TY - JOUR
T1 - The Known Unknowns
T2 - An Overview of the State of Blood-Based Protein Biomarkers of Mild Traumatic Brain Injury
AU - Mcdonald, Stuart J.
AU - Shultz, Sandy R.
AU - Agoston, Denes V.
N1 - Funding Information:
S.J.M., S.R.S., and D.V.A. acknowledge funding from the Australian National Health and Medical Research Council (Funder Refs: 2002689, 1159645).
Publisher Copyright:
© Copyright 2021, Mary Ann Liebert, Inc., publishers 2021.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Blood-based protein biomarkers have revolutionized several fields of medicine by enabling molecular level diagnosis, as well as monitoring disease progression and treatment efficacy. Traumatic brain injury (TBI) so far has benefitted only moderately from using protein biomarkers to improve injury outcome. Because of its complexity and dynamic nature, TBI, especially its most prevalent mild form (mild TBI; mTBI), presents unique challenges toward protein biomarker discovery and validation given that blood is frequently obtained and processed outside of the clinical laboratory (e.g., athletic fields, battlefield) under variable conditions. As it stands, the field of mTBI blood biomarkers faces a number of outstanding questions. Do elevated blood levels of currently used biomarkers - ubiquitin carboxy-terminal hydrolase L1, glial fibrillary acidic protein, neurofilament light chain, and tau/p-tau - truly mirror the extent of parenchymal damage? Do these different proteins represent distinct injury mechanisms? Is the blood-brain barrier a "brick wall"? What is the relationship between intra- versus extracranial values? Does prolonged elevation of blood levels reflect de novo release or extended protein half-lives? Does biological sex affect the pathobiological responses after mTBI and thus blood levels of protein biomarkers? At the practical level, it is unknown how pre-analytical variables - sample collection, preparation, handling, and stability - affect the quality and reliability of biomarker data. The ever-increasing sensitivity of assay systems and lack of quality control of samples, combined with the almost complete reliance on antibody-based assay platforms, represent important unsolved issues given that false-negative results can lead to false clinical decision making and adverse outcomes. This article serves as a commentary on the state of mTBI biomarkers and the landscape of significant challenges. We highlight and discusses several biological and methodological "known unknowns"and close with some practical recommendations.
AB - Blood-based protein biomarkers have revolutionized several fields of medicine by enabling molecular level diagnosis, as well as monitoring disease progression and treatment efficacy. Traumatic brain injury (TBI) so far has benefitted only moderately from using protein biomarkers to improve injury outcome. Because of its complexity and dynamic nature, TBI, especially its most prevalent mild form (mild TBI; mTBI), presents unique challenges toward protein biomarker discovery and validation given that blood is frequently obtained and processed outside of the clinical laboratory (e.g., athletic fields, battlefield) under variable conditions. As it stands, the field of mTBI blood biomarkers faces a number of outstanding questions. Do elevated blood levels of currently used biomarkers - ubiquitin carboxy-terminal hydrolase L1, glial fibrillary acidic protein, neurofilament light chain, and tau/p-tau - truly mirror the extent of parenchymal damage? Do these different proteins represent distinct injury mechanisms? Is the blood-brain barrier a "brick wall"? What is the relationship between intra- versus extracranial values? Does prolonged elevation of blood levels reflect de novo release or extended protein half-lives? Does biological sex affect the pathobiological responses after mTBI and thus blood levels of protein biomarkers? At the practical level, it is unknown how pre-analytical variables - sample collection, preparation, handling, and stability - affect the quality and reliability of biomarker data. The ever-increasing sensitivity of assay systems and lack of quality control of samples, combined with the almost complete reliance on antibody-based assay platforms, represent important unsolved issues given that false-negative results can lead to false clinical decision making and adverse outcomes. This article serves as a commentary on the state of mTBI biomarkers and the landscape of significant challenges. We highlight and discusses several biological and methodological "known unknowns"and close with some practical recommendations.
KW - blood-brain barrier
KW - concussion
KW - glymphatic system
KW - immunoassay
KW - pathophysiology
KW - pre-analytical variable
UR - http://www.scopus.com/inward/record.url?scp=85115182157&partnerID=8YFLogxK
U2 - 10.1089/neu.2021.0011
DO - 10.1089/neu.2021.0011
M3 - Review Article
C2 - 33906422
AN - SCOPUS:85115182157
SN - 0897-7151
VL - 38
SP - 2652
EP - 2666
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
IS - 19
ER -