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201. Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial.

Author

Peterschmitt, M. Judith, Saiki, Hidemoto, Hatano, Taku, Gasser, Thomas, Isaacson, Stuart H., Gaemers, Sebastiaan J.M., Minini, Pascal, Saubadu, Stéphane, Sharma, Jyoti, Walbillic, Samantha, Alcalay, Roy N., Cutter, Gary, Hattori, Nobutaka, Höglinger, Günter U., Marek, Kenneth, Schapira, Anthony H.V., Scherzer, Clemens R., Simuni, Tanya, Giladi, Nir, and Sardi, Sergio Pablo

Subjects
PARKINSON'S disease, PHARMACODYNAMICS, PHARMACOKINETICS, GENETIC mutation, PANIC attacks
Abstract

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor. Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD). Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18–80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. Results: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants. Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF. [ABSTRACT FROM AUTHOR]

Published
2022
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202. The genetic architecture of the human cerebral cortex

Author

Grasby, Katrina L, Jahanshad, Neda, Shatokhina, Natalia, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Zsembik, Leo C P, Pitcher, Toni L, Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Reay, William R, Redlich, Ronny, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Thomopoulos, Sophia I, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Zhu, Alyssa H, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Tansey, Katherine E, Teumer, Alexander, Thalamuthu, Anbupalam, Strike, Lachlan T, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, Agartz, Ingrid, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Alhusaini, Saud, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L, Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P, Artiges, Eric, Almeida, Marcio A A, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dennis, Michelle F, Alnæs, Dag, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Amlien, Inge K, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A, Kolskår, Knut, Painter, Jodie N, Andersson, Micael, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Matthews, Sarah, Mayoral Van Son, Jaqueline, McEwen, Sarah C, Ard, Tyler, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Opel, Nils, Martinot, Marie-Laure Paillère, Pike, G Bruce, Armstrong, Nicola J, Preda, Adrian, Quinlan, Erin B, Rasser, Paul E, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Tooney, Paul A, Torres, Fábio R, Veltman, Dick J, Voyvodic, James T, Ashley-Koch, Allison, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H H, Bis, Joshua C, Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Atkins, Joshua R, Ikram, M Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L, Mazoyer, Bernard, Mosley, Thomas H, Roshchupkin, Gennady V, Satizabal, Claudia L, Schmidt, Reinhold, Seshadri, Sudha, Bernard, Manon, Yang, Qiong, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, Consortium, EPIGEN, Consortium, IMAGEN, Consortium, SYS, Initiative, Parkinson’s Progression Markers, Alvim, Marina K M, Ames, David, Anderson, Tim J, Brouwer, Rachel M, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Baune, Bernhard T, Beckham, Jean C, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buimer, Elizabeth E L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Cairns, Murray J, Calhoun, Vince, Carr, Vaughan J, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Bülow, Robin, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Bürger, Christian, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Colodro-Conde, Lucía, Cannon, Dara M, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans A, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Chakravarty, Mallar, Hong, L Elliot, Hopkins, William D, Hulshoff Pol, Hilleke E, Jernigan, Terry L, Jönsson, Erik G, Kahn, René S, Kennedy, Martin A, Kircher, Tilo T J, Kochunov, Peter, Kwok, John B J, Chen, Qiang, Le Hellard, Stephanie, Loughland, Carmel M, Martin, Nicholas G, Martinot, Jean-Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Michie, Patricia T, Morey, Rajendra A, Mowry, Bryan, Cheung, Joshua W, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Pantelis, Christos, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Couvy-Duchesne, Baptiste, Roffman, Joshua L, Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schall, Ulrich, Schumann, Gunter, Scott, Rodney J, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Dale, Anders M, Sommer, Iris E, St Pourcain, Beate, Stein, Dan J, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Dalvie, Shareefa, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis, Witte, A Veronica, Darin, Abigail, Fleisher, Adam, de Araujo, Tânia K, Pierce, Aimee, Mintz, Akiva, Lerner, Alan, Reith, Alastair D, Hofman, Albert, Espay, Alberto, Ihlenfeld, Albrecht, Ing, Alex, Iranzo, Alex, Beiser, Alexa S, de Zubicaray, Greig I, Norbash, Alexander, Barbot, Alexis, Rudolph, Alice, Portillo, Alicia, Chalker, Alison, Levey, Allan I, Rosen, Allyson, Smith, Amanda, Catafau, Ana, de Zwarte, Sonja M C, Ulysse, Anaztasia, Uitterlinden, André G, Becker, Andreas, Budson, Andrew E, Kertesz, Andrew, Siderowf, Andrew, Bralten, Janita, den Braber, Anouk, Singleton, Andrew, James, Angela, Oliver, Angela, Mishra, Aniket, Hake, Ann Marie, Burke, Anna, Sarrael, Antero, Porsteinsson, Anton P, Stringaris, Argyris, McCoy, Arita, Doan, Nhat Trung, Villringer, Arno, Lenahan, Art, Toga, Arthur, Bokde, Arun, Rawlins, Ashlee, Lamb, Ashley, Lee, Athena, Raj, Balebail Ashok, Tran, Baochan, Dohm, Katharina, Ruggeri, Barbara, Saba, Barbara, Lane, Barton, Yanez, Beatriz, Ances, Beau, Dunlop, Becky, Mudge, Benita, Ravina, Bernard, Ittermann, Bernd, Ehrlich, Stefan, van Noort, Betteke, Lind, Betty, Shah, Bina, Stefanovic, Bojana, Goldstein, Bonnie S, Bonakdarpour, Borna, Matthews, Brandy R, Borowski, Bret, Ott, Brian R, Reynolds, Brigid, Engelbrecht, Hannah-Ruth, Mollenhauer, Brit, Miller, Bruce L, Psaty, Bruce M, Spann, Bryan M, Sadowsky, Carl, Linder, Carly, Franz, Carol E, Tanner, Caroline, Kopil, Catherine, Thomas, Cathi-Ann, Erk, Susanne, Ward, Chad, Bernick, Charles, Smith, Charles D, DeCarli, Charles, Caspell, Chelsea, Deeley, Cheryl, Riordan, Cheryl, Mathis, Chet, Onyike, Chiadi, Heyn, Chris Chinthaka, Fan, Chun Chieh, Hosein, Chris, Leach, Christi, Bÿchel, Christian, Gigliotti, Christina, Hunter, Christine, Belden, Christine M, Tzourio, Christophe, Coffey, Christopher, van Dyck, Christopher H, Clark, Christopher M, Fedko, Iryna O, Wu, Chuang-Kuo, Albers, Colleen S, Chu, Congying, Brand, Connie, Isensee, Corinna, van Duijn, Cornelia M, Bishop, Courtney, Bodge, Courtney, Foley, Sonya F, Tatsuoka, Curtis, Casaceli, Cynthia, Carlsson, Cynthia M, Mathews, Dana, D'Agostino, Daniel, Silverman, Daniel H S, Marson, Daniel, Berg, Daniela, Harvey, Danielle, Jennings, Danna, Ford, Judith M, Wolk, David A, Goldstein, David B, Bachman, David, Brooks, David, Clark, David, Geldmacher, David, Hart, David, Holtzman, David, Jones, David, Hibar, Derrek P, Fukunaga, Masaki, Knopman, David, Hewitt, David L, Perry, David, Russell, David, Standaert, David, Winkfield, David, Green, Davis Robert C, Fontaine, Deborah, Miller, Delwyn D, Gessert, Devon, Garrett, Melanie E, Kerwin, Diana, Willeke, Diana, Drost, Dick, Papadopoulos, Dimitri, Rowe, Dominic, Simpson, Donna M, Muni, Donna, Galasko, Douglas, Scharre, Douglas W, Fillmer, Ariane, Ge, Tian, Bartha, Rob, Celmins, Dzintra, Zimmerman, Earl A, Teng, Edmond, Tolosa, Eduardo, Coleman, Edward, Zamrini, Edward, Mitsis, Effie, Finger, Elizabeth, Giddaluru, Sudheer, Oates, Elizabeth, Sosa, Elizabeth, Woo, Ellen, Rogalski, Emily, Lethbridge, Emma, Dooley, Eoin, Foster, Eric, Reiman, Eric M, Quinlan, Erin Burke, Goldman, Aaron L, Franklin, Erin, Heinzen, Erin L, Fletcher, Evan, Sprenger, Fabienne, Crivello, Fabrice, Biondo, Francesca, Parfitt, Francine, Hefti, Franz, Beyer, Frauke, Nees, Frauke, Green, Melissa J, Leonard, Gabriel, Robert, Gabriel, Thai, Gaby, Marshall, Gad A, Barker, Gareth, Conrad, Gary, Tremont, Geoffrey, Bartzokis, George, Groenewold, Nynke A, Hsiung, Ging-Yuek Robin, Malferrari, Giulia, Chiang, Gloria, Pearlson, Godfrey D, Liang, Grace, Jicha, Greg, Sorensen, Greg, Todd, Gretchen, Jimenez, Gustavo, Grotegerd, Dominik, Zare, Habil, Grabe, Hans Jörgen, Vanderswag, Helen, Schmidt, Helena, Venkov, Heli, Lemaitre, Hervé, Gurholt, Tiril P, Grossman, Hillel, Shill, Holly, Soares, Holly, Lin, Honghuang, Capote, Horacio, Bergman, Howard, Chertkow, Howard, Feldman, Howard, Fillit, Howard, Rosen, Howard J, Gutman, Boris A, Koleva, Hristina, Fernandez, Hubert, Garavan, Hugh, Shim, Hyungsub, Grachev, Igor D, Richard, Irene, Filippi, Irina, Rachinsky, Irina, Wurster, Isabel, Lind, Penelope A, Hansell, Narelle K, Mintzer, Jacobo, Ziolkowski, Jaimie, Brewer, James, Lah, James J, Leverenz, James, Becker, James T, Tetrud, James, Singleton-Garvin, Jamika, Egebjerg, Jan, Cellar, Janet S, Harris, Mathew A, Pentilla, Jani, Brosch, Jared R, Tinklenberg, Jared, Karlawish, Jason H, Meyer, Javier Villanueva, Himali, Jayandra J, Poline, Jean-Baptiste, Gunter, Jeff, Kaye, Jeffrey A, Harrison, Marc B, Dalley, Jeffrey, Burns, Jeffrey M, Petrella, Jeffrey R, Mule, Jennifer, Salazar, Jennifer, Rotter, Jerome I, Yesavage, Jerome, Cedarbaum, Jesse, Jiang, Jiyang, Haswell, Courtney C, Allard, Joanne, Lord, Joanne L, Hetelle, Joel, Kwok, John B, Brockington, John, Morris, John C, Hsiao, John, Morris, John, Olichney, John, Trojanowki, John Q, Hauser, Michael, Rogers, John, Seibyl, John, Yankey, Jon, Dubow, Jordan S, Jankovic, Joseph, Quinn, Joseph, Kass, Joseph S, Taylor, Joy L, Heidebrink, Judith L, Herms, Stefan, Trollor, Julian, Fröhner, Juliane, Anderson, Karen, Blank, Karen, Crawford, Karen, Smith, Karen Ekstam, Bell, Karen L, Williams, Karen, Kieburtz, Karl, Heslenfeld, Dirk J, Gauss, Katharina, Gloer, Katherine, Johnson, Kathleen, Tingus, Kathleen, DeMarco, Kathryn, Sink, Kaycee M, Hawkins, Keith A, Johnson, Keith A, Kantarci, Kejal, Ho, New Fei, Faber, Kelley, Harless, Kelly, Makino, Kelly M, Marek, Kenneth, Spicer, Kenneth, Shianna, Kevin, Chen, Kewei, Nam, Ki Won, Martin, Kim, Poki-Walker, Kim, Hoehn, David, Seppi, Klaus, Johnson, Kris, Fargher, Kristin, Lipowski, Kristine, Espay, Kristy, Womack, Kyle, Chahine, Lama, Flashman, Laura A, Daedelow, Laura, Hoffmann, Per, Leary, Laura, Beckett, Laurel, Honig, Lawrence S, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Apostolova, Liana, Teodoro, Liberty, Rees, Linda, Pizzagalli, Fabrizio, Holleran, Laurena, Lewis, Lindsay, Hergesheimer, Lindsey, Silbert, Lisa C, Ravdin, Lisa, Taylor-Reinwald, Lisa, Uribe, Liz, Schneider, Lon S, Daiello, Lori A, Richer, Louis, Poustka, Luise, Hoogman, Martine, Pirpamer, Lukas, Mesulam, M Marcel, Ismail, M Saleem, Ranola, Madelaine, Korecka, Magdalena, Raichle, Marc, Seltzer, Marc, van der Brug, Marcel, Hottenga, Jouke-Jan, Mesulam, Marek-Marsel, Carrillo, Maria, Carroll, Maria, Knol, Maria J, Kataki, Maria, Greig-Custo, Maria T, Paillere, Marie-Laure, Albert, Marilyn, Love, Marissa Natelson, Ikeda, Masashi, Mintun, Mark A, Frasier, Mark, Logue, Mark, Minton, Mark, Loeffler, Markus, Scholz, Markus, Baca, Marne, Farlow, Martin R, Sadowski, Martin, Janowitz, Deborah, Creech, Mary L, Hynes, Mary L, Quiceno, Mary, Oakley, MaryAnn, Harris, Mat, Senjem, Matt, Bernstein, Matthew, Panizzon, Matthew S, Stern, Matthew, Becerra, Mauricio, Jansen, Iris E, Witbracht, Megan, Vernooij, Meike W, Brandabur, Melanie, Keltz, Melanie, Lamar, Melissa, Yang, Mia, Ahlijanian, Michael, Borrie, Michael, Neale, Michael C, Donohue, Michael, Jia, Tianye, Lyons, Michael J, Lin, Michael, Rapp, Michael, Smolka, Michael, Weiner, Michael W, Weiner, Michael, Figurski, Michal, Perron, Michel, Assaly, Michele, Luciano, Michelle, Jockwitz, Christiane, Rainka, Michelle, Dang, Mimi, Sheikh, Mohammed O, Ghanbari, Mohsen, Gaikwad, Mrunalini, Chowdhury, Munir, Trncic, Nadira, Amin, Najaf, Johnson, Nancy, Kanai, Ryota, Kowalksi, Nancy, Monahan, Nancy, Gillespie, Nathan A, Pacini, Nathaniel, Buckholtz, Neil, Kowall, Neil, Graff-Radford, Neill R, Fox, Nick, Pavese, Nicola, Karama, Sherif, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Relkin, Norman, Oyonumo, Ntekim E, Pomara, Nunzio, James, Olga, Ogunlana, Olu, Ching, Christopher R K, Kasperaviciute, Dalia, Carmichael, Owen, Doraiswamy, P Murali, Casalin, Paola, Barone, Paolo, Fatica, Parianne, Conrod, Patricia, Johnson, Patricia Lynn, Samuels, Patricia, Aisen, Paul, Malloy, Paul, Kaufmann, Tobias, Thompson, Paul, Ogrocki, Paula, Bezivin-Frere, Pauline, Maillard, Pauline, Fontoura, Paulo, Taylor, Peggy, Hogarth, Penelope, Gowland, Penny, Davies, Peter, Kelly, Sinead, Hardy, Peter, Snyder, Peter J, Snyder, Peter, Amouyel, Philippe, Muglia, Pierandrea, Tariot, Pierre, Lu, Po H, Varma, Pradeep, Vemuri, Prashanthi, Kikuchi, Masataka, Doody, Rachelle S, Carter, Raina, Shah, Raj C, Griffith, Randall, Yeh, Randy, Duara, Ranjan, Tarawneh, Rawan, James, Raymond, Turner, Raymond Scott, Klein, Marieke, Hernando, Raymundo, Silverstein, Rebecca, Sperling, Reisa A, Wilson, Renee, Carson, Richard E, Frank, Richard, El Khouli, Riham, Koeppe, Robert A, Santulli, Robert B, Knapp, Michael, Hauser, Robert, Umek, Robert, Radtke, Rodney, Killiany, Ronald, Petersen, Ronald, Rodriguez, Rosemarie, Miranda, Ruben, Knodt, Annchen R, Bruehl, Ruediger, Xia, Rui, Swerdlow, Russell H, Ottmann, Ruth, Millenet, Sabina, Borges-Neto, Salvador, Frank, Samuel, Black, Sandra, Weintraub, Sandra, Obradov, Sanja, Krämer, Bernd, Asthana, Sanjay, Vaishnavi, Sanjeev, Dolen, Sara, Mason, Sara S, Hohmann, Sarah, Kremen, Sarah, Miller, Sarah, Walter, Sarah, Herring, Scott, Neu, Scott, Lam, Max, Aydin, Semiha, Ahmad, Shahzad, Harlan, Sherry, Sirrel, Sherye A, Lasch, Shirley, Hu, Shu-Ching, Li, Shuo, Kittur, Smita, Chowdhury, Sohini, Lancaster, Thomas M, Pawluczyk, Sonia, Maingault, Sophie, Schneider, Stacy, Seiler, Stephan, Guthrie, Stephanie, Kielb, Stephanie, Reeder, Stephanie, Correia, Stephen, Pasternak, Stephen, McMahon, Mary Agnes B, Lee, Phil H, Salloway, Stephen, Johnson, Sterling, Williams, Steve, Chao, Steven, Arnold, Steven E, Paul, Steven, Potkin, Steven, Factor, Stewart, Isaacson, Stuart, Lett, Tristram A, Kim, Sungeun, Ainscough, Susan, Schultz, Susan K, Landau, Susan, Mendick, Susan, Rountree, Susan, Ostrowizki, Suzanne, Veillette, Suzanne, van der Lee, Sven J, Desrivieres, Sylvane, Lewis, Lindsay B, Lee, T-Y, Simuni, Tanya, Foroud, Tatiana, Foroud, Tatiana M, Wong, Terence Z, Villena, Teresa, Comery, Thomas, Obisesan, Thomas O, Lopes-Cendes, Iscia, Banaschewski, Tobias, Sherer, Todd, Montine, Tom, Paus, Tomáš, Robbins, Trevor, Bromberg, Uli, Völker, Uwe, Pavlik, Valory, Arnedo, Vanessa, Kiyasova, Vera, Bates, Vernice, Logovinsky, Veronika, Sossi, Vesna, Shibley, Victoria, Frouin, Vincent, Lee, Virginia, Poewe, Werner, Jagust, William, Brooks, William M, Macciardi, Fabio, Pavlosky, William, Potter, William, Kremen, William S, Longstreth, William T, Niessen, Wiro J, Jian, Xueqiu, Stern, Yaakov, Saba, Yasaman, Cabrera, Yuliana, Grimmer, Yvonne, Marquand, Andre F, Khachaturian, Zaven, Mari, Zoltan, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Stochastics, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Science and Society, Cognitive Psychology, IBBA, APH - Personalized Medicine, Complex Trait Genetics, APH - Methodology, Clinical Neuropsychology, Sociology and Social Gerontology, Amsterdam Neuroscience - Complex Trait Genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Neurology, Psychiatry, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Digital Health, Psychology, Precision Medicine Institute of Psychiatry, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Clinical Genetics, Epidemiology, Medical Informatics, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurodegeneratives Diseases Institute (IMN-UMR CNRS 5293), Centre National de la Recherche Scientifique (CNRS), General Paediatrics, ARD - Amsterdam Reproduction and Development, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Brain mapping, 0302 clinical medicine, Cognition, Cortex (anatomy), ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, 0303 health sciences, Brain Mapping, Multidisciplinary, COMMON VARIANTS, Parkinson Disease, Organ Size, Central sulcus, Magnetic Resonance Imaging, medicine.anatomical_structure, Cerebral cortex, Neuroinformatics, EXPRESSION, endocrine system, central sulcus, SURFACE-AREA, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, Attention deficit hyperactivity disorder, Humans, General, Gene, METAANALYSIS, 030304 developmental biology, Progenitor, CORTICAL SULCI, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic variants, Genetic Variation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, Genome-Wide Association Study, functional annotation, medicine.disease, Genetic architecture, 030104 developmental biology, Evolutionary biology, OBSERVER-INDEPENDENT CHARACTERIZATION, Multiple comparisons problem, ddc:320, genome-wide association, Neuroscience, 030217 neurology & neurosurgery
Abstract

Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group., The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020
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206. Longitudinal Measurements of Glucocerebrosidase activity in Parkinson's patients.

Author

Alcalay, Roy N, Alcalay, Roy N, Wolf, Pavlina, Chiang, Ming Sum Ruby, Helesicova, Karolina, Zhang, Xiaokui Kate, Merchant, Kalpana, Hutten, Samantha J, Scherzer, Clemens, Caspell-Garcia, Chelsea, Blauwendraat, Cornelis, Foroud, Tatiana, Nudelman, Kelly, Gan-Or, Ziv, Simuni, Tanya, Chahine, Lana M, Levy, Oren, Zheng, Dandi, Li, Gen, Sardi, Sergio Pablo, Parkinson’s Progression Markers Initiative, Alcalay, Roy N, Alcalay, Roy N, Wolf, Pavlina, Chiang, Ming Sum Ruby, Helesicova, Karolina, Zhang, Xiaokui Kate, Merchant, Kalpana, Hutten, Samantha J, Scherzer, Clemens, Caspell-Garcia, Chelsea, Blauwendraat, Cornelis, Foroud, Tatiana, Nudelman, Kelly, Gan-Or, Ziv, Simuni, Tanya, Chahine, Lana M, Levy, Oren, Zheng, Dandi, Li, Gen, Sardi, Sergio Pablo, and Parkinson’s Progression Markers Initiative

Abstract

ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

Published
2020

207. Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Author

Cudkowicz, Merit, Cudkowicz, Merit, Chase, Marianne, Coffey, Christopher, Ecklund, Dixie, Thornell, Brenda, Lungu, Codrin, Mahoney, Katy, Gutmann, Laurie, Shefner, Jeremy, Staley, Kevin, Bosch, Michael, Foster, Eric, Long, Jeffrey, Bayman, Emine, Torner, James, Yankey, Jon, Peters, Richard, Huff, Trevis, Conwit, Robin, Shinnar, Shlomo, Patch, Donna, Darras, Basil, Ellis, Audrey, Packer, Roger, Marder, Karen, Chiriboga, Claudia, Moran, Joyce, Nikolov, Blagovest, Factor, Stewart, Seeley, Carole, Greenberg, Steven, Amato, Anthony, DeGregorio, Sara, Simuni, Tanya, Ward, Tina, Kissel, John, Kolb, Stephen, Bartlett, Amy, Quinn, Joseph, Keith, Kellie, Levine, Steven, Gilles, Nadege, Coyle, Patricia, Lamb, Jessica, Wolfe, Gil, Crumlish, Annemarie, Mejico, Luis, Iqbal, Muhammad, Bowen, James, Tongco, Caryl, Nabors, Louis, Bashir, Khurram, Benge, Melanie, Canamar, Catherine, Glauser, Tracy, Woo, Daniel, Molloy, Angela, Clark, Peggy, Vollmer, Timothy, Stein, Alexander, Barohn, Richard, Dimachkie, Mazen, Le Pichon, Jean-Baptiste, Benatar, Michael, Steele, Julie, Wechsler, Lawrence, Clemens, Paula, Amity, Christine, Holloway, Robert, Annis, Christine, Goldberg, Mark, Andersen, Mariam, Iannaccone, Susan, Smith, A, Singleton, J, Doudova, Mariana, Haley, E, Quigg, Mark, Lowenhaupt, Stephanie, Malow, Beth, Adkins, Karen, Clifford, David, Teshome, Mengesha, Connolly, Noreen, Oskarsson, Björn, Dobkin, Bruce, McDonald, Craig, Henricson, Erik, Henchcliffe, Claire, Cudkowicz, Merit, Cudkowicz, Merit, Chase, Marianne, Coffey, Christopher, Ecklund, Dixie, Thornell, Brenda, Lungu, Codrin, Mahoney, Katy, Gutmann, Laurie, Shefner, Jeremy, Staley, Kevin, Bosch, Michael, Foster, Eric, Long, Jeffrey, Bayman, Emine, Torner, James, Yankey, Jon, Peters, Richard, Huff, Trevis, Conwit, Robin, Shinnar, Shlomo, Patch, Donna, Darras, Basil, Ellis, Audrey, Packer, Roger, Marder, Karen, Chiriboga, Claudia, Moran, Joyce, Nikolov, Blagovest, Factor, Stewart, Seeley, Carole, Greenberg, Steven, Amato, Anthony, DeGregorio, Sara, Simuni, Tanya, Ward, Tina, Kissel, John, Kolb, Stephen, Bartlett, Amy, Quinn, Joseph, Keith, Kellie, Levine, Steven, Gilles, Nadege, Coyle, Patricia, Lamb, Jessica, Wolfe, Gil, Crumlish, Annemarie, Mejico, Luis, Iqbal, Muhammad, Bowen, James, Tongco, Caryl, Nabors, Louis, Bashir, Khurram, Benge, Melanie, Canamar, Catherine, Glauser, Tracy, Woo, Daniel, Molloy, Angela, Clark, Peggy, Vollmer, Timothy, Stein, Alexander, Barohn, Richard, Dimachkie, Mazen, Le Pichon, Jean-Baptiste, Benatar, Michael, Steele, Julie, Wechsler, Lawrence, Clemens, Paula, Amity, Christine, Holloway, Robert, Annis, Christine, Goldberg, Mark, Andersen, Mariam, Iannaccone, Susan, Smith, A, Singleton, J, Doudova, Mariana, Haley, E, Quigg, Mark, Lowenhaupt, Stephanie, Malow, Beth, Adkins, Karen, Clifford, David, Teshome, Mengesha, Connolly, Noreen, Oskarsson, Björn, Dobkin, Bruce, McDonald, Craig, Henricson, Erik, and Henchcliffe, Claire

Abstract

IMPORTANCE: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. OBSERVATIONS: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral p

Published
2020

208. Re‐Analysis of the STEADY‐PD II Trial—Evidence for Slowing the Progression of Parkinson's Disease.

Author

Surmeier, D. James, Nguyen, Jack T., Lancki, Nicola, Venuto, Charles S., Oakes, David, Simuni, Tanya, and Wyse, Richard K.

Abstract

Background: Recent examination of the STEADY‐PD III isradipine clinical trial data concluded that early‐stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. Objectives: To test this hypothesis, the data from the STEADY‐PD II isradipine clinical trial, in which an extended‐release (ER) formulation of the drug was used, was re‐examined. Methods: The re‐analysis of the STEADY‐PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52‐week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. Results: Participant cohorts were well‐matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. Conclusions: These results are consistent with the recent secondary analysis of the STEADY‐PD III clinical trial—suggesting that clinically attainable brain exposure to isradipine may slow early‐stage PD progression. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Published
2022
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209. Self-triggered assistive stimulus training improves step initiation in persons with Parkinson’s disease

Author

Creath Robert A, Prettyman Michelle, Shulman Lisa, Hilliard Marjorie, Martinez Katherine, MacKinnon Colum D, Mille Marie-Laure, Simuni Tanya, Zhang Jane, and Rogers Mark W

Subjects
Step, Initiation, Parkinson’s, Freezing, Hesitation, Intervention, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Background Prior studies demonstrated that hesitation-prone persons with Parkinson’s disease (PDs) acutely improve step initiation using a novel self-triggered stimulus that enhances lateral weight shift prior to step onset. PDs showed reduced anticipatory postural adjustment (APA) durations, earlier step onsets, and faster 1st step speed immediately following stimulus exposure. Objective This study investigated the effects of long-term stimulus exposure. Methods Two groups of hesitation-prone subjects with Parkinson’s disease (PD) participated in a 6-week step-initiation training program involving one of two stimulus conditions: 1) Drop. The stance-side support surface was lowered quickly (1.5 cm); 2) Vibration. A short vibration (100 ms) was applied beneath the stance-side support surface. Stimuli were self-triggered by a 5% reduction in vertical force under the stance foot during the APA. Testing was at baseline, immediately post-training, and 6 weeks post-training. Measurements included timing and magnitude of ground reaction forces, and step speed and length. Results Both groups improved their APA force modulation after training. Contrary to previous results, neither group showed reduced APA durations or earlier step onset times. The vibration group showed 55% increase in step speed and a 39% increase in step length which were retained 6 weeks post-training. The drop group showed no stepping-performance improvements. Conclusions The acute sensitivity to the quickness-enhancing effects of stimulus exposure demonstrated in previous studies was supplanted by improved force modulation following prolonged stimulus exposure. The results suggest a potential approach to reduce the severity of start hesitation in PDs, but further study is needed to understand the relationship between short- and long-term effects of stimulus exposure.

Published
2013
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210. Subcutaneous Levodopa Infusion for Parkinson's Disease: 1‐Year Data from the Open‐Label BeyoND Study.

Author

Poewe, Werner, Stocchi, Fabrizio, Arkadir, David, Ebersbach, Georg, Ellenbogen, Aaron L., Giladi, Nir, Isaacson, Stuart H., Kieburtz, Karl, LeWitt, Peter, Olanow, C. Warren, Simuni, Tanya, Thomas, Astrid, Zlotogorski, Abraham, Adar, Liat, Case, Ryan, Oren, Sheila, Fuchs Orenbach, Shir, Rosenfeld, Olivia, Sasson, Nissim, and Yardeni, Tami

Abstract

Background: Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations. Objective: Evaluate 1‐year safety data. Methods: BeyoND is an open‐label study evaluating the long‐term safety of two ND0612 dosing regimens. Results: Of the 214 enrolled patients (24‐hour SC infusion: n = 90; 16‐hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants. Conclusions: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Published
2021
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211. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data.

Author

Pagano, Gennaro, Boess, Frank G., Taylor, Kirsten I., Ricci, Benedicte, Mollenhauer, Brit, Poewe, Werner, Boulay, Anne, Anzures-Cabrera, Judith, Vogt, Annamarie, Marchesi, Maddalena, Post, Anke, Nikolcheva, Tania, Kinney, Gene G., Zago, Wagner M., Ness, Daniel K., Svoboda, Hanno, Britschgi, Markus, Ostrowitzki, Susanne, Simuni, Tanya, and Marek, Kenneth

Subjects
PARKINSON'S disease, TREMOR, DISEASE progression, MONOAMINE oxidase, DIAGNOSIS, MOVEMENT disorders
Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. Trial Registration: NCT03100149. [ABSTRACT FROM AUTHOR]

Published
2021
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212. Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures

Author

Chahine, Lana M, Siderowf, Andrew, Barnes, Janel, Seedorff, Nicholas, Caspell-Garcia, Chelsea, Simuni, Tanya, Coffey, Christopher S, Galasko, Douglas, Mollenhauer, Brit, Arnedo, Vanessa, Daegele, Nichole, Frasier, Mark, Tanner, Caroline, Kieburtz, Karl, Marek, Kenneth, and The Parkinson’s Progression Markers Initiative

Subjects
Male, Dopamine Plasma Membrane Transport Proteins, Parkinson's Disease, Neurosciences, Brain, biomarkers, Parkinson Disease, The Parkinson’s Progression Markers Initiative, Middle Aged, Neurodegenerative, Severity of Illness Index, Brain Disorders, disease progression, Clinical Research, Neurological, Parkinson’s disease, surrogate endpoint, Humans, Female, sense organs, Prospective Studies, Biochemistry and Cell Biology, Aged
Abstract

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.

Published
2019

214. Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists

Author

Alcalay, Roy N., primary, Kehoe, Caitlin, additional, Shorr, Evan, additional, Battista, Roseanna, additional, Hall, Anne, additional, Simuni, Tanya, additional, Marder, Karen, additional, Wills, Anne-Marie, additional, Naito, Anna, additional, Beck, James C., additional, Schwarzschild, Michael A., additional, and Nance, Martha, additional

Published
2020
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215. Safety, pharmacokinetics, and pharmacodynamics of oral venglustat in Parkinson disease patients with a GBA mutation from Japan and the rest of the world: Results from part 1 of the MOVES-PD study

Author

Peterschmitt, M. Judith, primary, Saiki, Hidemoto, additional, Hatano, Taku, additional, Gasser, Thomas, additional, Isaacson, Stuart, additional, Kulisevsky, Jaime, additional, Simuni, Tanya, additional, Takahashi, Yuji, additional, Wills, Anne-Marie, additional, Guedes, Leonor Correia, additional, Svenningsson, Per, additional, Takahashi, Ryosuke, additional, Waters, Cheryl, additional, Katsuno, Masahisa, additional, Ji, Allena Ji, additional, Gaemers, Sebastiaan J.M., additional, Minini, Pascal, additional, Nembo, Blandine, additional, Sardi, Pablo, additional, Saubadu, Stéphane, additional, Sharma, Jyoti, additional, and Fischer, Tanya, additional

Published
2020
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217. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study

Author

Simuni, Tanya, primary, Uribe, Liz, additional, Cho, Hyunkeun Ryan, additional, Caspell-Garcia, Chelsea, additional, Coffey, Christopher S, additional, Siderowf, Andrew, additional, Trojanowski, John Q, additional, Shaw, Leslie M, additional, Seibyl, John, additional, Singleton, Andrew, additional, Toga, Arthur W, additional, Galasko, Doug, additional, Foroud, Tatiana, additional, Tosun, Duygu, additional, Poston, Kathleen, additional, Weintraub, Daniel, additional, Mollenhauer, Brit, additional, Tanner, Caroline M, additional, Kieburtz, Karl, additional, Chahine, Lana M, additional, Reimer, Alyssa, additional, Hutten, Samantha J, additional, Bressman, Susan, additional, Marek, Kenneth, additional, Arnedo, Vanessa, additional, Clark, Adrienne, additional, Fraiser, Mark, additional, Kopil, Catherine, additional, Chowdhury, Sohini, additional, Sherer, Todd, additional, Daegele, Nichole, additional, Casaceli, Cynthia, additional, Dorsey, Ray, additional, Wilson, Renee, additional, Mahes, Sugi, additional, Salerno, Christina, additional, Crawford, Karen, additional, Casalin, Paola, additional, Malferrari, Giulia, additional, Weisz, Mali Gani, additional, Orr-Urtreger, Avi, additional, Montine, Thomas, additional, Baglieri, Chris, additional, Christini, Amanda, additional, Russell, David, additional, Dahodwala, Nabila, additional, Giladi, Nir, additional, Factor, Stewart, additional, Hogarth, Penelope, additional, Standaert, David, additional, Hauser, Robert, additional, Jankovic, Joseph, additional, Saint-Hilaire, Marie, additional, Richard, Irene, additional, Shprecher, David, additional, Fernandez, Hubert, additional, Brockmann, Katrina, additional, Rosenthal, Liana, additional, Barone, Paolo, additional, Espay, Alberto, additional, Rowe, Dominic, additional, Marder, Karen, additional, Santiago, Anthony, additional, Hu, Shu-Ching, additional, Isaacson, Stuart, additional, Corvol, Jean-Christophe, additional, Ruiz Martinez, Javiar, additional, Tolosa, Eduardo, additional, Tai, Yen, additional, Politis, Marios, additional, Smejdir, Debra, additional, Rees, Linda, additional, Williams, Karen, additional, Kausar, Farah, additional, Richardson, Whitney, additional, Willeke, Diana, additional, Peacock, Shawnees, additional, Sommerfeld, Barbara, additional, Freed, Alison, additional, Wakeman, Katrina, additional, Blair, Courtney, additional, Guthrie, Stephanie, additional, Harrell, Leigh, additional, Hunter, Christine, additional, Thomas, Cathi-Ann, additional, James, Raymond, additional, Zimmerman, Grace, additional, Brown, Victoria, additional, Mule, Jennifer, additional, Hilt, Ella, additional, Ribb, Kori, additional, Ainscough, Susan, additional, Wethington, Misty, additional, Ranola, Madelaine, additional, Mejia Santana, Helen, additional, Moreno, Juliana, additional, Raymond, Deborah, additional, Speketer, Krista, additional, Carvajal, Lisbeth, additional, Carvalo, Stephanie, additional, Croitoru, Ioana, additional, Garrido, Alicia, additional, Payne, Laura Marie, additional, Viswanth, Veena, additional, Severt, Lawrence, additional, Facheris, Maurizio, additional, Soares, Holly, additional, Mintun, Mark A., additional, Cedarbaum, Jesse, additional, Taylor, Peggy, additional, Biglan, Kevin, additional, Vandenbroucke, Emily, additional, Haider Sheikh, Zulfiqar, additional, Bingol, Baris, additional, Fischer, Tanya, additional, Sardi, Pablo, additional, Forrat, Remi, additional, Reith, Alastair, additional, Egebjerg, Jan, additional, Ahlberg Hillert, Gabrielle, additional, Saba, Barbara, additional, Min, Chris, additional, Umek, Robert, additional, Mather, Joe, additional, De Santi, Susan, additional, Post, Anke, additional, Boess, Frank, additional, Taylor, Kirsten, additional, Grachev, Igor, additional, Avbersek, Andreja, additional, Muglia, Pierandrea, additional, Merchant, Kaplana, additional, and Tauscher, Johannes, additional

Published
2020
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218. Developing an Effective Multimodal Recruitment Plan: A case study of a Parkinson's disease trial demonstrates how one study team met its enrollment goals

Author

Siddiqi, Bernadette, Berk, Sarah, Biglan, Kevin, Greco, Brittany L., Holloway, Robert G., Kopil, Catherine M., Meunier, Claire, and Simuni, Tanya

Subjects
Case studies, Research, Analysis, Parkinson disease -- Case studies -- Research, Medical research, Clinical trials -- Analysis, Best practices
Abstract

The Michael J. Fox Foundation for Parkinson's Research (MJFF) aims to speed clinical research by removing obstacles that stand in the way of drug development. In pursuit of this mission, [...]

Published
2019

219. Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

Author

Simuni, Tanya, Siderowf, Andrew, Lasch, Shirley, Coffey, Chris S, Caspell-Garcia, Chelsea, Jennings, Danna, Tanner, Caroline M, Trojanowski, John Q, Shaw, Leslie M, Seibyl, John, Schuff, Norbert, Singleton, Andrew, Kieburtz, Karl, Toga, Arthur W, Mollenhauer, Brit, Galasko, Doug, Chahine, Lana M, Weintraub, Daniel, Foroud, Tatiana, Tosun, Duygu, Poston, Kathleen, Arnedo, Vanessa, Frasier, Mark, Sherer, Todd, Chowdhury, Sohini, Marek, Kenneth, and Parkinson's Progression Marker Initiative

Subjects
Male, Aging, Nortropanes, Parkinson's disease, Clinical Sciences, tau Proteins, disease subtypes, tremor dominant, Neurodegenerative, Cohort Studies, Clinical Research, gait disorder predominant, Parkinson's Progression Marker Initiative, Humans, skin and connective tissue diseases, Aged, Dopamine Plasma Membrane Transport Proteins, Amyloid beta-Peptides, Neurology & Neurosurgery, Age Factors, Neurosciences, Parkinson Disease, Human Movement and Sports Sciences, Middle Aged, Corpus Striatum, Peptide Fragments, Brain Disorders, postural instability, Neurological, Disease Progression, Female, sense organs
Abstract

OBJECTIVE:The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD. METHODS:We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures. RESULTS:A total of 423 PD participants were recruited, and 358 remain in the study at year 5. Baseline MDS-UPDRS total score was 32.4 (standard deviation 13.1), and the average annual change (assessed medications OFF for the treated participants) was 7.45 (11.6), 3.11 (11.7), 4(11.9), 4.7 (11.1), and 1.74(11.9) for years 1, 2, 3, 4, and 5, respectively (P

Published
2018

220. Correction: Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists

Author

Alcalay, Roy N., primary, Kehoe, Caitlin, additional, Shorr, Evan, additional, Battista, Roseanna, additional, Hall, Anne, additional, Simuni, Tanya, additional, Marder, Karen, additional, Wills, Anne-Marie, additional, Naito, Anna, additional, Beck, James C., additional, Schwarzschild, Michael A., additional, and Nance, Martha, additional

Published
2019
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221. Advance care planning in Parkinson’s disease: ethical challenges and future directions

Author

Sokol, Leonard L., primary, Young, Michael J., additional, Paparian, Jack, additional, Kluger, Benzi M., additional, Lum, Hillary D., additional, Besbris, Jessica, additional, Kramer, Neha M., additional, Lang, Anthony E., additional, Espay, Alberto J., additional, Dubaz, Ornella M., additional, Miyasaki, Janis M., additional, Matlock, Daniel D., additional, Simuni, Tanya, additional, and Cerf, Moran, additional

Published
2019
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222. Metadata Concepts for Advancing the Use of Digital Health Technologies in Clinical Research

Author

Badawy, Reham, primary, Hameed, Farhan, additional, Bataille, Lauren, additional, Little, Max A., additional, Claes, Kasper, additional, Saria, Suchi, additional, Cedarbaum, Jesse M., additional, Stephenson, Diane, additional, Neville, Jon, additional, Maetzler, Walter, additional, Espay, Alberto J., additional, Bloem, Bastiaan R., additional, Simuni, Tanya, additional, and Karlin, Daniel R., additional

Published
2019
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224. Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Author

Mollenhauer, Brit, primary, Dakna, Mohammed, additional, Liu, Tzu-Ying, additional, Galasko, Douglas, additional, Foroud, Tatiana, additional, Zetterberg, Henrik, additional, Schade, Sebastian, additional, Gera, Roland G., additional, Wang, Wenting, additional, Gao, Feng, additional, Kruse, Niels, additional, Frasier, Mark, additional, Chahine, Lana M., additional, Coffey, Christopher S., additional, Singleton, Andrew B., additional, Simuni, Tanya, additional, Weintraub, Daniel, additional, Seibyl, John, additional, Toga, Arthur W., additional, Tanner, Caroline M., additional, Kieburtz, Karl, additional, Marek, Kenneth, additional, Siderowf, Andrew, additional, Cedarbaum, Jesse M., additional, Hutten, Samantha J., additional, Trenkwalder, Claudia, additional, and Graham, Danielle, additional

Published
2019
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226. Development and validation of the automated imaging differentiation in parkinsonism (AID-P): a multicentre machine learning study

Author

Archer, Derek B, primary, Bricker, Justin T, additional, Chu, Winston T, additional, Burciu, Roxana G, additional, McCracken, Johanna L, additional, Lai, Song, additional, Coombes, Stephen A, additional, Fang, Ruogu, additional, Barmpoutis, Angelos, additional, Corcos, Daniel M, additional, Kurani, Ajay S, additional, Mitchell, Trina, additional, Black, Mieniecia L, additional, Herschel, Ellen, additional, Simuni, Tanya, additional, Parrish, Todd B, additional, Comella, Cynthia, additional, Xie, Tao, additional, Seppi, Klaus, additional, Bohnen, Nicolaas I, additional, Müller, Martijn LTM, additional, Albin, Roger L, additional, Krismer, Florian, additional, Du, Guangwei, additional, Lewis, Mechelle M, additional, Huang, Xuemei, additional, Li, Hong, additional, Pasternak, Ofer, additional, McFarland, Nikolaus R, additional, Okun, Michael S, additional, and Vaillancourt, David E, additional

Published
2019
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227. Neurite orientation dispersion and density imaging (NODDI) and free‐water imaging in Parkinsonism

Author

Mitchell, Trina, primary, Archer, Derek B., additional, Chu, Winston T., additional, Coombes, Stephen A., additional, Lai, Song, additional, Wilkes, Bradley J., additional, McFarland, Nikolaus R., additional, Okun, Michael S., additional, Black, Mieniecia L., additional, Herschel, Ellen, additional, Simuni, Tanya, additional, Comella, Cynthia, additional, Xie, Tao, additional, Li, Hong, additional, Parrish, Todd B., additional, Kurani, Ajay S., additional, Corcos, Daniel M., additional, and Vaillancourt, David E., additional

Published
2019
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229. Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson’s disease psychosis: an expert consensus

Author

Black, Kevin J., primary, Nasrallah, Henry, additional, Isaacson, Stuart, additional, Stacy, Mark, additional, Pahwa, Rajesh, additional, Adler, Charles H., additional, Alva, Gustavo, additional, Cooney, Jeffrey W., additional, Kremens, Daniel, additional, Menza, Matthew A., additional, Meyer, Johnathan M., additional, Patkar, Ashwin A., additional, Simuni, Tanya, additional, Morrissette, Debbi A., additional, and Stahl, Stephen M., additional

Published
2019
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231. Feasibility and safety of lumbar puncture in the Parkinson's disease research participants: Parkinson's Progression Marker Initiative (PPMI)

Author

Prakash, Neha, primary, Caspell-Garcia, Chelsea, additional, Coffey, Christopher, additional, Siderowf, Andrew, additional, Tanner, Caroline M., additional, Kieburtz, Karl, additional, Mollenhauer, Brit, additional, Galasko, Douglas, additional, Merchant, Kalpana, additional, Foroud, Tatiana, additional, Chahine, Lana M., additional, Weintraub, Daniel, additional, Casaceli, Cindy, additional, Dorsey, Ray, additional, Wilson, Renee, additional, Herzog, Margaret, additional, Daegele, Nichole, additional, Arnedo, Vanessa, additional, Frasier, Mark, additional, Sherer, Todd, additional, Marek, Ken, additional, Frank, Samuel, additional, Jennings, Danna, additional, Simuni, Tanya, additional, Marek, Kenneth, additional, Seibyl, John, additional, Tanner, Caroline, additional, Tosun-Turgut, Duygu, additional, Shaw, Leslie, additional, Trojanowski, John, additional, Singleton, Andrew, additional, Toga, Arthur, additional, Poewe, Werner, additional, Poston, Kathleen, additional, Chowdhury, Sohini, additional, Kopil, Catherine, additional, Casaceli, Cynthia, additional, Mahes, Sugi, additional, Salerno, Christina, additional, Crawford, Karen, additional, Casalin, Paola, additional, Malferrari, Giulia, additional, Weisz, Mali Gani, additional, Orr-Urtreger, Avi, additional, Montine, Thomas, additional, Russell, David, additional, Dahodwala, Nabila, additional, Giladi, Nir, additional, Factor, Stewart, additional, Hogarth, Penelope, additional, Standaert, David, additional, Hauser, Robert, additional, Jankovic, Joseph, additional, Saint-Hilaire, Marie, additional, Richard, Irene, additional, Shprecher, David, additional, Fernandez, Hubert, additional, Brockmann, Katrina, additional, Rosenthal, Liana, additional, Barone, Paolo, additional, Espay, Alberto, additional, Rowe, Dominic, additional, Marder, Karen, additional, Santiago, Anthony, additional, Bressman, Susan, additional, Hu, Shu-Ching, additional, Isaacson, Stuart, additional, Corvol, Jean-Christophe, additional, Martinez, Javiar Ruiz, additional, Tolosa, Eduardo, additional, Tai, Yen, additional, Politis, Marios, additional, Smejdir, Debra, additional, Rees, Linda, additional, Williams, Karen, additional, Kausar, Farah, additional, Richardson, Whitney, additional, Willeke, Diana, additional, Peacock, Shawnees, additional, Heim, Beatrice, additional, Mirelman, Anat, additional, Sommerfeld, Barbara, additional, Freed, Alison, additional, Wakeman, Katrina, additional, Blair, Courtney, additional, Guthrie, Stephanie, additional, Harrell, Leigh, additional, Hunter, Christine, additional, Thomas, Cathi-Ann, additional, James, Raymond, additional, Zimmerman, Grace, additional, Brown, Victoria, additional, Mule, Jennifer, additional, Hilt, Ella, additional, Ribb, Kori, additional, Ainscough, Susan, additional, Wethington, Misty, additional, Ranola, Madelaine, additional, Santana, Helen Mejia, additional, Moreno, Juliana, additional, Raymond, Deborah, additional, Speketer, Krista, additional, Carvajal, Lisbeth, additional, Carvalho, Stephanie, additional, Croitoru, Ioana, additional, Garrido, Alicia, additional, Payne, Laura Marie, additional, Viswanth, Veena, additional, Severt, Lawrence, additional, Facheris, Maurizio, additional, Soares, Holly, additional, Mintun, Mark A., additional, Cedarbaum, Jesse, additional, Taylor, Peggy, additional, Biglan, Kevin, additional, Vandenbroucke, Emily, additional, Sheikh, Zulfiqar Haider, additional, Bingol, Baris, additional, Fischer, Tanya, additional, Sardi, Pablo, additional, Forrat, Remi, additional, Reith, Alastair, additional, Egebjerg, Jan, additional, Hillert, Gabrielle Ahlberg, additional, Saba, Barbara, additional, Min, Chris, additional, Umek, Robert, additional, Mather, Joe, additional, De Santi, Susan, additional, Post, Anke, additional, Boess, Frank, additional, Taylor, Kirsten, additional, Grachev, Igor, additional, Avbersek, Andreja, additional, Muglia, Pierandrea, additional, Merchant, Kaplana, additional, and Tauscher, Johannes, additional

Published
2019
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232. Safety, tolerability and pharmacokinetics of oral venglustat in Parkinson’s disease patients with a GBA mutation (S4.002)

Author

Fischer, Tanya, primary, Gasser, Thomas, additional, Isaacson, Stuart, additional, Kulisevsky, Jaime, additional, Mir, Pablo, additional, Simuni, Tanya, additional, Wills, Anne Marie, additional, Guedes, Leonor Correia, additional, Svenningsson, Per, additional, Waters, Cheryl, additional, Ji, Allena, additional, Li, Jian, additional, Minini, Pacal, additional, Nembo, Blandine, additional, Sardi, S. Pablo, additional, Saubadu, Stéphane, additional, Sharma, Jyoti, additional, and Peterschmitt, M. Judith, additional

Published
2019
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235. Longitudinal Characterization of the Clinical and DAT Characteristics of Participants with Scans without Evidence of Dopaminergic Deficit (SWEDDs): PPMI Cohort (S10.005)

Author

Marek, Kenneth, primary, Simuni, Tanya, additional, Siderowf, Andrew, additional, Lafontant, David-Eirck, additional, Caspell-Garcia, Chelsea, additional, Coffey, Christopher, additional, Mollenhauer, Brit, additional, Tanner, Caroline, additional, Kieburtz, Karl, additional, Chahine, Lana, additional, and Seibyl, John, additional

Published
2019
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237. Assessing Tele-Health Outcomes in Multiyear Extensions of Parkinson’s Disease Trials (AT-HOME PD): Initiation of a Long-Term Observational Study (P2.8-011)

Author

Schneider, Ruth, primary, Anthwal, Shalini, additional, Kayson, Elise, additional, Omberg, Larsson, additional, Tarolli, Christopher, additional, Macklin, Eric, additional, Bataille, Lauren, additional, Dorsey, E. Ray, additional, Mangravite, Lara, additional, Schwarzschild, Michael, additional, and Simuni, Tanya, additional

Published
2019
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238. NILO-PD: A Phase 2A Study of Nilotinib in Patients with Advanced and Early Parkinson’s Disease: Study Design and Status Update (P3.8-035)

Author

Simuni, Tanya, primary, Fiske, Brian, additional, Merchant, Kalpana, additional, Coffey, Christopher, additional, Matthews, Helen, additional, Wyse, Richard K., additional, Brundin, Patrik, additional, Simon, David K., additional, Schwarzschild, Michael A., additional, Weiner, David, additional, Adams, Jamie, additional, Venuto, Charles, additional, Trusso, Laura, additional, Baker, Liana, additional, Kostrzebski, Melissa, additional, Ward, Tina, additional, and Rafaloff, Gary, additional

Published
2019
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242. Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

Author

Kremer, Thomas, Taylor, Kirsten I., Siebourg‐Polster, Juliane, Gerken, Thomas, Staempfli, Andreas, Czech, Christian, Dukart, Juergen, Galasko, Douglas, Foroud, Tatiana, Chahine, Lana M., Coffey, Christopher S., Simuni, Tanya, Weintraub, Daniel, Seibyl, John, Poston, Kathleen L., Toga, Arthur W., Tanner, Caroline M., Marek, Kenneth, Hutten, Samantha J., and Dziadek, Sebastian

Abstract

Background: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD). Objective: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis. Methods: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies. Results: Baseline levels of homovanillic acid (HVA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single‐photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug‐naive individuals, but some changed on starting levodopa treatment. Conclusions: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Published
2021
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243. Progress towards therapies for disease modification in Parkinson's disease.

Author

Vijiaratnam, Nirosen, Simuni, Tanya, Bandmann, Oliver, Morris, Huw R, and Foltynie, Thomas

Subjects
*PARKINSON'S disease, *EXPERIMENTAL design, *INDIVIDUALIZED medicine, *PARKINSON'S disease treatment, *DRUG therapy for Parkinson's disease, *DISEASE progression
Abstract

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches for the selection of therapeutic candidates but also to insufficient attention to detail in clinical trial design. Better understanding of Parkinson's disease pathogenesis associated with advances in laboratory models, the use of objective biomarkers of disease progression and target engagement, and a focus on agents known to be safe for human use, alongside the use of precision medicine approaches, should together greatly increase the likelihood for successful identification of disease-modifying treatments for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Published
2021
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244. This title is unavailable for guests, please login to see more information.

Author

Mollenhauer, Brit, Mollenhauer, Brit, Caspell‐Garcia, Chelsea J, Coffey, Christopher S, Taylor, Peggy, Singleton, Andy, Shaw, Leslie M, Trojanowski, John Q, Frasier, Mark, Simuni, Tanya, Iranzo, Alex, Oertel, Wolfgang, Siderowf, Andrew, Weintraub, Daniel, Seibyl, John, Toga, Arthur W, Tanner, Caroline M, Kieburtz, Karl, Chahine, Lana M, Marek, Kenneth, Galasko, Douglas, study, for the PPMI, Mollenhauer, Brit, Mollenhauer, Brit, Caspell‐Garcia, Chelsea J, Coffey, Christopher S, Taylor, Peggy, Singleton, Andy, Shaw, Leslie M, Trojanowski, John Q, Frasier, Mark, Simuni, Tanya, Iranzo, Alex, Oertel, Wolfgang, Siderowf, Andrew, Weintraub, Daniel, Seibyl, John, Toga, Arthur W, Tanner, Caroline M, Kieburtz, Karl, Chahine, Lana M, Marek, Kenneth, Galasko, Douglas, and study, for the PPMI

Published
2019

245. Feasibility and safety of lumbar puncture in the Parkinson's disease research participants: Parkinson's Progression Marker Initiative (PPMI).

Author

Prakash, Neha, Prakash, Neha, Caspell-Garcia, Chelsea, Coffey, Christopher, Siderowf, Andrew, Tanner, Caroline M, Kieburtz, Karl, Mollenhauer, Brit, Galasko, Douglas, Merchant, Kalpana, Foroud, Tatiana, Chahine, Lana M, Weintraub, Daniel, Casaceli, Cindy, Dorsey, Ray, Wilson, Renee, Herzog, Margaret, Daegele, Nichole, Arnedo, Vanessa, Frasier, Mark, Sherer, Todd, Marek, Ken, Frank, Samuel, Jennings, Danna, Simuni, Tanya, Parkinson's Progression Markers InitiativeSteering Committee, Study Cores, Site Investigators, Coordinators, Industry and Scientific Advisory Board, Prakash, Neha, Prakash, Neha, Caspell-Garcia, Chelsea, Coffey, Christopher, Siderowf, Andrew, Tanner, Caroline M, Kieburtz, Karl, Mollenhauer, Brit, Galasko, Douglas, Merchant, Kalpana, Foroud, Tatiana, Chahine, Lana M, Weintraub, Daniel, Casaceli, Cindy, Dorsey, Ray, Wilson, Renee, Herzog, Margaret, Daegele, Nichole, Arnedo, Vanessa, Frasier, Mark, Sherer, Todd, Marek, Ken, Frank, Samuel, Jennings, Danna, Simuni, Tanya, Parkinson's Progression Markers InitiativeSteering Committee, Study Cores, Site Investigators, Coordinators, and Industry and Scientific Advisory Board

Abstract

ObjectiveTo determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).BackgroundCerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants.Design/methodsParkinson's Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers. All PPMI participants undergo LP at baseline, 6, 12 months and yearly thereafter. CSF collection is performed by a trained investigator using predominantly atraumatic needles. Adverse events (AEs) are monitored by phone one week after LP completion. We analyzed safety data from baseline LPs.ResultsPPMI enrolled 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. CSF was collected at baseline in 97.5% of participants, of whom 5.4% underwent collection under fluoroscopy. 23% participants reported any related AEs, 68% of all AE were mild while 5.6% were severe. The most common AEs were headaches (13%) and low back pain (6.5%) and both occurred more commonly in HC and SWEDDs compared to PD participants. Factors associated with higher incidence of AEs across the cohorts included female gender, younger age and use of traumatic needles with larger diameter. AEs largely did not impact compliance with the future LPs.ConclusionsLPs are safe and feasible in PD research participants. Specific LP techniques (needle type and gauge) may reduce the overall incidence of AEs.

Published
2019

246. Predictors of time to initiation of symptomatic therapy in early Parkinson's disease.

Author

Simuni, Tanya, Simuni, Tanya, Long, Jeffrey D, Caspell-Garcia, Chelsea, Coffey, Christopher S, Lasch, Shirley, Tanner, Caroline M, Jennings, Danna, Kieburtz, Karl D, Marek, Kenneth, PPMI Investigators, Simuni, Tanya, Simuni, Tanya, Long, Jeffrey D, Caspell-Garcia, Chelsea, Coffey, Christopher S, Lasch, Shirley, Tanner, Caroline M, Jennings, Danna, Kieburtz, Karl D, Marek, Kenneth, and PPMI Investigators

Abstract

ObjectiveTo determine clinical and biological variables that predict time to initiation of symptomatic therapy in de novo Parkinson's disease patients.MethodsParkinson's Progression Markers Initiative is a longitudinal case-control study of de novo, untreated Parkinson's disease participants at enrolment. Participants contribute a wide range of motor and non-motor measures, including biofluids and imaging biomarkers. The machine learning method of random survival forests was used to examine the ability of baseline variables to predict time to initiation of symptomatic therapy since study enrollment (baseline).ResultsThere were 423 PD participants enrolled in PPMI and 33 initial baseline variables. Cross-validation results showed that the three-predictor subset of disease duration (time from diagnosis to enrollment), the modified Schwab and England activities of daily living scale, and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score modestly predicted time to initiation of symptomatic therapy (C = 0.70, pseudo-R (2) = 0.13). Prediction using the three variables was similar to using the entire set of 33. None of the biological variables increased accuracy of the prediction. A prognostic index for time to initiation of symptomatic therapy was created using the linear and nonlinear effects of the three top variables based on a post hoc Cox model.InterpretationOur findings using a novel machine learning method support previously reported clinical variables that predict time to initiation of symptomatic therapy. However, the inclusion of biological variables did not increase prediction accuracy. Our prognostic index constructed, based on the group-level survival curve can provide an indication of the risk of initiation of ST for PD patients based on functions of the three top predictors.

Published
2016

247. Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson’s Disease and a GBAMutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Author

Peterschmitt, M. Judith, Saiki, Hidemoto, Hatano, Taku, Gasser, Thomas, Isaacson, Stuart H., Gaemers, Sebastiaan J.M., Minini, Pascal, Saubadu, Stéphane, Sharma, Jyoti, Walbillic, Samantha, Alcalay, Roy N., Cutter, Gary, Hattori, Nobutaka, Höglinger, Günter U., Marek, Kenneth, Schapira, Anthony H.V., Scherzer, Clemens R., Simuni, Tanya, Giladi, Nir, Sardi, Sergio Pablo, and Fischer, Tanya Z.

Abstract

Background: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson’s disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor.Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBAmutations (GBA-PD).Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18–80 years with PD diagnosis and heterozygous GBAmutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics.Results: Participants (N?=?29) received venglustat (Japanese, n?=?9; non-Japanese, n?=?13) or placebo (n?=?3; n?=?4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants.Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF.

Published
2022
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249. Cognition among individuals along a spectrum of increased risk for Parkinson’s disease

Author

Chahine, Lana M, Urbe, Liz, Caspell-Garcia, Chelsea, Aarsland, Dag, Alcalay, Roy, Barone, Paolo, Burn, David, Espay, Alberto J, Hamilton, Jamie L, Hawkins, Keith A, Lasch, Shirley, Leverenz, James B, Litvan, Irene, Richard, Irene, Siderowf, Andrew, Coffey, Christopher S, Simuni, Tanya, Weintraub, Daniel, Parkinson’s Progression Markers Initiative, and Toft, Mathias

Subjects
0301 basic medicine, Male, Genetics and Molecular Biology (all), Aging, Heredity, Parkinson's disease, lcsh:Medicine, Social Sciences, Judgment of Line Orientation, Neurodegenerative, Neuropsychological Tests, Biochemistry, Cohort Studies, 0302 clinical medicine, Cognition, Hyposmia, Risk Factors, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Medicine and Health Sciences, 80 and over, Psychology, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Aged, 80 and over, Cognitive Impairment, Movement Disorders, Parkinson's Disease, Multidisciplinary, Cognitive Neurology, Neuropsychology, Montreal Cognitive Assessment, Neurodegenerative Diseases, Parkinson Disease, Middle Aged, 3. Good health, Neurology, Neurological, Cohort, Female, Disease Susceptibility, medicine.symptom, Research Article, Adult, medicine.medical_specialty, General Science & Technology, Cognitive Neuroscience, REM sleep behavior disorder, Risk Assessment, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Parkinson’s Progression Markers Initiative, Neuropsychological Testing, Aged, Dementia with Lewy bodies, business.industry, lcsh:R, Cognitive Psychology, Neurosciences, Biology and Life Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Mutation, Cognitive Science, lcsh:Q, business, 030217 neurology & neurosurgery, Biomarkers, Neuroscience
Abstract

Author(s): Chahine, Lana M; Urbe, Liz; Caspell-Garcia, Chelsea; Aarsland, Dag; Alcalay, Roy; Barone, Paolo; Burn, David; Espay, Alberto J; Hamilton, Jamie L; Hawkins, Keith A; Lasch, Shirley; Leverenz, James B; Litvan, Irene; Richard, Irene; Siderowf, Andrew; Coffey, Christopher S; Simuni, Tanya; Weintraub, Daniel; Parkinson’s Progression Markers Initiative | Abstract: INTRODUCTION:Several characteristics associated with increased risk for Parkinson's disease (PD) have been identified, including specific genotypes and various non-motor symptoms. Characterizing non-motor features, such as cognitive abilities, among individuals considered at-risk for PD is essential to improving prediction of future neurodegeneration. METHODS:Participants belonging to the following cohorts of the Parkinson Progression Markers Initiative (PPMI) study were included: de novo PD with dopamine transporter binding deficit (n = 423), idiopathic REM sleep behavior disorder (RBD, n = 39), hyposmia (n = 26) and non-PD mutation carrier (NMC; Leucine-rich repeat kinase 2 (LRRK2) G2019S (n = 88) and glucocerebrosidase (GBA) gene (n = 38) mutations)). Inclusion criteria enriched the RBD and hyposmia cohorts, but not the NMC cohort, with individuals with dopamine transporter binding deficit. Baseline neuropsychological performance was compared, and analyses were adjusted for age, sex, education, and depression. RESULTS:The RBD cohort performed significantly worse than the hyposmia and NMC cohorts on Symbol Digit Modality Test (mean (SD) 32.4 (9.16) vs. 41.8 (9.98), p = 0.002 and vs. 45.2 (10.9), pl0.001) and Judgment of Line Orientation (11.3 (2.36) vs.12.9 (1.87), p = 0.004 and vs. 12.9 (1.87), pl0.001). The RBD cohort also performed worse than the hyposmia cohort on the Montreal Cognitive Assessment (25.5 (4.13) vs. 27.3 (1.71), p = 0.02). Hyposmics did not differ from PD or NMC cohorts on any cognitive test score. CONCLUSION:Among individuals across a spectrum of risk for PD, cognitive function is worse among those with the characteristic most strongly associated with future risk of PD or dementia with Lewy bodies, namely RBD.

Published
2018
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250. Cognition among individuals along a spectrum of increased risk for Parkinson’s disease

Author

Chahine, Lana M., Urbe, Liz, Caspell-Garcia, Chelsea, Aarsland, Dag, Alcalay, Roy Nissim, Barone, Paolo, Burn, David, Espay, Alberto J., Hamilton, Jamie L., Hawkins, Keith A., Lasch, Shirley, Leverenz, James B., Litvan, Irene, Richard, Irene, Siderowf, Andrew, Coffey, Christopher S., Simuni, Tanya, Weintraub, Daniel, and Parkinson’s Progression Markers Initiative

Subjects
Cognition, Neurology, Parkinson's disease--Patients, Cognitive neuroscience, Diseases--Risk factors
Abstract

Introduction Several characteristics associated with increased risk for Parkinson’s disease (PD) have been identified, including specific genotypes and various non-motor symptoms. Characterizing non-motor features, such as cognitive abilities, among individuals considered at-risk for PD is essential to improving prediction of future neurodegeneration. Methods Participants belonging to the following cohorts of the Parkinson Progression Markers Initiative (PPMI) study were included: de novo PD with dopamine transporter binding deficit (n = 423), idiopathic REM sleep behavior disorder (RBD, n = 39), hyposmia (n = 26) and non-PD mutation carrier (NMC; Leucine-rich repeat kinase 2 (LRRK2) G2019S (n = 88) and glucocerebrosidase (GBA) gene (n = 38) mutations)). Inclusion criteria enriched the RBD and hyposmia cohorts, but not the NMC cohort, with individuals with dopamine transporter binding deficit. Baseline neuropsychological performance was compared, and analyses were adjusted for age, sex, education, and depression. Results The RBD cohort performed significantly worse than the hyposmia and NMC cohorts on Symbol Digit Modality Test (mean (SD) 32.4 (9.16) vs. 41.8 (9.98), p = 0.002 and vs. 45.2 (10.9), p

Published
2018
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