Assessing Glymphatic Function, Global Brain Activity, and Cognitive Performance in Adolescents Living With Perinatal HIV Exposure

The discovery of the glymphatic system has provided a theoretical framework for understanding neurofluid dynamics and waste clearance within the brain. Recent studies suggest that the function of the glymphatic system is also reflected in the resting-state spontaneous brain activity. However, whether and how these functions change in perinatally HIV-infected (PHIV) adolescents, a population characterized by neuroviral infection and antiviral treatment, is largely unknown. This study aims to investigate whether PHIV-exposed infected and uninfected adolescents exhibit changes in glymphatic function and spontaneous brain activity that differ from their healthy, typically developing peers, and if these changes are associated with pathways involving related gene and receptor expression. Sixteen adolescents with perinatally acquired HIV infection (HIV+), 18 perinatally HIV-exposed but uninfected adolescents (HEU), and 30 demographically matched typically developing (TD) adolescents were enrolled. Cognitive, clinical, structural, and functional MRI data were collected. Diffusion tensor imaging along the perivascular space (DTI-ALPS) was employed to characterize glymphatic function, and whole-brain functional connectivity based on resting-state fMRI was used to investigate the diffusion of global oscillatory signals. Further mediation analysis was conducted to delineate the interactive relationships among DTI-ALPS, whole-brain signal dynamics, and cognitive assessments. HIV+ and HEU adolescents exhibited comparable DTI-ALPS scores (p > 0.05), yet both groups showed significantly higher DTI-ALPS compared with TD peers (p < 0.05). These findings suggest that not only perinatal HIV infection but also perinatal HIV exposure significantly and profoundly impacts subsequent adolescent brain glymphatic function and whole-brain signal dynamics.