Identification of distinct and shared biomarker panels in different manifestations of cerebral small vessel disease through proteomic profiling.

Hristovska I, Binette AP, Kumar A, Wennström M, Gaiteri C, Karlsson L, Strandberg O, Janelidze S, van Westen D, Stomrud E, Palmqvist S, Ossenkoppele R, Mattsson-Carlgren N, Vogel JW, Hansson O

medRxiv - (-) - [2025-08-23; online 2025-08-23]

The pathophysiology underlying various manifestations of cerebral small vessel disease (cSVD) remains obscure. Using high-throughput proteomics, we identified common and distinct proteomic signatures of white matter lesions (WML), microbleeds, infarcts and their subtypes, measured in 1,670 living patients. Across all cSVD manifestations, proteins indicative of extracellular matrix dysregulation and vascular remodeling were elevated, including ELN, POSTN, CCN2 and especially MMP12, implicating endothelial and smooth muscle cells of the brain. These proteins were validated in CSF from two additional datasets, and a subset detected in plasma predicted future cerebrovascular events in the UK Biobank better than risk scores currently used in clinical practice. Analysis focusing on WMLs found microglial-associated proteins to be associated with faster WML progression, whereas specific neuron-derived proteins mediated the link between WMLs and longitudinal cognitive decline. These data provide a comprehensive atlas of cSVD biomarkers, and our findings provide a promising roadmap for future diagnostics and therapeutics.

PubMed 38947084

DOI 10.1101/2024.06.10.24308599

Crossref 10.1101/2024.06.10.24308599

pmc: PMC11213103
pii: 2024.06.10.24308599