High-dimensional proteomic analysis for pathophysiological classification of traumatic brain injury
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Pathophysiology and outcomes after traumatic brain injury (TBI) are complex and heterogeneous. Current classifications are uninformative about pathophysiology. Proteomic approaches with fluid-based biomarkers are ideal for exploring complex disease mechanisms, because they enable sensitive assessment of an expansive range of processes potentially relevant to TBI pathophysiology. We used novel high-dimensional, multiplex proteomic assays to assess altered plasma protein expression in acute TBI.
We analysed samples from 88 participants from the BIO-AX-TBI cohort [n = 38 moderate–severe TBI (Mayo Criteria), n = 22 non-TBI trauma and n = 28 non-injured controls] on two platforms: Alamar NULISA™ CNS Diseases and OLINK® Target 96 Inflammation. Patient participants were enrolled after hospital admission, and samples were taken at a single time point ≤10 days post-injury. Participants also had neurofilament light, GFAP, total tau, UCH-L1 (all Simoa®) and S100B (Millipore) data. The Alamar panel assesses 120 proteins, most of which were previously unexplored in TBI, plus proteins with known TBI specificity, such as GFAP. A subset (n = 29 TBI and n = 24 non-injured controls) also had subacute (10 days to 6 weeks post-injury) 3 T MRI measures of lesion volume and white matter injury (fractional anisotropy).
Differential expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin 2, UCH-L1 and visinin-like protein 1), astroglial markers (S100B and GFAP), neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid-beta-42 and 14-3-3γ), inflammatory cytokines (IL16, CCL2 and ficolin 2) and cell signalling- (SFRP1), cell metabolism- (MDH1) and autophagy-related (sequestome 1) proteins. Acute plasma levels of UCH-L1, PSEN1, total tau and pTau231 were correlated with subacute lesion volume. Sequestome 1 was positively correlated with white matter fractional anisotropy, whereas CCL2 was inversely correlated. Neuronal, astroglial, tau and neurodegenerative proteins were correlated with each other, IL16, MDH1 and sequestome 1. Exploratory clustering (k means) by acute protein expression identified three TBI subgroups that differed in injury patterns, but not in age or outcome. One TBI cluster had significantly lower white matter fractional anisotropy than control-predominant clusters but had significantly lower lesion subacute lesion volumes than another TBI cluster. Proteins that overlapped on two platforms had excellent (r > 0.8) correlations between values.
We identified TBI-specific changes in acute plasma levels of proteins involved in neurodegenerative disease, inflammatory and cellular processes. These changes were related to patterns of injury, thus demonstrating that processes previously studied only in animal models are also relevant in human TBI pathophysiology. Our study highlights how proteomic approaches might improve classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.
We analysed samples from 88 participants from the BIO-AX-TBI cohort [n = 38 moderate–severe TBI (Mayo Criteria), n = 22 non-TBI trauma and n = 28 non-injured controls] on two platforms: Alamar NULISA™ CNS Diseases and OLINK® Target 96 Inflammation. Patient participants were enrolled after hospital admission, and samples were taken at a single time point ≤10 days post-injury. Participants also had neurofilament light, GFAP, total tau, UCH-L1 (all Simoa®) and S100B (Millipore) data. The Alamar panel assesses 120 proteins, most of which were previously unexplored in TBI, plus proteins with known TBI specificity, such as GFAP. A subset (n = 29 TBI and n = 24 non-injured controls) also had subacute (10 days to 6 weeks post-injury) 3 T MRI measures of lesion volume and white matter injury (fractional anisotropy).
Differential expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin 2, UCH-L1 and visinin-like protein 1), astroglial markers (S100B and GFAP), neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid-beta-42 and 14-3-3γ), inflammatory cytokines (IL16, CCL2 and ficolin 2) and cell signalling- (SFRP1), cell metabolism- (MDH1) and autophagy-related (sequestome 1) proteins. Acute plasma levels of UCH-L1, PSEN1, total tau and pTau231 were correlated with subacute lesion volume. Sequestome 1 was positively correlated with white matter fractional anisotropy, whereas CCL2 was inversely correlated. Neuronal, astroglial, tau and neurodegenerative proteins were correlated with each other, IL16, MDH1 and sequestome 1. Exploratory clustering (k means) by acute protein expression identified three TBI subgroups that differed in injury patterns, but not in age or outcome. One TBI cluster had significantly lower white matter fractional anisotropy than control-predominant clusters but had significantly lower lesion subacute lesion volumes than another TBI cluster. Proteins that overlapped on two platforms had excellent (r > 0.8) correlations between values.
We identified TBI-specific changes in acute plasma levels of proteins involved in neurodegenerative disease, inflammatory and cellular processes. These changes were related to patterns of injury, thus demonstrating that processes previously studied only in animal models are also relevant in human TBI pathophysiology. Our study highlights how proteomic approaches might improve classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.
Date Issued
2025-03-01
Date Acceptance
2024-09-15
Citation
Brain, 2025, 148 (3), pp.1015-1030
ISSN
0006-8950
Publisher
Oxford University Press (OUP)
Start Page
1015
End Page
1030
Journal / Book Title
Brain
Volume
148
Issue
3
Copyright Statement
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39323289
PII: 7775599
Subjects
biomarker
inflammation
neurodegeneration
neuroimaging
Humans
Brain Injuries, Traumatic
Male
Female
Proteomics
Adult
Middle Aged
Biomarkers
tau Proteins
Aged
Young Adult
Glial Fibrillary Acidic Protein
Neurofilament Proteins
S100 Calcium Binding Protein beta Subunit
Ubiquitin Thiolesterase
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2024-09-26