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

Hristovska, Ines LU ; Pichet Binette, Alexa LU ; Kumar, Atul LU orcid ; Wennström, Malin LU ; Gaiteri, Chris LU ; Karlsson, Linda LU orcid ; Strandberg, Olof LU ; Janelidze, Shorena LU ; van Westen, Danielle LU orcid and Stomrud, Erik LU orcid , et al. (2026) In Nature Aging 6(3). p.703-721
Abstract

The pathophysiology underlying various manifestations of cerebral small-vessel disease (cSVD) remains poorly understood. Using high-throughput proteomics, we identified common and distinct proteomic signatures of white matter lesions (WMLs), microbleeds, infarcts and their subtypes, measured in 1,670 living patients. Across all cSVD manifestations, markers of extracellular matrix dysregulation and vascular remodeling were increased, including ELN, POSTN, CCN2 and especially MMP12, implicating endothelial and smooth muscle cells of the brain. These proteins were validated in cerebrospinal fluid from two additional datasets, and a subset detected in plasma predicted future cerebrovascular events in the UK Biobank better than risk scores... (More)

The pathophysiology underlying various manifestations of cerebral small-vessel disease (cSVD) remains poorly understood. Using high-throughput proteomics, we identified common and distinct proteomic signatures of white matter lesions (WMLs), microbleeds, infarcts and their subtypes, measured in 1,670 living patients. Across all cSVD manifestations, markers of extracellular matrix dysregulation and vascular remodeling were increased, including ELN, POSTN, CCN2 and especially MMP12, implicating endothelial and smooth muscle cells of the brain. These proteins were validated in cerebrospinal fluid 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 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.

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type
Contribution to journal
publication status
published
subject
in
Nature Aging
volume
6
issue
3
pages
19 pages
publisher
Springer
external identifiers
  • pmid:41735646
  • scopus:105031301864
ISSN
2662-8465
DOI
10.1038/s43587-026-01081-7
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2026.
id
aa7e8111-510c-4712-a097-4a78653af98c
date added to LUP
2026-04-07 16:36:30
date last changed
2026-04-08 07:45:57
@article{aa7e8111-510c-4712-a097-4a78653af98c,
  abstract     = {{<p>The pathophysiology underlying various manifestations of cerebral small-vessel disease (cSVD) remains poorly understood. Using high-throughput proteomics, we identified common and distinct proteomic signatures of white matter lesions (WMLs), microbleeds, infarcts and their subtypes, measured in 1,670 living patients. Across all cSVD manifestations, markers of extracellular matrix dysregulation and vascular remodeling were increased, including ELN, POSTN, CCN2 and especially MMP12, implicating endothelial and smooth muscle cells of the brain. These proteins were validated in cerebrospinal fluid 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 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.</p>}},
  author       = {{Hristovska, Ines and Pichet Binette, Alexa and Kumar, Atul and Wennström, Malin and Gaiteri, Chris and Karlsson, Linda and Strandberg, Olof and Janelidze, Shorena and van Westen, Danielle and Stomrud, Erik and Palmqvist, Sebastian and Ossenkoppele, Rik and Mattsson-Carlgren, Niklas and Vogel, Jacob W. and Hansson, Oskar}},
  issn         = {{2662-8465}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{703--721}},
  publisher    = {{Springer}},
  series       = {{Nature Aging}},
  title        = {{Identification of distinct and shared biomarker panels in different manifestations of cerebral small-vessel disease through proteomic profiling}},
  url          = {{http://dx.doi.org/10.1038/s43587-026-01081-7}},
  doi          = {{10.1038/s43587-026-01081-7}},
  volume       = {{6}},
  year         = {{2026}},
}