TY  - JOUR
AU  - Caro, Ilana
AU  - Western, Daniel
AU  - Namba, Shinichi
AU  - Sun, Na
AU  - Kawaguchi, Shuji
AU  - He, Yunye
AU  - Fujita, Masashi
AU  - Roshchupkin, Gennady
AU  - D'Aoust, Tim
AU  - Duperron, Marie-Gabrielle
AU  - Sargurupremraj, Muralidharan
AU  - Tsuchida, Ami
AU  - Koido, Masaru
AU  - Ahmadi, Marziehsadat
AU  - Yang, Chengran
AU  - Timsina, Jigyasha
AU  - Ibanez, Laura
AU  - Matsuda, Koichi
AU  - Suzuki, Yutaka
AU  - Oda, Yoshiya
AU  - Kanai, Akinori
AU  - Jandaghi, Pouria
AU  - Munter, Markus
AU  - Auld, Daniel
AU  - Astafeva, Iana
AU  - Puerta, Raquel
AU  - Rotter, Jerome I
AU  - Psaty, Bruce M
AU  - Bis, Joshua C
AU  - Longstreth, W. T.
AU  - Couffinhal, Thierry
AU  - García-González, Pablo
AU  - Pytel, Vanesa
AU  - Marquié, Marta
AU  - Cano, Amanda
AU  - Boada, Mercè
AU  - Joliot, Marc
AU  - Lathrop, Mark
AU  - Le Grand, Quentin
AU  - Launer, Lenore J
AU  - Wardlaw, Joanna M
AU  - Heiman, Myriam
AU  - Ruiz, Agustin
AU  - Matthews, Paul M
AU  - Seshadri, Sudha
AU  - Fornage, Myriam
AU  - Adams, Hieab
AU  - Mishra, Aniket
AU  - Trégouët, David-Alexandre
AU  - Okada, Yukinori
AU  - Kellis, Manolis
AU  - De Jager, Philip L
AU  - Tzourio, Christophe
AU  - Kamatani, Yoichiro
AU  - Matsuda, Fumihiko
AU  - Cruchaga, Carlos
AU  - Debette, Stéphanie
TI  - Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease.
JO  - Nature aging
VL  - 5
IS  - 12
SN  - 2662-8465
CY  - London
PB  - Nature Research
M1  - DZNE-2025-01372
SP  - 2514 - 2531
PY  - 2025
AB  - 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.
KW  - Cerebral Small Vessel Diseases: genetics
KW  - Cerebral Small Vessel Diseases: cerebrospinal fluid
KW  - Cerebral Small Vessel Diseases: blood
KW  - Cerebral Small Vessel Diseases: diagnostic imaging
KW  - Humans
KW  - Biomarkers: blood
KW  - Biomarkers: cerebrospinal fluid
KW  - Magnetic Resonance Imaging
KW  - Proteogenomics: methods
KW  - Mendelian Randomization Analysis
KW  - Male
KW  - Female
KW  - Aged
KW  - Biomarkers (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41266628
DO  - DOI:10.1038/s43587-025-01006-w
UR  - https://pub.dzne.de/record/282911
ER  -