149 - Cerebellar Spatial Transcriptomic Landscape of Neonates with Sudden Infant Death Syndrome (SIDS)

Poster Number: 149
Publication Number: 149.135

Javid Ghaemmaghami, Children's National Health System, Washington, D.C., DC, United States; Evan Goldstein, Children's National Health System, Washington, DC, United States; Adriana R. Valenzuela, Children's National Health Systems, Manassas Park, VA, United States; Vittorio Gallo, Children's National Health System, Washington, DC, United States; Panagiotis Kratimenos, Children's National, Washington, DC, United States

Background: Approximately 3500 infants die annually in the United States from sudden infant death syndrome (SIDS). The cerebellum makes direct connections with vital centers of brainstem nuclei, indicating a potential neurological link between abnormal cerebellar development and SIDS.

Objective: We hypothesized that cerebellar cytoarchitectural and molecular abnormalities in the human neonate result in neural circuitry disruption, leading to cardiorespiratory suppression and SIDS.

Design/Methods: We analyzed postmortem human cerebellum from term infants with SIDS and compared them with matched non-SIDS subjects to delineate mechanisms of SIDS pathogenesis. We performed neuropathological analysis combined with bulk, single-cell, and spatial transcriptomics.

Results: We compared postmortem human cerebellum of infants with SIDS with matched controls, and we found disrupted cytoarchitecture, including 1) Purkinje cell (PC) and Granule cell (GC) heterotopias. Furthermore, significant changes in the morphology of PCs were also observed, together with a thicker external GC layer (EGL), indicating arrested migration of the GCs from the EGL to the Internal granule cell layer (IGL). To investigate the molecular mechanisms underlying cerebellar abnormalities in SIDS pathogenesis, we defined the transcriptome of early postnatal human cerebellum using RNA-seq. We found a significant number (904) of differentially expressed genes (DEGs) between SIDS and matched controls, indicating complex changes in specific gene networks that regulate cerebellar functions in infants with SIDS. Using spatial and single-cell transcriptomics, we identified maturational signature differences in infants with SIDS compared to matched non-SIDS subjects.

Conclusion(s): The current studies provide a comprehensive analysis of cerebellar abnormalities that contribute to dysfunctional cerebellar-brainstem circuitry in infants with SIDS. Our study may contribute to developing novel biomarkers for primary or secondary preventative strategies of SIDS.