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2. Magnetic Oculomotor Prosthetics for Acquired Nystagmus

Author

Nachev, P, Rose, GE, Verity, DH, Manohar, SG, MacKenzie, K, Adams, G, Theodorou, M, Pankhurst, QA, and Kennard, C

Subjects
genetic structures, Original Article, PD, prism diopter, eye diseases, D, diopter
Abstract

Purpose Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector—the eye muscles themselves—where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times. Implementing this idea magnetically, herein we describe the successful implantation of a novel magnetic oculomotor prosthesis in a patient. Design Case report of a pilot, experimental intervention. Participant A 49-year-old man with longstanding, medication-resistant, upbeat nystagmus resulting from a paraneoplastic syndrome caused by stage 2A, grade I, nodular sclerosing Hodgkin's lymphoma. Methods We designed a 2-part, titanium-encased, rare-earth magnet oculomotor prosthesis, powered to damp nystagmus without interfering with the larger forces involved in saccades. Its damping effects were confirmed when applied externally. We proceeded to implant the device in the patient, comparing visual functions and high-resolution oculography before and after implantation and monitoring the patient for more than 4 years after surgery. Main Outcome Measures We recorded Snellen visual acuity before and after intervention, as well as the amplitude, drift velocity, frequency, and intensity of the nystagmus in each eye. Results The patient reported a clinically significant improvement of 1 line of Snellen acuity (from 6/9 bilaterally to 6/6 on the left and 6/5–2 on the right), reflecting an objectively measured reduction in the amplitude, drift velocity, frequency, and intensity of the nystagmus. These improvements were maintained throughout a follow-up of 4 years and enabled him to return to paid employment. Conclusions This work opens a new field of implantable therapeutic devices—oculomotor prosthetics—designed to modify eye movements dynamically by physical means in cases where a purely neural approach is ineffective. Applied to acquired nystagmus refractory to all other interventions, it is shown successfully to damp pathologic eye oscillations while allowing normal saccadic shifts of gaze.

Published
2017

5. Apathy associated with impaired recognition of happy facial expressions in Huntington's disease

Author

Osborne-Crowley, K., Andrews, S.C., Labuschagne, I., Nair, A., Scahill, R., Craufurd, D., Tabrizi, S.J., Stout, J.C., Campbell, C., Campbell, M., Frajman, E., Milchman, C., O'Regan, A., Coleman, A., Santos, R.D., Decolongon, J., Sturrock, A., Bardinet, E., Jauffret, C., Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Pourchot, P., Valabregue, R., Bechtel, N., Bohlen, S., Reilmann, R., Hoffman, A., Kraus, P., Landwehrmeyer, B., Bogaard, S.J.A. van den, Dumas, E.M., Grond, J. van der, t'Hart, E.P., Jurgens, C., Witjes-Ane, M.N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Berna, C., Crawford, H., Fox, N., Gibbard, C., Hobbs, N., Lahiri, N., Malone, I., Ordidge, R., Owen, G., Patel, A., Pepple, T., Read, J., Say, M., Whitehead, D., Wild, E., Keenan, S., Cash, D.M., Hicks, S., Kennard, C., Acharya, T., Axelson, E., Johnson, H., Langbehn, D., Wang, C., Lee, S., Monaco, W., Rosas, H., Queller, S., Whitlock, K., Borowsky, B., Tobin, A., and TRACK-HD Investigators

Subjects
Adult, Male, cognition, Emotions, emotion, apathy, Neuropathology, Article, social behavior, Huntington's disease, Rating scale, cognition disorders, medicine, Humans, Psychological testing, Apathy, Cognitive skill, Facial expression, General Neuroscience, Cognition, Middle Aged, medicine.disease, Facial Expression, Psychiatry and Mental health, Clinical Psychology, Huntington Disease, Social Perception, Female, Neurology (clinical), medicine.symptom, Psychology, Facial Recognition, Clinical psychology, Huntington’s disease
Abstract

Objectives: Previous research has demonstrated an association between emotion recognition and apathy in several neurological conditions involving fronto-striatal pathology, including Parkinson’s disease and brain injury. In line with these findings, we aimed to determine whether apathetic participants with early Huntington’s disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls. Methods: We included 43 participants from the TRACK-HD study who reported apathy on the Problem Behaviours Assessment – short version (PBA-S), 67 participants who reported no apathy, and 107 controls matched for age, sex, and level of education. During their baseline TRACK-HD visit, participants completed a battery of cognitive and psychological tests including an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS) and were assessed on the PBA-S. Results: Compared to the non-apathetic group and the control group, the apathetic group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology on the HADS and general disease progression (Unified Huntington’s Disease Rating Scale total motor score). This was despite no difference between the apathetic and non-apathetic group on overall cognitive functioning assessed by a cognitive composite score. Conclusions: Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on frontostriatal pathways may broadly explain associations between emotion recognition and apathy found across several patient groups, further work is needed to determine what relationships exist between recognition of specific emotions, distinct subtypes of apathy and underlying neuropathology. (JINS, 2019, 25, 453–461)

Published
2019

6. MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1

Author

Flower, M, Lomeikaite, V, Ciosi, M, Cumming, S, Morales, F, Lo, K, Hensman Moss, D, Jones, L, Holmans, P, Monckton, DG, Tabrizi, SJ, Kraus, P, Hoffman, R, Tobin, A, Borowsky, B, Keenan, S, Whitlock, KB, Queller, S, Campbell, C, Wang, C, Langbehn, D, Axelson, E, Johnson, H, Acharya, T, Cash, DM, Frost, C, Jones, R, Jurgens, C, Hart, EPT, Van Der Grond, J, Witjes- Ane, MNN, Roos, RAC, Dumas, EM, Van Den Bogaard, SJA, Stopford, C, Craufurd, D, Callaghan, J, Arran, N, Rosas, DD, Lee, S, Monaco, W, O'Regan, A, Milchman, C, Frajman, E, Labuschagne, I, Stout, J, Campbell, M, Andrews, SC, Bechtel, N, Reilmann, R, Bohlen, S, Kennard, C, Berna, C, Hicks, S, Durr, A, Pourchot, C, Bardinet, E, Nigaud, K, Valabrègue, R, Lehericy, S, Marelli, C, Jauffret, C, Justo, D, Leavitt, B, Decolongon, J, Sturrock, A, Coleman, A, Dar Santos, R, Patel, A, Gibbard, C, Whitehead, D, Wild, E, Owen, G, Crawford, H, Malone, I, Lahiri, N, Fox, NC, Hobbs, NZ, Scahill, RI, Ordidge, R, Pepple, T, Read, J, Say, MJ, Landwehrmeyer, B, Daidj, F, Bassez, G, Lignier, B, Couppey, F, Delmas, S, Deux, JF, Hankiewicz, K, Dogan, C, Minier, L, Chevalier, P, Hamadouche, A, Catt, M, Van Hees, V, Catt, S, Schwalber, A, Dittrich, J, Flower, M, Lomeikaite, V, Ciosi, M, Cumming, S, Morales, F, Lo, K, Hensman Moss, D, Jones, L, Holmans, P, Monckton, DG, Tabrizi, SJ, Kraus, P, Hoffman, R, Tobin, A, Borowsky, B, Keenan, S, Whitlock, KB, Queller, S, Campbell, C, Wang, C, Langbehn, D, Axelson, E, Johnson, H, Acharya, T, Cash, DM, Frost, C, Jones, R, Jurgens, C, Hart, EPT, Van Der Grond, J, Witjes- Ane, MNN, Roos, RAC, Dumas, EM, Van Den Bogaard, SJA, Stopford, C, Craufurd, D, Callaghan, J, Arran, N, Rosas, DD, Lee, S, Monaco, W, O'Regan, A, Milchman, C, Frajman, E, Labuschagne, I, Stout, J, Campbell, M, Andrews, SC, Bechtel, N, Reilmann, R, Bohlen, S, Kennard, C, Berna, C, Hicks, S, Durr, A, Pourchot, C, Bardinet, E, Nigaud, K, Valabrègue, R, Lehericy, S, Marelli, C, Jauffret, C, Justo, D, Leavitt, B, Decolongon, J, Sturrock, A, Coleman, A, Dar Santos, R, Patel, A, Gibbard, C, Whitehead, D, Wild, E, Owen, G, Crawford, H, Malone, I, Lahiri, N, Fox, NC, Hobbs, NZ, Scahill, RI, Ordidge, R, Pepple, T, Read, J, Say, MJ, Landwehrmeyer, B, Daidj, F, Bassez, G, Lignier, B, Couppey, F, Delmas, S, Deux, JF, Hankiewicz, K, Dogan, C, Minier, L, Chevalier, P, Hamadouche, A, Catt, M, Van Hees, V, Catt, S, Schwalber, A, and Dittrich, J

Abstract

The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington's disease and myotonic dystrophy type 1. A recent Huntington's disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington's disease. Using Illumina sequencing in Huntington's disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington's disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10-7) in Huntington's disease. RNA-Seq of whole blood in the Huntington's disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington's disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington's disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

Published
2019

7. Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Author

Moss, Davina J Hensman, Tabrizi, Sarah J, Mead, Simon, Lo, Kitty, Pardiñas, 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., Valabrègue, 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, Jørgen, Koivisto, Susana Pro, Päivärinta, Markku, Roos, Raymund A. C., Sebastián, A Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström, 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, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mütze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hélène, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Røren, Niini, Šašinková, 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, Müller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schöggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Müller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cécile, van Paemel, Dominique, Ribaï, Pascale, van Reijen, Dimphna, Klempír, Jirí, Majerová, Veronika, Roth, Jan, Stárková, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, Jørgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppönen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bénédicte, Guérid, Marie-Anne, Olivier, Audrey, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duché, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucrière, Danielle, Spampinato, Umberto, Barthélémy, Rekha, De Bruycker, Christelle, Carette, Maryline Cabaret Anne-Sophie, Defebvre, Eric Decorte Luc, Delliaux, Marie, Delval, Arnaud, Destee, Alain, Dujardin, Kathy, Lemaire, Marie-Hélène, Manouvrier, Sylvie, Peter, Mireille, Plomhouse, Lucie, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Vuillaume, Isabelle, Bellonet, Marcellin, Berrissoul, Hassan, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Godefroy, Olivier, Krystkowiak, Pierre, Mantaux, Béatrice, Roussel, Martine, Wannepain, Sandrine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frédérique, Mundler, Laura, Anheim, Mathieu, Julié, 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, Prüß, Harald, Spruth, Eike Jakob, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kotz, Peter, Prehn, Christian, Saft, Carsten, Lange, Herwig, Maiwald, Robert, Löhle, 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, Münchau, Alexander, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Gorzolla, Heike, Schrader, Christoph, Tacik, Pawel, Ribbat, Michael, Longinus, Bernhard, Bürk, Katrin, Möller, Jens Carsten, Rissling, Ida, Mühlau, Mark, Peinemann, Alexander, Städtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Hölzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythäuser, 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, Süßmuth, 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, Marchese, Roberta, 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., ’t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjørgo, Kathrine, Fannemel, Madeleine, Gørvell, Per F., Lorentzen, Eirin, Retterstøl, Lar, Stokke, Bodil, Bjørnevoll, 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, Wójcik, 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, Sebastián, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Núria, 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, María, García, Rocío García-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuñana, Mónica, Caldentey, Juan Garcia, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Frech, Fernando Alonso, Ruíz, Pedro J García, Martínez-Descals, Asunción, Guerrero, Rosa, Artiga, María José Saiz, Sánchez, 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, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodríguez, 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, Peña, José Chacón, Redondo, Lui, Carrillo, Fátima, Teresa Cáceres, María, 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, Wikström, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, 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, Ho, Carrie, 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, Klöppel, 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, Harrison, David, 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, Bentivoglio, Anna Rita (ORCID:0000-0002-9663-095X), Albanese, Alberto (ORCID:0000-0002-5864-0006), Moss, Davina J Hensman, Tabrizi, Sarah J, Mead, Simon, Lo, Kitty, Pardiñas, 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., Valabrègue, 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, Jørgen, Koivisto, Susana Pro, Päivärinta, Markku, Roos, Raymund A. C., Sebastián, A Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström, 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, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mütze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hélène, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Røren, Niini, Šašinková, 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, Müller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schöggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Müller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cécile, van Paemel, Dominique, Ribaï, Pascale, van Reijen, Dimphna, Klempír, Jirí, Majerová, Veronika, Roth, Jan, Stárková, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, Jørgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppönen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bénédicte, Guérid, Marie-Anne, Olivier, Audrey, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duché, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucrière, Danielle, Spampinato, Umberto, Barthélémy, Rekha, De Bruycker, Christelle, Carette, Maryline Cabaret Anne-Sophie, Defebvre, Eric Decorte Luc, Delliaux, Marie, Delval, Arnaud, Destee, Alain, Dujardin, Kathy, Lemaire, Marie-Hélène, Manouvrier, Sylvie, Peter, Mireille, Plomhouse, Lucie, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Vuillaume, Isabelle, Bellonet, Marcellin, Berrissoul, Hassan, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Godefroy, Olivier, Krystkowiak, Pierre, Mantaux, Béatrice, Roussel, Martine, Wannepain, Sandrine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frédérique, Mundler, Laura, Anheim, Mathieu, Julié, 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, Prüß, Harald, Spruth, Eike Jakob, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kotz, Peter, Prehn, Christian, Saft, Carsten, Lange, Herwig, Maiwald, Robert, Löhle, 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, Münchau, Alexander, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Gorzolla, Heike, Schrader, Christoph, Tacik, Pawel, Ribbat, Michael, Longinus, Bernhard, Bürk, Katrin, Möller, Jens Carsten, Rissling, Ida, Mühlau, Mark, Peinemann, Alexander, Städtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Hölzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythäuser, 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, Süßmuth, 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, Marchese, Roberta, 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., ’t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjørgo, Kathrine, Fannemel, Madeleine, Gørvell, Per F., Lorentzen, Eirin, Retterstøl, Lar, Stokke, Bodil, Bjørnevoll, 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, Wójcik, 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, Sebastián, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Núria, 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, María, García, Rocío García-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuñana, Mónica, Caldentey, Juan Garcia, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Frech, Fernando Alonso, Ruíz, Pedro J García, Martínez-Descals, Asunción, Guerrero, Rosa, Artiga, María José Saiz, Sánchez, 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, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodríguez, 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, Peña, José Chacón, Redondo, Lui, Carrillo, Fátima, Teresa Cáceres, María, 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, Wikström, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, 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, Ho, Carrie, 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, Klöppel, 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, Harrison, David, 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, Bentivoglio, Anna Rita (ORCID:0000-0002-9663-095X), and Albanese, Alberto (ORCID:0000-0002-5864-0006)

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 × 10−8DHFR p=8·37 × 10−7MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4DHFR p=8·45 × 10−4MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs55787

Published
2017

8. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis

Author

Tabrizi, S.J., Scahill, R.I., Durr, A., Roos, R.A.C., Leavitt, B.R., Jones, R., Landwehrmeyer, G.B., Fox, N.C., Johnson, H., Hicks, S.L., Kennard, C., Craufurd, D., Frost, C., Langbehn, D.R., Reilmann, R., Stout, J.C., TRACK-HD Investigators, Neurology, and NCA - Neurodegeneration

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Canada, International Cooperation, Movement, Nerve Tissue Proteins, Observation, Disease, Developmental psychology, Young Adult, Atrophy, Imaging, Three-Dimensional, Huntington's disease, medicine, Humans, Longitudinal Studies, Aged, Netherlands, Brain Mapping, Huntingtin Protein, Brain, Nuclear Proteins, Cognition, Voxel-based morphometry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Huntington Disease, Case-Control Studies, Brain size, Disease Progression, Observational study, voxel-based morphometry whole-brain atrophy structural neuropathology asymptomatic carriers alzheimers-disease regional atrophy cag repeat serial mri predict-hd progression, Female, Neurology (clinical), France, Psychology, Cognition Disorders, Asymptomatic carrier
Abstract

BACKGROUND: TRACK-HD is a prospective observational study of Huntington's disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings. METHODS: we did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. FINDINGS: 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05-0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44-0·76; p

Published
2016

10. A numerical study of red-green colour opponent properties in the primate retina

Author

Momiji, H, Hankins, MW, Bharath, AA, and Kennard, C

Subjects
genetic structures, sense organs, eye diseases
Abstract

It remains an important question whether neural function is mediated entirely by its tailored circuitry. A persistent debate in retinal colour vision is whether the centre and the surround of a ganglion cell receptive field receive dominant inputs either from L or M cones in an antagonistic manner (the selective wiring model) or mixed inputs (the mixed wiring model). Despite many anatomical, physiological and psychophysical experiments, a decisive conclusion has not been reached. An in-depth examination of what the pure mixed wiring mechanisms predicts is therefore important. These two models make different predictions both for the fovea and for the peripheral retina. Recently, a dynamic cellular model of the primate fovea was developed [Momiji et al. (2006) Vis. Res., 46, 365-381]. Unlike earlier models, it explicitly incorporates spatial non-uniformities, such as the random arrangement of L and M cones. Here, a related model is developed for the peripheral retina by incorporating anatomically reasonable degrees of convergence between cones, bipolar cells and ganglion cells. These two models, in which selective wiring mechanisms are absent, are applied to describe both foveal and peripheral colour vision. In numerical simulations, peripheral ganglion cells are less colour sensitive than foveal counterparts, but none-the-less display comparative sensitivities. Furthermore, peripheral colour sensitivity increases with temporal frequency, relative to foveal sensitivity. These results are congruent with recent physiological experiments.

Published
2016

15. Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Author

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

Published
2017
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17. Motion area V5/MT+ response to global motion in the absence of V1 resembles early visual cortex

Author

Ajina, S, Kennard, C, Rees, G, and Bridge, H

Subjects
hemianopia, Adult, Male, Eye Movements, Motion Perception, Original Articles, Middle Aged, Blindness, Magnetic Resonance Imaging, Functional Laterality, motion coherence, subcortical, Perceptual Disorders, Brain Injuries, Case-Control Studies, Image Processing, Computer-Assisted, functional MRI, Humans, Female, Visual Pathways, visual cortex, Visual Fields, Photic Stimulation, Aged
Abstract

Little is known about how non-V1 inputs influence motion area V5/MT+. Ajina et al. reveal that after V1 damage, V5/MT+ activity resembles that of early visual cortex, perhaps driven by similar subcortical inputs. While these inputs are normally overshadowed by V1 connections, acknowledging their contribution may improve neuronal models., Motion area V5/MT+ shows a variety of characteristic visual responses, often linked to perception, which are heavily influenced by its rich connectivity with the primary visual cortex (V1). This human motion area also receives a number of inputs from other visual regions, including direct subcortical connections and callosal connections with the contralateral hemisphere. Little is currently known about such alternative inputs to V5/MT+ and how they may drive and influence its activity. Using functional magnetic resonance imaging, the response of human V5/MT+ to increasing the proportion of coherent motion was measured in seven patients with unilateral V1 damage acquired during adulthood, and a group of healthy age-matched controls. When V1 was damaged, the typical V5/MT+ response to increasing coherence was lost. Rather, V5/MT+ in patients showed a negative trend with coherence that was similar to coherence-related activity in V1 of healthy control subjects. This shift to a response-pattern more typical of early visual cortex suggests that in the absence of V1, V5/MT+ activity may be shaped by similar direct subcortical input. This is likely to reflect intact residual pathways rather than a change in connectivity, and has important implications for blindsight function. It also confirms predictions that V1 is critically involved in normal V5/MT+ global motion processing, consistent with a convergent model of V1 input to V5/MT+. Historically, most attempts to model cortical visual responses do not consider the contribution of direct subcortical inputs that may bypass striate cortex, such as input to V5/MT+. We have shown that the signal change driven by these non-striate pathways can be measured, and suggest that models of the intact visual system may benefit from considering their contribution.

Published
2015

18. American aid to Israel doesn't add up

Author

Brown, Kennard C.

Subjects
International relations
Abstract

To The Dallas Morning News, Dec. 31, 2016 Are the money and aid sent to Israel investment or welfare? I ask this question in seriousness and hope for an informed [...]

Published
2017

26. Ocular motor abnormalities in neurodegenerative disorders.

Author

Antoniades, C A and Kennard, C

Subjects
*EYE movement disorders, *NEURODEGENERATION, *ALZHEIMER'S disease, *PARKINSON'S disease, *PROGRESSIVE supranuclear palsy
Abstract

Eye movements are a source of valuable information to both clinicians and scientists as abnormalities of them frequently act as clues to the localization of a disease process. Classically, they are divided into two main types: those that hold the gaze, keeping images steady on the retina (vestibulo-ocular and optokinetic reflexes) and those that shift gaze and redirect the line of sight to a new object of interest (saccades, vergence, and smooth pursuit). Here we will review some of the major ocular motor abnormalities present in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Published
2015
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27. 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, 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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, 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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

28. Brain mechanisms underlying option generation for behaviour

Author

Ang, Y, Husain, M, and Kennard, C

Subjects
cognitive neuroscience
Abstract

This thesis examines the highly interlinked fields of voluntary action, apathy and option generation. Substantial research have now implicated the medial frontal cortex in voluntary actions, but the exact roles of each region remain unclear. Seeking clarity on this is important because the lack of self-generated behaviour is characteristic of apathy, a debilitating condition prevalent in neurodegenerative diseases and occurring to varying degrees in healthy individuals. Unfortunately, the conceptualization of apathy is currently unclear. Proposals of its underlying cognitive mechanisms have also mostly focused on deficits in selecting between options and learning outcomes during feedback. Intriguingly, the possibility that an inability to self-generate options may contribute to apathy has never been examined. This is because neuroscientific research on option generation is sparse. Here, a major contribution was the advancement of our understanding of option generation for behaviour. As there was no suitable objective measure available in the current literature, a simple, quantitative and culture-free task to assess option generation was first developed. The task was then administered to patients with Parkinson‖s disease and utilised in two pharmacological studies of dopamine agonist (cabergoline) and antagonist (haloperidol). These provided the first direct evidence that dopamine modulates option generation for behaviour in humans, specifically in the aspects of fluency (generating many options) and uniqueness (how different each option is from others). The ability to generate options was also found to associate with apathy in the healthy population. Besides that, the multidimensional structure of apathy was examined via the development and rigorous validation of a new questionnaire known as the Apathy Motivation Index. Finally, a functional neuroimaging experiment in healthy individuals revealed that the pre-supplementary motor area plays a key role in planning during volitional decisions of what action to execute. Together, these findings have provided new insights and point to new directions for future work in this field.

Published
2018

29. Mechanisms underlying apathy in health and Parkinson's disease

Author

Muhammed, K, Kennard, C, Husain, M, and Brown, P

Subjects
Psychiatry, Neurology, Physiology, Psychology
Abstract

Apathy or lack of motivation is increasingly recognized to be a major factor affecting quality of life and prognosis in many neurological conditions. It is particularly prevalent in Parkinson’s disease, impacting on every disease stage, including de novo cases, and has been reported to affect up to 70% of cases. Despite the pervasiveness of apathy, challenges remain in its detection, clinical assessment and treatment. Several lines of evidence have implicated fronto-striatal reward related neural pathways in the genesis of apathy but the precise processes remain to be fully explained. This thesis examines the potential mechanisms of apathy using Parkinson’s disease as a model to study the condition. Novel oculomotor tasks that used eye movement and pupillary responses were developed to help assess if insensitivity to incentives could be an underlying component of apathy. This was examined in healthy young and elderly participants as well as in patients with Parkinson’s disease. Patients were tested both ON and OFF their normal dopaminergic medication so that the effect of dopamine could be assessed and the association with apathy determined. This was also performed in a pharmacological study in young participants with the use of Haloperidol, a dopaminergic D2-selective antagonist. Insensitivity to rewards modulated by dopamine was regarded to be a contributory mechanism of apathy in Parkinson’s disease and also applicable to general mechanisms of motivation in healthy populations.

Published
2018

30. Investigation of motion perception learning in healthy subjects, for application as a rehabilitative therapy for visual field defects following primary visual cortex damage

Author

Larcombe, S, Kennard, C, and Bridge, H

Subjects
Vision, Cognitive psychology, Visual perception, Rehabilitation, Neurosciences, Medicine, Psychology, Biology
Abstract

Perceptual learning is the ability to improve performance of a perceptual task, with repeated practice. The concept of perceptual learning in the adult visual system has been established for many years, however, the neural mechanisms which mediate it have proved complex to unravel. Improved understanding could be used to guide novel rehabilitative strategies for those with damage to the brain which a↵ects the primary visual cortex (V1) in the occipital lobe. Motion perception learning is thought to involve the brain area hMT+, which is located in the parieto-temporo- occipital cortex, distal from V1. It is possible that motion perception training may improve the vision or subjective quality of life for individuals with damage to V1. This project initially looked at the e↵ect of motion perception training in healthy individuals, in order to establish and quantify the potential behavioural and neural impact of behavioural training. A five-day motion perception training paradigm applied in these experiments produced robust improvement of motion perception in healthy participants. This learning was found to be partially transferable to untrained regions of the visual field. If the training timecourse was reduced to a single day, the location specificity of learning e↵ects was increased significantly. Functional MRI analysis indicated that the motion perception training paradigm applied here altered activity at extrastriate visual areas and frontotemporal decision areas. When motion perception training was combined with brain stimulation, it was shown that 20 minutes of anodal transcranial direct current stimulation (tDCS) over hMT+ had no impact on learning magnitude or timecourse. Finally, the motion perception training paradigm was applied as a case study in a patient with damage to V1. The results were promising but inconclusive with such a minimal dataset. Motion perception training produces robust improvements in perception in healthy individuals, which are likely mediated by visual extrastriate and decision-making areas of the brain. As such, motion perception training shows promise, with further development, as an avenue for rehabilitation of the visual system and visual perception following damage to the primary visual cortex.

Published
2016

31. Neural degeneration and plasticity following damage to the post-chiasmal visual pathway

Author

Millington, RS, Kennard, C, and Bridge, H

Subjects
Stroke, Medical Sciences, Perception
Abstract

Hemianopia is a disorder where a patient loses vision in one half of their visual field, following damage to the post-chiasmal visual pathway. If the hemianopia does not spontaneously resolve within the first few months, the prognosis for recovery is poor, with very few patients recovering vision in the affected area of the visual field. The reasons for this are unclear, although it is likely that both degeneration and plasticity in the visual system have an impact on patient outcome. The goal of this research is to investigate the changes that occur in hemianopia, and how these differ for lesions at different locations in the visual pathway and with differing underlying pathologies.Patients with hemianopia arising from different causes were recruited, including 17 with a hemianopia acquired in adulthood, 9 with congenital hemianopia, and 6 patients with hemianopia due to posterior cortical atrophy (PCA). Structural, functional, and diffusion-weighted MRI data were acquired for each patient, in order to examine changes in the structural and function of the visual pathways. Analyses focused on either atrophy, or plasticity and residual function. Atrophy was assessed in acquired and congenital hemianopia by quantifying transneuronal degeneration in the optic tract, which was present in all patients with long-term lesions. Degeneration was also assessed more generally in PCA, who have substantial loss of white and grey matter in posterior brain regions. Investigation of plasticity and residual function focused on the motion processing area (MT), quantifying the level of functional activity in MT, and assessing whether subcortical pathways from the pulvinar to MT exist in hemianopia. A wide degree of variation existed between patients in the extent to which motion processing was preserved, which had no clear link to lesion location, however was related to the size of the lesion.

Published
2016

32. Investigating the viability of motoric task performance as a clinical biomarker in Huntington’s and Parkinson’s disease

Author

Jayaraj, M, Kennard, C, Hicks, S, and Antoniades, C

Subjects
Theoretical Neuroscience, Medical Sciences, Behavioural Neuroscience, Physiology, Cognitive Neuroscience, Experimental psychology, Muscle & Nerve (Neuroscience), Cognition, Biosensors, Neurology, Neuropsychology, Biology (medical sciences), Cognitive development, Anatomy, Clinical Neuropsychology, Biomedical engineering, Biology, Neuroscience
Abstract

Evaluating hand tapping as a clinical biomarker in Parkinson and Huntington’s diseases, using an Android device was the objective of the study. A novel hand -tapping tool using an Android OS was developed over a year, which included 5 tapping tasks. The application was meant for installation on Samsung Galaxy 7” tablet devices. The tasks included finger tapping; metronome based tapping, simple and choice reaction time and was used to study a cross section of 45 controls of three different age groups, from 20-30 years, 35 -45 years and 65-80 years. Age and gender matched controls to Parkinson’s subjects (n=21) and Huntington’s disease patients (n=17) were assessed using the same tapping tasks. Baseline values for various tapping measures such as tapping rate, inter-tap interval, force, pro-tap (simple) reaction time, anti-tap(choice) reaction time were obtained. The study reported a significant difference between 20-30 year olds and 65-80 year olds in tapping rates and inter-tap-interval of the double target tapping task. Displacement, pro-tap time and anti-tap times were lower in 20-30s and 35-45 year olds compared to the 65-80s group. PD patients showed markedly lower values and were significantly different from controls in tapping rates, displacement of single target tapping, tapping rates and inter-tap-interval of double target tapping, pro-tap and anti-tap times and their standard deviation. HD patients had significantly lower values in inter-tap-intervals, displacement of single finger tapping, tapping rates, inter-tap interval and displacement of double target tapping, pro-tap and anti-tap reaction times. In conclusion, the study enabled us to identify tapping parameters and reaction time tests which have the potential to differentiate between Parkinson’s and Huntington’s patients with controls, therefore making motoric task performance a potentially viable clinical biomarker in HD and PD.

Published
2016

33. Changes in connectivity, structure and function following damage to the primary visual cortex

Author

Ajina, S, Bridge, H, and Kennard, C

Abstract

Residual vision, or blindsight, following damage to the primary visual cortex was first identified almost a century ago. However, the mechanism and pathways underlying this ability, as well as the extent of visual function, remain unclear and are a continuing source of speculation. The work presented here goes some way to try to address these questions, investigating 18 patients with V1 damage and homonymous visual field loss acquired in adulthood. Six experimental chapters explore the extent and potential for visual function after V1 damage, and apply novel neuroimaging paradigms and techniques to try to uncover the mechanisms and pathways that might be involved. A combination of psychophysics, functional and structural MRI was used to investigate responses to blind field stimulation in the dorsal and ventral streams. In addition, diffusion MRI tractography was performed and related to psychophysical performance, so that the three main pathways implicated in blindsight could be evaluated. Lastly, a small rehabilitation study was carried out to assess the effect of training in the blind hemifield, and to investigate whether there is any transfer of learning between the dorsal and ventral visual streams. The results from this work reinforce the suggestion that blindsight may be more common than was first thought, and may extend across a number of characteristics involving both visual streams. It is also suggested that visual function need not be completely unconscious, but that certain salient stimuli can elicit both non-visual and crude visual experience. The use of parametric functional imaging paradigms has enabled a number of properties of non-striate inputs to the extrastriate cortex to be revealed. Together with tractography, this points to an important role for the ipsilateral lateral geniculate nucleus in blindsight function. It is hoped that future work will build upon this, and that it may be possible to target these residual pathways in the rehabilitation of patients with V1 damage.

Published
2015

34. Differential effects of bilateral hippocampal CA3 damage on the implicit learning and recognition of complex event sequences.

Author

Miller TD, Kennard C, Gowland PA, Antoniades CA, and Rosenthal CR

Subjects
Humans, Male, Female, Middle Aged, Learning physiology, Memory, Episodic, Aged, Adult, Neuropsychological Tests, Recognition, Psychology physiology, CA3 Region, Hippocampal physiology, CA3 Region, Hippocampal physiopathology, CA3 Region, Hippocampal diagnostic imaging
Abstract

Learning regularities in the environment is a fundament of human cognition, which is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending ~50 years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at a single location was at chance. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.

Published
2024
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35. Molecular mechanism of GPCR spatial organization at the plasma membrane.

Author

Kockelkoren G, Lauritsen L, Shuttle CG, Kazepidou E, Vonkova I, Zhang Y, Breuer A, Kennard C, Brunetti RM, D'Este E, Weiner OD, Uline M, and Stamou D

Subjects
Cell Membrane metabolism, Receptors, G-Protein-Coupled metabolism, Signal Transduction
Abstract

G-protein-coupled receptors (GPCRs) mediate many critical physiological processes. Their spatial organization in plasma membrane (PM) domains is believed to encode signaling specificity and efficiency. However, the existence of domains and, crucially, the mechanism of formation of such putative domains remain elusive. Here, live-cell imaging (corrected for topography-induced imaging artifacts) conclusively established the existence of PM domains for GPCRs. Paradoxically, energetic coupling to extremely shallow PM curvature (<1 µm -1 ) emerged as the dominant, necessary and sufficient molecular mechanism of GPCR spatiotemporal organization. Experiments with different GPCRs, H-Ras, Piezo1 and epidermal growth factor receptor, suggest that the mechanism is general, yet protein specific, and can be regulated by ligands. These findings delineate a new spatiomechanical molecular mechanism that can transduce to domain-based signaling any mechanical or chemical stimulus that affects the morphology of the PM and suggest innovative therapeutic strategies targeting cellular shape., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2024
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36. Engineering Biological Nanopore Approaches toward Protein Sequencing.

Author

Wei X, Penkauskas T, Reiner JE, Kennard C, Uline MJ, Wang Q, Li S, Aksimentiev A, Robertson JWF, and Liu C

Subjects
Amino Acid Sequence, Proteins, Base Sequence, Amino Acids chemistry, Peptides chemistry, Nanopores
Abstract

Biotechnological innovations have vastly improved the capacity to perform large-scale protein studies, while the methods we have for identifying and quantifying individual proteins are still inadequate to perform protein sequencing at the single-molecule level. Nanopore-inspired systems devoted to understanding how single molecules behave have been extensively developed for applications in genome sequencing. These nanopore systems are emerging as prominent tools for protein identification, detection, and analysis, suggesting realistic prospects for novel protein sequencing. This review summarizes recent advances in biological nanopore sensors toward protein sequencing, from the identification of individual amino acids to the controlled translocation of peptides and proteins, with attention focused on device and algorithm development and the delineation of molecular mechanisms with the aid of simulations. Specifically, the review aims to offer recommendations for the advancement of nanopore-based protein sequencing from an engineering perspective, highlighting the need for collaborative efforts across multiple disciplines. These efforts should include chemical conjugation, protein engineering, molecular simulation, machine-learning-assisted identification, and electronic device fabrication to enable practical implementation in real-world scenarios.

Published
2023
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37. Syrian hamster convalescence from prototype SARS-CoV-2 confers measurable protection against the attenuated disease caused by the Omicron variant.

Author

Ryan KA, Bewley KR, Watson RJ, Burton C, Carnell O, Cavell BE, Challis A, Coombes NS, Davies ER, Edun-Huges J, Emery K, Fell R, Fotheringham SA, Gooch KE, Gowan K, Handley A, Harris DJ, Hesp R, Hunter L, Humphreys R, Johnson R, Kennard C, Knott D, Lister S, Morley D, Ngabo D, Osman KL, Paterson J, Penn EJ, Pullan ST, Richards KS, Summers S, Thomas SR, Weldon T, Wiblin NR, Rayner EL, Vipond RT, Hallis B, Salguero FJ, Funnell SGP, and Hall Y

Subjects
Animals, Cricetinae, Humans, Convalescence, Mesocricetus, SARS-CoV-2, COVID-19
Abstract

The mutation profile of the SARS-CoV-2 Omicron (lineage BA.1) variant posed a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2 ancestral isolate (Australia/VIC01/2020, VIC01) to protect against disease caused by BA.1. We established that BA.1 infection in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of the ancestral virus, with fewer clinical signs including less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of BA.1 50 days after an initial infection with ancestral virus. These data provide evidence that convalescent immunity against ancestral SARS-CoV-2 is protective against BA.1 in the Syrian hamster model of infection. Comparison with published pre-clinical and clinical data supports consistency of the model and its predictive value for the outcome in humans. Further, the ability to detect protection against the less severe disease caused by BA.1 demonstrates continued value of the Syrian hamster model for evaluation of BA.1-specific countermeasures., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ryan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2023
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38. SARS-CoV-2 Disease Severity in the Golden Syrian Hamster Model of Infection Is Related to the Volume of Intranasal Inoculum.

Author

Handley A, Ryan KA, Davies ER, Bewley KR, Carnell OT, Challis A, Coombes NS, Fotheringham SA, Gooch KE, Charlton M, Harris DJ, Kennard C, Ngabo D, Weldon TM, Salguero FJ, Funnell SGP, and Hall Y

Subjects
Cricetinae, Animals, Humans, Mesocricetus, SARS-CoV-2, Lung, Patient Acuity, Disease Models, Animal, COVID-19 pathology
Abstract

The golden Syrian hamster ( Mesocricetus auratus ) is now commonly used in preclinical research for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the assessment of vaccines, drugs and therapeutics. Here, we show that hamsters inoculated via the intranasal route with the same infectious virus dose of prototypical SARS-CoV-2 administered in a different volume present with different clinical signs, weight loss and viral shedding, with a reduced volume resulting in reduced severity of disease similar to that obtained by a 500-fold reduction in the challenge dose. The tissue burden of the virus and the severity of pulmonary pathology were also significantly affected by different challenge inoculum volumes. These findings suggest that a direct comparison between the severity of SARS-CoV-2 variants or studies assessing the efficacy of treatments determined by hamster studies cannot be made unless both the challenge dose and inoculation volume are matched when using the intranasal route. Additionally, analysis of sub-genomic and total genomic RNA PCR data demonstrated no link between sub-genomic and live viral titres and that sub-genomic analyses do not provide any information beyond that provided by more sensitive total genomic PCR.

Published
2023
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39. Influence of Aerosol Delivered BCG Vaccination on Immunological and Disease Parameters Following SARS-CoV-2 Challenge in Rhesus Macaques.

Author

White AD, Sibley L, Sarfas C, Morrison AL, Bewley K, Churchward C, Fotheringham S, Gkolfinos K, Gooch K, Handley A, Humphries HE, Hunter L, Kennard C, Longet S, Mabbutt A, Moffatt M, Rayner E, Tipton T, Watson R, Hall Y, Bodman-Smith M, Gleeson F, Dennis M, Salguero FJ, Carroll M, McShane H, Cookson W, Hopkin J, and Sharpe S

Subjects
Adaptive Immunity, Aerosols, Animals, Cross Reactions, Disease Models, Animal, Humans, Immunity, Heterologous, Immunity, Innate, Immunomodulation, Lymphocyte Activation, Macaca mulatta, Receptors, Antigen, T-Cell, gamma-delta metabolism, Vaccination, BCG Vaccine immunology, COVID-19 immunology, DNA, Viral analysis, SARS-CoV-2 physiology, T-Lymphocytes immunology
Abstract

The tuberculosis vaccine, Bacille Calmette-Guerin (BCG), also affords protection against non-tuberculous diseases attributable to heterologous immune mechanisms such as trained innate immunity, activation of non-conventional T-cells, and cross-reactive adaptive immunity. Aerosol vaccine delivery can target immune responses toward the primary site of infection for a respiratory pathogen. Therefore, we hypothesised that aerosol delivery of BCG would enhance cross-protective action against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and be a deployable intervention against coronavirus disease 2019 (COVID-19). Immune parameters were monitored in vaccinated and unvaccinated rhesus macaques for 28 days following aerosol BCG vaccination. High-dose SARS-CoV-2 challenge was applied by intranasal and intrabronchial instillation and animals culled 6-8 days later for assessment of viral, disease, and immunological parameters. Mycobacteria-specific cell-mediated immune responses were detected following aerosol BCG vaccination, but SARS-CoV-2-specific cellular- and antibody-mediated immunity was only measured following challenge. Early secretion of cytokine and chemokine markers associated with the innate cellular and adaptive antiviral immune response was detected following SARS-CoV-2 challenge in vaccinated animals, at concentrations that exceeded titres measured in unvaccinated macaques. Classical CD14+ monocytes and Vδ2 γδ T-cells quantified by whole-blood immunophenotyping increased rapidly in vaccinated animals following SARS-CoV-2 challenge, indicating a priming of innate immune cells and non-conventional T-cell populations. However, viral RNA quantified in nasal and pharyngeal swabs, bronchoalveolar lavage (BAL), and tissue samples collected at necropsy was equivalent in vaccinated and unvaccinated animals, and in-life CT imaging and histopathology scoring applied to pulmonary tissue sections indicated that the disease induced by SARS-CoV-2 challenge was comparable between vaccinated and unvaccinated groups. Hence, aerosol BCG vaccination did not induce, or enhance the induction of, SARS-CoV-2 cross-reactive adaptive cellular or humoral immunity, although an influence of BCG vaccination on the subsequent immune response to SARS-CoV-2 challenge was apparent in immune signatures indicative of trained innate immune mechanisms and primed unconventional T-cell populations. Nevertheless, aerosol BCG vaccination did not enhance the initial clearance of virus, nor reduce the occurrence of early disease pathology after high dose SARS-CoV-2 challenge. However, the heterologous immune mechanisms primed by BCG vaccination could contribute to the moderation of COVID-19 disease severity in more susceptible species following natural infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 White, Sibley, Sarfas, Morrison, Bewley, Churchward, Fotheringham, Gkolfinos, Gooch, Handley, Humphries, Hunter, Kennard, Longet, Mabbutt, Moffatt, Rayner, Tipton, Watson, Hall, Bodman-Smith, Gleeson, Dennis, Salguero, Carroll, McShane, Cookson, Hopkin and Sharpe.)

Published
2022
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40. Immunological and pathological outcomes of SARS-CoV-2 challenge following formalin-inactivated vaccine in ferrets and rhesus macaques.

Author

Bewley KR, Gooch K, Thomas KM, Longet S, Wiblin N, Hunter L, Chan K, Brown P, Russell RA, Ho C, Slack G, Humphries HE, Alden L, Allen L, Aram M, Baker N, Brunt E, Cobb R, Fotheringham S, Harris D, Kennard C, Leung S, Ryan K, Tolley H, Wand N, White A, Sibley L, Sarfas C, Pearson G, Rayner E, Xue X, Lambe T, Charlton S, Gilbert S, Sattentau QJ, Gleeson F, Hall Y, Funnell S, Sharpe S, Salguero FJ, Gorringe A, and Carroll M

Abstract

There is an urgent requirement for safe and effective vaccines to prevent COVID-19. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferrets and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen 7 days after infection in ferrets. This increased lung pathology was observed at day 7 but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.

Published
2021
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41. How Membrane Geometry Regulates Protein Sorting Independently of Mean Curvature.

Author

Larsen JB, Rosholm KR, Kennard C, Pedersen SL, Munch HK, Tkach V, Sakon JJ, Bjørnholm T, Weninger KR, Bendix PM, Jensen KJ, Hatzakis NS, Uline MJ, and Stamou D

Abstract

Biological membranes have distinct geometries that confer specific functions. However, the molecular mechanisms underlying the phenomenological geometry/function correlations remain elusive. We studied the effect of membrane geometry on the localization of membrane-bound proteins. Quantitative comparative experiments between the two most abundant cellular membrane geometries, spherical and cylindrical, revealed that geometry regulates the spatial segregation of proteins. The measured geometry-driven segregation reached 50-fold for membranes of the same mean curvature, demonstrating a crucial and hitherto unaccounted contribution by Gaussian curvature. Molecular-field theory calculations elucidated the underlying physical and molecular mechanisms. Our results reveal that distinct membrane geometries have specific physicochemical properties and thus establish a ubiquitous mechanistic foundation for unravelling the conserved correlations between biological function and membrane polymorphism., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Published
2020
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42. Human hippocampal CA3 damage disrupts both recent and remote episodic memories.

Author

Miller TD, Chong TT, Aimola Davies AM, Johnson MR, Irani SR, Husain M, Ng TW, Jacob S, Maddison P, Kennard C, Gowland PA, and Rosenthal CR

Subjects
Aged, Case-Control Studies, Female, Humans, Limbic Encephalitis diagnostic imaging, Limbic Encephalitis physiopathology, Magnetic Resonance Imaging, Male, Middle Aged, Temporal Lobe diagnostic imaging, CA3 Region, Hippocampal diagnostic imaging, CA3 Region, Hippocampal physiopathology, Memory, Episodic, Memory, Short-Term physiology
Abstract

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance., Competing Interests: TM, TC, AA, MJ, MH, TN, PM, CK, PG, CR No competing interests declared, SI Sarosh R Irani, Angela Vincent, and the Department of Clinical Neurology in Oxford receive royalties and payments for antibody assays are both named inventors on patent application WO/2010/046716 entitled 'Neurological Autoimmune Disorders'. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. Dr. Irani also reports personal fees from MedImmune, grants from Wellcome Trust, grants from UCB Pharma, grants from BMA (Vera Down and Margaret Temple grants), Fulbright UK-US Commission and Epilepsy Research UK, outside the submitted work. Dr. Irani served on the scientific advisory board for Encephalitis Society and MedImmune. SJ Dr. Jacob has been a scientific advisory board member for Alexion and Alynylam pharmaceuticals., (© 2020, Miller et al.)

Published
2020
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43. The effect of levodopa on saccades - Oxford Quantification in Parkinsonism study.

Author

Lu Z, Buchanan T, Kennard C, FitzGerald JJ, and Antoniades CA

Subjects
Aged, Aged, 80 and over, Eye Movement Measurements, Female, Humans, Male, Middle Aged, Dopamine Agents pharmacology, Levodopa pharmacology, Parkinson Disease drug therapy, Saccades drug effects
Abstract

Objectives: The evaluation of novel disease modifying drugs requires biomarkers that are simultaneously sensitive to disease state but resistant to the effects of background symptomatic treatment. Saccadic eye movement parameters have been proposed as a neurophysiological biomarker for Parkinson's disease (PD) and so it is important to know how they are affected by dopaminergic medication. Studies to date are conflicting: some have concluded that medication prolongs saccadic latencies while others suggest they are shortened. We aimed to characterise the effects of antiparkinsonian medication on prosaccadic and antisaccadic parameters in a large cohort of PD patients and age matched healthy controls and to survey the current literature in comparison to the study findings., Methods: We studied saccades both off and on medication in 38 PD patients and 34 healthy controls (HC). Latencies, amplitudes, velocities, and directional errors were evaluated, using a published standardised protocol. We then combined this study and previously published literature in a meta-analysis of the effects of antiparkinsonian medication on prosaccadic latency (PSL)., Results: PSL is significantly prolonged by dopaminergic medication in PD, from a mean of 222.7 ms in the OFF medication state to a mean of 236.0 ms in the ON medication state (p = 0.028). This effect size is comparable to the difference between PD OFF medication and healthy control values. There was no statistically significant change in any other saccadic parameter with medication. Of particular note, antisaccadic latency was almost exactly the same on and off medication (means of 414.9 ms and 417.2 ms respectively, p = 0.97), while being almost 20% longer in PD patients compared to healthy controls (HC mean 357.2 ms; PD ON vs HC p = 0.015; PD OFF vs HC p = 0.0066)., Conclusion: PSL is significantly affected by dopaminergic medication which may complicate its use as a biomarker in drug trials. Antisaccadic latency is particularly interesting in this regard because it shows a large disease effect with no medication effect., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published
2019
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44. Sustainability of community-based interventions for people affected by dementia: a protocol for the SCI-Dem realist review.

Author

Morton T, Atkinson T, Brooker D, Wong G, Evans S, and Kennard C

Subjects
Humans, Research Design, Review Literature as Topic, Community Health Services, Dementia therapy
Abstract

Introduction: With numbers set to increase globally, finding ways to better support people with dementia and their families is a matter of growing concern. Community-based interventions can play a key role in supporting people with early to moderate stage dementia postdiagnosis, helping delay decline and hospitalisation. However, provision of such interventions is fragmented, with significant gaps and no reliable funding model, hence innovative groups and schemes catering for a genuine need can struggle long term and frequently fold., Methods and Analysis: This realist review aims to expand our understanding of how best to implement and facilitate community-based interventions to run sustainably, focusing on contextually relevant explanations. We will gather and synthesise literature using a realist approach designed to accommodate and account for the complexity of 'real life' programmes, as implemented under different conditions in different settings, aiming to draw transferable conclusions about their sustainability that explain how and why context can influence outcomes. Our review will iteratively progress through five steps: (1) locate existing theories; (2) search for evidence (using Academic Search, AMED, CINAHL, EMBASE, MEDLINE, ProQuest, PsycINFO, PubMed, Scopus and Social Care Online, between May and September 2019); (3) article selection; (4) extracting and organising data; (5) synthesising the evidence and drawing conclusions. Data analysis will use a realist logic to explain what works, for whom, in what circumstances, in what respects, how and why. A stakeholder group will provide guidance and feedback throughout., Ethics and Dissemination: Ethical approval was not required. Recommendations drawn from results are likely to be of interest to a range of stakeholders including those commissioning, planning, running, supporting or attending such interventions, as well as policymakers, healthcare professionals and researchers. We will draw on the expertise of our stakeholder group regarding tailoring dissemination to each audience using a variety of materials, formats and channels., Competing Interests: Competing interests: GW is Joint Deputy Chair of the National Institute for Health Research Health Technology Assessment Programme Prioritisation Committee Panel A (Out of hospital)., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2019
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45. The neural basis of meta-volition.

Author

Nachev P, Roberts RE, Husain M, and Kennard C

Subjects
Adult, Behavior, Female, Functional Neuroimaging, Humans, Male, Young Adult, Brain physiology, Volition
Abstract

Volition is the power to act beyond simple, automatic responses. We can act voluntarily because we can choose to act otherwise than immediate, external circumstances dictate. But we can also choose to allow ourselves to be led automatically by events around us. The neural basis of this higher power to suspend volition- which we term meta-volition-is unknown. Here we show that inter-individual differences in meta-volition are reflected in extensive, highly lateralised differences in right frontal white matter as indexed by diffusion tensor imaging. Paradoxically, participants with enhanced white matter optimality in these regions are less able to exercise meta-volition, finding it harder to suspend volition. This suggests volition is dependent less on any hierarchical system of meta-volitional control than on the extent to which an extensive network subserving higher volitional powers is competitively dominant over others. A fundamentally parallel neural organisation of human voluntary action at the highest level is thereby implied., Competing Interests: The authors declare no competing interests.

Published
2019
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46. Amiloride does not protect retinal nerve fibre layer thickness in optic neuritis in a phase 2 randomised controlled trial.

Author

McKee JB, Cottriall CL, Elston J, Epps S, Evangelou N, Gerry S, Kennard C, Kong Y, Koelewyn A, Kueker W, Leite MI, Palace J, and Craner M

Subjects
Adult, Double-Blind Method, Evoked Potentials, Visual drug effects, Female, Humans, Male, Middle Aged, Optic Neuritis pathology, Retina pathology, Amiloride therapeutic use, Neuroprotective Agents therapeutic use, Optic Neuritis drug therapy, Retina drug effects
Abstract

Background: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC)., Objective: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON)., Methods: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18-55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( clinicaltrials.gov , NCT 01802489)., Results: Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer., Conclusion: Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.

Published
2019
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47. No Effect of Anodal Transcranial Direct Current Stimulation (tDCS) Over hMT+ on Motion Perception Learning.

Author

Larcombe SJ, Kennard C, O'Shea J, and Bridge H

Abstract

Background: Human visual cortical area hMT+, like its homolog MT in the macaque monkey, has been shown to be particularly selective to visual motion. After damage to the primary visual cortex (V1), patients often exhibit preserved ability to detect moving stimuli, which is associated with neural activity in area hMT+. As an anatomical substrate that underlies residual function in the absence of V1, promoting functional plasticity within hMT+ could potentially boost visual performance despite primary visual cortical damage. Objective: To establish in healthy participants whether it is possible to use transcranial direct current stimulation (tDCS) over hMT+ to potentiate learning of visual motion direction discrimination. Methods: Twenty-one participants were trained daily for 5 days on a visual motion direction discrimination task. Task difficulty was increased as performance improved, by decreasing the proportion of coherently moving dots, such that participants were always performing at psychophysical threshold. tDCS, either anodal or sham, was applied daily during 20 min of training. Task performance was assessed at baseline and at the end of the training period. Performance was also compared with a third group of 10 participants from an earlier study who had undergone the same procedures but without tDCS. Results: All participants showed improved task performance both during and after training. Contrary to our hypothesis, anodal tDCS did not further improve performance compared to sham stimulation or no stimulation. Bayesian statistics indicated weak evidence in favor of the null hypothesis. Conclusion: This study found no evidence for a robust effect of anodal tDCS over hMT+ on visual motion direction discrimination learning in the young healthy visual system, although more subtle effects may have been missed in the relatively small sample size.

Published
2019
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49. A Comparison of Change Blindness in Real-World and On-Screen Viewing of Museum Artefacts.

Author

Attwood JE, Kennard C, Harris J, Humphreys G, and Antoniades CA

Abstract

Change blindness is a phenomenon of visual perception that occurs when a stimulus undergoes a change without this being noticed by its observer. To date, the effect has been produced by changing images displayed on screen as well as changing people and objects in an individual's environment. In this experiment, we combine these two approaches to directly compare the levels of change blindness produced in real-world vs. on-screen viewing of museum artefacts. In the real-world viewing condition, one group of participants viewed a series of pairs of similar but slightly different artefacts across eye saccades, while in the on-screen viewing condition, a second group of participants viewed the same artefacts across camera pans on video captured from a head-mounted camera worn by the first set of participants. We present three main findings. First, that change blindness does occur in a museum setting when similar ancient artefacts are viewed briefly one after another in both real-world and on-screen viewing conditions. We discuss this finding in relation to the notion that visual perceptual performance may be enhanced within museums. Second, we found that there was no statistically significant difference between the mean levels of change blindness produced in real-world and on-screen viewing conditions (real-world 42.62%, on-screen 47.35%, X 2 = 1.626, p > 0.05 1 d.f.). We discuss possible implications of these results for understanding change blindness, such as the role of binocular vs. monocular vision and that of head and eye movements, as well as reflecting on the evolution of change detection systems, and the impact of the experimental design itself on our results. Third, we combined the data from both viewing conditions to identify groups of artefacts that were independently associated with high and low levels of change blindness, and show that change detection rates were influenced mainly by bottom-up factors, including the visible area and contrast of changes. Finally, we discuss the limitations of this experiment and look to future directions for research into museum perception, change blindness, real-world and on-screen comparisons, and the role of bottom-up and top-down factors in the perception of change.

Published
2018
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50. Increase in MST activity correlates with visual motion learning: A functional MRI study of perceptual learning.

Author

Larcombe SJ, Kennard C, and Bridge H

Subjects
Adult, Brain Mapping, Cerebrovascular Circulation physiology, Female, Functional Laterality physiology, Humans, Magnetic Resonance Imaging, Male, Neuronal Plasticity, Neuropsychological Tests, Oxygen blood, Photic Stimulation, Temporal Lobe diagnostic imaging, Visual Fields physiology, Visual Pathways diagnostic imaging, Young Adult, Discrimination, Psychological physiology, Learning physiology, Motion Perception physiology, Temporal Lobe physiology, Visual Pathways physiology
Abstract

Repeated practice of a specific task can improve visual performance, but the neural mechanisms underlying this improvement in performance are not yet well understood. Here we trained healthy participants on a visual motion task daily for 5 days in one visual hemifield. Before and after training, we used functional magnetic resonance imaging (fMRI) to measure the change in neural activity. We also imaged a control group of participants on two occasions who did not receive any task training. While in the MRI scanner, all participants completed the motion task in the trained and untrained visual hemifields separately. Following training, participants improved their ability to discriminate motion direction in the trained hemifield and, to a lesser extent, in the untrained hemifield. The amount of task learning correlated positively with the change in activity in the medial superior temporal (MST) area. MST is the anterior portion of the human motion complex (hMT+). MST changes were localized to the hemisphere contralateral to the region of the visual field, where perceptual training was delivered. Visual areas V2 and V3a showed an increase in activity between the first and second scan in the training group, but this was not correlated with performance. The contralateral anterior hippocampus and bilateral dorsolateral prefrontal cortex (DLPFC) and frontal pole showed changes in neural activity that also correlated with the amount of task learning. These findings emphasize the importance of MST in perceptual learning of a visual motion task. Hum Brain Mapp 39:145-156, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Published
2018
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