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Elevated miR-9 in Cerebrospinal Fluid Is Associated with Poor Functional Outcome After Subarachnoid Hemorrhage

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Abstract

This study evaluated microRNA (miRNA) changes in cerebrospinal fluid (CSF) and their association with the occurrence of delayed cerebral ischemia (DCI) and poor functional outcome after SAH. Forty-three selected miRNAs were measured in daily CSF samples from a discovery cohort of SAH patients admitted to Rigshospitalet, Copenhagen, Denmark, and compared with neurologically healthy patients. Findings were validated in CSF from a replication cohort of SAH patients admitted to Massachusetts General Hospital, Boston, Massachusetts. The CSF levels of miRNA over time were compared with the occurrence of DCI, and functional outcome after 3 months. miRNAs were quantified in 427 CSF samples from 63 SAH patients in the discovery cohort, in 104 CSF samples from 63 SAH patients in the replication cohort, and in 11 CSF samples from 11 neurologically healthy patients. The miRNA profile changed remarkably immediately after SAH. Elevated miR-9-3p was associated with a poor functional outcome in the discovery cohort (p < 0.0001) after correction for multiple testing (q < 0.01) and in the replication cohort (p < 0.01). Furthermore, elevated miR-9-5p was associated with a poor functional outcome in the discovery cohort (p < 0.01) after correction for multiple testing (q < 0.05). No miRNA was associated with DCI in both cohorts. miR-9-3p and miR-9-5p are elevated in the CSF following SAH and this elevation is associated with a poor functional outcome. These elevations have potential roles in the progression of cerebral injury and could add to early prognostication.

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Funding

S.B. was salaried by grants from the Research Board at Rigshospitalet, Copenhagen, Denmark and Lundbeckfonden (R212-2015-1987). Reagents for miRNA profiling were funded by Lundbeckfonden (R211-2015-3844), Grosserer Jakob Ehrenreich & Hustru Grete Ehrenreichs Fond, Brødrene Hartmanns Fond, Torben & Alice Frimodts Fond, Grosserer L.F.Foghts Fond, and Aase & Ejnar Danielsens Fond.

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Authors and Affiliations

  1. Department of Neuroanaesthesiology, The Neuroscience Centre, Rigshospitalet, Copenhagen, Denmark

    Søren Bache & Kirsten Møller

  2. Centre for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark

    Søren Bache, Maria Rossing & Finn Cilius Nielsen

  3. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Søren Bache, Christian Hassager, Lars Køber, Finn Cilius Nielsen & Kirsten Møller

  4. Department of Neurosurgery, The Neuroscience Centre, Rigshospitalet, Copenhagen, Denmark

    Rune Rasmussen

  5. Department of Neurology & Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Zoe Wolcott & William T. Kimberly

  6. Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark

    Rasmus Møgelvang, Christian Hassager & Lars Køber

  7. Department of Radiology, The Diagnostic Centre, Rigshospitalet, Copenhagen, Denmark

    Daniel Tolnai

  8. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark

    Julie L. Forman

Authors
  1. Søren Bache
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  2. Rune Rasmussen
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  3. Zoe Wolcott
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  4. Maria Rossing
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  5. Rasmus Møgelvang
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  7. Christian Hassager
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  8. Julie L. Forman
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  9. Lars Køber
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  11. William T. Kimberly
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  12. Kirsten Møller
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Corresponding author

Correspondence to Søren Bache.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

According to Danish and US laws, informed consent was obtained from either the patient or by their next of kin and general practitioner.

Data Sharing Statement

The full data sets from each of the two cohorts are available as a supplemental file. Original instrument files may be available subject to a data sharing agreement that meets the requirements of host institutions as well as Danish and US laws. All data are anonymized prior to sharing.

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Bache, S., Rasmussen, R., Wolcott, Z. et al. Elevated miR-9 in Cerebrospinal Fluid Is Associated with Poor Functional Outcome After Subarachnoid Hemorrhage. Transl. Stroke Res. 11, 1243–1252 (2020). https://doi.org/10.1007/s12975-020-00793-1

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  • DOI: https://doi.org/10.1007/s12975-020-00793-1

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