Evaluation of Glymphatic System Development in Neonatal Brain Via Diffusion Analysis Along the Perivascular Space (ALPS) Index

Background: The glymphatic system is a glial-dependent perivascular network, which is a recently discovered macroscopic waste clearance system associated with numerous neurological diseases. However, little is known about glymphatic system development in neonates. We sought to evaluate MRI indices of perivascular network in neonates and investigate its potential associations with maturation, sex, and preterm birth.Methods: In this retrospective study, diffusion magnetic resonance imaging (MRI) data in 418 neonates from the Developing Human Connectome Project were used for evaluating diffusion along the perivascular space (ALPS) index, a proxy for glymphatic system function. Linear regression modeling was performed to assess group differences in the ALPS index according to preterm birth and sex. Pearson’s correlation analysis and partial correlation analysis were performed to assess the association between the ALPS index and gestational age (GA) at birth as well as postmenstrual age (PMA) at MRI. Moderation analysis was performed to assess the moderation effect of preterm birth on the relationship between the ALPS index and PMA. Results: Compared to term neonates, preterm neonates exhibited lower ALPS indices (P < 0.001). The ALPS index positively correlated with PMA (r = 0.14, P = 0.004) and GA (r = 0.40, P < 0.001). Preterm birth (β = −0.009, SE = 0.004, P = 0.013) had a significant moderation effect on the relationship between the ALPS index and PMA. Sex had no significant direct effect (F = 0.220, P = 0.639) or moderation effect (sex * PMA, β = −0.003, SE = 0.004, P = 0.333) on ALPS index. Conclusion: Glymphatic system development is a dynamic process in neonates, which can be moderated by preterm birth, the ALPS index could serve as a sensitive biomarker for monitoring this process.Funding: This work has received funding by grants from the Guangdong Basic and Applied Basic Research Foundation (2020A1515011332 and 2022A1515012503), China and the Scientific andTechnological Project of Nanshan (NS2022007), China.Declaration of Interest: The authors have no conflicts of interest to declare.Ethical Approval: his retrospective study was approved by the appropriate institutional review board, and the requirement for informed consent was waived because publicly available datasets were used.