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Next-Generation RNA-Sequencing of Serum Small Extracellular Vesicles Discovers Potential Diagnostic Biomarkers for Dementia With Lewy Bodies

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Anto P. Rajkumar, Abdul Hye, Johannes Lange, Yazmin Rashid Manesh, Clive Ballard, Tormod Fladby, Dag Aarsland

King's Authors

Abstract

Objective: There is an urgent clinical need for identifying blood-based diagnostic biomarkers for Dementia with Lewy Bodies (DLB). Transcriptomic studies have reported unique RNA changes in postmortem DLB brains. Small extracellular vesicles (SEV) that transport RNA between brain and peripheral circulation enable identifying molecular changes in living human brain. Hence, we aimed to identify differentially expressed RNA in serum SEVs from people with DLB. Methods: We investigated serum SEV total RNA profiles in people with DLB (n = 10) and age and gender matched comparisons (n = 10) using next-generation RNA-sequencing. SEVs were separated by ultracentrifugation with density gradient and were characterized by nanoparticle analysis and western blotting. We verified the differential expression levels of identified differentially expressed genes (DEG) using high-throughput qPCR. Functional implications of identified DEG were evaluated using Ingenuity pathway analyses. Results: We identified 846 nominally significant DEG including 30 miRNAs in DLB serum SEVs. We identified significant downregulation of proinflammatory genes, IL1B, CXCL8, and IKBKB. Previously reported postmortem DLB brain DEGs were significantly enriched (χ2=4.99; df=1; p = 0.03) among the identified DEGs, and the differential expression of 40 postmortem DLB brain DEGs could be detected in serum SEVs of people living with DLB. Functional pathway and network analyses highlighted the importance of immunosenescence, ubiquitin proteasome system (UPS) dysfunction, DNA repair, and RNA post-transcriptional modification deficits in DLB pathology. Conclusion: Identified DEGs, especially reduced expression levels of inflammation, and UPS-associated RNA, may aid diagnosing DLB, and their biomarker potential warrants further investigation in larger clinical cohorts. Our findings corroborate the absence of chronic neuroinflammation in DLB.

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