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

Genomics; Perivascular spaceGenòmica; Espai perivascularGenómica; Espacio perivascularPerivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.Austrian Stroke Prevention Study (ASPS)/Austrian Stroke Prevention Family Study (ASPS-Fam) (E.H., P.G.G., H.S. and R.S.): We thank the staff and the participants for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment, E. Hofer for the technical assistance in creating the DNA bank, J. Semmler and A. Harb for DNA sequencing and DNA analyses by TaqMan assays, and I. Poelzl for supervising the quality management processes after ISO9001 in the biobanking and DNA analyses. The Medical University of Graz and the Steiermärkische Krankenanstaltengesellschaft support the databank of the ASPS/ASPS-Fam. The research reported in this article was funded by the Austrian Science Fund (FWF) (grant nos. PI904, P20545-P05 and P13180) and supported by the Austrian National Bank Anniversary Fund (grant no. P15435) and the Austrian Ministry of Science under the aegis of the EU Joint Programme–Neurodegenerative Disease Research (JPND): www.jpnd.eu. Epidemiology of Dementia in Singapore (EDIS) (S.H., C.Chen, C.-Y.C., T.Y.W. and W.Z.): The EDIS study is supported by the National Medical Research Council (NMRC), Singapore (NMRC/CG/NUHS/2010 (grant no. R-184-006-184-511), NMRC/CSA/038/2013) and a Ministry of Education Tier 1 grant (no. A-0006106-00-00). Framingham Heart Study (FHS) (J.R.R., A.B., J.J.H., S.L., P.P., C.L.S., Q.Y. and S.Seshadri): This work was supported by the National Heart, Lung and Blood Institute’s FHS Contract (no. N01-HC-25195, no. HHSN268201500001I and no. 75N92019D00031). This study was also supported by grants from the National Institute of Aging (R01 grant nos. AG031287, AG054076, AG049607, AG059421, AG059725; U01 grant nos. AG049505, AG052409) and the National Institute of Neurological Disorders and Stroke (R01 grant no. NS017950). Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract no. N02-HL64278. The computational work reported in this paper was performed on the Shared Computing Cluster which is administered by Boston University’s Research Computing Services. We also thank all the FHS study participants. Internet-based Students’ Health Research Enterprise (i-Share) study (C.B., J.Z., M.M., Q.LG., S. Schilling, Y.-C.Z., A.Tsuchida, M.-G.D., B.M., S.D. and C.T.): The i-Share study is conducted by the Universities of Bordeaux and Versailles Saint-Quentin-en-Yvelines (France). The i-Share study has received funding by the French National Agency (Agence Nationale de la Recherche, ANR), via the Investment for the Future program (grant nos. ANR-10-COHO-05 and ANR-18-RHUS-0002) and from the University of Bordeaux Initiative of Exellence (IdEX). This project has also received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program under grant agreement no. 640643 and from the Fondation pour la Recherche Médicale (grant no. DIC202161236446). Q.L.G. was supported by the Digital Public Health Graduate Program (DPH), a PhD program supported by the French Investment for the Future Program (grant no. 17-EURE-0019). Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study (ISSYS) (P.D., C.C. and I.F.-C.): This research was funded by the Instituto de Salud Carlos III (grant nos. PI10/0705, PI14/01535, PI17/02222), cofinanced by the European Regional Development Fund. Lothian Birth Cohort 1936 (LBC1936) (M.L., M.E.B., I.J.D., Z.M., S.M.M., M.C.V.H. and J.M.W.): We thank the LBC1936 cohort members and research staff involved in data collection, processing and preparation. The LBC1936 is supported by Age UK (Disconnected Mind program grant). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (grant no. MR/K026992/1). The brain imaging was performed in the Brain Research Imaging Centre (www.bric.ed.ac.uk), a center in the SINAPSE Collaboration (www.sinapse.ac.uk) supported by the Scottish Funding Council and Chief Scientist Office. Funding from the UK Biotechnology and Biological Sciences Research Council (BBSRC), the UK Medical Research Council (MRC), the Row Fogo Charitable Trust (M.C.V.H.) and the UK Dementia Research Institute, which receives its funding from the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK (J.M.W.), is gratefully acknowledged. Genotyping was supported by a grant from the BBSRC (no. BB/F019394/1). The Nagahama Study (T.K., S.M., M.O., K.S., Y.T., K.Y., A.Tsuchida, P.B., B.M., M.J., M.-G.D. and F.M.): We are grateful to the Nagahama City Office and nonprofit organization Zeroji Club for their help in conducting the study. This project is supported by operational funds of Kyoto University and the Top Global University Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan. We also received a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, research grants from the Japan Agency for Medical Research and Development for the Practical Research Project for Rare/Intractable Diseases, and the Comprehensive Research on Aging and Health Science for Dementia R&D. We thank C. Galmiche for rating PVS in the validation dataset for the artificial intelligence-based method. The Northern Manhattan Study (NOMAS) (N.D.D., T.J. and R.L.S.): We gratefully acknowledge and thank the NOMAS participants. Funding was awarded through grants from the National Institute of Neurological Disorders and Stroke (R01 grant no. NS 29993) and the Evelyn F. McKnight Brain Institute. Rotterdam Study (M.J.K., F.D., M.W.V., M.A.I. and H.H.H.A.): The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands. The GWAS datasets are supported by the Netherlands Organisation for Scientific Research (NWO) Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (grant no. 014-93-015; RIDE2), the Netherlands Genomics Initiative/NWO, the Netherlands Consortium for Healthy Aging, project no. 050-060-810. We thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera, M. Peters and C. Medina-Gomez for their help in creating the GWAS database; and K. Estrada, Y. Aulchenko and C. Medina-Gomez for the creation and analysis of imputed data. H.H.H.A. is supported by ZonMW grant no. 916.19.151. Study of Health in Pomerania (SHIP) (S.F., R.B., A.T., K.W., H.J.G. and U.V.): SHIP is part of the Community Medicine Research net (CMR) (http://www.medizin.uni-greifswald.de/icm) of the University Medicine Greifswald, which is funded by the Federal Ministry of Education and Research (grant nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant no. 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. This study was further supported by the EU-JPND Funding for BRIDGET (grant no. FKZ:01ED1615). H.J.G. has received travel grants and speakers’ honoraria from Fresenius Medical Care, Servier, Neuraxpharm and Janssen Cilag, as well as research funding from Fresenius Medical Care. Sydney Memory and Ageing Study (MAS) & Older Australian Twins Study (OATS) (R.M.T., N.J.A., H.B., J.J., M.P., A.T., J.N.T., P.S.S., W.W., K.A.M. and M.J.W.): Sydney MAS: The Sydney MAS has been funded by three National Health & Medical Research Council (NHMRC) Program Grants (grant nos. ID350833, ID568969 and APP1093083). Collection of WGS data was supported by the NHMRC National Institute for Dementia Research Grants no. APP1115575 and no. APP1115462. MRI scans were processed with the support of NHMRC Project Grants (grant nos. 510175 and 1025243) and an Australian Research Council (ARC) Discovery Project Grant (no. DP0774213) and the John Holden Family Foundation. We also thank the MRI Facility at NeuRA. We thank the participants and their informants for their time and generosity in contributing to this research. We also acknowledge the MAS research team: https://cheba.unsw.edu.au/research-projects/sydney-memory-and-ageing-study. OATS: The OATS study has been funded by an NHMRC and ARC Strategic Award Grant of the Ageing Well, Ageing Productively Program (grant no. 401162); NHMRC Project (seed) Grants (grant nos. 1024224 and 1025243); NHMRC Project Grants (grant nos. 1045325 and 1085606); and NHMRC Program Grants (grant nos. 568969 and 1093083). Collection of WGS data was supported by the NHMRC National Institute for Dementia Research Grants no. APP1115575 and no. APP1115462. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (no. 1079102) from the National Health and Medical Research Council. We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team (https://cheba.unsw.edu.au/project/older-australian-twins-study) to this study. Three-City Dijon Study (3C-Dijon) (S.D., M.-G.D., S. Schilling, C.T., B.M. and A.M.): This project is supported by a grant overseen by the French National Research Agency (ANR) as part of the ‘Investment for the Future Program’ no. ANR-18-RHUS-0002. It is also supported by a JPND project through the following funding organizations under the aegis of JPND: www.jpnd.eu: Australia, National Health and Medical Research Council; Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; the Netherlands, the Netherlands Organisation for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 643417, 640643, 667375 and 754517. The project also received funding from the French National Research Agency (ANR) through the VASCOGENE and SHIVA projects, and from the Initiative of Excellence of the University of Bordeaux (C-SMART project). Computations were performed on the Bordeaux Bioinformatics Center (CBiB) computer resources, University of Bordeaux. Funding support for additional computer resources at the CREDIM (Centre de Recherche et Développement en Informatique Médicale, University of Bordeaux) has been provided to S.D. by the Fondation Claude Pompidou. The Three-City (3C) Study: The 3C Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France and Ministry of Research–INSERM program ‘Cohortes et collections de données biologiques.’ C.T. and S.D. have received investigator-initiated research funding from the French National Research Agency (ANR) and from the Fondation Leducq. M.-G.D. received a grant from the ‘Fondation Bettencourt Schueller’. We thank P. Amouyel, U1167 Institut Pasteur de Lille - University of Lille - Inserm, for supporting funding of genome-wide genotyping of the 3C Study. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the labex DISTALZ and the Centre National de Génotypage. We thank A. Boland (CNG) for her technical help in preparing the DNA samples for analyses. UK Biobank (UKB) (M.J.K., F.D., M.W.V., M.A.I., H.H.H.A., A.M. and T.E.): This research has been conducted using the UK Resource under application no. 23509. McGill Genome Center (M.B., P.M., G.B. and M.Lathrop): Work done at the Canadian Center for Computational Genomics was supported by Genome Canada. Data analyses were enabled by computing and storage resources provided by Compute Canada and Calcul Québec. G.B. is supported by the Fonds de Recherche Santé Québec and the Canada Research Chair program. We thank all the participating cohorts for contributing to this study. We thank H. Jacqmin-Gadda, Bordeaux Population Health research center, University of Bordeaux/Inserm U1219 for statistical advice. We thank J. Thomas-Crusells, Bordeaux Population Health Research Center, University of Bordeaux/Inserm U1219, for editorial assistance. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript

Stroke

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. 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. 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]). 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

Brain

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease

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

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.Etude de cohorte sur la santé des étudiantsStopping cognitive decline and dementia by fighting covert cerebral small vessel diseaseStudy on Environmental and GenomeWide predictors of early structural brain Alterations in Young student

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.</p

Déterminants génétiques et signification clinique de la maladie des petites artères cérébrale.

Cerebral small vessel disease (cSVD) is a major cause of stroke, cognitive impairment and dementia. Magnetic resonance imaging (MRI) markers of cSVD comprise white matter hyperintensities (WMH), MRI-defined lacunes of presumed vascular origin (Lac), cerebral microbleeds (CMB) and dilated perivascular spaces (dPVS). A systematic review and meta-analysis on > 16,000 participants enabled to characterize the association of WMH, BI and CMB with risk of stroke and dementia, as well as their subtypes, and with mortality. Because of limited data on dPVS, we examined the longitudinal relationship of dPVS burden with incident stroke risk in the population-based 3C-Dijon study, and found a significant association between dPVS burden, especially in basal ganglia and hippocampus, and incident risk of any stroke and intracerebral hemorrhage. We then explored the heritability of dPVS burden using genome-wide genotypes and found highest heritability for dPVS burden compared with other MRI-markers of cSVD, especially in the white matter. Second we conducted a genome-wide association study (GWAS) meta-analysis of dPVS burden and identified two genome-wide significant loci associated with extensive dPVS burden in the white matter, implicated in brain development, brain vascular function and oncogenesis. We found significant genetic correlation of dPVS burden in basal ganglia with all stroke and ischemic stroke. Finally, we conducted an extension of this work in the Japanese Nagahama population-based study to: (i) compare the reproducibility of three dPVS visual rating scales (ii) conduct the first GWAS of WMH volume in a Japanese cohort, confirming the chr17q25.1 locus and identifying new loci associated with regional WMH volume. In conclusion, we provide novel information on the clinical significance of MRI-markers of cSVD, especially dPVS, and new insight into the genetic contribution to MRI-markers of cSVD, by conducting the first heritability assessment and GWAS meta-analysis of dPVS burden, and the first GWAS of WMH volume in a Japanese population.La maladie des petites artères cérébrales (MPAC) constitue une étiologie importante d’accident vasculaire cérébral (AVC), de déclin cognitif et de démence. Les marqueurs en imagerie par résonance magnétique (IRM) de MPAC comprennent les hypersignaux de la substance blanche (HSB), les infarctus lacunaires (IL), les microsaignements (MS) et les espaces dilatés périvasculaires (EdPV). Une revue systématique et méta-analyse incluant plus de 16,000 participants a permis de mieux caractériser l’association des HSB, IL et MS avec le risque d’AVC et de démence, ainsi que leurs sous-types, et la mortalité. En raison de données limitées sur les EdPV dans cette revue systématique, nous avons étudié l’association entre les EdPV et le risque incident d’AVC au sein de la cohorte 3C-Dijon en population générale et avons mis en évidence une association significative des EdPV, en particulier au niveau des noyaux gris centraux et de l’hippocampe, avec le risque incident d’AVC, surtout hémorragique. Nous avons ensuite estimé l’héritabilité des EdPV à partir de génotypes pangénomiques, mettant en évidence une héritabilité plus élevée que pour les autres marqueurs IRM de MPAC, notamment pour les EdPV au niveau de la substance blanche. Dans un second temps, nous avons réalisé une méta-analyse d’études d’associations génétiques pangénomiques (GWAS) des EdPV qui nous a permis d’identifier 2 loci significativement associés au seuil pangénomique avec une sévérité plus importante des EdPV au niveau de la substance blanche. Ces associations orientent vers des gènes impliqués dans le développement cérébral, le fonctionnement des vaisseaux cérébraux et la tumorigenèse. Nous avons mis en évidence une corrélation génétique significative entre les EdPV au niveau des noyaux gris centraux et les AVC (tout type) et les AVC ischémiques. Enfin, nous avons étendu ces recherches à la cohorte Nagahama en population générale japonaise afin de (i) comparer la reproductibilité des 3 principales échelles visuelles de quantification des EdPV dans cette cohorte, et (ii) de réaliser un GWAS des HSB en population japonaise, qui a permis de confirmer dans cette population le locus du chr17q25.1 et d’identifier de nouveaux loci associés avec le volume d’HSB dans différentes régions du cerveau. En conclusion, nous avons apporté de nouveaux éléments sur la signification clinique des marqueurs IRM de MPAC, en particulier les EdPV, et sur les déterminants génétiques des marqueurs IRM de MPAC, avec une première estimation de l’héritabilité et une première méta-analyse de GWAS des EdPV, et un premier GWAS des HSB en population japonaise

Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis.

IMPORTANCE: Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated. OBJECTIVE: To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia. DATA SOURCE: We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death. STUDY SELECTION: Data were taken from prospective, longitudinal cohort studies including 50 or more adults. DATA EXTRACTION AND SYNTHESIS: We performed inverse variance-weighted meta-analyses with random effects and z score-based meta-analyses for WMH burden. The significance threshold was P < .003 (17 independent tests). We complied with the Meta-analyses of Observational Studies in Epidemiology guidelines. MAIN OUTCOMES AND MEASURES: Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death. RESULTS: Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12; P < .001), ischemic stroke (HR, 2.39; 95% CI, 1.65-3.47; P < .001), intracerebral hemorrhage (HR, 3.17; 95% CI, 1.54-6.52; P = .002), dementia (HR, 1.84; 95% CI, 1.40-2.43; P < .001), Alzheimer disease (HR, 1.50; 95% CI, 1.22-1.84; P < .001), and death (HR, 2.00; 95% CI, 1.69-2.36; P < .001). Presence of MRI-defined BIs was associated with higher risk of incident stroke (HR, 2.38; 95% CI, 1.87-3.04; P < .001), ischemic stroke (HR, 2.18; 95% CI, 1.67-2.85; P < .001), intracerebral hemorrhage (HR, 3.81; 95% CI, 1.75-8.27; P < .001), and death (HR, 1.64; 95% CI, 1.40-1.91; P < .001). Presence of CMBs was associated with increased risk of stroke (HR, 1.98; 95% CI, 1.55-2.53; P < .001), ischemic stroke (HR, 1.92; 95% CI, 1.40-2.63; P < .001), intracerebral hemorrhage (HR, 3.82; 95% CI, 2.15-6.80; P < .001), and death (HR, 1.53; 95% CI, 1.31-1.80; P < .001). Data on PVS were limited and insufficient to conduct meta-analyses but suggested an association of high PVS burden with increased risk of stroke, dementia, and death; this requires confirmation. CONCLUSIONS AND RELEVANCE: We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI