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Leucine-Rich Alpha-2-Glycoprotein 1 is a Systemic Biomarker of Early Brain Injury and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

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Abstract

Background

After subarachnoid hemorrhage (SAH), early brain injury (EBI) and delayed cerebral ischemia (DCI) lead to poor outcomes. Discovery of biomarkers indicative of disease severity and predictive of DCI is important. We tested whether leucine-rich alpha-2-glycoprotein 1 (LRG1) is a marker of severity, DCI, and functional outcomes after SAH.

Methods

We performed untargeted proteomics using mass spectrometry in plasma samples collected at < 48 h of SAH in two independent discovery cohorts (n = 27 and n = 45) and identified LRG1 as a biomarker for DCI. To validate our findings, we used enzyme-linked immunosorbent assay and confirmed this finding in an internal validation cohort of plasma from 72 study participants with SAH (22 DCI and 50 non-DCI). Further, we investigated the relationship between LRG1 and markers of EBI, DCI, and poor functional outcomes (quantified by the modified Rankin Scale). We also measured cerebrospinal fluid (CSF) levels of LRG1 and investigated its relationship to EBI, DCI, and clinical outcomes.

Results

Untargeted proteomics revealed higher plasma LRG1 levels across EBI severity and DCI in both discovery cohorts. In the validation cohort, the levels of LRG1 were higher in the DCI group compared with the non-DCI group (mean (SD): 95 [44] vs. 72 [38] pg/ml, p < 0.05, Student’s t-test) and in study participants who proceeded to have poor functional outcomes (84 [39.3] vs. 72 [43.2] pg/ml, p < 0.05). Elevated plasma LRG1 levels were also associated with markers of EBI. However, CSF levels of LRG1 were not associated with EBI severity or the occurrence of DCI.

Conclusions

Plasma LRG1 is a biomarker for EBI, DCI, and functional outcomes after SAH. Further studies to elucidate the role of LRG1 in the pathophysiology of SAH are needed.

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Funding

Research reported in this manuscript was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award 1R61NS119640-01A1 and by the Clinical and Translational Proteomics Service Center at The University of Texas Health Science Center at Houston.

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Author notes

  1. Jude P. J. Savarraj and Devin W. McBride have contributed equally to this article.

Authors and Affiliations

  1. Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA

    Jude P. J. Savarraj, Devin W. McBride, Eunsu Park, Sarah Hinds, Atzhiry Paz, Aaron Gusdon, Ren Xuefang, Eunhee Kim & Huimahn Alex Choi

  2. The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Sheng Pan

  3. Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Hilda Ahnstedt, Gabriela Delevati Colpo & Louise McCullough

  4. Center for Precision Health, School of Biomedical Informatics and Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Zhongming Zhao

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Contributions

JPJS and HAC were involved in the conception and design of the study. JPJS and LZ were involved in analysis of data. JPJS, GH, DWM, AG, SP, and HA were involved in the acquisition of data. JPJS, LM, and HAC contributed substantially to drafting the manuscript and figures.

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Correspondence to Huimahn Alex Choi.

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Supplementary file1 (DOCX 25 kb)

Supplemental Table 1 Demographics of Cohort-1 and Cohort-2

Supplemental Table 2 Differences in demographics between DCI and no-DCI

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Savarraj, J.P.J., McBride, D.W., Park, E. et al. Leucine-Rich Alpha-2-Glycoprotein 1 is a Systemic Biomarker of Early Brain Injury and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage. Neurocrit Care 38, 771–780 (2023). https://doi.org/10.1007/s12028-022-01652-7

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