Multi-pool chemical exchange saturation transfer magnetic resonance imaging as a molecular-specific biomarker: detecting histopathological changes in neonatal hypoxic-ischemic encephalopathy.

Abstract

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) diagnosis is confounded by heterogeneous neural injury and metabolic dysfunction. Multi-pool chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) uniquely quantifies amide proton transfer, nuclear Overhauser enhancement, and magnetization transfer signals, providing multi-parametric assessment of HIE pathophysiology.

Objective: To investigate whether multi-pool CEST MRI can serve as a molecular-specific biomarker for histopathological alterations in HIE and assess its efficacy in grading disease severity.

Materials and methods: This prospective study included 20 neonates with HIE and 42 age-matched controls undergoing 3.0-T CEST MRI. Imaging data were spatially normalized to a neonatal atlas for region-specific analysis (caudate, putamen, thalamus, pallidum, amygdala, hippocampus). Group differences in CEST signals (amide proton transfer, nuclear Overhauser enhancement, magnetization transfer) were analyzed via Wilcoxon tests, with diagnostic performance evaluated through receiver operating characteristic analysis.

Results: Compared to controls, HIE neonates showed significant reductions in amide proton transfer (bilateral putamen, right hippocampus/pallidum/amygdala, left thalamus/caudate), nuclear Overhauser enhancement (left thalamus/caudate/putamen), and magnetization transfer signals (bilateral thalamus/pallidum/putamen, left caudate; all P<0.05). Subgroup analysis revealed progressive metabolic decline: moderate-to-severe HIE exhibited further amide proton transfer reduction in the right thalamus, nuclear Overhauser enhancement decreases in bilateral hippocampus, and magnetization transfer decreases in left hippocampus/thalamus compared to mild cases (all P<0.05). Notably, conventional amide proton transfer-weighted imaging showed no significant changes, as the reduction in amide proton transfer signal was offset by a concurrent decrease in the nuclear Overhauser enhancement, highlighting the superiority of multi-pool analysis. Left hippocampal nuclear Overhauser enhancement demonstrated exceptional severity discrimination (area under curve (AUC)=0.96), while a multi-region integrated model achieved perfect staging accuracy (AUC=1.00).

Conclusion: Multi-pool CEST MRI effectively captures histopathological changes in neonatal HIE, with left hippocampal nuclear Overhauser enhancement emerging as a precise biomarker for severity stratification. The combined dynamics of amide proton transfer, nuclear Overhauser enhancement, and magnetization transfer signals provide noninvasive insights into metabolic-pathological correlations, highlighting its transformative potential for early diagnosis and targeted therapeutic monitoring.