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

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

doi:10.1038/s43587-025-01006-w

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

Ilana Caro
, Daniel Western
, Shinichi Namba
, Na Sun
, Shuji Kawaguchi
, Yunye He
, Masashi Fujita
, Gennady Roshchupkin
, Tim D’Aoust
, Marie Gabrielle Duperron
, Muralidharan Sargurupremraj
, Ami Tsuchida
, Masaru Koido
, Marziehsadat Ahmadi
, Chengran Yang
, Jigyasha Timsina
, Laura Ibanez
, Koichi Matsuda
, Yutaka Suzuki
, Yoshiya Oda

Akinori Kanai, Pouria Jandaghi, Markus Munter, Daniel Auld, Iana Astafeva, Raquel Puerta, Jerome I. Rotter, Bruce M. Psaty, Joshua C. Bis, W. T. Longstreth, Thierry Couffinhal, Pablo García-González, Vanesa Pytel, Marta Marquié, Amanda Cano, Mercè Boada, Marc Joliot, Mark Lathrop, Quentin Le Grand, Lenore J. Launer, Joanna M. Wardlaw, Myriam Heiman, Agustin Ruiz, Paul M. Matthews, Sudha Seshadri, Myriam Fornage, Hieab Adams, Aniket Mishra, David Alexandre Trégouët, Yukinori Okada, Manolis Kellis, Philip L. De Jager, Christophe Tzourio, Yoichiro Kamatani, Fumihiko Matsuda, Carlos Cruchaga, Stéphanie Debette

Global Brain Health Latam

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2514-2531
Number of pages	18
Journal	Nature Aging
Volume	5
Issue number	12
DOIs	https://doi.org/10.1038/s43587-025-01006-w
State	Published - Dec 2025

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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., ... Debette, S. (2025). Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease. Nature Aging, 5(12), 2514-2531. https://doi.org/10.1038/s43587-025-01006-w

@article{da785f98301748658d5368a1c95220e2,

title = "Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease",

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.",

author = "Ilana Caro and Daniel Western and Shinichi Namba and Na Sun and Shuji Kawaguchi and Yunye He and Masashi Fujita and Gennady Roshchupkin and Tim D{\textquoteright}Aoust and Duperron, \{Marie Gabrielle\} and Muralidharan Sargurupremraj and Ami Tsuchida and Masaru Koido and Marziehsadat Ahmadi and Chengran Yang and Jigyasha Timsina and Laura Ibanez and Koichi Matsuda and Yutaka Suzuki and Yoshiya Oda and Akinori Kanai and Pouria Jandaghi and Markus Munter and Daniel Auld and Iana Astafeva and Raquel Puerta and Rotter, \{Jerome I.\} and Psaty, \{Bruce M.\} and Bis, \{Joshua C.\} and Longstreth, \{W. T.\} and Thierry Couffinhal and Pablo Garc{\'i}a-Gonz{\'a}lez and Vanesa Pytel and Marta Marqui{\'e} and Amanda Cano and Merc{\`e} Boada and Marc Joliot and Mark Lathrop and \{Le Grand\}, Quentin and Launer, \{Lenore J.\} and Wardlaw, \{Joanna M.\} and Myriam Heiman and Agustin Ruiz and Matthews, \{Paul M.\} and Sudha Seshadri and Myriam Fornage and Hieab Adams and Aniket Mishra and Tr{\'e}gou{\"e}t, \{David Alexandre\} and Yukinori Okada and Manolis Kellis and \{De Jager\}, \{Philip L.\} and Christophe Tzourio and Yoichiro Kamatani and Fumihiko Matsuda and Carlos Cruchaga and St{\'e}phanie Debette",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s43587-025-01006-w",

language = "English",

volume = "5",

pages = "2514--2531",

journal = "Nature Aging",

issn = "2662-8465",

publisher = "Springer",

number = "12",

}

Caro, I, Western, D, Namba, S, Sun, N, Kawaguchi, S, He, Y, Fujita, M, Roshchupkin, G, D’Aoust, T, Duperron, MG, 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, JI, Psaty, BM, Bis, JC, Longstreth, WT, Couffinhal, T, García-González, P, Pytel, V, Marquié, M, Cano, A, Boada, M, Joliot, M, Lathrop, M, Le Grand, Q, Launer, LJ, Wardlaw, JM, Heiman, M, Ruiz, A, Matthews, PM, Seshadri, S, Fornage, M, Adams, H, Mishra, A, Trégouët, DA, Okada, Y, Kellis, M, De Jager, PL, Tzourio, C, Kamatani, Y, Matsuda, F, Cruchaga, C & Debette, S 2025, 'Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease', Nature Aging, vol. 5, no. 12, pp. 2514-2531. https://doi.org/10.1038/s43587-025-01006-w

TY - JOUR

T1 - Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

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

PY - 2025/12

Y1 - 2025/12

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/105022594671

U2 - 10.1038/s43587-025-01006-w

DO - 10.1038/s43587-025-01006-w

M3 - Article

AN - SCOPUS:105022594671

SN - 2662-8465

VL - 5

SP - 2514

EP - 2531

JO - Nature Aging

JF - Nature Aging

IS - 12

ER -

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

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