Impaired glymphatic transport in hypoxic-ischemic encephalopathy

Jieyi Shen; Ying Yang; Fangfang Chen; Yang Zuo; Yidong Yang; Wei Wei; Ying Liu; Jie Wen

doi:10.1016/j.neuroimage.2025.121414

Impaired glymphatic transport in hypoxic-ischemic encephalopathy

Neuroimage. 2025 Sep:318:121414. doi: 10.1016/j.neuroimage.2025.121414. Epub 2025 Aug 5.

Authors

Jieyi Shen¹, Ying Yang², Fangfang Chen², Yang Zuo³, Yidong Yang³, Wei Wei⁴, Ying Liu⁵, Jie Wen⁶

Affiliations

¹ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
² Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
³ Department of Engineering and Applied Physics, University of Science and Technology of China, Hefei, Anhui, 230026, China.
⁴ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: weiweill@ustc.edu.cn.
⁵ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: liuying828@ustc.edu.cn.
⁶ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Department of Engineering and Applied Physics, University of Science and Technology of China, Hefei, Anhui, 230026, China; Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: jiewen@ustc.edu.cn.

PMID: 40769430
DOI: 10.1016/j.neuroimage.2025.121414

Abstract

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal brain injury. The glymphatic system aids in waste clearance via perivascular pathways and is crucial in maintaining brain functions. While studies have shown that diseases such as stroke and traumatic brain injury disrupt glymphatic function, the impact of HIE on this system remains largely unexplored. We utilized an HIE mouse model with dynamic contrast-enhanced MRI (DCE-MRI) to conduct both qualitative and quantitative assessment of glymphatic transports dysfunction in different brain regions. Fluorescent cerebrospinal fluid (CSF) tracers were used to investigate the effects of HIE on glymphatic system development. Mice brain sections were subjected to Aquaporin-4 (AQP4) immunohistochemical staining, allowing for detailed morphological assessment of AQP4 polarization in affected brain regions. HIE mice exhibited delayed glymphatic transport dynamics, with prolonged time-to-peak tracer enhancement and increased retention in olfactory bulb, basal forebrain, and hypothalamus regions. Quantitative kinetic analysis showed significant reductions in K_f (CSF-to-perivascular space transfer constants) and K_s (perivascular-to-parenchyma transfer constants), alongside elevated V_f (perivascular volume fractions) across cortical and subcortical structures. Fluorescent CSF tracer analysis indicates that HIE impaired glymphatic system maturation in neonatal mice. This impairment progressed to persistent glymphatic dysfunction. Histologically validated via immunofluorescence, HIE-induced astrocytic AQP4 mis-polarization directly correlates with glymphatic transport dysfunction, underscoring AQP4's critical role in glymphatic system integrity. Our multimodal imaging study combining DCE-MRI and CSF tracer analysis indicates that HIE can cause regional impairments of glymphatic function and adversely affect brain development.

Keywords: CSF transport kinetics; Dynamic contrast-enhanced MRI; Glymphatic system; Hypoxic-ischemic encephalopathy.

MeSH terms

Animals
Aquaporin 4 / metabolism
Brain* / diagnostic imaging
Brain* / metabolism
Brain* / pathology
Disease Models, Animal
Glymphatic System* / diagnostic imaging
Glymphatic System* / metabolism
Glymphatic System* / pathology
Glymphatic System* / physiopathology
Hypoxia-Ischemia, Brain* / diagnostic imaging
Hypoxia-Ischemia, Brain* / metabolism
Hypoxia-Ischemia, Brain* / pathology
Hypoxia-Ischemia, Brain* / physiopathology
Magnetic Resonance Imaging / methods
Mice
Mice, Inbred C57BL

Substances

Aquaporin 4
Aqp4 protein, mouse