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1. Working Memory-Related Effective Connectivity in Huntington’s Disease Patients

Author

Jacob Lahr, Lora Minkova, Sarah J. Tabrizi, Julie C. Stout, Stefan Klöppel, Elisa Scheller, the TrackOn-HD Investigators, A. Coleman, J. Decolongon, M. Fan, T. Koren, C. Jauffret, D. Justo, S. Lehericy, K. Nigaud, R. Valabrègue, A. Schoonderbeek, E. P. ‘t Hart, H. Crawford, S. Gregory, D. Hensman Moss, E. Johnson, J. Read, G. Owen, M. Papoutsi, C. Berna, A. Razi, G. Rees, R. I. Scahill, D. Craufurd, R. Reilmann, N. Weber, J. Stout, I. Labuschagne, M. Orth, G. B. Landwehrmeyer, D. Langbehn, H. Johnson, J. Long, and J. Mills

Subjects
functional magnetic resonance, Huntington’s disease, dynamic causal modelling, effective connectivity, cluster analysis, working memory, Neurology. Diseases of the nervous system, RC346-429
Abstract

Huntington’s disease (HD) is a genetically caused neurodegenerative disorder characterized by heterogeneous motor, psychiatric, and cognitive symptoms. Although motor symptoms may be the most prominent presentation, cognitive symptoms such as memory deficits and executive dysfunction typically co-occur. We used functional magnetic resonance imaging (fMRI) and task fMRI-based dynamic causal modeling (DCM) to evaluate HD-related changes in the neural network underlying working memory (WM). Sixty-four pre-symptomatic HD mutation carriers (preHD), 20 patients with early manifest HD symptoms (earlyHD), and 83 healthy control subjects performed an n-back fMRI task with two levels of WM load. Effective connectivity was assessed in five predefined regions of interest, comprising bilateral inferior parietal cortex, left anterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. HD mutation carriers performed less accurately and more slowly at high WM load compared with the control group. While between-group comparisons of brain activation did not reveal differential recruitment of the cortical WM network in mutation carriers, comparisons of brain connectivity as identified with DCM revealed a number of group differences across the whole WM network. Most strikingly, we observed decreasing connectivity from several regions toward right dorsolateral prefrontal cortex (rDLPFC) in preHD and even more so in earlyHD. The deterioration in rDLPFC connectivity complements results from previous studies and might mirror beginning cortical neural decline at premanifest and early manifest stages of HD. We were able to characterize effective connectivity in a WM network of HD mutation carriers yielding further insight into patterns of cognitive decline and accompanying neural deterioration.

Published
2018
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3. 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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4. Neues zur Huntington-Krankheit

Author

Georg Bernhard Landwehrmeyer, Michael Orth, Carsten Saft, R Reilmann, and Sigurd D. Süßmuth

Subjects
Gynecology, medicine.medical_specialty, Disease modification, business.industry, Medicine, Neurology (clinical), business
Abstract

Als im Jahr 1993 das krankheitsverursachende Gen der Huntington-Krankheit (HK) entdeckt wurde, schienen ein rasches Verstandnis der Pathogenese dieser hereditaren neurodegenerativen Erkrankung und eine kausale Therapie in greifbare Nahe geruckt zu sein. Allerdings gestaltet sich die Entwicklung einer wirksamen und fruh im Krankheitsprozess einsetzbaren Behandlung durch die komplexe Pathophysiologie der HK schwierig. Die volle Penetranz dieser monogenetischen Erkrankung ermoglicht es jedoch, modellhaft neurodegenerative Prozesse mit gestorter Proteinhomoostase und RNA-Toxizitat sowie rationale Ansatzpunkte fur kausal angreifende Therapien zu erforschen und Mutationstrager vor der Entwicklung klinisch erkennbarer Auffalligkeiten in Verlaufsstudien zu untersuchen. Diese Studien (TRACK-HD, PREDICT-HD) haben zur Identifika­tion von MRT-basierten Indikatoren der Neurodegeneration im pramanifesten Stadium gefuhrt, die mit messbaren, aber subtilen funktionellen Veranderungen korrelieren. Standardisierte Untersuchungen im Rahmen von Beobachtungsstudien wie REGISTRY und Fortschritte in den Methoden der Genetik erlauben daruber hinaus eine breitgefacherte Suche nach krankheitsmodifizierenden Einflussfaktoren. Die Therapie der HK ist zur Zeit noch auf symptomatische Masnahmen beschrankt, aber eine kontinuierliche arztliche Begleitung und eine an die unterschiedlichen Symptome der verschiedenen Krankheitsphasen angepasste Behandlung verbessern die Lebensqualitat der Betroffenen und ihrer Familien messbar. Neue Ansatzpunkte fur mechanismenbasierte therapeutische Interventionen geben konkreten Anlass zur Hoffnung, in absehbarer Zukunft den Krankheitsverlauf gunstig beeinflussen zu konnen. Dieser Artikel gibt eine Ubersicht uber den aktuellen Stand derzeitiger und zukunftiger Behandlungsstrategien sowie Fortschritte in der Biomarkerentwicklung.

Published
2013
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5. N03 Efficacy, Safety, And Tolerability Of Afq056 For The Treatment Of Chorea In Patients With Huntington's Disease

Author

Marie-Laure Rouzade-Dominguez, R Reilmann, Baltazar Gomez-Mancilla, Anne Elizabeth Rosser, Sigurd D. Süssmuth, Nicole Pezous, Donald Johns, Georg Bernhard Landwehrmeyer, Ludger Schöls, Fabrizio Gasparini, Hugh Rickards, Josef Priller, and Carsten Saft

Subjects
medicine.medical_specialty, business.industry, Chorea, medicine.disease, Placebo, Psychiatry and Mental health, chemistry.chemical_compound, Tolerability, Dyskinesia, chemistry, Huntington's disease, Internal medicine, medicine, Physical therapy, Mavoglurant, Surgery, Clinical significance, Neurology (clinical), medicine.symptom, Adverse effect, business
Abstract

Background Treatments of chorea in patients with HD have limited efficacy and side-effects. AFQ056, a selective metabotropic glutamate receptor-5 antagonist shown to reduce levodopa-induced dyskinesia in PD, was hypothesised to reduce chorea in HD. Objective To assess anti-choreatic efficacy, safety, and tolerability of AFQ056 (Mavoglurant) in HD. Methods This was a 32-day randomised, double-blind, parallel-group, placebo (pbo)-controlled, proof-of-concept study. Patients were 30–85 years old, with HD (CAG ≥36) in clinical stage I–III, and maximal chorea sum score >10 in the UHDRS-TMS. Patients were randomised (1:1) to AFQ056 (Days 1–12, titration 25–150mg bid; Days 13–28, 150mg bid; Days 29–32, 50mg bid) or pbo. Primary objectives were to assess efficacy of AFQ056 vs pbo at Day 28 on UHDRS-TMS maximal chorea sum score and orientation index (non-dominant hand) from quantitative-motor (Q-Motor) grasping task and to assess safety and tolerability of AFQ056. Key secondary efficacy assessments included total UHDRS-TMS, UHDRS-TMS Luria score, UHDRS-TMS finger taps, and additional Q-Motor measures. Results Overall 42 patients (mean age 55.2 years, HD duration 6.6 years) were randomised. At Day 28, there were no significant improvements on UHDRS-TMS maximal chorea sum score (p = 0.155) or orientation index (non-dominant hand, p = 0.626) in AFQ056-treated patients vs pbo. A significant reduction in Q-Motor speeded-tapping variability was observed favouring AFQ056 vs pbo (p = 0.011) and reverting at study end; this was accompanied by UHDRS-TMS finger-tapping scores showing a trend towards improvement. No significant treatment effects were observed at Day 28 on other key secondary endpoints. Adverse events were reported by 14 and 12 AFQ056- and pbo-treated patients, respectively. Conclusions AFQ056 did not reduce involuntary choreatic movements in HD. The Q-Motor findings in speeded-tapping may reflect an improvement in fine motor coordination, but their clinical relevance is unknown. Overall, AFQ056 was well tolerated. Study supported by Novartis Pharma AG.

Published
2014
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6. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data

Author

Blair R. Leavitt, Douglas R. Langbehn, R Reilmann, Gail Owen, Sarah J. Tabrizi, Bernhard Landwehrmeyer, Julie C. Stout, Rachael I. Scahill, Alexandra Durr, David Craufurd, Chris Frost, Beth Borowsky, Raymund A.C. Roos, and Hans J. Johnson

Subjects
Male, medicine.medical_specialty, Neuroimaging, Neuropsychological Tests, Cognition, Huntington's disease, Predictive Value of Tests, Internal medicine, Hand strength, medicine, Humans, Apathy, Longitudinal Studies, Least-Squares Analysis, Survival analysis, Aged, Proportional Hazards Models, Repetitive Sequences, Nucleic Acid, Neurologic Examination, Hand Strength, Proportional hazards model, Brain, Middle Aged, medicine.disease, Prognosis, Survival Analysis, Neostriatum, Affect, Huntington Disease, Phenotype, Predictive value of tests, Physical therapy, Disease Progression, Observational study, Female, Neurology (clinical), medicine.symptom, Age of onset, Psychology, Psychomotor Performance
Abstract

TRACK-HD is a multinational prospective observational study of Huntington's disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression.Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if ≥10·8 years and preHD-B if10·8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11-13 and HD2 if they had a score of 7-10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis.At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4·11 points [95% CI 1·49-6·73] greater than controls; p=0·003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0·34 points [95% CI 0·02-0·66] greater than controls; p=0·038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0·01 s [95% CI 0·01-0·02] longer than controls; p=0·0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter-tap interval were particularly sensitive (p=0·013 and 0·002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0·006 and 0·0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p0·0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD.We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design.CHDI Foundation.

Published
2013

9. Gait and posture in pre-manifest and symptomatic huntington's disease

Author

P Kraus, R Reilmann, R. Hoffmann, Bernhard Landwehrmeyer, H. Beckmann, Herwig W. Lange, S. Trautmann, N Bechtel, Carsten Saft, K. Barth, and S Rumpf

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, Gait (human), Huntington's disease, business.industry, Physiology (medical), medicine, Neurology (clinical), medicine.disease, business
Published
2011
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11. PET/MRI-based phenotyping of a transgenic rat model for Huntington's disease - a 16 months follow-up study

Author

Michael Schäfers, Michael Deppe, Huu P. Nguyen, S. von Hörsten, E Hölzner, N. Nagelmann, C. Bremer, Sven Hermann, S. Bohlen, J. Sommer, J. Heselhaus, R Reilmann, Harald Kugel, Olaf Riess, V. Lippross, and Andreas H. Jacobs

Subjects
Pathology, medicine.medical_specialty, Huntington's disease, Physiology (medical), Transgene, Rat model, Follow up studies, medicine, Neurology (clinical), Psychology, medicine.disease
Published
2011
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13. C14 Striatal Magnetic Resonance Spectroscopy of Transgenic HD Minipigs

Author

M Wirsig, F Frank, S Ott, E Hölzner, L Liebsch, Robin Schubert, R Reilmann, Nina Nagelmann, Verena Schuldenzucker, M Marcegaglia, Sarah Schramke, and Cornelius Faber

Subjects
business.industry, Nuclear magnetic resonance spectroscopy, Striatum, Creatine, Proton magnetic resonance, Psychiatry and Mental health, chemistry.chemical_compound, chemistry, Group differences, Tolerability, Medicine, Surgery, Statistical analysis, Neurology (clinical), business, Nuclear medicine, Voxel size
Abstract

Background Our study is the first phenotyping study on TgHD minipigs from the Institute of Animal Physiology and Genetics in Libechov (Czech Republic). MRI scans including anatomical, diffusion-weighted and spectroscopic sequences were performed to assess anatomical and metabolic changes in the brain. Proton Magnetic Resonance Spectroscopy (MRS) is a validated method for determining changes in the relative molecule concentration in HD patients and in TgHD mice. Aims For determining relative molecule concentrations in the striatum of the tgHD and wildtype minipigs we performed a baseline and a follow-up assessment. Feasibility and tolerability same as between group differences and longitudinal changes will be assessed. Methods/techniques The minipigs were scanned on a 3T Philips Achieva system at baseline and at one year follow-up. Single-voxel based spectroscopy (PRESS) of the striatum on the right and left hemisphere was acquired using the following parameters: TR: 2000 ms, TE: 32 ms, measured voxel size: 8 × 22 × 8mm, averages: 176, scan duration: 6 min. The concentration of N-Acetylasparate, myo-inositol, glutamate and glutamine relative to creatine was calculated by LCModel. Results/outcome In the data collected to date no significant differences were seen between the transgenic and the wildtype group at MRI 1 (baseline-6 month of age) and 2 (18 months of age). The spectra showed well-resolved lines of the major metabolites, which were observed at similar relative concentrations as expected for humans. The statistical analysis is pending and will be presented at the EHDN meeting. Conclusions In this pilot study cross-sectional baseline and longitudinal data from tgHD minipigs and controls was successfully acquired. Thus longitudinal changes between transgenic and wildtype may be expected later on due to the slowly progressive nature of HD. Acknowledgement Funded by the CHDI Foundation

Published
2014
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14. J02 Brain Training in HD: Enhancing Neural Plasticity using Real-time FMRI Neurofeedback Training

Author

R Reilmann, Marina Papoutsi, Langbehn, Sarah J. Tabrizi, Geraint Rees, and Nikolaus Weiskopf

Subjects
Hemoencephalography, Cognition, Premotor cortex, Psychiatry and Mental health, medicine.anatomical_structure, Motor imagery, Finger tapping, Neuroplasticity, Adjunctive treatment, medicine, Surgery, Neurology (clinical), Neurofeedback, Psychology, Neuroscience
Abstract

Background Despite the absence of overt clinical symptoms, pre-symptomatic stages of Huntington’s disease (HD) show marked atrophy in the striatum, accompanied by changes in neuronal function. To the extent that such changes in neuronal function support preserved behaviour, they are compensatory. Brain training can be used to support neural compensation by enhancing neural plasticity. Aims The present study tests the feasibility of using real-time fMRI (rt-fMRI) neurofeedback training in HD. The aim is to restore brain function, as well as cognitive and motor performance, by training patients to regulate the activity of brain regions, such as the premotor cortex (PMC), whose function has been affected by the disease and is linked to cognitive and motor impairment. Methods Early stage HD patients were trained to regulate their own brain activation using motor imagery and receiving near real-time, visual feedback on the level of their PMC activation (BOLD fMRI signal). Brain activation, as well as cognitive and motor capacity, was compared before and after training to establish training induced changes. Results Patients who successfully learned to regulate their brain activation, showed an increase in their PMC activation from the first to the last visit. Increased PMC and motor network activation was also observed following training in an unrelated paced finger tapping task and in the absence of explicit neurofeedback. This was further accompanied by improvements in cognitive and motor performance. Conclusions We provide preliminary evidence that rt-fMRI neurofeedback training can be used to induce neural re-organisation in HD and support motor and cognitive function. Because it is non-invasive and low-risk, it could be also used as an adjunctive treatment to other disease modifying therapies, such as cortical or striatal HTT gene-silencing, in order to enhance brain re-organisation and restore lost motor and cognitive function, following mutant HTT clearance.

Published
2014
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15. C17 Track TGHD Minipig - Startbox back and Forth Test

Author

Robin Schubert, R Reilmann, S Ott, M Wirsig, Verena Schuldenzucker, F Frank, E Hölzner, Sarah Schramke, and M Marcegaglia

Subjects
Psychiatry and Mental health, medicine.medical_specialty, Physical medicine and rehabilitation, medicine, Training phase, Surgery, Neurology (clinical), Psychology, Test (assessment)
Abstract

Background This study aims to investigate characteristics of the tgHD Libechov minipig as a model for HD. So far no cognitive and behavioural assessments are established for minipigs. The “startbox back and forth test” introduced here is part of the cognitive-behavioural battery under development. Aim The aim of this study is to assess the feasibility and tolerability of applying the “startbox back and forth test” in minipigs and explore its sensitivity to detect cross-sectional and longitudinal differences between tgHD and wt minipigs. Material and methods Fourteen tgHD (124 Q) and eighteen wt Libechov-minipigs were included. The setup the pigs are trained and tested in consists of a walkway and two startboxes (SB 1 and SB 2) on both ends, connected through trapdoors. In the training phase, minipigs are trained to run back and forth between SB 1 and SB 2 and are rewarded when reaching the opposite startbox. During the testing phase the pigs are not rewarded, while the option to run back and forth is maintained. The learning target in this test is not to run back and forth, because of the missing reward. During training and testing, completed runs within 5 min are counted. The test is stopped when a pig stays 1.5 min either in a startbox or in the walkway (assuming that it has learnt there is no reward to expect). Biannually, each pig completes two training sessions and subsequently the testing session is performed. Results All data has been successfully acquired in all tgHD and wt minipigs suggesting good tolerance of the method. An ANOVA analysis comparing the differences in behaviour between tgHD and wt minipigs is in progress. Conclusion The data collected to date demonstrates that application of the “startbox back and forth test” is feasible and well tolerated. It is hypothesised that recognition of the lack of being awarded is impaired in tgHD minipigs compared to controls. This is currently assessed and we expect to report first results at the meeting.

Published
2014
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16. A teaching film, video library and online certification for the Unified Huntington's Disease Rating Scale Total Motor Score

Author

HW Lange, Y Grimbergen, Anne Elizabeth Rosser, R Reilmann, R A C Roos, D Craufurd, D. Ecker, M. Dose, E Howard, Georg Bernhard Landwehrmeyer, P Kraus, Jean-Marc Burgunder, S. Bohlen, and A. Weindl

Subjects
Huntington's disease, Rating scale, business.industry, Applied psychology, medicine, Video Library, Neurology (clinical), Certification, medicine.disease, business, Motor score
Published
2009
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18. Quantitative motor phenotype assessment in pre-manifest and symptomatic Huntington's disease: tongue force analysis differentiates between disease stages and provides high phenotype correlation. Cross sectional results from the TRACK-HD Study

Author

Alexandra Durr, S.J.A. van den Bogaard, Bernhard Landwehrmeyer, A Sturrock, C Jauffret, Miranda J. Say, Langbehn, S. Bohlen, R A C Roos, James A. Mills, N Bechtel, Sarah J. Tabrizi, Blair R. Leavitt, Hans J. Johnson, Beth Borowsky, R Reilmann, and TP Archarya

Subjects
Pathology, medicine.medical_specialty, Phenotype correlation, business.industry, Disease stages, Track (disk drive), medicine.disease, Phenotype, Force analysis, medicine.anatomical_structure, Huntington's disease, Tongue, medicine, Neurology (clinical), business
Published
2009
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19. Objective motor phenotype assessment of gait and posture in pre-manifest and symptomatic Huntington's disease

Author

HW Lange, S Rumpf, P Kraus, H. Beckmann, Bernhard Landwehrmeyer, Carsten Saft, R. Hoffmann, N Bechtel, K. Barth, S. Trautmann, and R Reilmann

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, Gait (human), Huntington's disease, business.industry, medicine, Physical therapy, Neurology (clinical), medicine.disease, business, Phenotype
Published
2009
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20. Sensitivity of gait analysis to detect motor phenotype in pre-manifest and manifest Huntington's disease – cross-sectional results from the TRACK-HD Study

Author

A Sturrock, Bernhard Landwehrmeyer, Sarah J. Tabrizi, H. Beckmann, R Reilmann, R A C Roos, Blair R. Leavitt, Langbehn, S Rohm, C Jauffret, Hans J. Johnson, N Bechtel, Alexandra Durr, Julie C. Stout, S.J.A. van den Bogaard, Miranda J. Say, Beth Borowsky, James A. Mills, and TP Archarya

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, Huntington's disease, business.industry, Track (disk drive), Gait analysis, Medicine, Neurology (clinical), Sensitivity (control systems), business, medicine.disease, Phenotype
Published
2009
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21. In vivo assessment of neuronal dysfunction in rats transgenic for Huntington's disease using small animal FDG-PET and MRI – a 16 months follow-up study

Author

N. Nagelmann, Michael Schäfers, R Reilmann, Harald Kugel, Olaf Riess, J. Sommer, Michael Deppe, S. von Hörsten, V. Lippross, S. Bohlen, J. Heselhaus, C. Bremer, Sven Hermann, and Huu P. Nguyen

Subjects
Pathology, medicine.medical_specialty, Huntington's disease, In vivo, Small animal, Transgene, medicine, Follow up studies, Neurology (clinical), Psychology, medicine.disease
Published
2009
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22. Finger tapping as an objective motor phenotype marker in pre-manifest and symptomatic Huntington's disease – cross-sectional results from the TRACK-HD Study

Author

Miranda J. Say, Blair R. Leavitt, N Bechtel, A Sturrock, R Reilmann, James A. Mills, Julie C. Stout, Alexandra Durr, C Jauffret, TP Archarya, Sarah J. Tabrizi, Bernhard Landwehrmeyer, S.J.A. van den Bogaard, Langbehn, Hans J. Johnson, R A C Roos, and Beth Borowsky

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, Huntington's disease, Track (disk drive), Finger tapping, medicine, Neurology (clinical), Psychology, medicine.disease, Neuroscience, Phenotype
Published
2009
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26. On Chorea – quantitative and objective analysis – cross-sectional results of the TRACK-HD Study

Author

S.J.A. van den Bogaard, Blair R. Leavitt, A Sturrock, Miranda J. Say, R A C Roos, R Reilmann, C Jauffret, N Bechtel, Langbehn, Hans J. Johnson, Bernhard Landwehrmeyer, Beth Borowsky, James A. Mills, Sarah J. Tabrizi, Alexandra Durr, and TP Archarya

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, business.industry, Track (disk drive), Medicine, Objective analysis, Chorea, Neurology (clinical), medicine.symptom, business
Published
2009
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28. Impairments of postural control in patient's with Huntington's disease while sitting – a new motor phenotype biomarker?

Author

H. Beckmann, S Rumpf, P. H. Kraus, R Reilmann, HW Lange, N Bechtel, and S. Bohlen

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, Huntington's disease, medicine, Biomarker (medicine), In patient, Neurology (clinical), medicine.disease, Sitting, Psychology, Phenotype, Neuroscience, Postural control
Published
2008
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38. Grip-force variability in asymptomatic carriers of the Huntington gene – a biomarker for presymptomatic clinical studies?

Author

Erich Bernd Ringelstein, R. Bachmann, D. Bracht, M. Weckesser, HW Lange, S. Bohlen, F. Kirsten, R Reilmann, and Hubertus Lohmann

Subjects
medicine.medical_specialty, business.industry, Surrogate endpoint, Isometric exercise, medicine.disease, Asymptomatic, Atrophy, Physical medicine and rehabilitation, Statistical significance, medicine, Physical therapy, Biomarker (medicine), Neurology (clinical), Analysis of variance, medicine.symptom, business, Asymptomatic carrier
Abstract

Aims: Isometric grip force variability (GFV) in Huntington's Disease (HD) was shown to correlate with (1) the severity of motor deficits in HD as assessed in the UHDRS (Gordon et al. 2000), (2) the CAG-repeat length when normalized for age (Reilmann et al. 2004), and (3) the degree of atrophy observed in the caudate nucleus on MRI volumetry (Reilmann et al 2005). Furthermore grip force variability was shown to increase in the course of HD (Reilmann et al. 2001). Objective: To investigate whether GFV in a grasping and holding task is pathologically increased in clinically asymptomatic carriers of the Huntington gene. Subjects and methods: HD gene carriers (n=13) and age-and-sex-matched healthy controls (n=13) were instructed to grasp and lift an object (weight 250g or 500g) in the precision grip and hold it next to a marker 10cm high for 30 seconds. Thirteen trials were performed in each weight condition. Grip and lift forces were recorded using force transducers (Mini-30, ATI, USA). Object position was recorded using a 3D-tracking device (Fastrack, Polhemus, USA). Data was recorded and analyzed using a flexible laboratory computer system (SC/ZOOM, University of Umea, Sweden). Mean grip force and its coefficient of variation were calculated during a 20s period in the static holding phase. Gene carriers were clinically assessed by the UHDRS and exhibited total motor scores

Published
2006
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41. Assessment of isometric tongue forces – an objective and quantitative surrogate marker for amyotrophic lateral sclerosis?

Author

R. Bachmann, S. Bohlen, Florian Holtbernd, Michael Deppe, F. Kirsten, R Reilmann, and M. Wansing

Subjects
medicine.medical_specialty, medicine.anatomical_structure, Physical medicine and rehabilitation, Tongue, Surrogate endpoint, business.industry, medicine, Neurology (clinical), Isometric exercise, Amyotrophic lateral sclerosis, medicine.disease, business, Neuroscience
Published
2006
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43. C16 Track TGHD Minipig - Assessment of Motor Function

Author

S Ott, Verena Schuldenzucker, F Frank, R Reilmann, E Hölzner, M Marcegaglia, Sarah Schramke, Robin Schubert, and M Wirsig

Subjects
medicine.medical_specialty, business.industry, Motor function, Test (assessment), Psychiatry and Mental health, medicine.anatomical_structure, Physical medicine and rehabilitation, Tolerability, Test board, Tongue, Medicine, Training phase, Surgery, Neurology (clinical), Test phase, Analysis of variance, business
Abstract

Background This study aims to assess if tgHD Minipigs (124 Q) develop symptoms characteristic of human HD in comparison with wt Minipigs. To investigate this, we developed and test motor, cognitive and behavioural tests. Aims We here report novel motor function tests, the “Tongue-Test” and the “Hurdle-Test”, and assess their feasibility, tolerability, cross sectional and longitudinal results. Methods The wt (n = 18) and tg (n = 14) Minipigs have to perform the same motor function tests. The Tongue-Test is divided into a training phase and a test phase. During the training phase the pig is presented with a board containing 10 holes measuring the same in diameter and depth. A treat is placed in each hole and has to be picked up with the tongue. A training session lasts until the pig has successfully recovered all 10 treats. It is repeated three times unless a trial lasts more than 5 min, in which case the assessment is stopped. During the test phase the pig is presented with a board that looks the same as the one used in the training session. However, the holes in this test board increase in their depth and the number of successfully recovered treats is counted. The test is repeated three times. The Hurdle-Test assesses general motor function of the Minipigs while climbing over hurdles and contains a test 1phase only, since no specific training is needed. Six runs are performed. The test is videotaped for further analysis. Results Preliminary non-parametric statistics suggested that at baseline tg Minipigs perform both the Tongue and Hurdle-Test faster than wt Minipigs. No differences were seen at follow-up visit 1 (6 months) and 2 (12 months – assessments ongoing). Further analysis (ANOVA) is pending and will be presented at the EHDN meeting. Conclusion TgHD Minipis are capable to perform both the Tongue and Hurdle-Test successfully and repeatedly. Phenotypical characteristics of the tgHD versus wt comparison will be reported and discussed after completion of ANOVA analysis.

Published
2014
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44. C18 Track TGHD Minipig - Assessing Resource Holding Potential Behaviour as part of a Battery for Phenotyping TGHD Minipigs

Author

E Hölzner, F Frank, R Reilmann, Verena Schuldenzucker, M Wirsig, Robin Schubert, Sarah Schramke, M Marcegaglia, and S Ott

Subjects
Psychiatry and Mental health, business.industry, Medicine, Physiology, Surgery, Neurology (clinical), Resource holding potential, business
Abstract

Background The TRACK tgHD minipig project aims to evaluate the phenotype of the Libechov tgHD minipig model. Established tests for assessing different domains of possible phenotype manifestation in minipigs are lacking. The test introduced here is thought to primarily target behavioural dysfunction. Aim To assess the feasibility and tolerability of the application of the test in minipigs and explore the tgHD minipigs’ performance compared with that of wildtype (wt) minipigs. Methods/techniques Thirty-two minipigs – 18 wt and 14 tg (124 Q) – were tested at an age of 6–8 and 11–14 months. The animals were housed in six mixed groups (wt and tg). Tests were conducted in a narrow aisle divided in half by a door. During training, the minipigs learnt to enter the aisle from one side, wait at the door, leave the aisle on the other side and receive a highly favoured food treat here. During testing, two animals entered the aisle from either end. The door was then opened and the animals faced each other. A “win” was noted for reaching the opposite end of the aisle first, pushing the conspecific aside. All animals per group faced each other once. Number of wins per encounters were compared between wt and tg minipigs. Data were analysed using SPSS 22.0. Results/outcome Aged 6–8 months, wt minipigs won 42.86% ± 17.62% of the encounters, and tg minipigs 56.67% ± 31.10% (n.s.). Aged 11–14 months, wt minipigs reached 44.61% ± 31.45% wins per encounters, and tg minipigs 53.29% ± 25.73 (n.s.). Conclusion Capability to fight conspecifics to receive or defend resources, i.e. the resource holding potential (RHP), depends on physiological (e.g. age, weight, health status) and psychological factors. The results show that assessment of the RHP is feasible using the test applied in minipigs. So far genotype has not shown a significant effect when comparing wt and tgHD minipigs. However, we hypothesise the test may be sensitive to detect a phenotype the cohorts grow older.

Published
2014
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45. C19 Track Tghd Minipigs - A Discrimination Test As Part Of An Assessment Battery For Tghd Minipigs

Author

F Frank, R Reilmann, E Hölzner, S Ott, Sarah Schramke, Robin Schubert, M Marcegaglia, M Wirsig, and Verena Schuldenzucker

Subjects
Veterinary medicine, medicine.medical_specialty, Longitudinal data, business.industry, Audiology, Group comparison, Discrimination testing, Psychiatry and Mental health, Initial training, Huntingtin Gene, medicine, Surgery, Neurology (clinical), business, Animal facility
Abstract

Background The TRACK tgHD minipig study aims to evaluate the potential of the Libechov tgHD minipig model for pre-clinical studies by studying the phenotype of these animals. Established tests for assessing different domains of possible phenotype manifestation in minipigs are lacking. The “Discrimination Test” introduced here is thought to primarily target cognitive dysfunction. Aim To assess the feasibility and tolerability of the application of the “Discrimination Test” in minipigs and explore the tgHD minipigs’ performance compared with that of wildtype (wt) minipigs. Methods/techniques Thirty-two minipigs – 18 wt and 14 tg (with an N-terminal fragment of the huntingtin gene coding for 548aa with 124Q) – were included in the study. The minipigs were housed in six mixed groups (wt and tg) at the animal facility of the University of Muenster, Germany. The “Discrimination Test” was performed using a special setup. During initial training, the minipigs learnt to leave a startbox (SB A), enter a walkway, open a blue plastic box (bB) as opposed to red and yellow box (rB/yB), and return to SB A. The boxes’ position was changed clockwise in subsequent runs. During testing 1, time to leave SB A and open bB, and time to leave bB and return to SB A was recorded and a score was given based on attempts to open and/or investigate bB and/or rB and yB. During testing 2, yB had to be opened instead of bB and yB (intradimensional shift). Each pig completes training, testing 1 and testing 2 biannually. Results/outcome The animals show a good tolerance of the method. Cross sectional and longitudinal data analysis is in progress using SPSS 22.0. Conclusion The data collected to date shows that implementation of the “Discrimination Test” is feasible and well tolerated. It is hypothesised that performance of the test is impaired in tgHD minipigs compared to controls. We expect to report first between group comparisons at the meeting. Acknowledgement This study was funded by the CHDI foundation.

Published
2014
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46. C12 Volumetry of Nucleus Caudatus, Lateral Ventricles and Cerebrum of Founder and Second Generation Libechov Transgenic HD Minipigs

Author

Robin Schubert, Monika Baxa, M Marcegaglia, M Wirsig, E Hölzner, R Reilmann, Sarah Schramke, Nina Nagelmann, Stefan Juhas, F Frank, L Liebsch, Jan Motlik, Cornelius Faber, and Verena Schuldenzucker

Subjects
Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Cerebrum, Transgene, Magnetic resonance imaging, Nucleus Caudatus, Biology, Scan time, Psychiatry and Mental health, Lateral ventricles, medicine.anatomical_structure, Flip angle, medicine, Surgery, Neurology (clinical), Nuclear medicine, business, Voxel size
Abstract

Background Transgenic HD minipigs were examined with Magnetic Resonance Imaging for phenotyping the disease model. MRI scans were performed on the founder and second generation of transgenic HD minipigs from the Institute of Animal Physiology and Genetics in Libechov (Czech Republic). These scans include anatomical, diffusion-weighted and spectroscopic sequences. Aim For phenotyping, different brain regions of the transgenic HD and wildtype minipigs were investigated periodically. Methods/techniques Three transgenic HD and two wildtype minipigs were scanned on a 3T Philips Achieva system three times within four years. A 3D gradient echo data set was acquired in 32 min scan time using the following parameters: slices: 450, reconstructed voxel size: 0.5 mm isotropic, FOV: 296 × 296 × 225, NSA: 3, TR: 7.5 ms, TE: 3.4 ms, flip angle: 9 deg. The nucleus caudatus, the lateral ventricles and the cerebrum were segmented semi-manually using the software package “Amira®” and the corresponding volumes were calculated. Results/outcome So far no significant differences between the transgenic (n = 3) and wildtype (n = 2) group in the analysed volumes were observed. Conclusions/discussion In this pilot study, no changes in the brain regions assessed were identified. However, the very small number of animals included limits these observations. Due to the slowly progressive nature of HD, changes in the volume between transgenic and wildtype minipigs may be expected to be expressed at later time points. Acknowledgement Funded by the CHDI Foundation.

Published
2014
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47. N02 Safety And Tolerability Of Selisistat For The Treatment Of Huntington's Disease: Results From A Randomised, Double-blind, Placebo-controlled Phase Ii Trial

Author

Josef Priller, R Reilmann, Ruth Farmer, Anne Elizabeth Rosser, Caterina Mariotti, A Szynol, Georg Bernhard Landwehrmeyer, Carsten Saft, Ferdinando Squitieri, Chris Frost, Sigurd D. Süssmuth, David F. Fischer, Sarah J. Tabrizi, David Craufurd, Hugh Rickards, B Darpo, G Westerberg, Andrea H. Németh, MA Tessari, and Oliver Quarrell

Subjects
medicine.medical_specialty, Huntingtin, medicine.diagnostic_test, business.industry, medicine.disease, Placebo, Surgery, Psychiatry and Mental health, Pharmacokinetics, Huntington's disease, Tolerability, Internal medicine, medicine, Neurology (clinical), Liver function tests, business, Adverse effect, Blood sampling
Abstract

Background Selisistat is a first-in-class SirT1 inhibitor shown to be safe and well tolerated in healthy volunteers and HD patients in short-term studies. Objective To evaluate safety and tolerability of selisistat over 12 weeks in patients with Huntington’s disease (HD). Design/methods This was a double-blind, placebo-controlled, international multi-centre study of selisistat in individuals with Stage I-III HD. Participants (30–70 yrs) with genetically confirmed HD, a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of ≥ 5 and a Total Functional Capacity ≥ 5 were randomised (1:1:1) to selisistat 50 or 200 mg or placebo once daily for 12 weeks. Safety and tolerability were evaluated by monitoring adverse events, vital signs, ECG and laboratory safety data throughout the study. Blood sampling for pharmacokinetics and soluble mutant huntingtin levels were collected throughout. Results/outcome A total of 144 patients were randomised and 125 patients (87%) completed the study. There were 9 serious adverse events, three in each treatment group, including one death in the placebo group. The most common adverse events were reversible increases in liver function tests without accompanying increases in bilirubin. All of these occurred in the selisistat groups; while most of these increases were Conclusions Apart from increases in liver function tests in a subset of patients, selisistat was safe and well tolerated, and a trend for modulation of the levels of soluble mutant huntingtin was observed. Acknowledgement Supported by Siena Biotech SpA.

Published
2014
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48. G02 Longitudinal Development Of Cognitive Test Scores In Premanifest And Manifest Patients Of The Registry-cohort

Author

R Koch, N Weber, and R Reilmann

Subjects
medicine.medical_specialty, Cognition, Audiology, Confidence interval, Cognitive test, Developmental psychology, Psychiatry and Mental health, Cohort, medicine, Verbal fluency test, Surgery, Observational study, Neurology (clinical), Cognitive decline, Psychology, Stroop effect
Abstract

Background The REGISTRY study is one of the largest longitudinal observational studies in Huntington’s disease. One major assessment point in Registry is the UHDRS cognitive battery, including the Stroop test, the Symbol Digit Modalities Test (SDMT), and the verbal fluency test for letters. Aims Our aim was to investigate whether the UHDRS cognitive tests were sensitive to longitudinal change in HD patients and differentiated between premanifest and manifest subjects. Further, we were interested in the differential development of premanifest and manifest patients in these tests over time. Methods Patients were split in two groups by diagnostic confidence level (DCL), resulting in a premanifest group with DCL 1–3 (n = 670) and a manifest group with DCL 4 (n = 1634). Annual change in test scores was analysed using linear mixed models with fixed effects time, DCL at baseline and the interaction term timeXDCL. Results Mean overall score difference between DCL 1–3 and DCL 4 was significant for all tests, ranging from 14.87 points (p Conclusions All UHDRS cognitive tests in the REGISTRY study were able to differentiate between the premanifest and manifest patient groups. In the premanifest group only Stroop word reading and the SDMT depicted annual cognitive decline, while in the manifest group all tests did.

Published
2014
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50. I07 Impaired isometric force coordination in Huntington's disease

Author

R Reilmann, Herwig W. Lange, S. Bohlen, S. Horst, and Christian Sass

Subjects
medicine.medical_specialty, Gene carrier, Isometric exercise, Thumb, medicine.disease, Psychiatry and Mental health, Physical medicine and rehabilitation, medicine.anatomical_structure, Huntington's disease, medicine, Physical therapy, Surgery, Clinical severity, Neurology (clinical), Tongue protrusion, Psychology, Categorical scale, Motor score
Abstract

Background Assessment of motor phenotype and diagnosis of Huntington9s Disease (HD) are based on the Unified HD Rating Scale-Total Motor Score, a categorical scale. We have previously shown that impairments in tongue protrusion forces can be seen in premanifest and manifest HD and correlate with clinical severity as assessed by the Unified HD Rating Scale-Total Motor Score and the disease burden score (Reilmann et al. 2010). In this study we aimed to investigate whether similar impairments of force coordination can be found in different force matching tasks. Objective To assess whether impairments in isometric force coordination of the upper and lower extremities can be detected in manifest HD gene carriers compared to controls. Methods Using a precalibrated force transducer, the ability of subjects with symptomatic HD (n=31) to generate and maintain isometric TPF at different target force levels (1.5, and 5.0 N for thumb, 1.0, 5.0 and 10.0 N for big toe) was assessed and compared with age-matched controls (n=22) in a cross-sectional pilot study. Results All paradigms distinguish controls from symptomatic subjects. The static coefficient of variability (%), assessing the degree of deviation from the target force normalised to the mean force, was the most robust measure in all matching trials. Comparisons between tasks and correlations with clinical measures such as the TMS, DBS and TFC will be presented. Conclusions Assessment of force matching tasks by hand and feet may provide quantitative objective measures for severity of motor phenotype in symptomatic HD.

Published
2012
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