Approximately one-third of aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral vasospasm (DCV) 3–10 days after aneurysm rupture resulting in additional, permanent neurologic disability. Currently, no validated biomarker is available to determine the risk of DCV in aSAH patients. MicroRNAs (miRNAs) have been implicated in virtually all human diseases, including aSAH, and are found in extracellular biofluids including plasma and cerebrospinal fluid (CSF). We used a custom designed TaqMan Low Density Array miRNA panel to examine the levels of 47 selected brain and vasculature injury related miRNAs in CSF and plasma specimens collected from 31 patients with or without DCV at 3 and 7 days after aSAH, as well as from eight healthy controls. The analysis of the first 18-patient cohort revealed a striking differential expression pattern of the selected miRNAs in CSF and plasma of aSAH patients with DCV from those without DCV. Importantly, this differential expression was observed at the early time point (3 days after aSAH), before DCV event occurs. Seven miRNAs were identified as reliable DCV risk predictors along with a prediction model constructed based on an array of additional 19 miRNAs on the panel. These chosen miRNAs were then used to predict the risk of DCV in a separate, testing cohort of 15 patients. The accuracy of DCV risk prediction in the testing cohort reached 87%. The study demonstrates that our novel designed miRNA panel is an effective predictor of DCV risk and has strong applications in clinical management of aSAH patients.
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This work was supported by Grants 15-12A and 18-8A from the Kentucky Spinal Cord and Head Injury Research Trust (WXW and JES) and an endowment from the Kentucky Spinal Cord and Head Injury Research Trust (JS). Healthy control specimens were obtained from the University of Kentucky Alzheimer’s Disease Center (UK-ADC), supported by NIH Grant P30 AG280303.
The data presented in the study are deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) repository (https://www.ncbi.nlm.nih.gov/geo/), accession number GSE165608.
Wang, Wang-Xia; Springer, Joe E.; Xie, Kevin; Fardo, David W.; and Hatton, Kevin W., "A Highly Predictive MicroRNA Panel for Determining Delayed Cerebral Vasospasm Risk Following Aneurysmal Subarachnoid Hemorrhage" (2021). Sanders-Brown Center on Aging Faculty Publications. 169.
Supplementary Figure 1: Workflow and estimated time needed for miRNA isolation and TaqMan TLDA analysis.
Image_2_A Highly Predictive MicroRNA Panel for Determining Delayed Cerebral Vasospasm Risk Following Aneurysmal Subarachnoid Hemorrhage.jpg (350 kB)
Supplementary Figure 2: Distribution of miRNA expression values for 26 miRNAs between DCV+ and DCV- of the Group A cases. Each filled circle corresponds to a single case with “Yes” referring to DCV+ and “No” referring to DCV-.
Image_3_A Highly Predictive MicroRNA Panel for Determining Delayed Cerebral Vasospasm Risk Following Aneurysmal Subarachnoid Hemorrhage.jpg (372 kB)
Supplementary Figure 3: ROC curves constructed using CSF miRNA data (PBD3) from aSAHs (DCV+ plus DCV- group) and HCs.
Data_Sheet_1_A Highly Predictive MicroRNA Panel for Determining Delayed Cerebral Vasospasm Risk Following Aneurysmal Subarachnoid Hemorrhage.xlsx (79 kB)
Supplementary File 1: The file contains (1) variables without missing data; (2) DCV prediction cutoff value; (3) CSF dataset; (4) plasma dataset.