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. 2024 Feb 9;21(1):46.
doi: 10.1186/s12974-024-03034-6.

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project

Suzan van Amerongen  1   2   3 , Surya V Pulukuri  1 , Fatima Tuz-Zahra  4 , Yorghos Tripodis  1   4   5 , Jonathan D Cherry  1   5   6   7   8 , Charles Bernick  9 , Yonas E Geda  10 , Jennifer V Wethe  11 , Douglas I Katz  1   12   13 , Michael L Alosco  1   5   12 , Charles H Adler  14 , Laura J Balcer  15 , Nicholas J Ashton  16   17   18 , Kaj Blennow  16   17 , Henrik Zetterberg  16   17   18   19   20   21   22 , Daniel H Daneshvar  23 , Elizabeth A Colasurdo  24 , Jeffrey J Iliff  24   25 , Gail Li  24   25   26 , Elaine R Peskind  24   25 , Martha E Shenton #  27 , Eric M Reiman #  28 , Jeffrey L Cummings #  29 , Robert A Stern #  30   31   32   33 ; DIAGNOSE CTE Research Project Investigators
Collaborators, Affiliations

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project

Suzan van Amerongen et al. J Neuroinflammation. .

Abstract

Background: Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals.

Methods: Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES.

Results: CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations.

Conclusion: Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Keywords: Biomarkers; CSF; Chronic traumatic encephalopathy; IL-6; Neurodegeneration; Neurofilament light chain protein; Neuroinflammation; Neuropsychiatric symptoms; Repetitive head impacts; Traumatic encephalopathy syndrome.

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Conflict of interest statement

SVA: none to report. SVP: none to report. FTZ: none to report. YT: none to report. JDC: none to report. CB: receives research support from the Ultimate Fighting Championship, Top Rank promotions, and Haymon Boxing. YEG: receives funding from the NIH and Roche, and served on Lundbeck Advisory Board. JVW: None to report. DIK: 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 honoraria for a keynote address for the HealthSouth Annual Medical Directors Meeting. MLA: receives royalties from Oxford University Press for a textbook outside the submitted work. CHA: None to report. LJB is Editor-in-Chief of the Journal of Neuro-Ophthalmology. NJA: none to report. KB: has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. HZ: has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche. DHD: serves as an expert witness in legal cases involving brain injury and concussion and serves as an advisor and options holder for StataDx. EAC: None to report. JJI: None to report. GL: None to report. ERP: has served as consultant, on scientific advisory boards, or on data monitoring committees for Eli Lilly, Avanir, Acadia, Roche, Regeneron, and ALPHA-Cognition. EMR is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity, and a co-founder of ALZPath. MES: None to report. JLC has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, Aprinoia, AriBio, Artery, Biogen, BioVie, Bristol-Myers Squib, Cassava, Cerecin, Diadem, EIP Pharma, Eisai, GemVax, Genentech, GAP Innovations, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/EQT, Merck, NervGen, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, PRODEO, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Suven, SynapseBio, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He owns the copyright of the Neuropsychiatric Inventory. RAS 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), and consulting fees from Eisai.

Figures

Fig. 1
Fig. 1
Adjusted associations between CSF IL-6 and NBD total score. Partial regression plots with results from the entire cohort and age-stratified cohorts of former American football players, adjusted for covariates: age, BMI, race, total AUDIT score, APOE-ε4 carrier, revised Framingham Stroke Risk Profile score, and sleep apnea. Regression results were: β: 0.286, 95%: CI 0.120–0.452, FDR-p: 0.005 (entire cohort), β: 0.247, 95% CI: 0.013–0.481, FDR-p: 0.156 (age < 60), β: 0.366, 95% CI: 0.089–0.642, FDR-p: 0.126 (age ≥ 60)
Fig. 2
Fig. 2
Adjusted associations between Plasma NfL and Impulsivity. Partial regression plots with results from the entire cohort and age-stratified cohorts of former American football players, adjusted for covariates: age, BMI, race, total AUDIT score, APOE-ε4 carrier, revised Framingham Stroke Risk Profile score, and sleep apnea. Regression results were: β: 0.126, 95% CI: − 0.048–0.300, FDR-p: 0.260 (entire cohort), β: − 0.138, 95% CI: − 0.359–0.082, FDR-p: 0.360 (age < 60), β: 0.488, 95% CI: 0.254–0.723, FDR-p: 0.001 (age ≥ 60)
Fig. 3
Fig. 3
Adjusted associations between Plasma NfL and Executive Functioning and Processing Speed. Partial regression plots with results from the entire cohort and age-stratified cohorts of former American football players, adjusted for covariates: age, BMI, race, total AUDIT score, APOE-ε4 carrier, revised Framingham Stroke Risk Profile score, sleep apnea, and years of education. Regression results within the age ≥ 60 cohort: β: − 0.313, 95% CI: − 0.540– − 0.086, FDR-p: 0.03
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