Cerebrospinal Fluid Proteome Map Reveals Molecular Signatures of Reversible Cerebral Vasoconstriction Syndrome

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder characterized by repetitive thunderclap headaches and reversible cerebral vasoconstriction. The pathophysiological mechanism of this mysterious syndrome remains underexplored and there is no clinically available...

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Published in:Molecular & cellular proteomics 2024-07, Vol.23 (7), p.100794, Article 100794
Main Authors: Yang, Jhih-Ci, Chen, Shih-Pin, Wang, Yen-Feng, Chang, Chan-Hua, Chang, Kun-Hao, Fuh, Jong-Ling, Chow, Lok-Hi, Han, Chia-Li, Chen, Yu-Ju, Wang, Shuu-Jiun
Format: Article
Language:English
Subjects:
blood-brain barrier
cerebrospinal fluid
data-independent acquisition
proteomics
reversible cerebral vasoconstriction syndrome (RCVS)
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Summary:Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder characterized by repetitive thunderclap headaches and reversible cerebral vasoconstriction. The pathophysiological mechanism of this mysterious syndrome remains underexplored and there is no clinically available molecular biomarker. To provide insight into the pathogenesis of RCVS, this study reported the first landscape of dysregulated proteome of cerebrospinal fluid (CSF) in patients with RCVS (n  =  21) compared to the age- and sex-matched controls (n  =  20) using data-independent acquisition mass spectrometry. Protein–protein interaction and functional enrichment analysis were employed to construct functional protein networks using the RCVS proteome. An RCVS-CSF proteome library resource of 1054 proteins was established, which illuminated large groups of upregulated proteins enriched in the brain and blood-brain barrier (BBB). Personalized RCVS-CSF proteomic profiles from 17 RCVS patients and 20 controls reveal proteomic changes involving the complement system, adhesion molecules, and extracellular matrix, which may contribute to the disruption of BBB and dysregulation of neurovascular units. Moreover, an additional validation cohort validated a panel of biomarker candidates and a two-protein signature predicted by machine learning model to discriminate RCVS patients from controls with an area under the curve of 0.997. This study reveals the first RCVS proteome and a potential pathogenetic mechanism of BBB and neurovascular unit dysfunction. It also nominates potential biomarker candidates that are mechanistically plausible for RCVS, which may offer potential diagnostic and therapeutic opportunities beyond the clinical manifestations. [Display omitted] •First exploration of the dysregulated proteome of CSF in RCVS.•Establishment of a RCVS-CSF proteome library resource with 1054 proteins.•Dysregulated CSF proteomics suggest neurovascular unit and BBB pathogenesis.•Nomination of protein marker candidates to assist RCVS diagnosis. The first proteome profiling of cerebrospinal fluid (CSF) from reversible cerebral vasoconstriction syndrome (RCVS) patients sheds light on the mysterious pathophysiology of the disease. A RCVS-CSF spectral library was constructed to facilitate deep personalized CSF profiling by data-independent acquisition. The findings reveal the first RCVS proteome and suggest a potential pathogenetic mechanism involving dysfunction of blood-brain barrie
ISSN:1535-9476
1535-9484
1535-9484
DOI:10.1016/j.mcpro.2024.100794