Host Transcriptomics Identifies Unique Host Gene Expression Patterns in Focal Cerebral Arteriopathy of Childhood
Mary Rolfes1, Prashanth Ramachandran3, Ravi Dandekar2, Maham Zia2, Kathleen Colao2, Nancy Hills2, Martineau Louiné2, Mary Wang2, Michael Wilson4, Heather Fullerton5
1Neurology, UCSF, 2UCSF, 3Royal Melbourne Hospital, 4University of California San Francisco, 5University of CA - San Fransico
Objective:
To assess the host immune response in focal cerebral arteriopathy of childhood.
Background:
Pediatric arterial ischemic stroke (AIS) is a major cause of childhood disability. Focal cerebral arteriopathy (FCA), characterized by unilateral stenosis of the anterior circulation, accounts for up to one-quarter of pediatric AIS with a recurrence risk of up 25%. Understanding the host response to FCA might inform post-stroke therapeutic targets to improve recovery and prevent recurrence.
Design/Methods:
From 12/2016-1/2022, 22 North American centers enrolled AIS cases (28 days – 18 years) and stroke-free controls. Bulk RNA sequencing was performed on peripheral blood collected within 72 hours of AIS and compared to stroke-free controls. AIS cases were classified as arteriopathic, cardioembolic or idiopathic. Unsupervised clustering and differential gene expression analysis identified unique gene expression patterns between FCA cases and controls (adjusted p-value <0.05). Ingenuity Pathway Analysis assessed for dysregulated molecular pathways.
Results:
AIS cases (n=194) were a median age of 11.9 years and 55% male. The subgroup of FCA cases (n=30) were a median age of 12.5 years and 57% male. Controls (n=95) were a median age of 11.8 years and 48% male. Unsupervised clustering demonstrated clustering of FCA cases. 1258 genes were differentially expressed between FCA cases and controls. 122 genes had a fold change > |2|. Significantly upregulated pathways correlated with pro-inflammatory immune responses including STAT3, p38 MAPK, and activin inhibin signaling pathways. Th1 and Th2 signaling pathways were most downregulated.
Conclusions:
This is the first study to investigate the host response of FCA using host transcriptomics. Our findings provide new insight into the underlying pathogenesis of FCA. Upregulated pathways may serve as future therapeutic targets with the potential to improve outcomes and prevent stroke recurrence in this vulnerable population. Additional analyses comparing FCA to idiopathic and cardioembolic subtypes may provide further insight into the unique inflammatory response in FCA.