Search

Your search keyword '"Matthews, P.M."' showing total 21 results
Start Over Author "Matthews, P.M." Publication Year Range Last 10 years
21 results on '"Matthews, P.M."'

2. Identification of early neurodegenerative pathways in progressive multiple sclerosis

Author

Kaufmann, M., Schaupp, A.L., Sun, R., Coscia, F., Dendrou, C.A., Cortes, A., Kaur, G., Evans, H.G., Mollbrink, A., Navarro, J.F., Sonner, J.K., Mayer, C., DeLuca, G.C., Lundeberg, J., Matthews, P.M., Attfield, K.E., Friese, M.A., Mann, M., and Fugger, L.

Subjects
Cancer Research
Abstract

Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

Published
2022

3. Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Author

Dehghan, A., Pinto, R.C., Karaman, I., Huang, J., Durainayagam, B.R., Ghanbari, M., Nazeer, A., Zhong, Q., Liggi, S., Whiley, L., Mustafa, R., Kivipelto, M., Solomon, A., Ngandu, T., Kanekiyo, T., Aikawa, T., Radulescu, C.I., Barnes, S.J., Graça, G., Chekmeneva, E., Camuzeaux, S., Lewis, M.R., Kaluarachchi, M.R., Ikram, M.A., Holmes, E., Tzoulaki, I., Matthews, P.M., Griffin, J.L., Elliott, P., Dehghan, A., Pinto, R.C., Karaman, I., Huang, J., Durainayagam, B.R., Ghanbari, M., Nazeer, A., Zhong, Q., Liggi, S., Whiley, L., Mustafa, R., Kivipelto, M., Solomon, A., Ngandu, T., Kanekiyo, T., Aikawa, T., Radulescu, C.I., Barnes, S.J., Graça, G., Chekmeneva, E., Camuzeaux, S., Lewis, M.R., Kaluarachchi, M.R., Ikram, M.A., Holmes, E., Tzoulaki, I., Matthews, P.M., Griffin, J.L., and Elliott, P.

Abstract

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10−5 to 1.3 × 10−44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10−5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Published
2022

4. Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine (Nature, (2020), 587, 7834, (377-386), 10.1038/s41586-020-2715-9)

Author

Rajewsky, N. Almouzni, G. Gorski, S.A. Aerts, S. Amit, I. Bertero, M.G. Bock, C. Bredenoord, A.L. Cavalli, G. Chiocca, S. Clevers, H. De Strooper, B. Eggert, A. Ellenberg, J. Fernández, X.M. Figlerowicz, M. Gasser, S.M. Hubner, N. Kjems, J. Knoblich, J.A. Krabbe, G. Lichter, P. Linnarsson, S. Marine, J.-C. Marioni, J.C. Marti-Renom, M.A. Netea, M.G. Nickel, D. Nollmann, M. Novak, H.R. Parkinson, H. Piccolo, S. Pinheiro, I. Pombo, A. Popp, C. Reik, W. Roman-Roman, S. Rosenstiel, P. Schultze, J.L. Stegle, O. Tanay, A. Testa, G. Thanos, D. Theis, F.J. Torres-Padilla, M.-E. Valencia, A. Vallot, C. van Oudenaarden, A. Vidal, M. Voet, T. Alberi, L. Alexander, S. Alexandrov, T. Arenas, E. Bagni, C. Balderas, R. Bandelli, A. Becher, B. Becker, M. Beerenwinkel, N. Benkirane, M. Beyer, M. Bickmore, W.A. Biessen, E.E.A.L. Blomberg, N. Blumcke, I. Bodenmiller, B. Borroni, B. Boumpas, D.T. Bourgeron, T. Bowers, S. Braeken, D. Brooksbank, C. Brose, N. Bruining, H. Bury, J. Caporale, N. Cattoretti, G. Chabane, N. Chneiweiss, H. Cook, S.A. Curatolo, P. de Jonge, M.I. Deplancke, B. de Witte, P. Dimmeler, S. Draganski, B. Drews, A. Dumbrava, C. Engelhardt, S. Gasser, T. Giamarellos-Bourboulis, E.J. Graff, C. Grün, D. Gut, I.G. Hansson, O. Henshall, D.C. Herland, A. Heutink, P. Heymans, S.R.B. Heyn, H. Huch, M. Huitinga, I. Jackowiak, P. Jongsma, K.R. Journot, L. Junker, J.P. Katz, S. Kehren, J. Kempa, S. Kirchhof, P. Klein, C. Koralewska, N. Korbel, J.O. Kühnemund, M. Lamond, A.I. Lauwers, E. Le Ber, I. Leinonen, V. López-Tobón, A. Lundberg, E. Lunkes, A. Maatz, H. Mann, M. Marelli, L. Matser, V. Matthews, P.M. Mechta-Grigoriou, F. Menon, R. Nielsen, A.F. Pagani, M. Pasterkamp, R.J. Pitkänen, A. Popescu, V. Pottier, C. Puisieux, A. Rademakers, R. Reiling, D. Reiner, O. Remondini, D. Ritchie, C. Rohrer, J.D. Saliba, A.-E. Sanchez-Valle, R. Santosuosso, A. Sauter, A. Scheltema, R.A. Scheltens, P. Schiller, H.B. Schneider, A. Seibler, P. Sheehan-Rooney, K. Shields, D.J. Sleegers, K. Smit, A.B. Smith, K.G.C. Smolders, I. Synofzik, M. Tam, W.L. Teichmann, S.A. Thom, M. Turco, M.Y. van Beusekom, H.M.M. Vandenberghe, R. Van den Hoecke, S. van de Poel, I. van der Ven, A. van der Zee, J. van Lunzen, J. van Minnebruggen, G. van Oudenaarden, A. Van Paesschen, W. van Swieten, J.C. van Vught, R. Verhage, M. Verstreken, P. Villa, C.E. Vogel, J. von Kalle, C. Walter, J. Weckhuysen, S. Weichert, W. Wood, L. Ziegler, A.-G. Zipp, F. LifeTime Community Working Groups

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Abstract

In this Perspective, owing to an error in the HTML, the surname of author Alejandro López-Tobón of the LifeTime Community Working Groups consortium was indexed as ‘Tobon’ rather than ‘López-Tobón’ and the accents were missing. The HTML version of the original Perspective has been corrected; the PDF and print versions were always correct. © 2021, The Author(s).

Published
2021

5. Tensor dropout for robust learning

Author

Kolbeinsson, A. Kossaifi, J. Panagakis, Y. Bulat, A. Kumar, A.A. Tzoulaki, I. Matthews, P.M.

Abstract

CNNs achieve high levels of performance by leveraging deep, over-parametrized neural architectures, trained on large datasets. However, they exhibit limited generalization abilities outside their training domain and lack robustness to corruptions such as noise and adversarial attacks. To improve robustness and obtain more computationally and memory efficient models, better inductive biases are needed. To provide such inductive biases, tensor layers have been successfully proposed to leverage multi-linear structure through higher-order computations. In this paper, we propose tensor dropout, a randomization technique that can be applied to tensor factorizations, such as those parametrizing tensor layers. In particular, we study tensor regression layers, parametrized by low-rank weight tensors and augmented with our proposed tensor dropout. We empirically show that our approach improves generalization for image classification on ImageNet and CIFAR-100. We also establish state-of-the-art accuracy for phenotypic trait prediction on the largest available dataset of brain MRI (U.K. Biobank), where multi-linear structure is paramount. In all cases, we demonstrate superior performance and significantly improved robustness, both to noisy inputs and to adversarial attacks. We establish the theoretical validity of our approach and the regularizing effect of tensor dropout by demonstrating the link between randomized tensor regression with tensor dropout and deterministic regularized tensor regression. © 2007-2012 IEEE.

Published
2021

11. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Sargurupremraj, M., Suzuki, H., Jian, X.Q., Sarnowski, C., Evans, T.E., Bis, J.C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N.J., Hofer, E., Yanek, L.R., Hagenaars, S.P., Kumar, R.B., Akker, E.B. van den, McWhirter, R.E., Trompet, S., Mishra, A., Saba, Y., Satizabal, C.L., Beaudet, G., Petit, L., Tsuchida, A., Zago, L., Schilling, S., Sigurdsson, S., Gottesman, R.F., Lewis, C.E., Aggarwal, N.T., Lopez, O.L., Smith, J.A., Hernandez, M.C.V., Grond, J. van der, Wright, M.J., Knol, M.J., Dorr, M., Thomson, R.J., Bordes, C., Grand, Q. le, Duperron, M.G., Smith, A.V., Knopman, D.S., Schreiner, P.J., Evans, D.A., Rotter, J.I., Beiser, A.S., Maniega, S.M., Beekman, M., Trollor, J., Stott, D.J., Vernooij, M.W., Wittfeld, K., Niessen, W.J., Soumare, A., Boerwinkle, E., Sidney, S., Turner, S.T., Davies, G., Thalamuthu, A., Volker, U., Buchem, M.A. van, Bryan, R.N., Dupuis, J., Bastin, M.E., Ames, D., Teumer, A., Amouyel, P., Kwok, J.B., Bulow, R., Deary, I.J., Schofield, P.R., Brodaty, H., Jiang, J.Y., Tabara, Y., Setoh, K., Miyamoto, S., Yoshida, K., Nagata, M., Kamatani, Y., Matsuda, F., Psaty, B.M., Bennett, D.A., Jager, P.L. de, Mosley, T.H., Sachdev, P.S., Schmidt, R., Warren, H.R., Evangelou, E., Tregouet, D.A., Ikram, M.A., Wen, W., DeCarli, C., Srikanth, V.K., Jukema, J.W., Slagboom, E.P., Kardia, S.L.R., Okada, Y., Mazoyer, B., Wardlaw, J.M., Nyquist, P.A., Mather, K.A., Grabe, H.J., Schmidt, H., Duijn, C.M. van, Gudnason, V., Longstreth, W.T., Launer, L.J., Lathrop, M., Seshadri, S., Tzourio, C., Adams, H.H., Matthews, P.M., Fornage, M., Debette, S., Int Network Thrombosis INVENT Cons, and Int Headache Genomics Consortium I

Subjects
Adult, Male, Science, BLOOD-PRESSURE, Risk Assessment, behavioral disciplines and activities, GENETIC ARCHITECTURE, Young Adult, Alzheimer Disease, Risk Factors, mental disorders, WHITE-MATTER HYPERINTENSITIES, WIDE ASSOCIATION, Humans, International Headache Genomics Consortium (IHGC), CELL-TYPES, Medical History Taking, METAANALYSIS, AGING RESEARCH, Aged, RISK, Aged, 80 and over, Science & Technology, Mendelian Randomization Analysis, Middle Aged, COGNITIVE IMPAIRMENT, White Matter, Multidisciplinary Sciences, Stroke, Diffusion Tensor Imaging, Genetic Loci, Cerebral Small Vessel Diseases, Hypertension, MENDELIAN RANDOMIZATION, Science & Technology - Other Topics, Female, International Network against Thrombosis (INVENT) Consortium, Genome-Wide Association Study
Abstract

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=2.5x10-7) 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. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Published
2020

12. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor

Author

Wei, G.Z., Martin, K.A., Xing, P.Y., Agrawal, R., Whiley, L., Wood, T.K., Hejndorf, S., Ng, Y.Z., Low, J.Z.Y., Rossant, J., Nechanitzky, R., Holmes, E., Nicholson, J.K., Tan, E-K, Matthews, P.M., Pettersson, S., Wei, G.Z., Martin, K.A., Xing, P.Y., Agrawal, R., Whiley, L., Wood, T.K., Hejndorf, S., Ng, Y.Z., Low, J.Z.Y., Rossant, J., Nechanitzky, R., Holmes, E., Nicholson, J.K., Tan, E-K, Matthews, P.M., and Pettersson, S.

Abstract

While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR−/−) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR–mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.

Published
2021

13. Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders

Author

Kolbeinsson, A. Filippi, S. Panagakis, Y. Matthews, P.M. Elliott, P. Dehghan, A. Tzoulaki, I.

Abstract

Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict “healthy” brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk. © 2020, The Author(s).

Published
2020

14. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), Debette, S. (Stéphanie), Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), and Debette, S. (Stéphanie)

Abstract

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.

Published
2020
Full Text
View/download PDF

15. LifeTime and improving European healthcare through cell-based interceptive medicine

Author

Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), Zipp, F. (Frauke), Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), and Zipp, F. (Frauke)

Abstract

LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.

Published
2020
Full Text
View/download PDF

16. Improving data availability for brain image biobanking in healthy subjects: Practice-based suggestions from an international multidisciplinary working group

Author

Shenkin, S.D. (Susan D.), Pernet, C. (Cyril), Nichols, T.E. (Thomas), Poline, J.B. (Jean Baptiste), Matthews, P.M. (Paul M.), Lugt, A. (Aad) van der, Mackay, C. (Clare), Lanyon, L. (Linda), Mazoyer, B. (Bernard), Boardman, J.P., Thompson, P.M. (Paul), Fox, N.C. (Nick), Marcus, D.S. (Daniel S.), Sheikh, A. (Aziz), Cox, S.R. (Simon R.), Anblagan, D. (Devasuda), Job, D.E. (Dominic E.), Dickie, D.A. (David Alexander), Rodriguez, D. (David), Wardlaw, J.M. (J.), Shenkin, S.D. (Susan D.), Pernet, C. (Cyril), Nichols, T.E. (Thomas), Poline, J.B. (Jean Baptiste), Matthews, P.M. (Paul M.), Lugt, A. (Aad) van der, Mackay, C. (Clare), Lanyon, L. (Linda), Mazoyer, B. (Bernard), Boardman, J.P., Thompson, P.M. (Paul), Fox, N.C. (Nick), Marcus, D.S. (Daniel S.), Sheikh, A. (Aziz), Cox, S.R. (Simon R.), Anblagan, D. (Devasuda), Job, D.E. (Dominic E.), Dickie, D.A. (David Alexander), Rodriguez, D. (David), and Wardlaw, J.M. (J.)

Abstract

Brain imaging is now ubiquitous in clinical practice and research. The case for bringing together large amounts of image data from well-characterised healthy subjects and those with a range of common brain diseases across the life course is now compelling. This report follows a meeting of international experts from multiple disciplines, all interested in brain image biobanking. The meeting included neuroimaging experts (clinical and non-clinical), computer scientists, epidemiologists, clinicians, ethicists, and lawyers involved in creating brain image banks. The meeting followed a structured format to discuss current and emerging brain image banks; applications such as atlases; conceptual and statistical problems (e.g. defining 'normality'); legal, ethical and technological issues (e.g. consents, potential for data linkage, data security, harmonisation, data storage and enabling of research data sharing). We summarise the lessons learned from the experiences of a wide range of individual image banks, and provide practical recommendations to enhance creation, use and reuse of neuroimaging data. Our aim is to maximise the benefit of the image data, provided voluntarily by research participants and funded by many organisations, for human health. Our ultimate vision is of a federated network of brain image biobanks accessible for large studies of brain structure and function.

Published
2017
Full Text
View/download PDF

17. Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease

Author

Guio, F. De, Jouvent, E., Biessels, G.J., Black, S.E., Brayne, C., Chen, C., Cordonnier, C., Leeuw, F.E. de, Dichgans, M., Doubal, F., Duering, M., Dufouil, C., Duzel, E., Fazekas, F., Hachinski, V., Ikram, M.A., Linn, J., Matthews, P.M., Mazoyer, B., Mok, V., Norrving, B., O'Brien, J.T., Pantoni, L., Ropele, S., Sachdev, P., Schmidt, R., Seshadri, S., Smith, E.E., Sposato, L.A., Stephan, B., Swartz, R.H., Tzourio, C., Buchem, M. van, Lugt, A. van der, Oostenbrugge, R., Vernooij, M.W., Viswanathan, A., Werring, D., Wollenweber, F., Wardlaw, J.M., Chabriat, H., Guio, F. De, Jouvent, E., Biessels, G.J., Black, S.E., Brayne, C., Chen, C., Cordonnier, C., Leeuw, F.E. de, Dichgans, M., Doubal, F., Duering, M., Dufouil, C., Duzel, E., Fazekas, F., Hachinski, V., Ikram, M.A., Linn, J., Matthews, P.M., Mazoyer, B., Mok, V., Norrving, B., O'Brien, J.T., Pantoni, L., Ropele, S., Sachdev, P., Schmidt, R., Seshadri, S., Smith, E.E., Sposato, L.A., Stephan, B., Swartz, R.H., Tzourio, C., Buchem, M. van, Lugt, A. van der, Oostenbrugge, R., Vernooij, M.W., Viswanathan, A., Werring, D., Wollenweber, F., Wardlaw, J.M., and Chabriat, H.

Abstract

Item does not contain fulltext, Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease.

Published
2016

18. Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease

Author

De Guio, F. (François), Jouvent, E. (Eric), Biessels, G.J. (Geert Jan), Black, S.E. (Sandra), Brayne, C. (Carol), Chen, C. (Christopher), Cordonnier, C. (Charlotte), Leeuw, H.F. (Frank) de, Kubisch, C. (Christian), Doubal, F. (Fergus), Duering, M. (Marco), Dufouil, C. (Carole), Duzel, E. (Emrah), Fazekas, F. (Franz), Hachinski, V. (Vladimir), Ikram, M.K. (Kamran), Linn, J. (Jennifer), Matthews, P.M. (P.), Mazoyer, B. (Bernard), Mok, V. (Vincent), Norrving, B. (Bo), O'Brien, J.T. (John T.), Pantoni, L. (Leonardo), Ropele, S. (Stefan), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Seshadri, S. (Sudha), Smith, E.E. (Eric), Sposato, L.A. (Luciano A), Stephan, B.C.M., Swartz, R.H. (Richard H.), Tzourio, C. (Christophe), Buchem, M.A. (Mark) van, Lugt, A. (Aad) van der, Oostenbrugge, R.J. (Robert) van, Vernooij, M.W. (Meike), Viswanathan, A. (Anand), Werring, D.J. (David), Wollenweber, F. (Frank), Wardlaw, J.M. (J.), Chabriat, H. (Hugues), De Guio, F. (François), Jouvent, E. (Eric), Biessels, G.J. (Geert Jan), Black, S.E. (Sandra), Brayne, C. (Carol), Chen, C. (Christopher), Cordonnier, C. (Charlotte), Leeuw, H.F. (Frank) de, Kubisch, C. (Christian), Doubal, F. (Fergus), Duering, M. (Marco), Dufouil, C. (Carole), Duzel, E. (Emrah), Fazekas, F. (Franz), Hachinski, V. (Vladimir), Ikram, M.K. (Kamran), Linn, J. (Jennifer), Matthews, P.M. (P.), Mazoyer, B. (Bernard), Mok, V. (Vincent), Norrving, B. (Bo), O'Brien, J.T. (John T.), Pantoni, L. (Leonardo), Ropele, S. (Stefan), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Seshadri, S. (Sudha), Smith, E.E. (Eric), Sposato, L.A. (Luciano A), Stephan, B.C.M., Swartz, R.H. (Richard H.), Tzourio, C. (Christophe), Buchem, M.A. (Mark) van, Lugt, A. (Aad) van der, Oostenbrugge, R.J. (Robert) van, Vernooij, M.W. (Meike), Viswanathan, A. (Anand), Werring, D.J. (David), Wollenweber, F. (Frank), Wardlaw, J.M. (J.), and Chabriat, H. (Hugues)

Abstract

Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease.

Published
2016
Full Text
View/download PDF

21. LifeTime and improving European healthcare through cell-based interceptive medicine

Author

Rajewsky, N., Almouzni, G., Gorski, S., Aerts, S., Amit, I., Bertero, M., Bock, C., Bredenoord, A., Cavalli, G., Chiocca, S., Clevers, H., Strooper, B., Eggert, A., Ellenberg, J., Fernández, X., Figlerowicz, M., Gasser, S., Hubner, N., Kjems, J., Knoblich, J., Krabbe, G., Lichter, P., Linnarsson, S., Marine, J., Marioni, J., Marti-Renom, M., Netea, M., Nickel, D., Nollmann, M., Novak, H., Parkinson, H., Piccolo, S., Pinheiro, I., Pombo, A., Popp, C., Reik, W., Roman-Roman, S., Rosenstiel, P., Schultze, J., Stegle, O., Tanay, A., Testa, G., Thanos, D., Theis, F., Torres-Padilla, M., Valencia, A., Vallot, C., van Oudenaarden, A., Vidal, M., Voet, T., Alberi, L., Alexander, S., Alexandrov, T., Arenas, E., Bagni, C., Balderas, R., Bandelli, A., Becher, B., Becker, M., Beerenwinkel, N., Benkirame, M., Beyer, M., Bickmore, W., Biessen, E., Blomberg, N., Blumcke, I., Bodenmiller, B., Borroni, B., Boumpas, D., Bourgeron, T., Bowers, S., Braeken, D., Brooksbank, C., Brose, N., Bruining, H., Bury, J., Caporale, N., Cattoretti, G., Chabane, N., Chneiweiss, H., Cook, S., Curatolo, P., de Jonge, M., Deplancke, B., de Witte, P., Dimmeler, S., Draganski, B., Drews, A., Dumbrava, C., Engelhardt, S., Gasser, T., Giamarellos-Bourboulis, E., Graff, C., Grün, D., Gut, I., Hansson, O., Henshall, D., Herland, A., Heutink, P., Heymans, S., Heyn, H., Huch, M., Huitinga, I., Jackowiak, P., Jongsma, K., Journot, L., Junker, J., Katz, S., Kehren, J., Kempa, S., Kirchhof, P., Klein, C., Koralewska, N., Korbel, J., Kühnemund, M., Lamond, A., Lauwers, E., Le Ber, I., Leinonen, V., Tobon, A., Lundberg, E., Lunkes, A., Maatz, H., Mann, M., Marelli, L., Matser, V., Matthews, P., Mechta-Grigoriou, F., Menon, R., Nielsen, A., Pagani, M., Pasterkamp, R., Pitkänen, A., Popescu, V., Pottier, C., Puisieux, A., Rademakers, R., Reiling, D., Reiner, O., Remondini, D., Ritchie, C., Rohrer, J., Saliba, A., Sanchez-Valle, R., Santosuosso, A., Sauter, A., Scheltema, R., Scheltens, P., Schiller, H., Schneider, A., Seibler, P., Sheehan-Rooney, K., Shields, D., Sleegers, K., Smit, A., Smith, K., Smolders, I., Synofzik, M., Tam, W., Teichmann, S., Thom, M., Turco, M., van Beusekom, H., Vandenberghe, R., den Hoecke, S., de Poel, I., van der Ven, A., van der Zee, J., van Lunzen, J., van Minnebruggen, G., Paesschen, W., van Swieten, J., van Vught, R., Verhage, M., Verstreken, P., Villa, C., Vogel, J., von Kalle, C., Walter, J., Weckhuysen, S., Weichert, W., Wood, L., Ziegler, A., Zipp, F., HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Medical Research Council (MRC), UK DRI Ltd, TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany., Barcelona Supercomputing Center, LifeTime Community Working Groups, Cardiology, Neurology, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, Rajewsky N., Almouzni G., Gorski S.A., Aerts S., Amit I., Bertero M.G., Bock C., Bredenoord A.L., Cavalli G., Chiocca S., Clevers H., De Strooper B., Eggert A., Ellenberg J., Fernandez X.M., Figlerowicz M., Gasser S.M., Hubner N., Kjems J., Knoblich J.A., Krabbe G., Lichter P., Linnarsson S., Marine J.-C., Marioni J.C., Marti-Renom M.A., Netea M.G., Nickel D., Nollmann M., Novak H.R., Parkinson H., Piccolo S., Pinheiro I., Pombo A., Popp C., Reik W., Roman-Roman S., Rosenstiel P., Schultze J.L., Stegle O., Tanay A., Testa G., Thanos D., Theis F.J., Torres-Padilla M.-E., Valencia A., Vallot C., van Oudenaarden A., Vidal M., Voet T., Alberi L., Alexander S., Alexandrov T., Arenas E., Bagni C., Balderas R., Bandelli A., Becher B., Becker M., Beerenwinkel N., Benkirame M., Beyer M., Bickmore W., Biessen E.E.A.L., Blomberg N., Blumcke I., Bodenmiller B., Borroni B., Boumpas D.T., Bourgeron T., Bowers S., Braeken D., Brooksbank C., Brose N., Bruining H., Bury J., Caporale N., Cattoretti G., Chabane N., Chneiweiss H., Cook S.A., Curatolo P., de Jonge M.I., Deplancke B., de Witte P., Dimmeler S., Draganski B., Drews A., Dumbrava C., Engelhardt S., Gasser T., Giamarellos-Bourboulis E.J., Graff C., Grun D., Gut I., Hansson O., Henshall D.C., Herland A., Heutink P., Heymans S.R.B., Heyn H., Huch M., Huitinga I., Jackowiak P., Jongsma K.R., Journot L., Junker J.P., Katz S., Kehren J., Kempa S., Kirchhof P., Klein C., Koralewska N., Korbel J.O., Kuhnemund M., Lamond A.I., Lauwers E., Le Ber I., Leinonen V., Tobon A.L., Lundberg E., Lunkes A., Maatz H., Mann M., Marelli L., Matser V., Matthews P.M., Mechta-Grigoriou F., Menon R., Nielsen A.F., Pagani M., Pasterkamp R.J., Pitkanen A., Popescu V., Pottier C., Puisieux A., Rademakers R., Reiling D., Reiner O., Remondini D., Ritchie C., Rohrer J.D., Saliba A.-E., Sanchez-Valle R., Santosuosso A., Sauter A., Scheltema R.A., Scheltens P., Schiller H.B., Schneider A., Seibler P., Sheehan-Rooney K., Shields D., Sleegers K., Smit A.B., Smith K.G.C., Smolders I., Synofzik M., Tam W.L., Teichmann S., Thom M., Turco M.Y., van Beusekom H.M.M., Vandenberghe R., Van den Hoecke S., Van de Poel I., van der Ven A., van der Zee J., van Lunzen J., van Minnebruggen G., Van Paesschen W., van Swieten J., van Vught R., Verhage M., Verstreken P., Villa C.E., Vogel J., von Kalle C., Walter J., Weckhuysen S., Weichert W., Wood L., Ziegler A.-G., Zipp F., Center for Neurogenomics and Cognitive Research, Functional Genomics, Rajewsky, N, Almouzni, G, Gorski, S, Aerts, S, Amit, I, Bertero, M, Bock, C, Bredenoord, A, Cavalli, G, Chiocca, S, Clevers, H, De Strooper, B, Eggert, A, Ellenberg, J, Fernández, X, Figlerowicz, M, Gasser, S, Hubner, N, Kjems, J, Knoblich, J, Krabbe, G, Lichter, P, Linnarsson, S, Marine, J, Marioni, J, Marti-Renom, M, Netea, M, Nickel, D, Nollmann, M, Novak, H, Parkinson, H, Piccolo, S, Pinheiro, I, Pombo, A, Popp, C, Reik, W, Roman-Roman, S, Rosenstiel, P, Schultze, J, Stegle, O, Tanay, A, Testa, G, Thanos, D, Theis, F, Torres-Padilla, M, Valencia, A, Vallot, C, van Oudenaarden, A, Vidal, M, Voet, T, Cattoretti, G, Alliance for Modulation in Epilepsy, Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology, RS: Carim - H02 Cardiomyopathy, MUMC+: MA Med Staf Spec Cardiologie (9), and Cardiologie

Subjects
0301 basic medicine, Male, Artificial intelligence, Legislation, Medical, [SDV]Life Sciences [q-bio], Molecular datasets, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Cell- and Tissue-Based Therapy, Diseases, LifeTime Community Working Groups, Disease, Biomarkers, Systems biology, Health data, Pharmacology, Toxicology and Pharmaceutics(all), 0302 clinical medicine, Conjunts de dades, ethics [Delivery of Health Care], Health care, Pathology, Medicine, European healthcare, BRAIN, Single-cell multi-omics, GENE-EXPRESSION, Multidisciplinary, methods [Medicine], Education, Medical, Settore BIO/13, Intel.ligència artificial, 3. Good health, ALZHEIMERS-DISEASE, Europe, Health, Management system, Perspective, Female, ddc:500, Single-Cell Analysis, Biomarkers, Diseases, Systems biology, Complex diseases, Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], medicine.medical_specialty, General Science & Technology, Cells, MEDLINE, cell-based interceptive medicine, LifeTime Initiative, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Clinical datasets, Artificial Intelligence, REVEALS, LifeTime Community, standards [Medicine], Humans, OMICS, RECONSTRUCTION, Intensive care medicine, trends [Medicine], trends [Delivery of Health Care], business.industry, Disease progression, standards [Delivery of Health Care], methods [Delivery of Health Care], 030104 developmental biology, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], single cell, personalized therapy, machine learning, bioinformatics, systems biology, disease, cell-based interceptive medicine, Early Diagnosis, Cardiovascular and Metabolic Diseases, Human medicine, business, Delivery of Health Care, 030217 neurology & neurosurgery, Cell based
Abstract

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade., The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.

Published
2020
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results