Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. Genomics can provide a strong foundation for mechanistic studies and drug target discovery. While large-scale proteomic investigations have recently been conducted for stroke and dementia, with promising findings, studies on proteomics of cSVD have been conducted on limited sets of proteins, in small studies of European ancestry (N < 5,000), and in plasma only14–18. The researchers hypothesize that, while plasma may enable easy-access biomarker measurements, CSF, the fluid circulating in perivascular spaces, could reveal a more accurate biological fingerprint of cSVD.
Methods
The researchers including Stéphanie Debette, director of the VBHI, Agustín Riuz, member of the VBHI Scientific Advisory Board and David-Alexandre Tregouët, member of the VBHI Board of Director, used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces).
They describe a new biological fingerprint of 49 protein-cSVD associations, predominantly in the CSF.
They implemented a multipronged follow-up, across :
- fluids,
- platforms, and
- ancestries (Europeans and East-Asian),
including testing associations of direct plasma protein measurements with MRI-cSVD.
Results
cSVD-proteins were enriched in extracellular matrix and immune response pathways, and in genes enriched in microglia and specific microglial states (integration with single-nucleus RNA sequencing).
Immune-related proteins were associated with MRI-cSVD already at age twenty. Half of cSVD-proteins were associated with stroke, dementia, or both, and seven cSVD-proteins are targets for known drugs (used for other indications in directions compatible with beneficial therapeutic effects).
This work provides an extensive, first in vivo biological fingerprint of cSVD derived from large-scale proteogenomics studies in CSF and blood.
The results highlight important biological processes underlying cSVD at the molecular and cellular levels, pointing to shared pathways between cSVD and AD of potential therapeutic relevance and early life mechanisms involving immunity and inflammation.
This proteogenomic signature paves the way for deriving circulating biomarkers and exploring drug development and repositioning opportunities.
Scientific publication in preprint
S.Debette, I.Caro, D.Western, S.Namba et al, Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease. 2024 https://doi.org/10.21203/rs.3.rs-4535534/v1
