Quantification of brain tissue injury and prediction of prognosis using serum GFAP and UCH-L1: A multicenter prospective cohort study

Abstract

Background:

It remains unclear whether the serum levels of the brain injury biomarkers (glial fibrillary acidic protein [GFAP] and ubiquitin C-terminal hydrolase-L1 [UCH-L1]) can be used to quantitatively evaluate brain tissue injury and predict prognosis in patients with intravenous thrombolysis (IVT).

Aim:

This study investigates the association between serum GFAP and UCH-L1 levels with functional outcomes in patients receiving IVT.

Methods:

Patients were prospectively enrolled from 16 hospitals. We measured serum GFAP and UCH-L1 levels 24 hours after IVT. Infarct volume, hemorrhagic transformation (HT), and short- and long-term prognostic indicators were evaluated. GFAP and UCH-L1 cutoff levels for predicting 3-month unfavorable outcomes were derived, and a biomarker-based model was established and subjected to internal and external validation.

Results:

This study included 1028 patients. Higher GFAP and UCH-L1 levels were independently associated with larger infarct volume, HT, higher 24-hour and 7-day National Institutes of Health Stroke Scale scores, and 3-month modified Rankin Scale scores. The cutoff levels for GFAP and UCH-L1 (116 and 292 pg/mL, respectively) predicted patients with 3-month unfavorable outcomes with a specificity and positive predictive value (PPV) of 97.56% (95% confidence interval [CI], 94.51–99.00) and 88.68% (95% CI, 76.28–95.31), respectively, in the training cohort. In the testing and validation cohorts, specificity was 97.83% (95% CI, 91.62–99.62) and 96.90% (95% CI, 91.77–99.00), respectively, and PPV was 90.00% (95% CI, 66.87–98.25) and 75.00% (95% CI, 47.41–91.67), respectively. Furthermore, the biomarker-based nomogram model showed good predictability of 3-month prognosis in the different cohorts.

Conclusions:

Serum GFAP and UCH-L1 levels can be used to quantitatively evaluate brain tissue injury and predict the prognosis of patients with IVT.

Graphical abstract

Keywords

Glial fibrillary acidic protein ubiquitin C-terminal hydrolase-L1 intravenous thrombolysis prognosis

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References

GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the global burden of disease study 2019. Lancet Neurol 2021; 20: 795–820.

Yang

Lee

Intravenous thrombolysis for acute ischemic stroke: from alteplase to tenecteplase. Brain Circ 2023; 9: 61–63.

Kalra

Khatter

Ramanathan

, et al. Serum GFAP for stroke diagnosis in regions with limited access to brain imaging (be fast India). Eur Stroke J 2021; 6: 176–184.

Bazarian

Biberthaler

Welch

, et al. Serum GFAP and UCH-l1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol 2018; 17: 782–789.

Sun

, et al. Changes of ubiquitin C-terminal hydrolase-L1 levels in serum and urine of patients with white matter lesions. J Neurol Sci 2015; 357: 215–221.

Zylyftari

Luger

Blums

, et al. GFAP point-of-care measurement for prehospital diagnosis of intracranial hemorrhage in acute coma. Crit Care 2024; 28: 109.

Ferrari

Rossi

Ricciardi

, et al. Quantification and prospective evaluation of serum NFL and GFAP as blood-derived biomarkers of outcome in acute ischemic stroke patients. J Cereb Blood Flow Metab 2023; 43: 1601–1611.

Foerch

Niessner

Back

, et al. Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke. Clin Chem 2012; 58: 237–245.

Perry

Lucarelli

Penny-Dimri

, et al. Glial fibrillary acidic protein for the early diagnosis of intracerebral hemorrhage: systematic review and meta-analysis of diagnostic test accuracy. Int J Stroke 2019; 14: 390–399.

10.

Ren

Kobeissy

Alawieh

, et al. Assessment of serum UCH-l1 and GFAP in acute stroke patients. Sci Rep 2016; 6: 24588.

11.

Wang

Yang

Sarkis

Torres

Raghavan

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro-injuries. Expert Opin Ther Targets 2017; 21: 627–638.

12.

Vandenbroucke

von Elm

Altman

, et al. Strengthening the reporting of observational studies in epidemiology (strobe): explanation and elaboration. PLoS Med 2007; 4: e297.

13.

Wang

Cui

, et al. The china national stroke registry for patients with acute cerebrovascular events: design, rationale, and baseline patient characteristics. Int J Stroke 2011; 6: 355–361.

14.

Sacco

Adams

Albers

, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association council on stroke: co-sponsored by the council on cardiovascular radiology and intervention: the American academy of neurology affirms the value of this guideline. Circulation 2006; 113: e409–e449.

15.

Adams

Jr Bendixen

Kappelle

, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 1993; 24: 35–41.

16.

von Kummer

Broderick

Campbell

, et al. The Heidelberg bleeding classification: classification of bleeding events after ischemic stroke and reperfusion therapy. Stroke 2015; 46: 2981–2986.

17.

Zhang

, et al. The impact of serial remote ischemic conditioning on dynamic cerebral autoregulation and brain injury related biomarkers. Front Physiol 2022; 13: 835173.

18.

DeLong

Clarke-Pearson

DL.

Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44: 837–845.

19.

Fiorelli

Bastianello

von Kummer

, et al. Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke 1999; 30: 2280–2284.

20.

Eng

Ghirnikar

Lee

YL.

Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 2000; 25: 1439–1451.

21.

Abbott. Abbott receives FDA clearance for whole blood rapid test to help with assessment of concussion at the patient’s bedside. Abbott MediaRoom, https://abbott.mediaroom.com/2024-04-01-Abbott-Receives-FDA-Clearance-for-Whole-Blood-Rapid-Test-to-Help-with-Assessment-of-Concussion-at-the-Patients-Bedside (2024, accessed 18 July 2025).

22.

Kalra

Zylyftari

Blums

, et al. Rapid diagnosis of intracerebral hemorrhage in patients with acute stroke by measuring prehospital GFAP levels on a point-of-care device (detect). Neurology 2025; 105: e213823.

23.

Fang

, et al. Remote ischemic conditioning attenuates blood-brain barrier disruption after recombinant tissue plasminogen activator treatment via reducing PDGF-CC. Pharmacol Res 2023; 187: 106641.

24.

Chen

Cui

, et al. Effect of remote ischemic conditioning vs usual care on neurologic function in patients with acute moderate ischemic stroke: the RICAMIS randomized clinical trial. JAMA 2022; 328: 627–636.

25.

Zhang

Lin

Zhang

Wang

Shi

SL.

Serum glial fibrillary acidic protein as a biomarker for differentiating intracerebral hemorrhage and ischemic stroke in patients with symptoms of acute stroke: a systematic review and meta-analysis. Neurol Sci 2013; 34: 1887–1892.

26.

Yigit

Atescelik

Yilmaz

Goktekin

Gurger

Ilhan

Investigation of UCH-L1 levels in ischemic stroke, intracranial hemorrhage and metabolic disorder induced impaired consciousness. Am J Emerg Med 2017; 35: 1895–1898.

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