High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

crossref(2024)

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摘要
Pathophysiology and outcomes after Traumatic Brain Injury (TBI) are complex and highly heterogenous. Current classifications are uninformative about pathophysiology, which limits prognostication and treatment. Fluid-based biomarkers can identify pathways and proteins relevant to TBI pathophysiology. Proteomic approaches are well suited to exploring complex mechanisms of disease, as they enable sensitive assessment of an expansive range of proteins. We used novel high-dimensional, multiplex proteomic assays to study changes in plasma protein expression in acute moderate-severe TBI. We analysed samples from 88 participants in the longitudinal BIO-AX-TBI cohort (n=38 TBI within 10 days of injury, n=22 non-TBI trauma, n=28 non-injured controls) on two platforms: Alamar NULISA™ CNS Diseases and OLINK® Target 96 Inflammation. Participants also had data available from Simoa® (neurofilament light, GFAP, total tau, UCHL1) and Millipore (S100B). The Alamar panel assesses 120 proteins, most of which have not been investigated before in TBI, as well as proteins, such as GFAP, which differentiate TBI from non-injured and non-TBI trauma controls. A subset (n=29 TBI, n=24 non-injured controls) also had subacute 3T MRI measures of lesion volume and white matter injury (fractional anisotropy, scanned 10 days to 6 weeks after injury). Differential Expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin2, UCHL1, visinin-like protein1), astroglial markers (S100B, GFAP), tau and other neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid beta42, 14-3-3γ), inflammatory cytokines (IL16, CCL2, ficolin2), cell signalling (SFRP1), cell metabolism (MDH1) and autophagy related (sequestome1) proteins. Acute plasma levels of UCHL1, PSEN1, total tau and pTau231 correlated with subacute lesion volume, while sequestome1 was correlated with whole white matter skeleton fractional anisotropy and CCL2 was inversely correlated with corpus callosum FA. Neuronal, astroglial, tau and neurodegenerative proteins correlated with each other, and IL16, MDH1 and sequestome1. Clustering ( k means) by acute protein expression identified 3 TBI subgroups which had differential injury patterns, but did not differ in age or outcome. 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 amyloid processing, inflammatory and cellular processes such as autophagy. These changes were related to patterns of injury, thus demonstrating that processes previously only studied in animal models are also relevant in human TBI pathophysiology. Our study highlights the potential of proteomic analysis to improve the classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development. ### Competing Interest Statement Alamar Biosciences provided complimentary testing of samples, but were not involved in the analysis or interpretation of results, or write-up of the manuscript beyond confirming that no proprietary information has been included. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). DJS has received an honorarium from the Rugby Football Union for participation in an expert concussion panel. DJS receives payment by Rugby Football Union, The Football Association and Premiership Rugby for private clinical services at the Institute of Sports Exercise and Health. There are no other conflicts of interest.
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