Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

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.

Authors

Institutions

Publication Details

Journal
Nature Aging
Published
2025-11-20
DOI
https://doi.org/10.1038/s43587-025-01006-w
Citations
1
Primary Topic
Cerebrovascular and genetic disorders
Type
article
Field-Weighted Citation Impact
1.39

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

Hieab H.H. Adams, Bruce M. Psaty, Joanna Marguerite Wardlaw, Masashi Fujita et al.
1 citations
Nature Aging
Cerebrovascular and genetic disorders
1.39
article

Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

Hieab H.H. Adams, Bruce M. Psaty, Joanna Marguerite Wardlaw, Masashi Fujita, Myriam Heiman, Marta Marquié, Sudha S. Seshadri, Agustı́n Ruiz, Aniket Mishra, Lenore J. Launer, Marc Joliot, Daniel Western, Na Sun, Masaru Koido, Gennady V. Roshchupkin, Thierry Couffinhal, Yoichiro Kamatani, Marie-Gabrielle Duperron, Ami Tsuchida, Yukinori Okada, Chengran Yang, Shinichi Namba, Carlos C Cruchaga, Jerome I. Rotter, Amanda C. Cano, Philip L. De Jager, Shuji Kawaguchi, Merçé Boada, Vanesa Pytel, Muralidharan Sargurupremraj, Yutaka Suzuki, Christophe Tzourio, Pouria Jandaghi, Joshua C. Bis, Paul M. Matthews, David‐Alexandre Trégouët, Koichi Matsuda, Akinori Kanai, Laura Ibáñez, Yoshiya Oda, Stéphanie Debette, Quentin Le Grand, Daniel Auld, Raquel Puerta, G.M. Lathrop, Pablo García‐González, Yunye He, Ilana Caro, Manolis Kellis, Markus Munter, Tim D’Aoust, Iana Astafeva, Myriam Fornage, Fumihiko Matsuda, Jigyasha Timsina, W.T. Longstreth, Marziehsadat Ahmadi
article en
1 citations

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.

Nature AgingVol. 5(12)
Broad Institute (US), Centre National de la Recherche Scientifique (FR), Radboud University Nijmegen (NL), Université de Bordeaux (FR), Inserm (FR), The University of Texas at San Antonio Health Science Center (US), University of Washington (US), Washington University in St. Louis (US), Adolfo Ibáñez University (CL), Kyoto University (JP), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Columbia University Irving Medical Center (US), Instituto de Salud Carlos III (ES), UCLA Medical Center (US), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), Radboud University Medical Center (NL), Centre Hospitalier Universitaire de Bordeaux (FR), Universitat Internacional de Catalunya (ES), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Institut des Maladies Neurodégénératives (FR), Bordeaux Population Health (FR), Institute for Neurodegenerative Disorders (US), McGill Genome Centre (CA), UK Dementia Research Institute (GB), Brown Foundation (US), Institute on Aging (US), National Institute on Aging (US), RIKEN Center for Integrative Medical Sciences (JP), Institut du Cerveau (FR), Harbor–UCLA Medical Center (US), Imperial College London (GB), Massachusetts Institute of Technology (US), The University of Tokyo (JP), The University of Texas Health Science Center at Houston (US), The University of Osaka (JP), University of Edinburgh (GB)
Japan Foundation for Applied Enzymology, Japan Agency for Medical Research and Development, Agentschap Innoveren en Ondernemen, EU Joint Programme – Neurodegenerative Disease Research, European Federation of Pharmaceutical Industries and Associations, UK Research and Innovation, National Institute for Health and Care Research, Imperial College London, Imperial College Healthcare NHS Trust, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Ministerio de Ciencia e Innovación, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Grifols, UK Dementia Research Institute, Medical Research Council, Japan Society for the Promotion of Science, Instituto de Salud Carlos III, European Regional Development Fund, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Moonshot Research and Development Program
Openalex Percentile: Top 14%
Cerebrovascular and genetic disorders
1.39
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.