Most purported brain-released plasma circular RNAs detected in stroke likely originate from white blood cells.

The identification and development of reliable acute stroke blood biomarkers could limit life-threatening delays stemming from mistriage. Recent investigations have reported a set of 24 plasma circRNAs believed to be released from the brain into circulation during acute ischemic events with potential to serve as such biomarkers. However, limitations associated with the methods employed for biomarker discovery in these studies raise the possibility that these circRNAs actually originate from non-neural sources. Here, we sought to clarify the probability that these 24 plasma circRNAs truly originate from the brain by examining source tissue expression levels. Specifically, we leveraged genome-wide RNA sequencing data from a large cohort of human donors to assess their expression levels in 31 distinct tissue types including brain. 17 of the 24 (70.8%) candidate circRNAs exhibited their single highest expression levels in blood relative to all other tissue types included in our analysis, while only 1 (4.2%) exhibited its single highest expression levels in brain. The observed body-wide expression profiles suggest that a majority of the 24 candidate plasma circRNAs assessed in our analysis originate from circulating white blood cells and not the brain as originally believed, which would dramatically reduce their potential utility as acute stroke biomarkers.