Plasma proteomics uncovers divergent molecular signatures in ischemic stroke and intracerebral hemorrhage
Por:
Núñez-Jurado, D, Fernández-Vega, A, del Río, C, Penalba, A, Llucià-Carol, L, Muiño-Acuña, E, Ezcurra-Díaz, G, Guasch-Jiménez, M, Cullell, N, Serrano-Heras, G, Arias-Salazar, L, Vives-Bauza, C, Tur, S, Urra, X, Castellanos, M, Krupinski, J, Freijo-Guerrero, M, Jiménez-Conde, J, Fernández-Pérez, I, Segura, T, Marti-Fabregas, J, Férnandez-Cadenas, I, Montaner, J
Publicada:
28 oct 2025
Resumen:
Background Timely differentiation between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is critical for guiding appropriate acute management strategies. While neuroimaging is the diagnostic gold standard, its accessibility is often limited in urgent clinical settings. Blood biomarkers offer a promising, scalable diagnostic alternative; however, no validated panel is yet available for distinguishing stroke subtypes during the hyperacute phase. Methods In a multicenter study, plasma samples were collected within 6 h of symptom onset. A total of 3,072 proteins were measured using Olink (R) proximity extension assays. We applied differential expression analysis, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and receiver operating characteristic (ROC) curve evaluation. To interpret the biological relevance of the findings, we conducted functional enrichment and protein-protein interaction (PPI) analyses. Results Among the 388 patients (344 IS, 44 ICH), 2,531 proteins were retained; 878 reached nominal significance (p < 0.05), and 67 remained significant after multiple-testing correction (FDR-adjusted p < 0.05). Of these, 844 were overexpressed in ICH and 34 in IS. GFAP, a glial marker, emerged as the most discriminative biomarker for ICH versus IS (AUC = 0.887; sensitivity: 80%, specificity: 90%), followed by BCAN (AUC = 0.820), SNAP25 (AUC = 0.797), and SPOCK1 (AUC = 0.786). For IS, S100A12 (AUC = 0.677) and MNDA (AUC = 0.657) showed the best performance. Multivariate analyses confirmed the presence of distinct proteomic patterns, with enrichment revealing a significant overrepresentation of neurodevelopmental and synaptic pathways. In PPI networks, GFAP and LYN emerged as central hubs. Conclusion This study reveals a robust plasma proteomic signature distinguishing IS from ICH within hours of onset. These results lay the groundwork for scalable, blood-based diagnostics to guide early stroke management when imaging is delayed or unavailable.
Filiaciones:
Núñez-Jurado, D:
Univ Seville, Virgen Macarena Univ Hosp, Inst Biomed Seville, Neurovasc Res Grp,IBiS,CSIC, Ave Dr Fedriani 3, Seville 41009, Spain
Virgen Macarena Univ Hosp, Dept Clin Biochem, Seville 41009, Spain
Fernández-Vega, A:
Univ Seville, Virgen Macarena Univ Hosp, Inst Biomed Seville, Neurovasc Res Grp,IBiS,CSIC, Ave Dr Fedriani 3, Seville 41009, Spain
del Río, C:
Univ Seville, Virgen Macarena Univ Hosp, Inst Biomed Seville, Neurovasc Res Grp,IBiS,CSIC, Ave Dr Fedriani 3, Seville 41009, Spain
Univ Seville, Dept Cell Biol, Seville 41013, Spain
Penalba, A:
Univ Autonoma Barcelona, Vall dHebron Inst Res, Neurovasc Res Lab, Barcelona 08035, Spain
Llucià-Carol, L:
Inst Recerca St Pau, Stroke Pharmacogen & Genet Grp, Barcelona 08041, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Muiño-Acuña, E:
Inst Recerca St Pau, Stroke Pharmacogen & Genet Grp, Barcelona 08041, Spain
Ezcurra-Díaz, G:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau, Dept Neurol, Stroke Unit, Barcelona 08025, Spain
Guasch-Jiménez, M:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau, Dept Neurol, Stroke Unit, Barcelona 08025, Spain
Cullell, N:
Inst Recerca St Pau, Stroke Pharmacogen & Genet Grp, Barcelona 08041, Spain
Hosp Mutua Terrassa, Fdn Docencia & Recerca Mutua Terrassa 1, Stroke Pharmacogen & Genet Lab, Barcelona 08221, Spain
Serrano-Heras, G:
Albacete Univ Hosp Complex CHUA, Res Unit, Albacete 02008, Spain
Arias-Salazar, L:
Albacete Univ Hosp Complex CHUA, Res Unit, Albacete 02008, Spain
Vives-Bauza, C:
Hosp Univ Son Espases, Dept Neurol, Mallorca 07120, Spain
Tur, S:
Hosp Univ Son Espases, Dept Neurol, Mallorca 07120, Spain
Urra, X:
Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Inst Neurosci,Funct Unit Cerebrovasc Dis, Barcelona 08036, Spain
Castellanos, M:
Univ A Coruna, Biomed Res Inst, Hlth Sci Fac, Dept Neurol, La Coruna 15006, Spain
Krupinski, J:
Hosp Mutua Terrassa, Fdn Docencia & Recerca Mutua Terrassa 1, Stroke Pharmacogen & Genet Lab, Barcelona 08221, Spain
Freijo-Guerrero, M:
Cruces Univ Hosp, Biobizkaia Hlth Res Inst, Stroke Unit Neurol Serv, Baracaldo 48903, Spain
Jiménez-Conde, J:
Hosp Mar, Dept Neurol, Neurovasc Res Grp, Inst Invest Med,Hosp Mar IMIM, Barcelona 08003, Spain
Fernández-Pérez, I:
Hosp Mar, Dept Neurol, Neurovasc Res Grp, Inst Invest Med,Hosp Mar IMIM, Barcelona 08003, Spain
Segura, T:
Gen Univ Hosp Albacete, Dept Neurol, Albacete 02006, Spain
Marti-Fabregas, J:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau, Dept Neurol, Stroke Unit, Barcelona 08025, Spain
Férnandez-Cadenas, I:
Inst Recerca St Pau, Stroke Pharmacogen & Genet Grp, Barcelona 08041, Spain
Montaner, J:
Univ Seville, Virgen Macarena Univ Hosp, Inst Biomed Seville, Neurovasc Res Grp,IBiS,CSIC, Ave Dr Fedriani 3, Seville 41009, Spain
Green Accepted, Green Submitted, gold
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