Evaluation of Glymphatic System Development in Neonatal Brain via Diffusion Analysis along the Perivascular Space Index

Objective Glymphatic system 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 diffusion along the perivascular space (ALPS) index, a proxy for glymphatic system function, in neonates and investigate its potential associations with maturation, sex, and preterm birth. Methods Diffusion magnetic resonance imaging (MRI) data in 418 neonates, including 92 preterm neonates (57 males) and 326 term neonates (175 males), from the Developing Human Connectome Project were used for evaluating ALPS index. Linear regression modeling was performed to assess group differences in the ALPS index according to preterm birth and sex. Pearson's and partial correlation analysis were performed to assess the association between the ALPS index and gestational age (GA) 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 ( p = 0.004) and GA ( p < 0.001). Preterm birth ( p = 0.013) had a significant moderation effect on the relationship between the ALPS index and PMA. Sex had no significant direct effect ( p = 0.639) or moderation effect ( p = 0.333) on ALPS index. Interpretation 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. ANN NEUROL 2024;96:970–980