Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project
Authors: van Amerongen Suzan , Pulukuri Surya V. , Tuz-Zahra Fatima , Tripodis Yorghos , Cherry Jonathan D. , Bernick Charles , Geda Yonas E. , Wethe Jennifer V. , Katz Douglas I. , Alosco Michael L. , Adler Charles H. , Balcer Laura J. , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Daneshvar Daniel H. , Colasurdo Elizabeth A. , Iliff Jeffrey J. , Li Gail , Peskind Elaine R. , Shenton Martha E. , Reiman Eric M. , Cummings Jeffrey L. , Stern Robert A. ,   for the DIAGNOSE CTE Research Project Investigators, Chen Kewei , Protas Hillary , Reiman Eric , Su Yi , Boker Connie , Alosco Michael L. , Au Rhoda , Cantu Robert C. , Farrer Lindsay , Helm Robert , Katz Douglas I. , Kowall Neil , Mez Jesse , Mercier Gustavo , Otis James , Stern Robert A. , Weller Jason , Bragg Tahlia , Simkin Irene , Trujillo-Rodriguez Diana , van Amerongen Suzan , Andino Alondra , Conneely Shannon , Diamond Courtney , Fagle Tessa , Haller Olivia , Hunt Tennyson , Gullotti Nicole , Kossow Bailey , Kugelmass Carrie , Mariani Megan , Mayville Brian , McLaughlin Kathleen , Nanna Mary , DiPopolo Marty , Platt Taylor , Pulukuri Surya , Rice Fiona , Sestak Madison , Simkin Irene , McClean Michael , Tripodis Yorghos , Annis Douglas , Chaisson Christine , Dixon Diane B. , Finney Carolyn , Gallagher Kerrin , Hartlage Kaitlin , Lu Jun , Martin Brett , Ojo Emmanuel , Palmisano Joseph N. , Pine Brittany , Ramachandran Janani , Baucom Zachary , Tuz-Zahra Fatima , Yhang Eukyung , Bouix Sylvain , Fitzsimmons Jennifer , Lin Alexander P. , Koerte Inga K. , Pasternak Ofer , Shenton Martha E. , Arciniega Hector , Billah Tashrif , Bonke Elena , Breedlove Katherine , Carrington Holly , Coello Eduardo , Coleman Michael J. , John Omar , Jung Leonard , Liao Huijun , Loy Maria , Rizzoni Elizabeth , Schultz Vivian , Silva Annelise , Vessey Brynn , Wiegand Tim L. T. , Banks Sarah , Bernick Charles , Miller Jason , Ritter Aaron , Sabbagh Marwan , de la Cruz Raelynn , Durant Jan , Golceker Morgan , Harmon Nicolette , Kaylegian Jaeson , Long Rachelle , Nance Christin , Sandoval Priscilla , Staples Miranda , Turner Robert W. , Clark Emma F. , Marek Kenneth L. , Serrano Andrew , Adler Charles H. , Dodick David W. , Geda Yonas , Wethe Jennifer V. , Duffy Amy , Falk Bryce , Howard Marci , Montague Michelle , Osgood Thomas , Babcock Debra , Bellgowan Patrick , Balcer Laura , Barr William , Goldberg Judith , Joseph Binu , Kirov Ivan , Lui Yvonne , Marmar Charles , Wisniewski Thomas , Al-Kharafi Alhassan , George Allan , Hasanaj Lisena , Martin Sammie , Riley Edward , Runge William , Serrano Liliana , Ashton Nicholas , Zetterberg Henrik , Blennow Kaj , Cummings Jeffrey L. , Iliff Jeffrey , Li Gail , Janssen Deidre , Meabon James , Peskind Elaine R. , Piantino Juan , Schindler Abigail , Thomas Ronald , Colasurdo Elizabeth , Shofer Jane , Marcus Daniel S. , Gurney Jenny , Greenwald Richard , Johnson Keith A. 
Published: February 2024

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.