38 - Posthemorrhagic Hydrocephalus of Prematurity Damages the Glymphatic System and Confers Added Risk of Hyperactivity and Cognitive Deficits
Monday, May 1, 2023
9:30 AM – 11:30 AM ET
Poster Number: 38 Publication Number: 38.435
Tim Heck, Johns Hopkins University School of Medicine, Glen Burnie, MD, United States; Yuma Kitase, Johns Hopkins school of Medicine, Baltimore, MD, United States; Alexander Gall, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins Children's Center, Baltimore, MD, United States; Lauren Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Neonatal-Perinatal Medicine Fellow Johns Hopkins University School of Medicine Glen Burnie, Maryland, United States
Background: Children with posthemorrhagic hydrocephalus of prematurity (PHHP) cope with a triple-hit of brain injury from very preterm birth, early brain hemorrhage, and hydrocephalus. While children with PHHP typically receive care for their PHHP, cerebral palsy, and epilepsy, they do not typically receive screening and ongoing care for their cognitive and behavioral deficits throughout childhood.
Objective: We hypothesized that rats with PHHP would exhibit a different phenotype than rats with preterm brain injury alone. We predicted these changes would include deficits in activity regulation, cognition, and CSF dynamics.
Design/Methods: To mimic brain injury from preterm birth, pregnant dams underwent laparotomy on embryonic day 18 with transient uterine artery occlusion and intra-amniotic lipopolysaccharide. Shams underwent laparotomy only. For PHHP, rats of both sexes with preterm brain injury were randomly allocated to receive littermate lysed red blood cells on postnatal day 1 (P1). On P35, rats were tested in an Open Field (OF) for 15 minutes and data were analyzed using Anymaze. At P60, different cohorts underwent touchscreen testing of visual discrimination, reversal learning, and glymphatic tracing with fluorescent dyes. Data were compared with two-way ANOVA with Turkey’s post hoc correction with p< 0.05 as significant (N=11-17/group).
Results: Rats with PHHP exhibit hyperactivity in OF compared to littermates with preterm injury. Specifically, rats with PHHP travelled at a greater overall speed compared to rats with preterm injury or shams (both p≤0.001), along with higher maximal speed (p=0.006 and p=0.03). Rats with PHHP have poor cognitive flexibility and commit more errors during testing of visual discrimination than their peers with preterm injury (p=0.04), with disseminated glymphatic diffusion, CSF stagnation, and abnormal AQP4 localization and polarization (p< 0.05 for all).
Conclusion(s): Rats with PHHP display a clinical phenotype of even worse hyperactivity and cognitive deficits compared to rats with preterm injury alone. The investigation of cellular processes and CSF dynamics with clinically relevant outcome measures such as activity and behavior clarify how adult cognitive outcomes unique to PHHP relate to structural and functional brain injury. Additional studies merging function with CSF dynamics are necessary to inform future clinical trial design and identify advanced biomarkers associated with cognitive outcomes.
