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A large study reveals new mechanisms of cerebral small vessel disease

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A large genomic study of perivascular spaces published in the Nature Medicine journal on April 17th 2023 reveals new biological mechanisms involved in cerebral small vessel disease, a leading cause of stroke and dementia.

Photo : Brain MRI showing significant perivascular space loading in the white matter © Nature Medicine
Brain MRI showing significant perivascular space loading in the white matter © Nature Medicine

This study, which is the result of an international collaboration coordinated in France by teams from the Bordeaux Population Health research centre (University of Bordeaux and Inserm) and the Institute of Neurodegenerative Diseases, could lead to the identification of new drug treatments.

Cerebral small vessel disease is an age-related disease resulting from an alteration in the structure and function of the small arteries responsible for irrigating the brain. It is a major cause of stroke and dementia for which there is currently no specific drug treatment. Perivascular spaces (PVS), detectable on brain MRI, are physiological spaces surrounding the walls of small cerebral blood vessels. They are part of the brain lesions produced by this disease.

 

 

This first genomic study on PVS identified 24 regions of the genome associated with a higher PVS burden in over 40,000 participants. The majority of these regions, in people aged 65 years on average and mainly of European origin, were also associated with PVS in two smaller studies, including young adults in their 20s (i-Share study) and participants from East Asia.

The new study also highlighted the fact that a large number of genes associated with PVS are involved in brain developmental diseases and expressed in brain vascular cells before birth, suggesting a link between this marker of cerebral small vessel disease and developmental processes. Bioinformatic analyses point to a dozen genes that should be explored as priority targets for developing potential new drug treatments.

Stéphanie Debette @ Arthur Pequin

This study sheds unprecedented light on the biological mechanisms underlying cerebral small vessel disease, suggesting that they may be linked to much earlier phenomena than previously suspected. This could have important implications for strategies to prevent cerebral small vessel disease, stroke and related dementia.

S. Debette, professor of epidemiology and neurologist at the University of Bordeaux and Bordeaux University Hospital, director of the Bordeaux Population Health research centre (University of Bordeaux and Inserm) and corresponding author of the study.

PVS burden is highly hereditary, but its genetic determinants were previously unknown. Two-thirds of the identified genes point to biological pathways that do not appear to be mediated by known vascular risk factors (such as high blood pressure), opening the way to new therapeutic possibilities. However, the results also highlight the important role of hypertension in the extent of PVS and show that a high burden of this marker detectable on imaging would be strongly linked to the risk of stroke.

This study provides completely new information on the biology of PVS and their contribution to cerebral small vessel disease, a major cause of stroke and dementia worldwide, providing leads for prioritising preventive drug targets.

M.-G. Duperron, researcher and physician – head of the Inserm-Bettencourt clinic at the University of Bordeaux, Inserm and Bordeaux University Hospital, first author of the study.

The study was based on DNA samples from over 40,000 participants from numerous cohorts and general population biobanks around the world, participating in different international scientific consortia (CHARGE, BRIDGET and ISGC).

The project was carried out thanks to numerous research funds, including from the RHU SHIVA project, which benefits from a State grant managed by the French National Research Agency (ANR) within the framework of the Investments for the Future programme.

This collaborative study was coordinated by researchers from the Bordeaux Population Health research centre (University of Bordeaux and Inserm) and the Institute of Neurodegenerative Diseases in Bordeaux. It was co-coordinated by researchers from the Latin American Brain Health (BrainLat) institute of the Adolfo Ibáñez University in Santiago (Chile) and the Erasmus MC University Medical Center in Rotterdam (the Netherlands), in close collaboration with research teams from the Biggs Institute, UT Health San Antonio (USA), the University of Edinburgh (UK) and Kyoto University (Japan).

Researcher contact

  • Stéphanie Debette

    Professor of epidemiology and neurologist at the University of Bordeaux, Inserm and Bordeaux University Hospital, director of the Bordeaux Population Health research centre

    stephanie.debette%40u-bordeaux.fr

Bibliographic references

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease (2023).

Marie-Gabrielle Duperron, Maria J. Knol, Quentin Le Grand, Tavia E. Evans, Aniket Mishra, Ami Tsuchida, et al. Nature Medicine. doi : 10.1038/s41591-023-02268-w

Link to the publication