Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Duperron, Marie‐Gabrielle; Knol, Maria J.; Evans, Tavia E.; Mishra, Aniket; Tsuchida, Ami; Roshchupkin, Gennady V.; Konuma, Takahiro; Trégouët, David‐Alexandre; Romero, José R.; Frenzel, Stefan; Luciano, Michelle; Hofer, Edith; Bourgey, Mathieu; Delgado, Pilar; Hilal, Saima; Tankard, Rick M.; Dubost, Florian; Shin, Jean; Saba, Yasaman; Armstrong, Nicola J.; Bordes, Constance; Beiser, Alexa S.; Brodaty, Henry; Bülow, Robin; Carrera, Caty; Chen, Christopher; Cheng, Ching‐Yu; Deary, Ian J.; Gampawar, Piyush; Himali, Jayandra J.; Jiang, Jiyang; Kawaguchi, Takahisa; Li, Shuo; Macalli, Mélissa; Marquis, Pascale; Morris, Zoë; Maniega, Susana Muñoz; Miyamoto, Susumu; Okawa, Masakazu; Paradise, Matthew; Parva, Pedram; Rundek, Tatjana; Sargurupremraj, Muralidharan; Schilling, Sabrina; Setoh, Kazuya; Soukarieh, Omar; Tabara, Yasuharu; Teumer, Alexander; Thalamuthu, Anbupalam; Trollor, Julian N.; Hernández, Maria C. Valdés; Vernooij, Meike W.; Völker, Uwe; Wittfeld, Katharina; Wong, Tien Yin; Wright, Margaret J.; Zhang, Junyi; Zhao, Wanting; Zhu, Yi-Cheng; Schmidt, Helena; Sachdev, Perminder S.; Wang, Wen; Yoshida, Kazumichi; Joutel, Anne; Sacco, Ralph L.; Bourque, Guillaume; Grand, Quentin Le; Lathrop, Mark; Paus, Tomáš; Fernández‐Cadenas, Israel; Yang, Qiong; Mazoyer, Bernard; Boutinaud, Philippe; Okada, Yukinori; Grabe, Hans‐Jörgen; Mather, Karen A.; Schmidt, Reinhold; Joliot, Marc; Ikram, M. Arfan; Matsuda, Fumihiko; Tzourio, Christophe; Seshadri, Sudha; Adams, Hieab H.H.; Debette, Stéphanie

doi:10.1038/s41591-023-02268-w

Cited by 36 publications

(20 citation statements)

References 80 publications

(117 reference statements)

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“…In terms of population characteristics, application and method development studies shared similar distribution (i.e., proportion). Median sample size of PVS application studies was N = 161 (IQR = 482.5), with two multicentre epidemiological studies with sample sizes greater than 30,000 (Evans et al, 2023; Duperron et al, 2023) and five with more than 1,000. Broad population type and age-groupings used in application studies compared to method development and improvement studies are presented in Tables 3 and 4, respectively.…”

Section: Resultsmentioning

confidence: 99%

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A Systematic Review and Meta-Analysis of Automated Methods for Quantifying Enlarged Perivascular Spaces in the Brain

Waymont,

Valdés Hernández,

Bernal

et al. 2024

Preprint

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Research into magnetic resonance imaging (MRI)- visible perivascular spaces (PVS) has recently increased, as results from studies in different diseases and populations are cementing their association with sleep, disease phenotypes, and overall health indicators. With the establishment of worldwide consortia and the availability of large databases, computational methods that allow to automatically process all this wealth of information are becoming increasingly relevant. Several computational approaches have been proposed to assess PVS from MRI, and efforts have been made to summarise and appraise the most widely applied ones. We systematically reviewed and meta-analysed all publications available up to September 2023 describing the development, improvement, or application of computational PVS quantification methods from MRI. We analysed 67 approaches and 60 applications of their implementation, from 112 publications. The two most widely applied were the use of a morphological filter to enhance PVS-like structures, with Frangi being the choice preferred by most, and the use of a U-Net configuration with or without residual connections. Older adults or population studies comprising adults from 18 years old onwards were, overall, more frequent than studies using clinical samples. PVS were mainly assessed from T2-weighted MRI acquired in 1.5T and/or 3T scanners, although combinations using it with T1-weighted and FLAIR images were also abundant. Common associations researched included age, sex, hypertension, diabetes, white matter hyperintensities, sleep and cognition, with occupation-related, ethnicity, and genetic/hereditable traits being also explored. Despite promising improvements to overcome barriers such as noise and differentiation from other confounds, a need for joined efforts for a wider testing and increasing availability of the most promising methods is now paramount.

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Section: Resultsmentioning

confidence: 99%

“…There were significant differences in PVS volume fraction across racial/ethnic groups. (Duperron et al, 2023) Investigate GWAS associations of SVD markers. Only 2/18 cohorts applied a quantitative approach to score PVS burden automatically, which was later dichotomised on the top quartile for uniformity with the rest of the cohorts.…”

Section: Lbc1936 N = 540mentioning

confidence: 99%

A Systematic Review and Meta-Analysis of Automated Methods for Quantifying Enlarged Perivascular Spaces in the Brain

Waymont,

Valdés Hernández,

Bernal

et al. 2024

Preprint

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“…The PVS data in European populations were obtained from a meta-analysis of 18 cohorts, including 9,317 case and 29,281 control individuals for WM-PVS, 8,950 case and 29,953 control individuals for BG-PVS, and 9,163 case and 29,708 control individuals for HIP-PVS (Duperron et al, 2023). PVSs were defined as fluid-filled spaces with the same signal as the cerebrospinal fluid and no high signal rim on T2-weighted or FLAIR sequences.…”

Section: Methodsmentioning

confidence: 99%

Association Between Major Depressive Disorder and the Development of Cerebral Small Vessel Disease: A Mendelian Randomization Study

Lu,

Luo,

Yang

et al. 2023

Preprint

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BackgroundAlthough observational studies indicate a complex, bidirectional association between major depressive disorder (MDD) and cerebral small vessel disease (CSVD), the results are frequently inconsistent. This study investigated the potential correlation of MDD with both CSVD clinical outcomes and imaging markers, utilizing a bidirectional Mendelian randomization (MR) study design.MethodsInstrumental variables for both MDD and CSVD were extracted from the latest or most extensive genome-wide association study (GWAS) data available for each phenotype. Clinical outcomes and imaging markers of CSVD were defined using several parameters. The inverse variance weighting (IVW) method with additional sensitivity and heterogeneity analyses was used. Furthermore, a separate GWAS for depression was used to validate our significant findings.ResultsIn the forward MR analyses, the genetically predicted risk of MDD was positively associated with two CSVD phenotypes showing microscopic white matter (WM) damage: mean diffusivity (IVW OR = 2.191, 95 % CI 1.226 to 3.917, p = 0.008) and WM-enlarged perivascular space (OR = 1.053 95 % CI 1.006 to 1.101, p = 0.026). The use of an independent database for depression yielded no significant risk of depression associated with these two CSVD traits. Furthermore, reverse MR analyses showed no evidence of reverse causality between MDD and an altered CSVD risk.ConclusionsThis study utilizing MR imaging findings supports a substantial causal association between MDD and CSVD-related indicators of impaired WM microstructure. It is necessary to exercise caution when extending these results to individuals with depression.

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“…15 The outcome dataset was composed of the most recent GWASs of each cSVD phenotype: lacunar stroke (6030 cases and 248 929 controls), WMH volume (N=48 454), CMBs (N=25 862), and PVSs (white matter [WM] PVSs, N=38 598; basal ganglia (BG) PVSs, N=38 903; and hippocampal PVSs, N=38 871). [16][17][18][19] 25(OH) D concentration was mostly measured at the initial assessment visit of the UK Biobank, and rank-based inverse-normal transformation was applied. Information on the month of assessment was included as a covariate, taking into account the well-known seasonal variation associated with 25(OH)D concentration, 20 in addition to information on supplement intake.…”

Section: Datamentioning

confidence: 99%

Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study

Lee

Kim

Lee

et al. 2023

Stroke

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BACKGROUND: Previous observational studies reported that a lower serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with a higher burden of cerebral small vessel disease (cSVD). The causality of this association is uncertain, but it would be clinically important, given that 25(OH)D can be a target for intervention. We tried to examine the causal effect of 25(OH)D concentration on cSVD-related phenotypes using a Mendelian randomization approach. METHODS: Genetic instruments for each serum 25(OH)D concentration and cSVD-related phenotypes (lacunar stroke, white matter hyperintensity, cerebral microbleeds, and perivascular spaces) were derived from large-scale genome-wide association studies. We performed 2-sample Mendelian randomization analyses with multiple post hoc sensitivity analyses. A bidirectional Mendelian randomization approach was also used to explore the possibility of reverse causation. RESULTS: We failed to find any significant causal effect of 25(OH)D concentration on cSVD-related phenotypes (odds ratio [95% CI], 1.00 [0.87–1.16], 1.01 [0.96–1.07], 1.06 [0.85–1.33], 1.00 [0.97–1.03], 1.02 [0.99–1.04], 1.01 [0.99–1.04] for lacunar stroke, white matter hyperintensity, cerebral microbleeds, and white matter, basal ganglia, hippocampal perivascular spaces, respectively). These results were reproduced in the sensitivity analyses accounting for genetic pleiotropy. Conversely, when we examined the effects of cSVD phenotypes on 25(OH)D concentration, cerebral microbleeds were negatively associated with 25(OH)D concentration (0.94 [0.92–0.96]). CONCLUSIONS: Given the adequate statistical power (>0.8) of the analyses, our findings suggest that the previously reported association between 25(OH)D concentration and cSVD phenotypes might not be causal and partly attributed to reverse causation.

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Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Cited by 36 publications

References 80 publications

A Systematic Review and Meta-Analysis of Automated Methods for Quantifying Enlarged Perivascular Spaces in the Brain

A Systematic Review and Meta-Analysis of Automated Methods for Quantifying Enlarged Perivascular Spaces in the Brain

Association Between Major Depressive Disorder and the Development of Cerebral Small Vessel Disease: A Mendelian Randomization Study

Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study

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