Proteomic discovery study of cerebrospinal fluid after aneurysmal subarachnoid hemorrhage

Abstract

Background: proteomic analysis of cerebrospinal fluid (CSF) has the potential to provide insight into the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and target trials to improve outcome. The aim of this study was to perform a definitive proteomic analysis of CSF following aSAH to identify proteins associated with neurological injury.

Methods: retrospective proteomic analysis of CSF was collected at neurosurgical centers in the United Kingdom between 2013 and 2023 either from external ventricular drain or lumbar puncture on day 7 after aSAH. Adults with confirmed aSAH were included. Exclusions were pregnancy, severe comorbidities, inability to follow-up, and those not expected to survive 24 hours. Proteomic analysis was performed using mass spectrometry to identify CSF proteins differentially expressed between patients with good (modified Rankin Scale score of 0–2) and poor (modified Rankin Scale score of 3–6) outcomes at 6 months following aSAH. Controlling for CSF albumin (a marker of blood-brain interface permeability and volume of hemorrhage), differentially expressed proteins were identified. Differential pathway activity was explored using protein interaction, gene set enrichment and TopMD analyses.

Results: a total of 152 patients were included (101 good and 51 poor outcome), and 4952 unique proteins were identified across all samples. The CSF proteomic profile differed between good and poor outcome individuals as evidenced by clustering of individuals by outcome using topological data analysis. Controlling for CSF albumin 16 intracellular and secreted proteins were differentially expressed between good and poor outcome patients. Two cellular pathways were identified to have differential activity by all 3 pathway analysis approaches: the PI3K-Akt signaling pathway and glycolysis/gluconeogenesis.

Conclusions: in this study, 16 proteins were differentially expressed between good and poor outcome aSAH patients. The proteomic evidence, both on an individual protein and pathway level highlights that inflammation and oxidative injury are associated with the pathophysiology of neurological injury following aSAH. These results support the exploration of treatments targeting these pathways to improve outcome after aSAH.

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Identifiers

ORCID for Ben Gaastra: orcid.org/0000-0002-7517-6882

ORCID for Luis Coy: orcid.org/0000-0001-6466-6408

ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

ORCID for Paul Skipp: orcid.org/0000-0002-2995-2959

ORCID for Diederik Bulters: orcid.org/0000-0001-9884-9050

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