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Observational Study
. 2025 May 27;104(10):e213584.
doi: 10.1212/WNL.0000000000213584. Epub 2025 Apr 21.

Catecholamine Dysregulation in Former American Football Players: Findings From the DIAGNOSE CTE Research Project

Suzan van Amerongen  1   2 , Elaine R Peskind  3   4 , Yorghos Tripodis  5   6 , Charles H Adler  7 , Laura J Balcer  8 , Charles Bernick  9 , Michael L Alosco  6   10   11 , Douglas Katz  11   12 , Sarah J Banks  13 , William B Barr  8 , Robert C Cantu  6   14 , David W Dodick  7   15 , Yonas E Geda  16 , Jesse Mez  6   10   11 , Jennifer V Wethe  17 , Jason L Weller  18   19 , Daniel H Daneshvar  20 , Joseph Palmisano  21 , Tess Fagle  6 , Minna Holleck  6 , Bailey Kossow  6 , Surya Pulukuri  6 , Fatima Tuz-Zahra  5 , Elizabeth Colasurdo  4 , Carl Sikkema  4 , Jeffrey Iliff  3   4 , Ge Li  3   4   22 , Martha E Shenton  23 , Eric M Reiman  24 , Jeffrey L Cummings  25 , Robert A Stern  6   10   11   26 ; DIAGNOSE CTE Research Project
Collaborators, Affiliations
Observational Study

Catecholamine Dysregulation in Former American Football Players: Findings From the DIAGNOSE CTE Research Project

Suzan van Amerongen et al. Neurology. .

Abstract

Background and objectives: Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism.

Methods: In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups.

Results: The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup.

Discussion: We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.

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Conflict of interest statement

S. van Amerongen reports no disclosures relevant to the manuscript. E.R. Peskind served as consultant, on scientific advisory boards, or on data monitoring committees for Eli Lilly, Avanir, Acadia, Roche, Regeneron, and ALPHA-Cognition. Y. Tripodis and C.H. Adler report no disclosures relevant to the manuscript. L.J. Balcer is editor-in-chief of the Journal of Neuro-Ophthalmology. C. Bernick receives research support from the Ultimate Fighting Championship, Top Rank promotions, and Haymon Boxing. M.L. Alosco receives royalties from Oxford University Press Inc.; has received a single time honorarium from the Michael J. Fox Foundation for services unrelated to this study; and reports research support from Life Molecular Imaging Inc. and Rainwater Charitable Foundation Inc. D. Katz received royalties from Springer/Demos Publishing for a textbook on brain injury; serves as an expert witness in legal cases involving brain injury and concussion; receives a stipend from Encompass Health as program medical director for brain injury and chair of the annual Neurorehabilitation conference; and has received an honorarium for a keynote address for the HealthSouth Annual Medical Directors Meeting. S.J. Banks reports no disclosures relevant to the manuscript. W.B. Barr provides expert witness testimony in legal cases involving concussion and CTE. R.C. Cantu is senior advisor to the NFL Head Neck & Spine Committee; is Vice President, National Operating Committee on Standards for Athletic Equipment; is Chair, Scientific Advisory Committee, Co-Founder, and Medical Director, Concussion Legacy Foundation; is a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation; and receives royalties for published books from Houghton Mifflin Harcourt. D.W. Dodick has consulted for Amgen, Atria, CapiThera Ltd., Cerecin, Ceruvia Lifesciences LLC, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, Escient, GlaxoSmithKline, Halion, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer; has received honoraria from the American Academy of Neurology, the Headache Cooperative of the Pacific, the Headache Cooperative of New England, the Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company (Clinical Education Alliance LLC), Teva (speaking), Amgen Japan (speaking), Eli Lilly Canada (speaking), Lundbeck (speaking), Pfizer (speaking), Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, the Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, Medica Communications LLC, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press; holds nonprofit board membership for the American Brain Foundation, the American Migraine Foundation, ONE Neurology, the Precon Health Foundation, the Global Patient Advocacy Coalition, the Atria Health Collaborative, the Atria Academy of Science and Medicine, the Arizona Brain Injury Alliance, the Domestic Violence HOPE Foundation/Panfila, and the CSF Leak Foundation; has received research support from the Department of Defense, the National Institutes of Health, the Henry Jackson Foundation, the Sperling Foundation, the American Migraine Foundation, the Henry Jackson Foundation, and the Patient Centered Outcomes Research Institute (PCORI); has stock options/is a shareholder/has patents/is a member of the board of directors for Ctrl M (options), Aural Analytics (options), Axon Therapeutics (board/options), ExSano (options), Palion (options), Keimon Medical (options), Man and Science, Healint (options), Theranica (options), Second Opinion/Mobile Health (options), Epien (options), Nocira (options), Matterhorn (shares), Ontologics (shares), King-Devick Technologies (options/board), Precon Health (options/board), ScotiaLyfe (Board), EigenLyfe (Options/Board), AYYA Biosciences (options), Axon Therapeutics (options/board), Cephalgia Group (options/board), Atria Health (options/employee); Patent 17189376.1–1466: Title: Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (Non-royalty–bearing); and has submitted a patent application for Synaquell (Precon Health). Y.E. Geda receives funding from the NIH and Roche and served on the Lundbeck Advisory Board. J. Mez, J.V. Wethe, and J.L. Weller report no disclosures relevant to the manuscript. D.H. Daneshvar serves as an expert witness in legal cases involving brain injury and concussion and serves as an advisor and options holder for StataDx. J. Palmisano, T. Fagle, M. Holleck, B. Kossow, S. Pulukuri, F. Tuz-Zahra, E. Colasurdo, and C. Sikkema report no disclosures relevant to the manuscript. J. Iliff serves as the Chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. G. Li and M.E. Shenton report no disclosures relevant to the manuscript. E.M. Reiman is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity, and a cofounder of ALZPath. J.L. Cummings has provided consultation to Acadia, Acumen, ALZpath, Annovis, Aprinoia, Artery, Biogen, Biohaven, BioXcel, Bristol Myers Squibb, Eisai, Fosun, the GAP Foundation, Green Valley, Janssen, Karuna, Kinoxis, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, MoCA Cognition, New Amsterdam, Novo Nordisk, Optoceutics, Otsuka, Oxford Brain Diagnostics, Praxis, Prothena, ReMYND, Roche, Scottish Brain Sciences, Signant Health, Simcere, Sinaptica, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. R.A. Stern is a member of the Board of Directors of King-Devick Technologies Inc. (Chicago, IL); and receives royalties for published neuropsychological tests from Psychological Assessment Resources Inc. (Lutz, FL) and consulting fees from Eisai. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Study Sample Flowchart
COL = former college football; PRO = former professional football; RHIs = repetitive head impacts; UE = asymptomatic unexposed male.
Figure 2
Figure 2. Biomarker Concentrations Across Exposure Groups
Box plots visualizing adjusted means of log-transformed catecholamine concentrations, with p values obtained from ANCOVA models, including covariates age, self-identified race, BMI, and use of catecholamine agents. ANCOVA = analysis of covariance; COL = former college football; DA = dopamine; DHPG = dihydroxyphenylglycol; DOPAC = 3,4-dihydroxyphenylacetic acid; l-DOPA = 3,4-dihydroxyphenylalanine; NE = norepinephrine; PRO + COL = former professional and college (groups combined); PRO = former professional football; UE = asymptomatic unexposed male.
Figure 3
Figure 3. Association Between Biomarkers and Impulsivity in Former Football Players
Partial regression plots visualizing associations between biomarker concentrations and impulsivity, adjusted for covariates age, BMI, self-identified race, and use of catecholamine agents. Plots were selected based on their relevance and significant findings within the COL group. BMI = body mass index; COL = former college football; DA = dopamine; DHPG = dihydroxyphenylglycol; DOPAC = 3,4-dihydroxyphenylacetic acid; l-DOPA = 3,4-dihydroxyphenylalanine; NE = norepinephrine; PRO = former professional football.
See this image and copyright information in PMC

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