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Background and purpose <p>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.</p> Methods <p>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.</p> Results <p>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), <span>d</span>-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&#xa0;h.</p> Conclusions <p>Fluid biomarkers exhibit a temporally evolving signature: early coagulopathy (<span>d</span>-dimer), glial activation (GFAP, S100B), and inflammation (IL-6), followed by neuronal necrosis (NSE) and oxidative stress (IMA) within 24&#xa0;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.</p>

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Early-phase fluid diagnostic biomarkers in acute ischemic stroke: a hybrid umbrella review

  • 期刊论文

  • 发表日期：

    2026年2月18日

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  • Alessandro Bombaci,
  • Federico Emanuele Pozzi,
  • Salvatore Mazzeo,
  • Elisa Bortolin,
  • Giulia Bruschi,
  • Maria Vittoria Corbari,
  • Alberto Astengo,
  • Gianluca Stufano,
  • Sergio Soeren Rossi,
  • Maria Paola Perini,
  • Giuseppe Rotondo,
  • Novellino Fabiana,
  • Massimo Filippi,
  • Maria Salsone

摘要

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.