Early-phase fluid diagnostic biomarkers in acute ischemic stroke: a hybrid umbrella review
Alessandro Bombaci1,2, Federico Emanuele Pozzi1, Salvatore Mazzeo1,2
1Unità Di Neurologia, IRCSS Policlinico San Donato, San Donato Milanese, Milan, Italy.
Background And Purpose:
Acute 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.
Methods:
We 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.
Results:
We 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.
Conclusions:
Fluid 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-κB, 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.
