Journal Article

DZNE-2025-01372

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease.

Caro, I. ; Western, D. ; Namba, S. ; Sun, N. ; Kawaguchi, S. ; He, Y. ; Fujita, M. ; Roshchupkin, G. ; D'Aoust, T. ; Duperron, M.-G. ; Sargurupremraj, M. ; Tsuchida, A. ; Koido, M. ; Ahmadi, M. ; Yang, C. ; Timsina, J. ; Ibanez, L. ; Matsuda, K. ; Suzuki, Y. ; Oda, Y. ; Kanai, A. ; Jandaghi, P. ; Munter, M. ; Auld, D. ; Astafeva, I. ; Puerta, R. ; Rotter, J. I. ; Psaty, B. M. ; Bis, J. C. ; Longstreth, W. T. ; Couffinhal, T. ; García-González, P. ; Pytel, V. ; Marquié, M. ; Cano, A. ; Boada, M. ; Joliot, M. ; Lathrop, M. ; Le Grand, Q.DZNE* ; Launer, L. J. ; Wardlaw, J. M. ; Heiman, M. ; Ruiz, A. ; Matthews, P. M. ; Seshadri, S. ; Fornage, M. ; Adams, H. ; Mishra, A. ; Trégouët, D.-A. ; Okada, Y. ; Kellis, M. ; De Jager, P. L. ; Tzourio, C. ; Kamatani, Y. ; Matsuda, F. ; Cruchaga, C. ; Debette, S.

2025
Nature Research London

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Please use a persistent id in citations: doi:10.1038/s43587-025-01006-w

Abstract: Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning.

Keyword(s): Cerebral Small Vessel Diseases: genetics (MeSH) ; Cerebral Small Vessel Diseases: cerebrospinal fluid (MeSH) ; Cerebral Small Vessel Diseases: blood (MeSH) ; Cerebral Small Vessel Diseases: diagnostic imaging (MeSH) ; Humans (MeSH) ; Biomarkers: blood (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Proteogenomics: methods (MeSH) ; Mendelian Randomization Analysis (MeSH) ; Male (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Biomarkers

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Contributing Institute(s):

1. Population Health Sciences (AG Breteler)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2025

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Nature ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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