Unbiased Screen of Circulating Cerebrospinal Fluid MiroRNA Identifies miR-144-3p as a Predictor of Long-term Outcome in Subarachnoid Hemorrhage
Fang Yu1, Ruyu Shi2, Alptug H. Kaynar3, Deborah Hollingshead2, Julia Veitinger4, Jong Woo Lee5, Liangge Hsu5, Rose Du5, Patrick M. Kochanek2, Sherry H-Y Chou4
1Westchester Medical Center, 2University of Pittsburgh, 3Columbia University, 4Northwestern University, 5Harvard Medical School
Objective:

To identify potential microRNA biomarker in SAH outcome.

Background:

Cell-free circulating cerebrospinal fluid (CSF) miRNAs send posttranscriptional signals to remote organs and mediate diverse biological functions. In neurological diseases, the expression of CSF miRNAs reflects distinct pathophysiological processes in the brain and predict SAH outcome.

Design/Methods:

In this prospective cohort study of 65 SAH patients and 15 controls, we stored serial CSF during acute phase SAH and assessed functional outcome measured by modified Rankin Score (mRS) at 3 and 6-months.  Angiographic vasospasm was recorded if any cerebral vessel caliber decreased >50% on post-SAH day 7. Clinical and radiographical severity were evaluated by Hunt and Hess (HH) and modified Fisher (miFisher) grades. Unbiased screen of 798 miRs were performed in cell-free CSF using Nanostring nCounter system with spike-in controls. 

Results:

SAH cohort has mean age of 55.8 years, 67.7% females, 46.9% and 36.5% with unfavorable 3-month and 6-month outcome, respectively. 49.2% developed vasospasm. 66.2% had HH ≥3. We identified 795 microRNAs in both SAH subjects and controls. Compared with controls, CSF miR-144-3p is one of the most differentially expressed miRNAs with highest fold change in SAH CSF, and persistently increased in SAH compared to control throughout post SAH days 1-5 (p values: 3.96e-25, 1.29e-21, 3.36e-24, respectively). Higher CSF miR-144-3p on post-SAH days 1, 3 and 5 are consistently associated with unfavorable outcomes at 3-month (p values: 0.033, 0.046 and 0.009) and at 6-month (p values: 0.013, 0.020 and 0.053, respectively for days 1, 3 and 5).

Conclusions:
MiR-144-3p is among the most abundantly expressed microRNA in SAH CSF. It is significantly elevated in SAH compared to controls and might be associated with unfavorable long term SAH outcome. It is a potential prognostic biomarker for SAH. Future studies are needed to understand potential mechanistic effects of miR-144-3p on SAH brain injury.
10.1212/WNL.0000000000212928
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