Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project
Year: 2024
Type: article
Study design: Observational Study
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.
Source: Journal of Neuroinflammation
Authors: Suzan van Amerongen, Surya V. Pulukuri, Fatima Tuz-Zahra, Yorghos Tripodis, Jonathan D. Cherry, Charles Bernick, Yonas E. Geda, Jennifer V. Wethe, Douglas I. Katz, Michael L. Alosco, Charles H. Adler, Laura J. Balcer, Nicholas J. Ashton, Kaj Blennow, Henrik Zetterberg, Daniel H. Daneshvar, Elizabeth A. Colasurdo, Jeffrey J. Iliff, Gail Li, Elaine R. Peskind, Martha E. Shenton, Eric M. Reiman, Jeffrey L. Cummings, Robert A. Stern, Kewei Chen, Hillary Protas, Eric Reiman, Yi Su, Connie Boker, Michael L. Alosco, Rhoda Au, Robert C. Cantu, Lindsay Farrer, Robert Helm, Douglas I. Katz, Neil Kowall, Jesse Mez, Gustavo Mercier, James Otis, Robert A. Stern, Jason Weller, Tahlia Bragg, Irene Simkin, Diana Trujillo-Rodriguez, Suzan van Amerongen, Alondra Andino, Shannon Conneely, Courtney Diamond, Tessa Fagle, Olivia Haller, Tennyson Hunt, Nicole Gullotti, Bailey Kossow, Carrie Kugelmass, Megan Mariani, Brian Mayville, Kathleen McLaughlin, Mary Nanna, Marty DiPopolo, Taylor Platt, Surya Pulukuri, Fiona Rice, Madison Sestak, Irene Simkin, Michael McClean, Yorghos Tripodis, Douglas Annis, Christine Chaisson, Diane B. Dixon, Carolyn Finney, Kerrin Gallagher, Kaitlin Hartlage, Jun Lu, Brett Martin, Emmanuel Ojo, Joseph N. Palmisano, Brittany Pine, Janani Ramachandran, Zachary Baucom, Fatima Tuz-Zahra, Eukyung Yhang, Sylvain Bouix, Jennifer Fitzsimmons, Alexander P. Lin, Inga K. Koerte, Ofer Pasternak, Martha E. Shenton, Hector Arciniega, Tashrif Billah, Elena Bonke, Katherine Breedlove, Holly Carrington, Eduardo Coello, Michael J. Coleman, Omar John, Leonard Jung, Huijun Liao, Maria Loy, Elizabeth Rizzoni, Vivian Schultz, Annelise Silva, Brynn Vessey, Tim L. T. Wiegand, Sarah Banks, Charles Bernick, Jason Miller, Aaron Ritter, Marwan Sabbagh, Raelynn de la Cruz, Jan Durant, Morgan Golceker, Nicolette Harmon, Jaeson Kaylegian, Rachelle Long, Christin Nance, Priscilla Sandoval, Miranda Staples, Robert W. Turner, Emma F. Clark, Kenneth L. Marek, Andrew Serrano, Charles H. Adler, David W. Dodick, Yonas Geda, Jennifer V. Wethe, Amy Duffy, Bryce Falk, Marci Howard, Michelle Montague, Thomas Osgood, Debra Babcock, Patrick Bellgowan, Laura Balcer, William Barr, Judith Goldberg, Binu Joseph, Ivan Kirov, Yvonne Lui, Charles Marmar, Thomas Wisniewski, Alhassan Al-Kharafi, Allan George, Lisena Hasanaj, Sammie Martin, Edward Riley, William Runge, Liliana Serrano, Nicholas Ashton, Henrik Zetterberg, Kaj Blennow, Jeffrey L. Cummings, Jeffrey Iliff, Gail Li, Deidre Janssen, James Meabon, Elaine R. Peskind, Juan Piantino, Abigail Schindler, Ronald Thomas, Elizabeth Colasurdo, Jane Shofer, Daniel S. Marcus, Jenny Gurney, Richard Greenwald, Keith A. Johnson
Institutions: Boston University, Amsterdam Neuroscience, Amsterdam UMC Location Vrije Universiteit Amsterdam, United States Department of Veterans Affairs, Edith Nourse Rogers Memorial Veterans Hospital, VA Boston Healthcare System, Cleveland Clinic, Lou Ruvo Brain Institute, Barrow Neurological Institute, Mayo Clinic in Arizona, Encompass Health (United States), Mayo Clinic, New York University, King's College London, Sahlgrenska University Hospital, University of Gothenburg, University of Wisconsin–Madison, UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, Harvard University, University of Washington, VA Puget Sound Health Care System, Brigham and Women's Hospital, Translational Genomics Research Institute, University of Arizona, Banner Alzheimer’s Institute, Arizona Alzheimer’s Consortium, Arizona State University, University of Nevada, Las Vegas
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
OpenAlex ID: W4391691934