70–5.09, p = 0.21). The sample sizes for donors with a history of msTBI who were 60 years and over and younger than 60 were insufficient to conduct analyses (n = 24 and 12, respectively).
Non-CTE neuropathologies
There were no significant associations between TBI with LOC or msTBI and any of the neurodegenerative or cerebrovascular pathologies (Table 5).
Table 5.
Association Between Traumatic Brain Injury and Neurodegenerative and Cerebrovascular Pathology
| |
TBI w/LOC |
msTBI |
||||
|---|---|---|---|---|---|---|
| Outcome | Est. | 95% CI | p | Est. | 95% CI | p |
| Alzheimer's disease | 0.91 | 0.57-1.46 | 0.70 | 0.96 | 0.37-2.52 | 0.94 |
| Lewy body disease | 0.99 | 0.62-1.60 | 0.99 | 1.08 | 0.41-2.81 | 0.88 |
| FTLD | 0.94 | 0.49-1.79 | 0.84 | 0.34 | 0.05-2.59 | 0.30 |
| TDP-43 inclusions | 1.13 | 0.73-1.76 | 0.59 | 1.47 | 0.61-3.55 | 0.39 |
| Braak Stage | 0.86 | 0.62-1.20 | 0.37 | 0.69 | 0.35-1.35 | 0.28 |
| CERAD neuritic plaque score | 0.84 | 0.56-1.25 | 0.37 | 0.93 | 0.41-2.10 | 0.86 |
| Ischemic Injury Scale score | -0.07 | -0.55-0.40 | 0.76 | 0.66 | -0.33-1.65 | 0.19 |
TBI, traumatic brain injury; LOC, loss of consciousness; msTBI, moderate to severe TBI; CI, confidence interval; FTLD, frontotemporal lobar degeneration; TDP, transactive response deoxyribonucleic acid-binding protein.
All estimates are odds ratios with exception of ischemic injury scale, which is unstandardized beta. Binary logistic regression tested the associations for binary outcomes, including Alzheimer's disease, Lewy body disease, and FTLD. Ordinal logistic regression tested the association for Braak stage (stage 0, I/II, III/IV, V/VI) and CERAD neuritic plaque score (no, sparse, moderate, frequent). Linear regression was used for the ischemic injury scale score, which is a summary composite severity of hippocampal sclerosis, infarcts/lacune (absent/present), microinfarcts (absent/present), microbleeds (absent/present), laminar necrosis, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, white matter rarefaction, and cribriform state. Models controlled for age at death and years of football play.
Because of missing data, sample sizes included: Alzheimer's disease, FTLD, and CERAD neuritic plaque score: 579; Lewy body disease: 578; TDP-43 inclusions: 554; Braak stage: 572; ischemic injury scale score: 524.
Post hoc power analyses
We conducted post hoc power analyses to confirm that we were statistically powered to detect significant effects for TBI. Based on a sample size of 345 who had TBI with LOC and 235 who had TBI without LOC (n = 580), the logistic regression models predicting CTE neuropathology binary outcomes (yes/no, CTE stage) were 80% powered to detect an OR of 1.4 at a two-tailed alpha of 0.05.
Discussion
The current study examined the relationship between history of TBI and CTE neuropathology in 580 brain donors with a history of playing American football. Findings indicated that history of TBI with LOC and msTBI were not associated with CTE neuropathology or severity, nor did TBI with LOC or msTBI moderate the effect of years of football play (a proxy for duration of RHI) on CTE neuropathology. While higher rates of CTE neuropathology were identified among those without a history of msTBI, this effect was diminished when years of American football play was added to the model. Consistent with previous research from the UNITE Brain Bank,8 years of American football play was strongly associated with CTE neuropathology status and severity. Analyses did not identify significant relationships between history of TBI with LOC and history of msTBI with other neurodegenerative and cerebrovascular pathologies.
Duration of play is the primary risk factor for the development of CTE neuropathology among former American football players.7,8,42 Among 266 brain donors (223 with autopsy-confirmed CTE), more years of American football play was associated with a 1.30 odds (per year played) for having CTE neuropathology.8 Another study found neuropathological evidence of autopsy-confirmed CTE only among CCS athletes in their neurodegenerative disease brain bank.5 CTE neuropathology will not develop in everyone exposed to RHI, and the role of potential risk or modifying factors is unclear.
Previous small studies have investigated TBI. CTE neuropathology was not detected in the 33 donors with a history of a single TBI from falls, motor vehicle accidents, domestic violence, or assaults.5 Another study found that number of concussions was not significantly associated with CTE neuropathology status or severity.8
As the largest study of its kind, the current findings are consistent with past findings and demonstrate a lack of an association between informant-derived estimates of TBI exposure and CTE neuropathology in former football players. It is possible that, while TBI has the potential to lead to acute neuropathological changes including the development of tau deposition,43 ultimate progression from these acute changes to diagnosis of CTE on neuropathological assessment may be dependent on factors that have not yet been studied.44 The findings also emphasize the importance of assessing and accounting for RHI and TBI when modeling long-term outcomes associated with lifetime head trauma exposure of diverse etiologies.
History of TBI has been associated with all-cause dementia,13–15,17 as well as AD dementia. Interpretation of the relationship between TBI with and without LOC and AD dementia is complicated by the use of clinical diagnoses versus AD confirmed by autopsy or biomarker data.38,45,46 Further, in studies that have included neuropathological findings, there has been variability in the types of neurodegenerative and cerebrovascular neuropathological changes associated with TBI.20–23
Current findings did not identify significant relationships between history of TBI with LOC or msTBI and a range of neurodegenerative and cerebrovascular markers in this sample of donors who played football. It is possible that the association between duration of play and neurodegenerative conditions may have accounted for the majority of the variance in this sample, as has been shown previously,41,48 resulting in the lack of association between history of TBI with LOC or msTBI with numerous neurodegenerative and cerebrovascular markers.
There remain several limitations associated with the sample, in addition to the use of retrospective data. Because the overall donor sample largely comprised individuals who played American football, nearly all donors were male. We also excluded donors who did not have a history of playing American football because of small sample sizes of other sources of RHI and to obtain homogenous RHI exposure. As an example, the next most represented sport in this data set was soccer, and only 28 brain donors played soccer (and not American football).
The current results only generalize to male American football players, particularly those who are symptomatic. Note that while symptomatic status is not part of the brain bank eligibility criteria, those who have symptoms tend to be more likely to donate. Therefore, there is an inherent selection bias, and this is further evidenced by differences in the distribution of causes of death in this sample compared with those reported in a mortality cohort study of former National Football League players.47
Most donors also had a history of TBI, and current analyses lacked a no RHI/no TBI reference group. Therefore, our findings only reflect the role of TBI in the setting of football exposure. Future inclusion of a larger sample of donors without a history of TBI would allow for important group-level comparisons. Given that all clinical data were collected post-mortem and were not corroborated by medical records, data represented retrospective recall from an informant at one point in time, which may have introduced bias and/or the potential for inaccuracies. The potential for misclassification of donors into the incorrect TBI group (e.g., an individual with a history of TBI that may have been unknown or unreported by the informant thereby being classified in the no TBI group) is a particular concern because it has the potential to result in bias toward the null.
Finally, the small sample of donors with a history of msTBI may have resulted in underpowered analyses for this subset. We are also unable to distinguish msTBI obtained in the context of RHI (in the context of RHI from football) versus other settings (e.g., motor vehicle accident) and, given evidence that individuals with a history of msTBI had fewer years of play, it is possible that they also had reduced RHI.
Conclusions
Before the current study, there have been no large post-mortem studies examining the association between exposure to TBI with LOC and CTE pathology risk in a sample with well-characterized history of exposure to RHI. Our findings do not suggest that TBI with LOC or msTBI influences risk for CTE neuropathology in former American football players. Instead, the current findings continue to support exposure to RHI as the primary risk factor for CTE neuropathology.
Transparency, Rigor and Reproducibility Summary
The analysis plan was not formally pre-registered because it is non-human subject research. The team member with oversight and primary responsibility for the analysis plan was Dr. Yorghos Tripodis. This study is part of a larger ongoing study known as the UNITE study. The UNITE study has been ongoing since approximately 2014; we leveraged the UNITE study to conduct this ancillary study and used the sample size at the time of 2021 data freeze. Sample size was 710 brain donors, which was reduced to 580 following exclusions; 235 donors with no history of TBI or history of TBI without loss of consciousness and 345 donors with a history of TBI with loss of consciousness. The sample was restricted to brain donors who played football (n = 125 excluded) because this sub-group offers homogeneity in their demographic and RHI exposure characteristics to facilitate inferences and interpretation of associations. Five donors were excluded due to missing data on primary study variables, namely CTE neuropathology status and TBI. Aspects of data collection (i.e., interviews with donor informants) were performed by investigators who were aware of relevant participant characteristics but blinded to neuropathology. Neuropathological examination was conducted by investigators (neuropathologists) who were blinded to relevant characteristics of the participants (i.e., clinical history). All equipment and software used to perform acquisition and analysis are widely available. Key inclusion criteria are established standards in the field. Statistical analyses were performed by Dr. Alosco with oversight from Dr. Tripodis, a biostatistician with expertise in this field of study. A false discovery rate (FDR) adjusted p value less than or equal to 0.05 defined statistical significance for primary models. Aspects of the data are shared and publicly available through FITBIR. Data is also available upon reasonable request.
Authors' Contributions
JEC: conceptualization, methodology, writing – original draft, writing – review & editing. CEJ: conceptualization, methodology, writing – original draft, writing – review & editing. YT: formal analysis, methodology, validation, writing – review & editing. CN: conceptualization, writing – review and editing. KDC: conceptualization, methodology, writing – review and editing. EP: writing – original draft, writing – review and editing. MU: investigation, project administration, writing – review and editing. BA: investigation, writing – review and editing. EN: investigation, writing – review and editing. BM: data curation, methodology, writing – review and editing. JP: data curation, methodology, writing – review and editing. DIK: investigation, writing – review and editing. BD: investigation, writing – review and editing. DHD: investigation, writing – review and editing. LEG: investigation, writing – review and editing. NWK: investigation, writing – review and editing. RCC: investigation, writing - review and editing. RAS: investigation, writing – review and editing. BRH: investigation, project administration, writing – review and editing. JFC: writing – review and editing. JM: investigation, project administration, methodology, conceptualization, writing – review and editing. TDS: investigation, project administration, methodology, conceptualization, writing – review and editing. ACM: investigation, project administration, methodology, conceptualization, writing – review and editing. MLA: conceptualization, formal analysis, investigation, methodology, project administration, supervision, writing – original draft, writing – review and editing.
Funding Information
This work was supported by grant funding from the NIH (K23NS102399; P30AG072978; U54NS115266), as well as the Nick and Lynn Buoniconti Foundation.
Author Disclosure Statement
No competing financial interests exist.
Potential Conflicts Of Interest
CJN is a volunteer member of the Mackey-White Committee of the NFL Players Association and compensated advisor to Oxeia Biopharmaceuticals. KDC reports payments from various law firms as a medical legal expert on TBI. DHD reports options holder and scientific advisor at Stata Dx and is a medical legal expert on TBI cases. LEG has received funding from the WWE and Ivivi Health Sciences. RCC is a paid consultant to the NFL Head Neck and Spine Committee, NOCSAE, Concussion Legacy Foundation, receives royalties from book publications, and compensation from expert legal opinion. RAS is a member of the Mackey-White Committee of the NFL Players Association. He is a paid consultant to Biogen (Cambridge, MA). He receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL) and is a member of the Board of Directors of King-Devick Technologies (Chicago, IL). ACM is a member of the Mackey-White Committee of the NFL Players Association. MLA reports honorarium from Michael J. Fox Foundation for services unrelated to this study. He receives research support from Life Molecular Imaging Inc and Rainwater Charitable Foundation Inc. He also receives royalties from Oxford University Press, Inc.
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