Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts

Christina Devoto; Rany Vorn; Sara Mithani; Timothy B Meier; Chen Lai; Steven P Broglio; Thomas McAllister; Christopher C Giza; Daniel Huber; Jaroslaw Harezlak; Kenneth L Cameron; Gerald McGinty; Jonathan Jackson; Kevin Guskiewicz; Jason P Mihalik; Alison Brooks; Stefan Duma; Steven Rowson; Lindsay D Nelson; Paul Pasquina; Christine Turtzo; Lawrence Latour; Michael A McCrea; Jessica M Gill

doi:10.3389/fneur.2023.1202967

Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts

Front Neurol. 2023 Aug 17:14:1202967. doi: 10.3389/fneur.2023.1202967. eCollection 2023.

Authors

Christina Devoto^#¹, Rany Vorn^#^{2

3}, Sara Mithani⁴, Timothy B Meier⁵, Chen Lai⁶, Steven P Broglio⁷, Thomas McAllister⁸, Christopher C Giza⁹, Daniel Huber⁵, Jaroslaw Harezlak¹⁰, Kenneth L Cameron¹¹, Gerald McGinty¹², Jonathan Jackson¹², Kevin Guskiewicz¹³, Jason P Mihalik¹³, Alison Brooks¹⁴, Stefan Duma¹⁵, Steven Rowson¹⁵, Lindsay D Nelson⁵, Paul Pasquina⁶, Christine Turtzo², Lawrence Latour², Michael A McCrea⁵, Jessica M Gill^{3

16}

Affiliations

¹ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States.
² National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
³ School of Nursing, Johns Hopkins University, Baltimore, MD, United States.
⁴ School of Nursing, University of Texas Health at San Antonio, San Antonio, TX, United States.
⁵ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States.
⁶ Center for Neuroscience and Regenerative Medicine, Uniformed Services University and Health Science, Bethesda, MD, United States.
⁷ Michigan Concussion Center, University of Michigan, Ann Arbor, MI, United States.
⁸ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States.
⁹ Departments of Pediatrics and Neurosurgery, UCLA Steve Tisch BrainSPORT Program, University of California, Los Angeles, Los Angeles, CA, United States.
¹⁰ Department of Epidemiology and Biostatistics School of Public Health-Bloomington, Indiana University, Bloomington, IN, United States.
¹¹ John A. Feagin Sports Medicine Fellowship, Keller Army Hospital, West Point, NY, United States.
¹² United States Air Force Academy, Colorado Springs, CO, United States.
¹³ Matthew Gfeller Center, Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
¹⁴ Department of Orthopedics and Sports Medicine, University of Wisconsin, Madison, WI, United States.
¹⁵ Department of Biomedical Engineering, Virginia Tech, Blacksburg, VA, United States.
¹⁶ Department of Neurology, Johns Hopkins University, Baltimore, MD, United States.

^# Contributed equally.

Abstract

Objective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes.

Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay.

Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05).

Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.

Keywords: brain trauma; concussion; mTBI; mild traumatic brain injury; p-tau181; sports related concussion.

Copyright © 2023 Devoto, Vorn, Mithani, Meier, Lai, Broglio, McAllister, Giza, Huber, Harezlak, Cameron, McGinty, Jackson, Guskiewicz, Mihalik, Brooks, Duma, Rowson, Nelson, Pasquina, Turtzo, Latour, McCrea and Gill.

Grants and funding

Data collection and sharing for this project were conducted with support from the National Institute of Neurological Disease and Stroke (NINDS) Intramural Program, the Center for Neuroscience and Regenerative Medicine, the National Collegiate Athletic Association (NCAA), and the Department of Defense (DoD). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014, is the awarding and administering acquisition office. This study was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Combat Casualty Care Research Program, endorsed by the Department of Defense, through the Joint Program Committee 6/Combat Casualty Care Research Program-Psychological Health and Traumatic Brain Injury Program under Award No. W81XWH1420151. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the National Institutes of Health, Uniformed Services University, the Department of Defense (DoD), the U.S. Government, or the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.