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1. Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

Author

Francesco Arba, Giovanni Orlandi, Benedetta Piccardi, Anna Maria Gori, Francesca Massaro, Rosanna Abbate, Mascia Nesi, Alessio Giannini, Giorgio Bono, Vanessa Palumbo, Paolo Bovi, Danilo Toni, Silvia Biagini, Rossana Tassi, Enrico Fainardi, Maria Sessa, Patrizia Nencini, Giovanni Pracucci, Betti Giusti, Francesco Perini, Domenico Consoli, Domenico Inzitari, and Antonia Nucera

Subjects
Pathology, medicine.medical_specialty, acute stroke, endothelial dysfunction, intercellular adhesion molecule, Small vessel disease, vascular cell adhesion molecule, vascular endothelial growth factor, Disease, 030204 cardiovascular system & hematology, Pathogenesis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Original Research Articles, Ischaemic stroke, medicine, Endothelial dysfunction, Acute stroke, business.industry, Small vessel disease, endothelial dysfunction, intercellular adhesion molecule, vascular cell adhesion molecule, vascular endothelial growth factor, acute stroke, Intercellular adhesion molecule, medicine.disease, Vascular endothelial growth factor, chemistry, Neurology (clinical), Small vessel, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract

Introduction Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. Patients and methods In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. Results A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (β = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (β = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (β = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (β = 0.26; p = 0.006). Discussion Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease. Conclusions Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.

Published
2018
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2. Identification of genetic variants associated with Huntington's disease progression

Author

Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. Gørvell, Eirin Lorentzen, Lars Retterstøl, Bodil Stokke, Inga Bjørnevoll, Sigrid Botne Sando, Artur Dziadkiewicz, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Magdalena Blaszcyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasinska-Myga, Gabriela Klodowska-Duda, Gregorz Opala, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Bocwinska, Kamila Bojakowska-Jaremek, Malgorzata Dec, Malgorzata Krawczyk, Monika Rudzinska, Elzbieta Szczygiel, Andrzej Szczudlik, Anna Wasielewska, Magdalena Wójcik, Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempolowicz, Anna Gogol, Piotr Janik, Hubert Kwiecinski, Zygmunt Jamrozik, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stepniak, Anna Sulek, Elzbieta Zdzienicka, Karolina Zieora-Jakutowicz, Joaquim J Ferreira, Miguel Coelho, Tiago Mendes, Anabela Valadas, Carlos Andrade, Miguel Gago, Carolina Garrett, Maria Rosália Guerra, Carmen Durán Herrera, Patrocinio Moreno Garcia, Miquel Aguilar Barbera, Dolors Badenes Guia, Laura Casas Hernanz, Judit López Catena, Pilar Quiléz Ferrer, Ana Rojo Sebastián, Gemma Tome Carruesco, Jordi Bas, Núria Busquets, Matilde Calopa, Misericordia Floriach Robert, Celia Mareca Viladrich, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Esther Cubo, Cecilia Gil Polo, Natividad Mariscal, Perez Jessica Rivadeneyra, Francisco Barrero, Blas Morales, María Fenollar, Rocío García-Ramos García, Paloma Ortega, Clara Villanueva, Javier Alegre, Mónica Bascuñana, Juan Garcia Caldentey, Marta Fatás Ventura, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Fernando Alonso Frech, Pedro J García Ruíz, Asunción Martínez-Descals, Rosa Guerrero, María José Saiz Artiga, Vicenta Sánchez, María Fuensanta Noguera Perea, Lorenza Fortuna, Salvadora Manzanares, Gema Reinante, María Martirio Antequera Torres, Laura Vivancos Moreau, Sonia González González, Luis Menéndez Guisasola, Carlos Salvador, Esther Suaréz San Martín, Inés Legarda Ramirez, Aranzazú Gorospe, Mónica Rodriguez Lopera, Penelope Navas Arques, María José Torres Rodríguez, Barbara Vives Pastor, Itziar Gaston, Maria Dolores Martinez-Jaurrieta, Jose Manuel Garcia Moreno, Carolina Mendez Lucena, Fatima Damas, Hermoso Eva Pacheco Cortegana, José Chacón Peña, Luis Redondo, Fátima Carrillo, María Teresa Cáceres, Pablo Mir, María José Lama Suarez, Laura Vargas-González, Maria E. Bosca, Francisco Castera Brugada, Juan Andres Burguera, Anabel Campos, Garcia Carmen Peiró Vilaplana, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Petra Linnsand, Liselotte Neleborn-Lingefjärd, Magnus Wentzel, Ghada Loutfi, Carina Olofsson, Eva-Lena Stattin, Laila Westman, Birgitta Wikström, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Maria Hauer, Roman Gonzenbach, Hans H. Jung, Violeta Mihaylova, Jens Petersen, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughan, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Matthew Armstrong, Roger A. Barker, Deidre O'Keefe, Anna Di Pietro, Kate Fisher, Anna Goodman, Susan Hill, Ann Kershaw, Sarah Mason, Nicole Paterson, Lucy Raymond, Rachel Swain, Natalie Valle Guzman, Monica Busse, Cynthia Butcher, Catherine Clenaghan, Sarah Hunt, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Maureen Edwards, Carrie Ho, Teresa Hughes, Marie McGill, Pauline Pearson, Mary Porteous, Paul Smith, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Liz Burrows, Carol Chu, Amy Fletcher, Deena Gallantrae, Stephanie Hamer, Alison Harding, Stefan Klöppel, Alison Kraus, Fiona Laver, Monica Lewis, Mandy Longthorpe, Ivana Markova, Ashok Raman, Nicola Robertson, Mark Silva, Aileen Thomson, Sue Wild, Pam Yardumian, Carole Evans, Deena Gallentrae, Emma Hobson, Stuart Jamieson, Hannah Musgrave, Liz Rowett, Jean Toscano, Colin Bourne, Jackie Clapton, Carole Clayton, Heather Dipple, Dawn Freire-Patino, Janet Grant, Diana Gross, Caroline Hallam, Julia Middleton, Ann Murch, Catherine Thompson, Sundus Alusi, Rhys Davies, Kevin Foy, Emily Gerrans, Louise Pate, Thomasin Andrews, Andrew Dougherty, Charlotte Golding, Fred Kavalier, Hana Laing, Alison Lashwood, Dene Robertson, Deborah Ruddy, Alastair Santhouse, Anna Whaite, Stefania Bruno, Karen Doherty, Salman Haider, Davina Hensman, Nayana Lahiri, Marianne Novak, Aakta Patel, Elisabeth Rosser, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Dawn Rogers, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Richard Armstrong, Kathryn Dixon, Andrea H Nemeth, Gill Siuda, Ruth Valentine, David Harrison, Max Hughes, Andrew Parkinson, Beverley Soltysiak, Oliver Bandmann, Alyson Bradbury, Paul Gill, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Mbombe Kazoka, Kirsty O'Donovan, Cat Taylor, Katherine Tidswell, Oliver Quarrell, Puay Ngoh Lau, Emmanul Pica, Louis Tan, Univ Angers, Okina, Moss, Davina J. Hensman, Tabrizi, Sarah J, Mead, Simon, Kitty, Lo, Pardiã±as, Antonio F, Holmans, Peter, Jones, Lesley, Langbehn, Dougla, Coleman, A., Santos, R. Dar, Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. Jauff, Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrãgue, R., van den Bogaard, S. J. A., Dumas, E. M., van der Grond, J., T'Hart, E. P., Jurgens, C., Witjes-Ane, M. -. N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Hobbs, N., Lahiri, N., Ordidge, R., Owen, G., Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A. Hoff, Kraus, P., Axelson, E., Wang, C., Acharya, T., Lee, S., Monaco, W., Campbell, C., Queller, S., Whitlock, K., Campbell, M., Frajman, E., Milchman, C., O'Regan, A., Labuschagne, I., Stout, J., Landwehrmeyer, B., Craufurd, D., Scahill, R., Hicks, S., Kennard, C., Johnson, H., Tobin, A., Rosas, H. D., Reilmann, R., Borowsky, B., Pourchot, C., Andrews, S. C., Bachoud-Lévi, Anne-Catherine, Bentivoglio, Anna Rita, Biunno, Ida, Bonelli, Raphael, Burgunder, Jean-Marc, Dunnett, Stephen, Ferreira, Joaquim, Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Landwehrmeyer, G. Bernhard, Levey, Jamie, Ramos-Arroyo, Maria A., Nielsen, Jã¸rgen, Koivisto, Susana Pro, Pã¤ivã¤rinta, Markku, Roos, Raymund A. C., Sebastiã¡n, A. Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlstrã¶m, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Garde, Monica Bascuñana, Betz, Sabrina, Bos, Reineke, Callaghan, Jenny, Come, Adrien, Guedes, Leonor Correia, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Gilling, Mette, Gustafsson, Lena, Handley, Olivia J, Hvalstedt, Carina, Held, Christine, Koppers, Kerstin, Lamanna, Claudia, Laurã , Matilde, Descals, Asunción Martínez, Martinez-Horta, Saã¼l, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mã¼tze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hã©lãne, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Rã¸ren, Niini, Å aå¡inkovã¡, Pavla, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, da Silva, Wildson Vieira, van Walsem, Marleen R, Whalstedt, Carina, Witjes-Ané, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Bonelli, Raphael M., Lilek, Sabine, Hecht, Karen, Herranhof, Brigitte, Holl, Anna, Kapfhammer, Hans-Peter, Koppitz, Michael, Magnet, Marku, Mã¼ller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schã¶ggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Mã¼ller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cã©cile, van Paemel, Dominique, Ribaã¯, Pascale, van Reijen, Dimphna, Klempã­r, Jirã­, Majerovã¡, Veronika, Roth, Jan, Stã¡rkovã¡, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, Jørgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppã¶nen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bã©nã©dicte, Guã©rid, Marie-Anne, Olivier, Audrey, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duchã©, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucriãre, Danielle, Spampinato, Umberto, Barthã©lã©my, Rekha, De Bruycker, Christelle, Carette, Maryline Cabaret Anne-Sophie, Defebvre, Eric Decorte Luc, Delliaux, Marie, Delval, Arnaud, Destee, Alain, Dujardin, Kathy, Lemaire, Marie-HélÃne, Manouvrier, Sylvie, Peter, Mireille, Plomhouse, Lucie, Sablonniãre, Bernard, Simonin, Clã©mence, Thibault-Tanchou, Stã©phanie, Vuillaume, Isabelle, Bellonet, Marcellin, Berrissoul, Hassan, Blin, Stã©phanie, Courtin, Franã§oise, Duru, Cã©cile, Fasquel, Vã©ronique, Godefroy, Olivier, Krystkowiak, Pierre, Mantaux, Bã©atrice, Roussel, Martine, Wannepain, Sandrine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frã©dã©rique, Mundler, Laura, Anheim, Mathieu, Juliã©, Celine, Boukbiza, Ouhaid Lagha, Longato, Nadine, Rudolf, Gabrielle, Tranchant, Christine, Zimmermann, Marie-Agathe, Kosinski, Christoph Michael, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johanne, Schlangen, Christiane, Werner, Cornelius J., Gelderblom, Harald, Priller, Josef, Prã¼ã , Harald, Spruth, Eike Jakob, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kotz, Peter, Prehn, Christian, Saft, Carsten, Lange, Herwig, Maiwald, Robert, Lã¶hle, Matthia, Maass, Antonia, Schmidt, Simone, Bosredon, Cecile, Storch, Alexander, Wolz, Annett, Wolz, Martin, Capetian, Philipp, Lambeck, Johann, Zucker, Birgit, Boelmans, Kai, Ganos, Christo, Heinicke, Walburgi, Hidding, Ute, Lewerenz, Jan, Mã¼nchau, Alexander, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Gorzolla, Heike, Schrader, Christoph, Tacik, Pawel, Ribbat, Michael, Longinus, Bernhard, Bã¼rk, Katrin, Mã¶ller, Jens Carsten, Rissling, Ida, Mã¼hlau, Mark, Peinemann, Alexander, Stã¤dtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Hã¶lzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythã¤user, Gabriele, Marquard, Ralf, Raab, Tina, Wiedemann, Alexandra, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lang, Christina, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Sã¼ã muth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Cormio, Claudia, Sciruicchio, Vittorio, Serpino, Claudia, de Tommaso, Marina, Capellari, Sabina, Cortelli, Pietro, Galassi, Roberto, Rizzo, Giovanni, Poda, Roberto, Scaglione, Cesa, Bertini, Elisabetta, Ghelli, Elena, Ginestroni, Andrea, Massaro, Francesca, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Romoli, Anna Maria, Sorbi, Sandro, Abbruzzese, Giovanni, di Poggio, Monica Bandettini, Ferrandes, Giovanna, Mandich, Paola, Roberta, Marchese, Albanese, Alberto, Di Bella, Daniela, Castaldo, Anna, Di Donato, Stefano, Gellera, Cinzia, Genitrini, Silvia, Mariotti, Caterina, Nanetti, Lorenzo, Paridi, Dominga, Soliveri, Paola, Tomasello, Chiara, De Michele, Giuseppe, Di Maio, Luigi, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, Cinzia Valeria, Salvatore, Elena, Sorrentino, Pierpaolo, Amico, Enrico, Favellato, Mariagrazia, Griguoli, Annamaria, Mazzante, Irene, Petrollini, Martina, Squitieri, Ferdinando, D'Alessio, Barbara, Esposito, Chiara, Bentivoglio, Rita, Frontali, Marina, Guidubaldi, Arianna, Ialongo, Tamara, Jacopini, Gioia, Piano, Carla, Romano, Silvia, Soleti, Francesco, Spadaro, Maria, van Hout, Monique S. E., Verhoeven, Marloes E., van Vugt, Jeroen P. P., de Weert, A. Marit, Bolwijn, J. J. W., Dekker, M., Kremer, B., Leenders, K. L., van Oostrom, J. C. H., van den Bogaard, Simon J. A., Dumas, Eve M., â t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria Rosália, Herrera, Carmen Durán, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, Jesús Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marã­a, Garcã­a, Rocío García-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Frech, Fernando Alonso, Ruã­z, Pedro J. García, Martínez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, María José Saiz, Sã¡nchez, Vicenta, Perea, María Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, María Martirio Antequera, Moreau, Laura Vivanco, González González, Sonia, Guisasola, Luis Menéndez, Salvador, Carlo, Martã­n, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazãº, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodrã­guez, María José Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, José Chacón, Redondo, Lui, Carrillo, Fã¡tima, Teresa Cáceres, Marã­a, Mir, Pablo, Suarez, María José Lama, Vargas-González, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen Peiró, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-Lingefjärd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators

Subjects
0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Published
2017
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3. Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke

Author

Alice Sereni, Anna Maria Gori, Francesco Perini, Giorgio Bono, Rosanna Abbate, Benedetta Piccardi, Francesco Arba, Danilo Toni, Vanessa Palumbo, Francesca Massaro, Enrico Fainardi, Maria Sessa, Giovanni Pracucci, Rossana Tassi, Paolo Bovi, Betti Giusti, Giovanni Orlandi, Antonia Nucera, Mascia Nesi, Domenico Consoli, Domenico Inzitari, and Patrizia Nencini

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Neurology, Time Factors, Tomography Scanners, X-Ray Computed, medicine.medical_treatment, Tissue inhibitor of matrix metalloproteinase, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Bayesian multivariate linear regression, Internal medicine, Medicine, Acute stroke, Humans, Stroke, Aged, Aged, 80 and over, Analysis of Variance, Neuroscience (all), Tissue Inhibitor of Metalloproteinase-1, business.industry, General Neuroscience, Confounding, Leukoaraiosis, Tissue Inhibitor of Metalloproteinases, Thrombolysis, Vascular surgery, Middle Aged, medicine.disease, Small vessel disease, Matrix metalloproteinase, 030104 developmental biology, Cross-Sectional Studies, Italy, Neurology (clinical), Cardiology and Cardiovascular Medicine, Cerebral Small Vessel Diseases, Tissue Plasminogen Activator, Cardiology, Female, business, Tomography, X-Ray Computed, 030217 neurology & neurosurgery
Abstract

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (β = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (β = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (β = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (β = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.

Published
2019

4. Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis

Author

Benedetta Piccardi, Maria Rosaria Tola, Francesco Perini, Giovanni Pracucci, Eleonora Innocenti, Rossana Tassi, Danilo Toni, Marialuisa Zedde, Domenico Consoli, Domenico Inzitari, Maria Luisa DeLodovici, Maria Sessa, Paolo Bovi, Anna Maria Gori, Mario Guidotti, Patrizia Nencini, Vanessa Palumbo, Betti Giusti, Mascia Nesi, Rosanna Abbate, Elena Sticchi, Alice Sereni, Giuseppe Micieli, Giovanni Orlandi, Paolina Tonelli, Antonia Nucera, and Francesca Massaro

Subjects
Male, medicine.medical_specialty, thrombolysis, Time Factors, medicine.medical_treatment, Inflammation, 030204 cardiovascular system & hematology, Lesion, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, ischemic stroke, Medicine, Humans, Thrombolytic Therapy, Stroke, Aged, business.industry, Hemorrhagic transformation, inflammation, metalloproteinase, Neurology, Neurology (clinical), Cardiology and Cardiovascular Medicine, Atrial fibrillation, Thrombolysis, Original Articles, medicine.disease, Clinical research, Logistic Models, Treatment Outcome, ROC Curve, Predictive value of tests, Heart failure, Multivariate Analysis, Physical therapy, Cardiology, Metalloproteases, Cytokines, Female, medicine.symptom, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Inflammatory mediators and metalloproteinases are altered in acute ischemic stroke (AIS) and play a detrimental effect on clinical severity and hemorrhagic transformation of the ischemic brain lesion. Using data from the Italian multicenter observational MAGIC (MArker bioloGici nell’Ictus Cerebrale) Study, we evaluated the effect of inflammatory and metalloproteinases profiles on three-month functional outcome, hemorrhagic transformation and mortality in 327 patients with AIS treated with intravenous thrombolys in according to SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy) criteria. Circulating biomarkers were assessed at baseline and 24 h after thrombolysis. Adjusting for age, sex, baseline glycemia and National Institute of Health Stroke Scale, history of atrial fibrillation or congestive heart failure, and of inflammatory diseases or infections, baseline alpha-2macroglobulin (A2M), baseline serum amyloid protein (SAP) and pre-post tissue-plasminogen activator (tPA) variations (Δ) of metalloproteinase 9, remained significantly and independently associated with three-month death [OR (95% CI):A2M:2.99 (1.19–7.53); SAP:5.46 (1.64–18.74); Δmetalloproteinase 9:1.60 (1.12–2.27)]. The addition of baseline A2M and Δmetalloproteinase 9 or baseline SAP and Δmetalloproteinase 9 (model-2 or model-3) to clinical variables (model-1) significantly improved the area under curve for prediction of death [model-2 with A2M: p = 0.0205; model-3 with SAP: p = 0.001]. In conclusion, among AIS patients treated with thrombolysis, circulating A2M, SAP and Δmetalloproteinase 9 are independent markers of poor outcome. These results may prompt controlled clinical research about agents antagonizing their effect.

Published
2017

5. Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis

Author

S. Latorraca, Benedetta Nacmias, Irene Piaceri, Siro Bagnoli, M Del Mastio, Andrea Tedde, Sandro Sorbi, Francesca Massaro, A Corrado, and Marco Paganini

Subjects
Adult, Genotype, SOD1, Disease, Biology, medicine.disease_cause, Genetic analysis, TARDBP, Superoxide Dismutase-1, Genetics, medicine, Humans, Genetic Testing, Amyotrophic lateral sclerosis, Gene, Genetic Association Studies, Genetics (clinical), Aged, Genes, Dominant, Aged, 80 and over, Mutation, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Genetic Variation, Middle Aged, medicine.disease, Phenotype, Pedigree, DNA-Binding Proteins, Italy, Female
Abstract

Piaceri I, Del Mastio M, Tedde A, Bagnoli S, Latorraca S, Massaro F, Paganini M, Corrado A, Sorbi S, Nacmias B. Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder. The majority of cases are sporadic ALS (SALS), with 5–10% being familial ALS (FALS), and are inherited mostly as autosomal dominant. Mutations in Cu/Zn superoxide dismutase (SOD1) and the TAR DNA-binding protein (TARDBP) gene are the most commonly known cause of ALS. We analyzed these genes in 61 Italian ALS patients using high-resolution melting analysis to confirm the role of SOD1 and TARDBP in the physiopathology of ALS. The screenings showed a single mutation in SOD1 (Asp109Tyr) and three in TARBDP (Ala382Thr, Gly295Ser, Gly294Val) in five unrelated ALS patients. This report enlarges the spectrum of clinical phenotypes associated with genetic mutations in SOD1 and TARDBP genes confirming the variability of phenotypes associated with the same mutation and emphasizes the importance of genetic analysis. The different genotype–phenotype correlations suggest the implication of other factors possibly influencing clinical manifestation of the disease, such as an epigenetic or epistatic effect with other genes not yet identified.

Published
2011
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6. Dramatic Reduction of Microemboli after Heparin Infusion in Progressing Stroke due to Aortic Arch Atheroma

Author

Alba Caruso, Marinella Marinoni, Sandro Sorbi, Francesca Massaro, GianPaolo Anzola, Fabiana Alari, Graziano Arnetoli, and Massimo Del Sette

Subjects
Aortic arch, medicine.medical_specialty, business.industry, medicine.medical_treatment, Heparin, medicine.disease, Progressing stroke, Surgery, Text mining, Atheroma, Neurology, medicine.artery, Internal medicine, medicine, Cardiology, Neurology (clinical), business, Reduction (orthopedic surgery), medicine.drug
Published
2007
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7. Unbalanced Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinases Ratios Predict Hemorrhagic Transformation of Lesion in Ischemic Stroke Patients Treated with Thrombolysis: Results from the MAGIC Study

Author

Giuseppe Micieli, Domenico Consoli, Patrizia Nencini, Domenico Inzitari, Francesca Massaro, Benedetta Piccardi, Norina Marcello, Maria Rosaria Tola, Alice Sereni, Paolina Tonelli, Rossana Tassi, Antonia Nucera, Maria Sessa, Giovanni Orlandi, Francesco Perini, Mascia Nesi, Danilo Toni, Maria Luisa DeLodovici, Giovanni Pracucci, Betti Giusti, Rosanna Abbate, Elena Sticchi, Anna Maria Gori, Mario Guidotti, Vanessa Palumbo, Giorgio Bono, Paolo Bovi, and Eleonora Innocenti

Subjects
medicine.medical_specialty, Pathology, Neurology, medicine.medical_treatment, Matrix metalloproteinase, stroke subtypes, Gastroenterology, lcsh:RC346-429, metalloproteinases, Lesion, Internal medicine, death, Medicine, Stroke, lcsh:Neurology. Diseases of the nervous system, TIMP1, Original Research, thrombolytic therapy, business.industry, tissue inhibitor of metalloproteinases, Odds ratio, Thrombolysis, medicine.disease, stroke, Confidence interval, Death, Hemorrhagic transformation, Metalloproteinases, Stroke subtypes, Thrombolytic therapy, Tissue inhibitor of metalloproteinases, hemorrhagic transformation, Neurology (clinical), medicine.symptom, business, Neuroscience
Abstract

Background Experimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients. Methods Blood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes Results Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17–2.38], p = 0.005; 1.74 [1.21–2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17–2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007). Discussion Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.

Published
2015
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8. Generalized chorea–ballism in acute non ketotic hyperglycemia: Findings from diffusion-weighted magnetic resonance imaging

Author

Francesca Massaro, Gianna Zanfranceschi, Pasquale Palumbo, Mario Falcini, and Andrea Pratesi

Subjects
Nuclear magnetic resonance, Neurology, Hyperglycinemia, Chorea-ballism, business.industry, medicine, Neurology (clinical), Geriatrics and Gerontology, medicine.disease, business, Diffusion-Weighted Magnetic Resonance Imaging
Published
2012
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9. How Risk Profiles of Investors Affect Robo-Advised Portfolios

Author

Dmitri Boreiko and Francesca Massarotti

Subjects
FinTech, robo-advisors, investment advise, portfolio management, portfolio optimisation, Electronic computers. Computer science, QA75.5-76.95
Abstract

Automated financial advising (robo-advising) has become an established practice in wealth management, yet very few studies have looked at the cross-section of the robo-advisors and the factors explaining the persistent variability in their portfolio allocation recommendations. Using a sample of 53 advising platforms from the US and Germany, we show that the underlying algorithms manage to identify different risk profiles, although substantial variability is evident even within the same investor types' groups. The robo-advisor expertise in a particular asset class seems to play a significant role, as does the geographical location, while the breadth of the offered investment choice (number of portfolios) across the robo-advisors under study does not seem to have an effect.

Published
2020
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