Background and purposeAcute ischemic stroke (AIS) is a time-critical emergency in which rapid diagnosis within established therapeutic windows is essential to optimize outcomes. Fluid biomarkers offer a promising adjunct to clinical and neuroimaging assessment but their temporal dynamics in the acute phases remain incompletely characterized.MethodsWe performed a hybrid umbrella review of systematic reviews and meta-analyses evaluating fluid biomarkers in AIS versus controls or stroke mimics. Quantitative synthesis of primary studies (random effects meta-analysis of standardized mean differences) was stratified by clinically relevant time windows. Heterogeneity, small-study effects, and excess significance bias were assessed.ResultsWe included 27 publications (18 biochemistry, 1 metabolomic, 10 transcriptomic, 5 cell-free-DNA [cfDNA]). Across all time points, the largest effect sizes were observed for neuron-specific enolase (NSE), ischemia-modified albumin (IMA), d-dimer, S100B, GFAP, and IL-6. Looking at metabolites, studies revealed early accumulation of lactate, succinate, glutamate and lysophosphatidylcholines, alongside depletion of arginine, citrulline, and citrate. A catalog of 220 micro-RNAs (132 upregulated; 108 downregulated) identified robust markers (miR-16-5p, let-7e-5p, miR-107, miR-451a, and miR-126-3p). 46 circulating RNAs and 55 long-non-coding RNAs were consistently dysregulated. Five studies reported elevated nuclear and mitochondrial cfDNA within 6 h.ConclusionsFluid biomarkers exhibit a temporally evolving signature: early coagulopathy (d-dimer), glial activation (GFAP, S100B), and inflammation (IL-6), followed by neuronal necrosis (NSE) and oxidative stress (IMA) within 24 h. Multi-omic integration, including metabolomics, transcriptomics and cfDNA, highlights convergent pathways (PI3K/Akt, NF-kappa B, immunometabolism) and supports the development of rapid, point-of-care panels. Standardized sampling windows and harmonized assay protocols are essential for clinical translation and prospective validation in prehospital settings.
Early-phase fluid diagnostic biomarkers in acute ischemic stroke: a hybrid umbrella review / Bombaci, A.; Pozzi, F. E.; Mazzeo, S.; Bortolin, E.; Bruschi, G.; Corbari, M. V.; Astengo, A.; Stufano, G.; Rossi, S. S.; Perini, M. P.; Rotondo, G.; Fabiana, N.; Filippi, M.; Salsone, M.. - In: JOURNAL OF NEUROLOGY. - ISSN 0340-5354. - 273:2(2026). [10.1007/s00415-026-13702-7]
Early-phase fluid diagnostic biomarkers in acute ischemic stroke: a hybrid umbrella review
Bombaci A.Co-primo
;Mazzeo S.;Bortolin E.;Bruschi G.;Filippi M.Penultimo
;Salsone M.
Ultimo
2026-01-01
Abstract
Background and purposeAcute ischemic stroke (AIS) is a time-critical emergency in which rapid diagnosis within established therapeutic windows is essential to optimize outcomes. Fluid biomarkers offer a promising adjunct to clinical and neuroimaging assessment but their temporal dynamics in the acute phases remain incompletely characterized.MethodsWe performed a hybrid umbrella review of systematic reviews and meta-analyses evaluating fluid biomarkers in AIS versus controls or stroke mimics. Quantitative synthesis of primary studies (random effects meta-analysis of standardized mean differences) was stratified by clinically relevant time windows. Heterogeneity, small-study effects, and excess significance bias were assessed.ResultsWe included 27 publications (18 biochemistry, 1 metabolomic, 10 transcriptomic, 5 cell-free-DNA [cfDNA]). Across all time points, the largest effect sizes were observed for neuron-specific enolase (NSE), ischemia-modified albumin (IMA), d-dimer, S100B, GFAP, and IL-6. Looking at metabolites, studies revealed early accumulation of lactate, succinate, glutamate and lysophosphatidylcholines, alongside depletion of arginine, citrulline, and citrate. A catalog of 220 micro-RNAs (132 upregulated; 108 downregulated) identified robust markers (miR-16-5p, let-7e-5p, miR-107, miR-451a, and miR-126-3p). 46 circulating RNAs and 55 long-non-coding RNAs were consistently dysregulated. Five studies reported elevated nuclear and mitochondrial cfDNA within 6 h.ConclusionsFluid biomarkers exhibit a temporally evolving signature: early coagulopathy (d-dimer), glial activation (GFAP, S100B), and inflammation (IL-6), followed by neuronal necrosis (NSE) and oxidative stress (IMA) within 24 h. Multi-omic integration, including metabolomics, transcriptomics and cfDNA, highlights convergent pathways (PI3K/Akt, NF-kappa B, immunometabolism) and supports the development of rapid, point-of-care panels. Standardized sampling windows and harmonized assay protocols are essential for clinical translation and prospective validation in prehospital settings.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
