402 - Neurorepair of Perinatal Brain Injury Mirrors Functional Activation and Cognitive Performance Secondary to Neuroimmunomodulation

Poster Number: 402
Publication Number: 402.236

Yuma Kitase, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Nethra Madurai, Johns Hopkins Hospital, Lutherville-Timonium, MD, United States; Shannon E. Kirk, Johns Hopkins University School of Medicine, Finksburg, MD, United States; Eric M. Chin, Kennedy Krieger Institute, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins University, Baltimore, MD, United States; Lauren L. Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Background: Chorioamnionitis (CHORIO) leads to preterm birth and increases risk of cerebral palsy (CP). The precise mechanism linking CHORIO to long-term structural and functional changes is unknown. Functional magnetic resonance imaging (fMRI) along with sophisticated assessment of cognitive function using touchscreen technology allows non-invasive interrogation of brain networks. We hypothesized that improvement of fMRI and cognitive performance would be predictive of successful neurorepair in adulthood following neuroimmunomodulation in the perinatal period.

Objective: To assess fMRI and touchscreen metrics as biomarkers of neuroimmunomodulatory drug efficacy.

Design/Methods: We used a well-established model of CP due to CHORIO in rats (bilateral uterine artery occlusion and intra-amniotic injection of lipopolysaccharide). Sham controls receive laparotomy alone. After prenatal injury, cohorts of male and female pups were randomized to receive saline, CXCR2 antagonist (SB225002, 3mg/kg, postnatal day 1 (P1-P5)) or EPO (2000U/kg)+MLT (20mg/kg) P2-P10 (n=7-16/group). fMRI and DTI were done at P70. Cognitive function using touchscreen technology and gait were also tested. Mean amplitude of low-frequency fluctuation (mALFF) was compared between groups using a non-parametric ranksum test with Holm-Bonferroni multiple comparisons correction. Statistical differences for other metrics used a two-way ANOVA with Bonferroni post-hoc correction p< 0.05, n=10-15).

Results: Adults with CHORIO have significant reductions in thalamic mALFF and profound deficits in executive function and cognitive flexibility (p < 0.05). They also develop a spastic-like gait along with decreased anatomical connectivity and reduced microstructural integrity in major white matter tracts (p < 0.01). Treatment with EPO+MLT improved fMRI and reversed deficits in mALFF and cognitive flexibility (p < 0.05). While transient CXCR2 blockade improved DTI and gait metrics (p < 0.05), it did not attenuate deficits in executive function or thalamic mALFF. Conclusion(s): fMRI and cognitive assessment with touchscreen technology has sufficient resolution to detect changes in functional CNS networks, including repair with different neuroimmunomodulatory agents. EPO+MLT therapy attenuated functional deficits and functional connectivity. Biobehavioral and functional imaging biomarkers detects facets of neural repair by neuroimmunomodulation in a preclinical model of CP.