Biomarkers for Early Detection and Therapeutic Monitoring of Abnormal Brain Development in Mild Fetal Growth Restriction

Abstract

Fetal growth restriction (FGR), driven by intrauterine hypoperfusion, delays brain development and heightens the risk of neurodevelopmental disorders. Nonetheless, current diagnostic strategies rarely capture the subtle neuropathology that emerges in mild FGR. To overcome this limitation, we employed an innovative rodent model that replicates mild FGR through gradual and chronic intrauterine hypoperfusion, mirroring clinical conditions overlooked by conventional severe or acute FGR models. Global proteomics of cerebrospinal fluid identified Alpha-2-Macroglobulin, Neuroserpin, CD200, and Polyubiquitin-B as biomarkers correlated with birth weight and persisting postnatally. Their expression reflected changes in brain tissue and serum, was linked to behavioral deficits, and partially recovered under mesenchymal stem/stromal cell treatment—indicating potential for therapeutic monitoring. Notably, Neuroserpin, brain-specific, emerged as a robust indicator of FGR-related neurodevelopmental impairment. This study is the first to propose low-invasive serum biomarkers for early postnatal detection of mild FGR-induced brain abnormalities, enabling neonatal screening, targeted interventions, and improved long-term outcomes.

Note:
Funding Information: This work was supported by Nagoya University Hospital Funding for Clinical Development 2018 (YS), the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Fund for the Promotion of Joint International Research (Fostering Joint International Research (B)) 21KK0176 (MT), JSPS Grant-in-Aid for Early-Career Scientists 19K17324 (AO) and 18K15668 (YK), JSPS Grant- in-Aid for JSPS Research Fellows 18J01110 (AO), the Uehara Memorial Foundation (AO), the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatric (AO), the Toyoaki Scholarship Foundation (AO), the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care (AO), and the Public Foundation of Chubu Science and Technology Center (AO). The funders had no role in the preparation of the manuscript or the decision to publish it.

Declaration of Interests: AO, YK, SS, MT, MH and YS declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AO, YK, SS, MT, MH and YS have a patent for the application of quantitative assessment index for fetal growth restriction. JC, and KU declare that they have no competing interests.

Keywords: Fetal Growth Restriction, Intrauterine Hypoperfusion, Neurodevelopmental Disorders, Biomarker Discovery, Neuroserpin, Alpha-2-Macroglobulin, OX2-membrane glycoprotein, Polyubiquitin-B, Mesenchymal Stem/Stromal Cells, Therapeutic Monitoring