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. 2021 Jul 12;11:14324. doi: 10.1038/s41598-021-93498-w

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Study design and number of patients in each phase. Discovery and replication phases were conducted within the ISSYS cohort (patients with hypertension, aged 50–70, and without dementia and stroke at the baseline visit). In both phases of the study, progression of WMH was defined as a total RPS score greater than or equal to 3. In the discovery phase, cases and controls were matched by age, sex, and baseline WMH burden, while in the replication phase, cases and controls were matched by age and sex. Parts of this figure were supported by Servier Medical Art (https://smart.servier.com/) with permission under the Creative Commons Attribution 3.0 Unported License. The figure was constructed using Microsoft Office Powerpoint 365 (version 2013, https://www.microsoft.com/en-us/microsoft-365/powerpoint), GNU image manipulation software (GIMP, version 2.10.22, https://www.gimp.org/) and ‘ggplot’ library (version 3.3.2, https://ggplot2.tidyverse.org/) included in R software. (R version 3.6.3, 2020-02-29; 2020 The R Foundation for Statistical Computing, https://www.r-project.org/). ASAH2, neutral ceramidase; ISSYS, Investigating Silent Strokes in hYpertensives Study; MET, hepatocyte growth factor receptor; MMP9, matrix metalloproteinase-9; RPS, Rotterdam progression scale; WMH, white matter hyperintensities.