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. Author manuscript; available in PMC: 2025 Mar 1.
Published in final edited form as: Parkinsonism Relat Disord. 2023 Nov 14;120:105903. doi: 10.1016/j.parkreldis.2023.105903

Examination of Parkinsonism in Former Elite American Football Players

Michael L Alosco 1, Charles H Adler 2, David W Dodick 2, Yorghos Tripodis 3, Laura J Balcer 4, Charles Bernick 5, Sarah J Banks 6, William B Barr 7, Jennifer V Wethe 8, Joseph N Palmisano 9, Brett Martin 9, Kaitlin Hartlage 9, Robert C Cantu 10, Yonas E Geda 11, Douglas I Katz 1, Jesse Mez 1,12, Jeffery L Cummings 13, Martha E Shenton 14,15, Eric M Reiman 16, Robert A Stern 1,17, DIAGNOSE CTE Research Project
PMCID: PMC10922636  NIHMSID: NIHMS1948261  PMID: 37981539

Abstract

Background:

Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature.

Objective:

Former football players were prospectively assessed for parkinsonism.

Methods:

120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher’s Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise.

Results:

Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p=0.037) but not college players (p=0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 sec, p<0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes.

Conclusions:

Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

Keywords: Traumatic Encephalopathy Syndrome, Parkinsonism, Chronic Traumatic Encephalopathy

INTRODUCTION

Autopsy studies have associated traumatic brain injury (TBI) with diverse pathologies, including those that can cause parkinsonism (i.e., Lewy body disease, LBD).1-8 Exposure to repetitive head impacts (RHI) from American football and other contact sports can also result in long-term neurological disorders, such as the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE),9-14 LBD,15 and other pathologies.10,16-20 The historical origins of CTE date to 1928 when the term ‘punch drunk’ was used to describe a clinical syndrome in Olympic boxers that included parkinsonism.21 Other case reports described a similar clinical syndrome associated with boxing (e.g., ‘dementia pugilistica’),22,23 with emphasis on parkinsonism. CTE was initially found in a single former American football player in 2005,24 but now the neuropathology of CTE is well-defined based on autopsy studies of football players and other athletes exposed to RHI.12,13,25 Characterization of the clinical presentation of CTE is of high priority to facilitate accurate pre-mortem diagnosis. The revised 2021 NINDS Research Criteria for the clinical syndrome of CTE, traumatic encephalopathy syndrome (TES), has parkinsonism as a supportive but not core feature,26,27 and designates levels of certainty for underlying CTE pathology (TES-suggestive, TES-possible, TES-probable).

A mortality study found increased risk of death due to Parkinson’s disease (PD) in 3,439 former National Football League (NFL) players who played between 1959-1988.28 However, there is a lack of prospective objective examination studies of parkinsonism in former football players, a population at high risk for CTE.12,14 Those that exist have been based on informant reports of brain donors.12,27 To our knowledge the only objective examination study found no differences in motor signs and symptoms between 45 former Canadian Football League players and 25 age- and education-matched controls without a history of concussion.29 Systematic research on parkinsonism in the setting of RHI exposure, including amongst former American football players, is a knowledge gap that needs to be addressed.

The present study, 4x larger than the previously reported study, examined motor function in former college and professional American football players from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project30 using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS),31 and other measures. Motor measures were compared between the former football players and same-age asymptomatic men without a history of RHI or TBI. We also evaluated the association between motor function and the 2021 TES research diagnostic criteria.[26]

METHODS

Participants and Study Design

Participants were from the DIAGNOSE CTE Research Project.30 The study enrolled 240 males, ages 45-74, including 120 former NFL players, 60 former college football players, and 60 asymptomatic men without a history of RHI or TBI. Baseline evaluations were completed between September 2016 and February 2020. Inclusion and exclusion criteria are described elsewhere.30 In brief, the former college football players must have played ≥6 years of organized football with ≥3 years at the college level. Former professional football players must have played ≥12 years of organized football, including ≥3 in college and ≥4 in the NFL. They must have played one of the following positions at their highest level of play: offensive lineman, defensive lineman, linebacker, running back, receiver, or defensive back. Individuals whose primary position was kicker or quarterback were not included as players at these positions have much less exposure to RHI than the other positions in American football. Although recruitment for the former football players was not based on cognitive (or neuropsychiatric) status, most football players had subjective cognitive, mood, and/or behavioral concerns at screening. A complete description of the symptomatic status of the DIAGNOSE CTE sample has been described elsewhere.32

The inclusion criteria for the asymptomatic unexposed men included no history of TBI or RHI, no participation in organized contact sports or military combat, absence of self-reported formal diagnosis or treatment of psychiatric illness or cognitive impairment, no self-reported cognitive, behavioral or mood symptoms at study telephone screening and a body mass index ≥24. All participants were required to have an informant and adequate decisional capacity at the time of their baseline visit to participate. Additional details of enrollment criteria and recruitment methods have been reported.30

Participants were evaluated at either Boston University Chobanian & Avedisian School of Medicine, Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Mayo Clinic College of Medicine in Arizona, or NYU Langone Medical Center. Participants underwent a two-day baseline study visit that included a comprehensive motor examination and other procedures not relevant to this study detailed elsewhere.30 All sites received approval by their Institutional Review Board. Participants provided written informed consent. Research was completed in accordance with Helsinki Declaration.

MDS-UPDRS, parkinsonism, and TES diagnoses

Board-certified neurologists assessed participants for parkinsonism using the MDS-UPDRS motor examination.33 Neurologists were not blinded to group status. Each examination component is rated on a 0-4 scale (0 = normal; 1 = slight; 2 = mild; 3 = moderate; and 4 = severe). Scores were summed to yield a Part III total score. For each participant, the MDS-UPDRS findings were presented at a multidisciplinary diagnostic consensus conference, along with other histories, where consensus-based diagnosis of parkinsonism was determined and TES diagnoses were adjudicated using the 2021 TES criteria.[26] This included TES yes/no based on substantial exposure to RHI, core clinical features (i.e., cognitive impairment and/or neurobehavioral dysregulation), progressive course, and symptoms not being fully accounted for by another disorder. Level of CTE certainty (i.e., suggestive, possible, probable) was determined based on the clinical course, functional difficulties, and supportive features. Parkinsonism is one supportive feature of TES criteria that is used to determine CTE level of certainty and therefore associations between assessments of parkinsonism and CTE certainty levels were not tested. A complete description of consensus procedures is provided in Alosco et al.30 Briefly, the consensus conferences include various clinicians (neuropsychologists, neurologists, psychiatrists, neurosurgeon) across 7 insitutions. One clinician from at least three of the four participant evaluation sites were required, along with a minimum of two neurologists and two neuropsychologists (from different centers) as a quorum for the consensus conferences. At each consensus conference, symptoms, symptom course, medical and psychiatric history, neurodevelopmental history and other clinical data were presented followed by test scores from their DIAGNOSE CTE evaluation (including self-report cognitive, neuropsychiatric, sleep and neurological measures). Based on the presentation of this data, clinicians came to consensus on each individual component of the TES criteria and overall TES diagnoses.

Parkinsonism was defined as the presence of bradykinesia plus either rest tremor or rigidity. As there is no single definition for parkinsonism using the MDS-UPDRS part III exam scoring, for this study bradykinesia required a score of ≥1 for two limb motor tests on the same side of the body (arm/leg) or a score of ≥2 on one limb motor test. Rest tremor required a score for a limb or the jaw of ≥2 (includes both tremor amplitude and duration components) while limb rigidity (not neck) required a score of ≥1 of any limb with no other clear etiology. The presence of bradykinesia alone was not sufficient to meet the criteria for diagnosis of parkinsonism. Additionally, bradykinesia of the face, speech, body, as well as findings for posture, gait, freezing, arising from a chair, and postural instability on the MDS-UPDRS were not used for a diagnosis of parkinsonism but were used for other data analysis.

Timed Up and Go (TUG)

The TUG test assessed mobility and balance.34-37 The participant began in a seated position in a chair, and was asked to stand from the chair, walk to a marked line 10 feet away at a normal pace, turn, walk back to the chair at a normal pace, and sit down. Two trials were performed, total time to completion in seconds for each trial was recorded, and the outcome variable was the mean of the two trials.

Sample Characteristics

Semi-structured interviews were performed, supplemented by online questionnaires, to collect data on demographics, medical and psychiatric history, athletic history, and other variables not relevant to the present study. An aliquot of whole blood was used for APOE genotyping. Race and ethnicity were self-reported. Because a majority of the sample was Black or White there was insufficient representation of other racial groups to statistically examine them separately. All racial groups are presented in Table 1. The Alcohol Use Disorder Identification Test (AUDIT) was used to assess symptoms of unhealthy alcohol use behaviors.38 The Montreal Cognitive Assessment (MoCA) was used to provide data on global cognitive status of the sample.

Table 1.

Sample Characteristics of Former American Football Players and Same Age Asymptomatic Unexposed Men

Former
Football
Players
(n = 178)		 Former
Professional
Players
(n = 120)		 Former
College
Players
(n = 58)		 Asymptomatic
Unexposed Men
(n = 60)		 P-valued
Demographics
Age, mean (SD, range) years 57.07 (8.13, 45-74) 59.09 (7.83, 45-74) 52.90 (7.16, 45-74) 59.27 (8.26, 45-74) PRO: 0.89
COL: <0.01
Education, mean (SD) years 16.72 (1.45) 16.58 (1.11) 17.03 (1.95) 17.32 (3.40) PRO: 0.10
COL: 0.57
Race, n (%) PRO: 0.67
COL: 0.01
 American Indian or Alaska Native 0 0 0 0
 Black or African American 63 (35.4) 52 (43.3) 11 (19.0) 24 (40.0)
 Native Hawaiian or other Pacific Islander 0 0 0 1 (1.7)
 White 112 (62.9) 66 (55.0) 46 (79.3) 35 (58.3)
 Multiple races 3 (1.7) 2 (1.7) 1 (1.7) 0
Athletic
Total years of football, mean (SD) years 15.87 (4.38) 18.02 (3.34) 11.42 (2.52) - --
TES and Genetic Status
TES CTE level of certainty, n (%)a --
 No 62 (35.0) 36 (30.3) 26 (44.8) --
 Suggestive 35 (19.8) 21 (17.6) 14 (24.1)
 Possible 21 (11.9) 15 (12.6) 6 (10.3)
 Probable 59 (33.3) 47 (39.5) 12 (20.7)
ε4 carrier, n (%)b 53 (30.8) 33 (28.7) 20 (35.1) 11 (19.6) PRO: 0.20
COL: 0.07
Global Cognitive Status, mean (SD)
Montreal Cognitive Assessmentc 24.69 (3.41) 24.32 (3.46) 25.47 (3.19) 26.50 (2.33) PRO: <0.01
COL: 0.05
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n=number; SD= standard deviation; TES= Traumatic Encephalopathy Syndrome; CTE= Chronic Traumatic Encephalopathy; PRO = former professional American football players; COL = former college American football players. The total sample size is based on participants who had complete data on the MDS-UPDRS Part III (n = 2 former college football players were excluded). athere was missing data for one former professional player; bthere was missing data for 10 participants; cMissing data for 1 former professional football player; dIndependent samples t-test compared the former professional and college football players, separately, to the asymptomatic unexposed men on continuous outcomes and chi-square or Fisher’s exact test (for cell sizes <10) were used for binary outcomes. Race was examined as Black versus non-Black.

Sample Size

The final sample size included 120 former professional football players, 58 former college football players (two were excluded due to missing data), and 60 asymptomatic unexposed men. Missing data resulted in a sample size of 232 for analyses of the TUG data.

Statistical Analyses

Independent samples t-test and chi-square or Fisher’s exact test compared the former football players (college and professional separately) and the asymptomatic unexposed men on demographic, athletic, clinical, and genetic factors. The primary independent variables included football players versus asymptomatic unexposed men, TES status (yes/no) and TES level of CTE certainty (TES no, TES-CTE suggestive, TES-CTE possible, and TES-CTE probable). When compared to the asymptomatic unexposed men, analyses were done that examined college and professional football players separately. The primary outcomes included parkinsonism (yes/no), MDS-UPDRS Part III total score, and TUG completion time (mean of Trials 1 and 2). Fisher’s Exact Test was used to test the association between football play (professional versus unexposed men, college versus unexposed men) and TES parkinsonism diagnosis. As described in the Results, cell sizes for parkinsonism were low and less than 10 in the unexposed men. Thus, we were not statistically powered to conduct binary logistic regression or other similar models that allowed for adjustment of covariates. However, the association between parkinsonism and relevant covariates was examined. Univariate analysis of covariance (ANCOVA) compared the former football players and the asymptomatic unexposed men on the MDS-UPDRS Part III summary score and TUG completion time, controlling for age and BMI.

Fisher’s Exact Test was used to test the association between TES yes/no and odds for having parkinsonism among the former football players. ANCOVA models controlling for age and BMI compared the TES yes/no groups (among former football players only) on the MDS-UPDRS Part III summary score and TUG completion time. The TUG time was compared across the TES level of certainty groups in the former football players (i.e., TES no, TES-CTE suggestive, TES-CTE possible, TES-CTE probable). Differences in parkinsonism and the MDS-UPDRS Part III summary across the level of CTE certainty groups were not compared because they informed the certainty levels.

Among the former football players, the association between proxies of exposure to RHI (i.e., years of football play, age of first exposure to football, position played at highest level, level played)14,39 and MDS-UPDRS Part III total score and TUG completion time using multivariable linear regressions were tested, controlling for age and BMI.

Analyses that examined the association between age of first exposure and outcomes also controlled for total years of football play. A p-value less than 0.05 defined statistical significance. Analyses were performed in SPSS version 27.

DATA SHARING

Data from the DIAGNOSE CTE Research Project will be available to qualified investigators through the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System, through the National Institutes of Health Center for Information Technology: https://fitbir.nih.gov/content/access-data. DIAGNOSE CTE Research Project data, including those reported in this study, will also be available to qualified investigators through a project-specific data-sharing portal. Interested investigators should contact Dr. Robert A. Stern, bobstern@bu.edu.

RESULTS

Sample Characteristics

Sample characteristics are shown in Table 1. There were no differences between the former professional football players and asymptomatic unexposed men in terms of age, race, years of education, or APOE ε4 carrier status. However, former professional football players had lower MoCA scores (p<0.01). The former college football players were younger and more likely to self-report being White compared to the asymptomatic unexposed men; there were no other group differences for the former college football players. Compared with the asymptomatic unexposed men, the former football players (both college and professional) had higher scores on the AUDIT, a higher BMI and were more likely to have various orthopedic injuries (Table 2). No asymptomatic unexposed man and only 3% of former players were taking any type of neuroleptic. Three former football players (2 college, 1 professional) self-reported being diagnosed with Parkinson’s disease (Table 3) with two being prescribed pramipexole and one carbidopa/levodopa.

Table 2.

Relevant Comorbid Medical Factors in Former Professional and College American Football Players and Same Age Asymptomatic Unexposed Men

Former
Football
Players
(n = 178)		 Former
Professional
(n = 120)		 Former
College
(n = 58)		 Asymptomatic
Unexposed
Men
(n = 60)		 P-valued
Body mass index, mean (SD) kg/m2 32.62 (4.66) 31.99 (4.46) 33.93 (4.84) 30.78 (4.52) PRO: 0.09
COL: <0.01
AUDIT, mean (SD) 5.01 (5.71) 4.80 (5.55) 5.45 (6.07) 3.00 (3.26) PRO: 0.01
COL: 0.01
Hip replacement, n (%)a 17 (19.6) 12 (10.1) 5 (8.6) 0 PRO: 0.01
COL: 0.03
Knee replacement, n (%) 22 (12.4) 21 (17.5) 1 (1.7) 2 (3.3) PRO: 0.01
COL: 1.00
Other joint replacement, n (%) 13 (7.3) 11 (9.2) 2 (3.4) 1 (1.7) PRO: 0.06
COL: 0.62
Back surgery, n (%) 27 (15.2) 22 (18.3) 5 (8.6) 2 (3.3) PRO: 0.01
COL: 0.27
Other orthopedic surgeries, n (%)b 137 (77.0) 101 (84.2) 36 (62.1) 11 (18.3) PRO: <0.01
COL: <0.01
History of fractured bones, n (%)c 134 (75.3) 89 (74.2) 45 (77.6) 26 (43.3) PRO: <0.01
COL: <0.01
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Note. n=number; SD= standard deviation; PRO = former professional college football players; COL = former college football players. The total sample size is based on participants who had complete data on the MDS-UPDRS Part III (n = 2 former college football players were excluded). For former football players, an = 1 with missing data; bn=2 unknown (PRO) and the orthopedic surgeries consisted of a constellation of various upper and lower extremity surgeries; cn=4 unknown (n = 1 asymptomatic unexposed men, n=2 COL, n=1 PRO). dIndependent samples t-test compared the former professional and college football players, separately, to the asymptomatic unexposed men on continuous outcomes and Fisher’s exact test (for cell sizes <10) were used for binary outcomes.

Table 3.

Motor Signs in Former American Professional Football Players and Same Age Asymptomatic Unexposed Men

Former
Football
Players
(n = 178)		 Former
Professional
(n = 120)		 Former
College
(n = 58)		 Asymptomatic
Unexposed
Men
(n = 60)		 P-valued
Self-reported diagnosis of Parkinson’s disease, n (%) 3 (1.7) 1 (0.8) 2 (3.4) 0 --
MDS-UPDRS Part III Total score, mean (SD) 3.20 (5.46) 3.32 (5.69) 2.97 (4.99) 2.60 (3.94) PRO vs Unexp.: 0.53
COL vs Unexp.: 0.67
Parkinsonism, n (%) 22 (12.4) 16 (13.3) 6 (10.3) 2 (3.3) PRO vs Unexp.: 0.037
COL vs Unexp.: 0.16
Timed Up and Go, mean (SD) seconds of Trials 1-2 12.84 (3.20) 13.09 (3.06) 12.33 (2.61) 11.35 (2.33) PRO vs Unexp.: <0.01
COL vs Unexp.: 0.07
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n=number; SD= standard deviation; TES= Traumatic Encephalopathy Syndrome; PRO = former professional American football players; COL = former college American football players.

Univariate analysis of covariance (ANCOVA), controlling for age and BMI, compared the former American football players (separately by level of play) and the asymptomatic unexposed men on the MDS-UPDRS Part III total score, and the Timed Up and Go test (mean of trials 1 and 2). Due to small cell sizes, Fisher’s Exact Test examined association between football play (by level of play) and diagnosis of parkinsonism. N = 232 for the Timed Up and Go test due to missing data

Among the former football players, bivariate correlations showed a higher BMI was associated with higher MDS-UPDRS Part III total score (r = 0.18, p = 0.02). There was no association between age (p = 0.94), years of education (p = 0.10), race (p = 0.15), APOE ε4 carrier status (p = 0.59), or AUDIT (p = 0.35) with the MDS-UPDRS Part III total score. For the TUG, higher BMI (r=0.21, p=0.001) and Black race (compared with non-Black, mean difference = 1.57, p<0.01) were assocatied with longer completion time on the TUG.

Parkinsonism, MDS-UPDRS, and TUG

Table 3 has the motor findings in the sample. A total of 22 of the 178 (12.4%) former football players met criteria for parkinsonism (bradykinesia plus either rest tremor or rigidity or both). 16 (13.3%) former professional football players and 6 (10.3%) former college football players met criteria for parkinsonism while only 2 (3.3%) of the unexposed men met criteria for parkinsonism. Unadjusted Fisher’s Exact Test showed that compared to the asymptomatic unexposed men rates of parkinsonism were higher in the former professional football players (p=0.037) but not the former college football players (p=0.16). The p-value diminished for former professional football players when the football player with PD was excluded (p= 0.06). While other analyses adjusted for age and BMI, we were not able to for this analysis due to the small cell sizes of parkinsonism and inability to conduct binary logistic regression. That said, there were no differences between those with and without parkinsonsim in terms of age (p=0.86) or BMI (p=0.08). As shown in Tables 1 and 2, professional football players and the asymptomatic unexposed men also did not differ on age and BMI.

The ANCOVA showed no significant differences between the former football players (college or professional) and asymptomatic unexposed men on the MDS-UPDRS Part III total score. Across the 18 items on Part III of the MDS-UPDRS, motor abnormalities (defined as an individual item score of ≥1) in the former football players revealed a range of 6.7-18% had bradykinesia of a limb compared to 3.3-13.3% of the unexposed men and that rest tremor was infrequent. Only 5 former football players had a rest tremor, 2 with rest tremors in both hands and 3 with rest tremor of one hand. Fisher’s Exact Test showed no significant differences between the former football players and asymptomatic unexposed men on most of the individual UPDRS items with the exception of gait and action tremor.

For the TUG, the former professional football players had a longer time to completion compared with asymptomatic unexposed men (13.09 versus 11.35 sec, p < 0.01). There were no group differences between the former college football players and asymptomatic unexposed men (p = 0.18). Three former professional football players had a TUG completion time >3 SD from the mean. Group differences remained when outliers were removed (p = 0.001). Group differences remained when the following orthopedic-related variables were included in the model: hip replacement, knee replacement, other joint replacement, and history of back surgery. Findings remained similar when the football players who reported being diagnosed with PD were excluded.

Association between TES and the MDS-UPDRS and TUG

Among the former football players, TES status was not associated with parkinsonism, MDS-UPDRS Part III total scores or TUG completion time (Table 4). In terms of TES level of CTE certainty, there were main effects for TUG completion time (p = 0.02). The pairwise comparisons from the ANCOVA (based on estimated marginal means that accounted for model covariates) showed that the former football players who had TES-CTE probable took a longer time to complete the TUG compared with TES no (p = 0.006) and TES-CTE possible participants (p = 0.02). No other significant differences were observed across the TES groups.

Table 4.

Motor Signs in Former American Professional Football Players with and without Traumatic Encephalopathy Syndrome

TES No
(n = 62)		 TES Yes
(n = 115)		 P-values TES CTE
Suggestive
(n = 35)		 TES CTE
Possible
(n = 21)		 TES CTE
Probable
(n = 59)		 P-values
Parkinsonism, n (%) 5 (8.1) 17 (14.8) 0.24 3 (8.6) 2 (9.5) 12 (20.3) --
MDS-UPDRS Part III total score, mean (SD) 2.58 (3.83) 3.50 (6.17) 0.25 2.00 (12.70) 4.24 (4.92) 4.14 (7.70) --
Timed Up and Go, mean (SD) seconds of Trials 1-2 12.34 (2.49) 13.12 (3.13) 0.08 12.70 (2.53) 12.08 (2.30) 13.78 (3.60) 0.02
(Prob>TES-;
Prob>Poss)
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n=number; SD= standard deviation; TES= Traumatic Encephalopathy Syndrome; CTE= Chronic Traumatic Encephalopathy

*

Analysis of covariance (ANCOVA), controlling for age and BMI, compared the TES Yes/No groups on MDS-UPDRS Part III summary score and the Timed Up and Go. Unadjusted Fisher’s Exact Test examined the association between TES Yes/No groups and Parkinsonism. Differences in Parkinsonism and the MDS-UPDRS Part III summary across the level of CTE certainty groups were not compared because they informed certainty diagnoses. ANCOVA controlling for age and body mass index, compared the TES groups (TES no, TES CTE suggestive, TES CTE possible, TES CTE probable) on the total Timed Up and Go test (mean of Trials 1 and 2). P-value is based on estimated marginal mean differences atht account for the aforementioned covariates.

N = 177 due to missing TES data. Sample size reduced to 172 for Timed Up and Go due to missing data.

Proxies of Exposure to RHI in Former Football Players

Regression analyses controlling for age and BMI showed no significant associations between years of football played and the MDS-UPDRS Part III total score (p = 0.42) and TUG completion time (p = 0.21). There were also no associations between age of first exposure to football and the MDS-UPDRS Part III total score (p = 0.54) and TUG completion time (p = 0.57), controlling for age, BMI, and years of football play. There were no differences between lineman and non-lineman on the MDS-UPDRS Part III total score (p = 0.89) and TUG completion time (p = 0.27). Regarding level of play (i.e., professional versus college), there were no differences between former college and professional football players on the MDS-UPDRS Part III total score (p = 0.50) and TUG completion time (p = 0.05). None of the proxies of exposure to RHI were associated parkinsonism (ps>0.05 for all).

DISCUSSION

This study characterized parkinsonism, motor performance, and gait speed and mobility, in a large sample of former American football players compared with similar age asymptomatic unexposed men. More former professional football players met criteria for parkinsonism, as defined for this investigation. However, the effect size was small and scores on total as well as the individual items on the MDS-UPDRS part III were low and did not differ between groups. The former professional football players and those with the greatest likelihood for having CTE pathology based on clinical symptoms (i.e., TES-CTE probable) had reduced walking speed as measured by the TUG. While differences on the TUG remained when orthopedic surgeries were added to the model, the contribution of these medical factors cannot be fully ruled out given the much higher rates in the former football players. There were no associations between proxies of exposure to RHI (years played, age of first exposure, college or professional) and the motor outcomes.

Previous studies have demonstrated varying degrees of risk for parkinsonism following TBI.40-43 When focusing on those exposed to RHI, parkinsonism and PD have historically been well-documented in boxers21-23 but have been less examined in former football players or other contact sport athletes. There was a 1.69x increased risk of death due to PD in 3,439 former NFL football players who played at least 5 years between 1959-1988 followed through 2007, when compared to the general US population.28 Former professional soccer players had a hazard ratio of 2.15 for mortality with PD compared to controls.44 Despite these findings, the evidence for the presence of parkinsonism in former football players is equivocal. Tarazi et al. found no difference in motor symptoms and signs between 45 former Canadian Football League players and 25 age- and education-matched controls without a history of concussion.29 More recently, a history of football play was found to be associated with increased odds for having a reported diagnosis of parkinsonism or PD in 1875 men (729 played football, 1146 non-football athletes) from the Michael J Fox Foundation online Fox Insight study.45 That sample was enriched for having Parkinson disease (i.e., 85.4% reported being diagnosed) and included all levels of football play. In the present study, the rate of parkinsonism (as defined for this study) in the former football players was 12.4% but the rate was only higher for former professional football players (13.3%) and MDS-UPDRS scores were low. Reasons for discrepancy from the previously described study on football and Parkinson disese in the Fox Insight include the population being studied, sample size, differences in comparison groups, and differences in operationalization of parkinsonism or Parkinson disease (e.g., objective evaluation versus self-reported diagnosis). Rates of parkinsonism in this sample can be compared to the one study of the prevalence of parkinsonism, not Parkinson disease. Llibre-Guerra et al found parkinsonism in 8.8% males 65 and older in Latin America.46 Most epidemiological studies report the incidence or prevalence of PD which is much less frequent than parkinsonism and cannot be used for comparison purposes with the current study.

Compared to asymptomatic unexposed men, former professional but not college football players had longer completion times on the TUG. TUG completion times were also longer among former football players who had TES-CTE probable compared with those who had no TES or TES-CTE possible. The causes of these findings are unclear and likely multifaceted.

Years of American football play, level of American football played, position played, and age of first exposure to American football were not associated with the motor outcomes. In the 1875 men from the Fox Insight study, there was a dose response association between years of football play and odds for having a reported parkinsonism or Parkinson disease diagnosis.45 However, there was much more variability in level and years of play in that sample compared with the restricted range in this sample due to the current cohort all being elite football players. Compared to boxers, parkinsonism may be less common in American football players due to differences in the biomechanics of head trauma and subsequent differential effects on the brain, including regions affected.47,48 Preliminary evidence has shown that boxers exhibit more severe tau pathology in the cerebellar dentate nuclei compared to American football players.48 Boxers are thought to have a twisting motion of the brainstem, ultimately leading to a loss of consciousness or altered mental state.48 This mechanism of impact is different from football players who are exposed to impacts that are mostly linear.48 It is also possible that the restricted variability in motor outcomes limited our statistical power to detect RHI and motor associations. The subtleties of the observed motor abnormalities could partially be attributed to the fact that the participant’s average age at the time of examination is younger than the average age at onset of Parkinson disease, which often does not start until the mid-sixties.49 As with any group of elite male athletes in the age range studied, orthopedic issues, rather than neurologic dysfunction, may have elevated scores of motor testing, although examinations tried to take those into consideration. Finally, we did not include refined metrics of exposure to RHI and those used might not have captured the aspects of RHI exposure that best predict motor symptomatology (e.g., intensity or rotational forces of head impacts).

There were limitations to this study. The former football players, who were inherently required to have exposure to RHI (from football) were selected to span the symptom continuum. In contrast, the comparison group were selected only if they lacked symptoms. In this context, the findings provide additional evidence for low parkinsonism in the former football players given the recruitment design would be expected to magnify group differences. Generalizability of these results are limited to male former elite American football players. Even among the former football players, the findings might have certain restrictions on generalizability given not all positions were included in the study (e.g., quarterbacks, kickers). The former football players had a greater number of orthopedic comorbidities as well as higher BMI and alcohol use (Table 2), and it is not possible to fully determine their role in the findings, particularly given we were not statistically powered for some analyses to include covariates due to the small cell sizes (e.g., parkinsonism). While the sample sizes were small, this is one of the largest prospective studies of parkinsonism in former elite American football players and a strength of the study is that it had no reliance on retrospective symptom recall. Another strength of the study was the detailed consensus conferences that were used to categorize participants as having TES and level of CTE certainty.26 However, the reliability and validity of these criteria have not been confirmed by autopsy examination for CTE or other neuropathologies. While these consensus conferences take into consideration participants complete history, there are ongoing investigations on the role of medical co-morbidities in the symptom presentation of former American football players. Similarly, we do not have DaTscan data to analyze as it was not collected as part of the DIAGNOSE CTE Research Project. We also chose not to include biomarkers of amyloid, tau, or neurodegeneration into this study as there is not enough statistical power given the few participants with parkinsonism in the sample.

In conclusion, the presence of parkinsonism in this sample of American football players was low. The association between American football play and parkinsonism is inconclusive and likely dependent on factors related to sample selection and size and comparison groups used among other methodological reasons. The mechanism of injury, based on the type of RHI or sport, may also be a key factor to consider in which clinical findings such as parkinsonism occur.

Highlights.

  • When adjusted for covariates and multiple comparisons there was no difference in the prevalence of parkinsonism or motor findings on the MDS-UPDRS in former American football players compared to asymptomatic unexposed men

  • Former players did have slowness on the Timed Up and Go (TUG) compared to the asymptomatic unexposed men

  • TUG times were also slower in former football players who had TES-CTE probable compared with those who had no TES and TES-CTE possible

Funding:

This work was funded by the National Institute of Neurological Disorders and Stroke (NINDS), through a U01 Research Project Cooperative Agreement (U01NS093334).

Footnotes

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Financial Disclosures

CHA consulted for Avion, CND Life Sciences, Jazz, and Precon Health. LJB is Editor-in-Chief of the Journal of Neuro-Ophthalmology, and is a paid consultant to Biogen (Cambridge, MA, USA). CB receives research support from the Ultimate Fighting Championship, Top Rank promotions, Haymon Boxing, Las Vegas Raiders, and Professional Bull Riders. He is a paid consultant for Aurora Concussion Therapy Systems, Inc. (St. Paul, MN). JLC has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Biohaven, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI pharmaceutical, assessment, and investment companies. EMR is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Retromer Therapeutics, and Vaxxinity, and a co-founder of ALZPath. RAS is a paid consultant to Biogen (Cambridge, MA, USA) and Lundbeck (Copenhagen, Denmark). He is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL, USA), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL, USA). He has been a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation. DWD reports the following conflicts: Consulting: Genentech, Amgen, Allergan, Abbvie, Lundbeck, Biohaven, Pfizer, Atria Health, CapiThera Ltd., Cerecin, Cooltech, Ceruvia Lifesciences LLC, Ctrl M, Allergan, Biohaven, GSK, Lundbeck, Eli Lilly, Novartis, Impel, Salvia, Satsuma, Theranica, WL Gore, Nocira, Perfood, Praxis, AYYA Biosciences, Revance. Payment or honoraria for lectures, presentations, educational events: Amgen, Novartis, Eli Lilly, Teva, Allergan, Abbvie, Lundbeck, Biohaven, Pfizer. Amgen, Novartis, Eli Lilly, Allergan, Abbvie, Lundbeck, Biohaven Honoraria: Vector psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Research Support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: American Migraine Foundation. American Brain Foundation. International Headache Society Global Patient Advocacy Coalition Stock Options/Shareholder/Patents/Board of Directors: Aural analytics (options), ExSano (options), Cephalgia Group (Stock options/Board), Axon Therapeutics (stock options/Board), Man and Science (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Matterhorn (Shares/Board), Ontologics (Shares/Board), King-Devick Technologies (Options/Board), Precon Health (Options/Board), AYYA Biosciences (Options), Atria Health (options). Patent 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (Non-royalty bearing). Patent application submitted: Synaquell (Precon Health)

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Financial Disclosure/Conflict of Interest: No conflicts of interest. Individual financial disclosures at the end of the document

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