Abstract Details

Title Host Transcriptomics Identifies Unique Host Gene Expression Patterns in Focal Cerebral Arteriopathy of Childhood

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S6 - Stroke Pathophysiology and Prediction (4:54 PM-5:06 PM)

Poster/Presentation
Number 008

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.

Objective To assess the host immune response in focal cerebral arteriopathy of childhood.

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.

Authors/Disclosures
Mary Karalius, MD (UCSF) PRESENTER	Dr. Karalius has nothing to disclose.
Prashanth S. Ramachandran, Jr., MBBS (Royal Melbourne Hospital)	Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen.
Ravi Dandekar	No disclosure on file
Maham Zia (UCSF)	No disclosure on file
Kathleen Colao (UCSF)	No disclosure on file
Nancy Hills	No disclosure on file
Martineau Louine, MD (UCSF)	Dr. Louine has nothing to disclose.
Shiyin Wang (UCSF)	No disclosure on file
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from UCSF Weill Institute for Neurosciences. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.
Heather J. Fullerton, MD (University of CA - San Fransico)	The institution of Dr. Fullerton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer. The institution of Dr. Fullerton has received research support from NIH, AHA, Benioff Foundation.