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

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

Journal

Journal of neuroinflammation

ISSN: 1742-2094

Titre abrégé: J Neuroinflammation

Pays: England

ID NLM: 101222974

Informations de publication

Date de publication:
09 Feb 2024

Historique:

received: 25 10 2023

accepted: 30 01 2024

medline: 10 2 2024

pubmed: 10 2 2024

entrez: 9 2 2024

Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND BACKGROUND

METHODS 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 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 CONCLUSIONS

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.

Identifiants

DOI: 10.1186/s12974-024-03034-6 PMID: 38336728

pubmed: 38336728

doi: 10.1186/s12974-024-03034-6

pii: 10.1186/s12974-024-03034-6

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

Subventions

Organisme : NIH HHS

ID : U01NS093334

Pays : United States

Investigateurs

Kewei Chen (K)

Hillary Protas (H)

Eric Reiman (E)

Yi Su (Y)

Connie Boker (C)

Michael L Alosco (ML)

Rhoda Au (R)

Robert C Cantu (RC)

Lindsay Farrer (L)

Robert Helm (R)

Douglas I Katz (DI)

Neil Kowall (N)

Jesse Mez (J)

Gustavo Mercier (G)

James Otis (J)

Robert A Stern (RA)

Jason Weller (J)

Tahlia Bragg (T)

Irene Simkin (I)

Diana Trujillo-Rodriguez (D)

Suzan van Amerongen (S)

Alondra Andino (A)

Shannon Conneely (S)

Courtney Diamond (C)

Tessa Fagle (T)

Olivia Haller (O)

Tennyson Hunt (T)

Nicole Gullotti (N)

Bailey Kossow (B)

Carrie Kugelmass (C)

Megan Mariani (M)

Brian Mayville (B)

Kathleen McLaughlin (K)

Mary Nanna (M)

Marty DiPopolo (M)

Taylor Platt (T)

Surya Pulukuri (S)

Fiona Rice (F)

Madison Sestak (M)

Irene Simkin (I)

Michael McClean (M)

Yorghos Tripodis (Y)

Douglas Annis (D)

Christine Chaisson (C)

Diane B Dixon (DB)

Carolyn Finney (C)

Kerrin Gallagher (K)

Kaitlin Hartlage (K)

Jun Lu (J)

Brett Martin (B)

Emmanuel Ojo (E)

Joseph N Palmisano (JN)

Brittany Pine (B)

Janani Ramachandran (J)

Zachary Baucom (Z)

Fatima Tuz-Zahra (F)

Eukyung Yhang (E)

Sylvain Bouix (S)

Jennifer Fitzsimmons (J)

Alexander P Lin (AP)

Inga K Koerte (IK)

Ofer Pasternak (O)

Martha E Shenton (ME)

Hector Arciniega (H)

Tashrif Billah (T)

Elena Bonke (E)

Katherine Breedlove (K)

Holly Carrington (H)

Eduardo Coello (E)

Michael J Coleman (MJ)

Omar John (O)

Leonard Jung (L)

Huijun Liao (H)

Maria Loy (M)

Elizabeth Rizzoni (E)

Vivian Schultz (V)

Annelise Silva (A)

Brynn Vessey (B)

Tim L T Wiegand (TLT)

Sarah Banks (S)

Charles Bernick (C)

Jason Miller (J)

Aaron Ritter (A)

Marwan Sabbagh (M)

Raelynn de la Cruz (R)

Jan Durant (J)

Morgan Golceker (M)

Nicolette Harmon (N)

Jaeson Kaylegian (J)

Rachelle Long (R)

Christin Nance (C)

Priscilla Sandoval (P)

Miranda Staples (M)

Robert W Turner (RW)

Emma F Clark (EF)

Kenneth L Marek (KL)

Andrew Serrano (A)

Charles H Adler (CH)

David W Dodick (DW)

Yonas Geda (Y)

Jennifer V Wethe (JV)

Amy Duffy (A)

Bryce Falk (B)

Marci Howard (M)

Michelle Montague (M)

Thomas Osgood (T)

Debra Babcock (D)

Patrick Bellgowan (P)

Laura Balcer (L)

William Barr (W)

Judith Goldberg (J)

Binu Joseph (B)

Ivan Kirov (I)

Yvonne Lui (Y)

Charles Marmar (C)

Thomas Wisniewski (T)

Alhassan Al-Kharafi (A)

Allan George (A)

Lisena Hasanaj (L)

Sammie Martin (S)

Edward Riley (E)

William Runge (W)

Liliana Serrano (L)

Nicholas Ashton (N)

Henrik Zetterberg (H)

Kaj Blennow (K)

Jeffrey L Cummings (JL)

Jeffrey Iliff (J)

Gail Li (G)

Deidre Janssen (D)

James Meabon (J)

Elaine R Peskind (ER)

Juan Piantino (J)

Abigail Schindler (A)

Ronald Thomas (R)

Elizabeth Colasurdo (E)

Jane Shofer (J)

Daniel S Marcus (DS)

Jenny Gurney (J)

Richard Greenwald (R)

Keith A Johnson (KA)

Informations de copyright

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