Amyloid-β 11 C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

著者: Enchi Liu, Mark E. Schmidt, Richard Margolin, Reisa A. Sperling, Robert A. Koeppe, N. Scott Mason, William E. Klunk, Chester A. Mathis, Stephen Salloway, Nick C. Fox, David Hill, Andrea S. Les, Peter Collins, Keith M. Gregg, Jianing Di, Yuan Lü, Iulia Cristina Tudor, Bradley T. Wyman, Kevin Booth, S Broome, Eric Yuen, Michael Grundman, H. Robert Brashear, Stephen Salloway, Reisa A. Sperling, Murray A. Raskind, Marwan N. Sabbagh, Lawrence S. Honig, Anton P. Porsteinsson, Steven H. Ferris, David Weisman, Lynne Harris, Betty Diamond, A. Casher, V. Thomas, Daniel R. Rhodes, Celine Olivia, Andrea Years, Anthony Rosenzweig, Ronald Klein, Steven E. Arnold, V. Boruta, A Blue-Schaller, James McGowan, J. Wurziger, Özkan Yalkinoglu, J. Wurziger, Martina Kirsch, Christian Schindler, Arthur Spirling, M. Ohnesorge, Andreas Kluge, Martha McCartney, Thomas Stubbs, K. J. Sweeney, Keith A. Johnson, Roberto Santangelo, Benjamin K.P. Woo, Marcelo F. DiCarli, Steven Williams, J. M. Passler, D. Cheng, Wendy J. Ingram, S. Jutras, Moshe Shay, A. McGlew, S. Warner-Coviello, Rakesh Nandan, Paul Rees, Varun Mehra, Juliana Velosa Porras, S. Bryant, E. Bartolome, Carl K. Hoh, Jennifer M. Murphy, Salmaan Sharif, Monte S. Buchsbaum, K E Kortman, István Kovács, Neelee Chini, Lisa Brown, Gus Alva, Ajjai Alva, J. Kellogg, Mathilde Lykke, Markus Rabe, B. Shih, Joseph C. Wu, Carl K. Hoh, Monte S. Buchsbaum, Pierre N. Tariot, R. Yaari, Scott A. Small, M. Chavira, Eric M. Reiman, H. Brand, Lisa Cooper, W. Dennis-Busier, Dan Bandy, James D. Seward, John M. Weir, Carlos N. Monarrez, D. Ware Branch, J.B. Langbaum, A. Mohammand, Christopher A. Ross, Louise Mullen, S. Goodwin, Adam Fleisher, A. Burke, Laura Jakimovich, D. Costanzo, T. Drimer-Kagan, Cheryl L. Holt, Nellie High, Kathy Wright, Stephanie Reeder, Katherine H. Saunders, Nils Richter, Sheila Vadovicky, E. Salomon, R. Lopez, Megan Frantz, Jose Isidro Minero, Carolyn Langlois, Gursharan Chana, Erika Hamilton, S. Media-Rodriguez, D. Lefranc, Milan Luk, A. Herrero San Martín, Kay Weiler, M. Baker, L. Martinez-Lujan, Marwan N. Sabbagh, Sandra A. Jacobson, CM Belden, David A. Holladay, R. Cottam, Holly A. Shill, Jerri D. Edwards, Donald J. Connor, Keith L. Davis, D. Allinich, Joan Sala, Markus W. Covert, Joanne Ceimo, C. Molnar, M. Malek-Ahmadi, E. Schwartz, P. A. Conrad, Jean Lopez, E. Karoll, A. Rangel, Cristina Delcò, Zoran Obradov, Katrin Kohl, B M Montalvo, Dan Bandy, C. Chong, Robert A. Stern, Anil K. Nair, R. Green, Ilona M. Kopits, Glenn D. Barest, Rohini N. Nadgir, A. Mandell, Noyan Gokce, Jane Mwicigi, Asad Mian, J. Wang, Carlo Rossi, Shirley Poon, J. Callaghan, Osamu Sakai, Hui Hong, Sheelakumari Raghavan, Prajakta Joshi, E. Francis Cook, Keith A. Johnson, Eric Steinberg, Thomas McGowan, Marcelo F. DiCarli, Patricia Lynn Johnson, W. Qui, Guillermo Marshall, Dorene M. Rentz, Scott McGinnis, Keith A. Johnson, Lauren E. Olson, Mark R. Frey, Alireza Atri, Meghan Searl, Reisa A. Sperling, James M. Mountz, Katherine Frishe, Ottavio V. Vitolo, Rebecca E. Amariglio, Marcelo F. Di Carli, Martha Vander Vliet, Laura Horkey, Mykol Larvie, Nancy J. Donovan, Natacha Lorius, B. Boot, D. G. Sapir, Krishna Chandra Roy, S. Kim, Stephen Salloway, Dieter Lederer, W. Fennelly, B. Blackham, Joel R. Primack, Diane Monast, C. Kechichian, Paul Malloy, V. Sofios, Steven A. Weinman, Roberto Santoro, Kathryn Bandeira de Mello, Colleen J. Maxwell, Martin J. Gardner, Kenneth C. Rickler, Nicole McLaughlin, Keith A. Johnson, Lincoln Tirpaeck, D. Jerue, Irene Piryatinsky, Marcelo F. Di Carli, D. Cheng, Richard Marsland, Phillip Read, Ania Mikos, Desiree Medeiros, Fiona Kinney, Deborah Dahl, Adrian H. Thurstin, Richard May, Helen L. Reeves, R. Colin Garner, Timothy A. Steele, Lelland C. Tolbert, K. Lindbergh, Michael D. Redwine, Jeffrey Hammel, Ronald E. Savage, Stuart C. White, Neil Kirby, X. Wang, Sebastian Berg, Gary A. Rosenberg, Michèle Campopiano, L. Dobkin, S. Richard-Aasen, Jérôme Champ, Chris Dutka, Marina Celanovic, Jared Minkel, John Wilson, N. Belt, Leon Flamm, Richard Kasdan, Douglas I. Katz, L.P. Chandler, R. T. Clegg, H Duncan, J. Moutz, Jay R. Harris, C. Gautier, L. Champ, Victoria Louise Reid, C. Ravella, Pradeep Garg, Christopher W. Jones, Karen Pulford, Maria DeSantis, T. Annas, Carol Moore, J Kunze, Pramod Kumar Garg, Jennifer Lail, Katharine A. Kirby, C. Doherr, Juliet N. Barker, X. Wang, Sebastian Berg, Gary A. Rosenberg, Michèle Campopiano, L. Dobkin, S. Richard-Aasen, Jérôme Champ, Chris Dutka, Marina Celanovic, Jared Minkel, John Wilson, N. Belt, Leon Flamm, Richard Kasdan, Douglas I. Katz, L.P. Chandler, R. T. Clegg, H Duncan, J. Moutz, Jay R. Harris, C. Gautier, L. Champ, Victoria J. M. Reid, C. Ravella, Pramod Kumar Garg, Christopher W. Jones, Karen Pulford, Omid Omidvar, Armen Goenjian, Neeral R. Patel, David P. Walling, Ann D. Cohen, Anthony Harris, Jaclyn A. Stephens, Claudio Mori, F Larios Arceo, June Brand, Carlos C. Segui, E. Foster, Antônio M. Cabral, R. K. Iler, G M Bonomo, J. Freinhar, Manh Huy, Joseph C. Wu, Matthew W. Kemp, Camille A. Issa, Shirley Reynolds, Thế Dũng Bùi, Lauren Marlotte, Cameron J. Britton, Roberto D. Lachica, Charles Webb, Augustine Guinto, C. Zaky, Sara Te, Chika Tanimura, Aiko Fukuma, Clinton Lloyd, Amy B. Wise, Rex Pui Kin Lam, David Botros, Lisa G. Rosas, Graham Boyd, Robert L. Gladding, Sven Becker, Alan Norris, Alan Flores, A. Parikh, Lori Baker, Derek Stephens, Martı́n Martı́nez, Catriona Keenan, T. Waight, T. Ho, K. Lorine, Nima Ramezan‐Arab, Victor C. Yang, James Chih‐Hsin Yang, Sara Kashani, Kristen Spoor, Esubalew Tesfahun Ayele, Lawrence S. Honig, Karen L. Bell, S. Janicki, E. Dominguez-Rivera, R. Tejeda, D. Cheng, Masanori Ichise, María Dolores Gordillo Gordillo, L. Mules, Andréia Maria Camargos Rocha, Joshua R. Steinerman, James M. Noble, M. Nash, Darin E. Olson, Jacqueline M. Miller, Karin Schindler, Josh Turknett, G. Yarbrough, Charlotte Panter, LaTeshia Thomas-Seaton, Karl Young, Sara P. Myers, L. Vedanarayanan, S. Golson, L. Previto-Craft, A. Bruflodt, David A. Krendel, Patrick Kennedy, A. A. Schiff, M. Williamson, Y. Houssami, S Rozin, Nick Townsend, A. Brazeale, Y. Mohajermilani, A. Cutsuries, M. Micheli, Carolyn C. Meltzer, S. Bruflodt, Sharon D. Chandler, C. Flemister, M. T. Whiting, David Gbadebo, Stephen L. Mayo, R. A. JACKSON, Nerina Jane Caltabiano, Cooper G. Hazelrig, Donald S. Marks, Donald R. Marks, L. A. Corwin, Maria T. Munoz Cunio, Nakeisha Ricks, Lauren A. Brogna, Gudrun Schober, Keith A. Johnson, D. Cheng, John A. Ferraro, Marcelo F. Di Carli, Michelle R. Madore, V. Birbiglia, L. Parsons, E. Kearney, S. Pelissier, Christine Orzechowski, Carol F. Lippa, Gediminas Gliebus, Andrea Rosso, Jason Silversteen, M. Hepler, David J. Irwin, Robert A. Koenigsberg, Kandan Kulandaivel, Syed Muhammad Kashif Kazmi, Terry Paylor, L. Durmala, Charles C. Edwards, Steven E. Arnold, S. Kharkar, Atul Kalanuria, Prakash Ambady, Joel Eppig, Cecilia Nieves, Gilbert Mbeo, Anahid Kabasakalian, Jerri D. Edwards, D. Spruill, Allan I. Levey, James J. Lah, Larry E. Tune, Dietrich Stout, Janet Cellar, Meng Su, Samantha Rogers, Michelle Ollivierre, Margaret Masterson, Thomas S. Wingo, Leigh M. Strozier, Susan Peterson-Hazan, Matthew Jones, Carolyn C. Meltzer, C. N. Hales, Wenli Hu, S. Stennett, Lavezza Zanders, J. Kozarsky, Jooryung Huh, Kyle Perkins, Keith R. Edwards, Benjamin M. Rosenthal, C Gorman, Julia Button, John D. O’Connor, E. Boorse, A. Button, Traci DePalma, C. Senzon, S. Staunton, Wayne K. Goodman, N. Rieben, Johanna A. Higgins, Raymond Scott Turner, Brigid Reynolds, Keith A. Johnson, Chad Ward, Oyetunji T. Kolawole, Sharon R. Browning, Andy Brown, K A Behan, Aaron P. Schultz, F. Berokowitz, Steven E. Arnold, A. Gebrou, R. Lawrence, Paul Aisen, Carlo Tornatore, Jinjian Zhu, D. Duarte, Djanilson Barbosa dos Santos, Natasha Janicic-Kahric, Patrycja Zielińska, F. Aurelio Sita, Mark Stevenson, Kathleen Redington, F. Watkins, Jeff D. Williamson, Stephan A. Mayer, Belinda Davis, Patricia Wittmer, Mark Forrest Gordon, J. Standfield, Hunter Smith, Pramod Kumar Garg, D Chamberlain, Leslie Gordineer, Benjamin Matthews, Ann Marie Hake, Daniel Rexroth, Frederick W. Unverzagt, K. Havison, Kate M. Fleming, Loredana Donadio, Bruce L. Miller, Kristen Turchi, Joshua Fletcher, Miranda M. Lim, E. Van Hook, Catherine Brewer, Bonnie Klank, Cláudia Ramos, Kerri L. Cavanaugh, S. Elizabeth Zauber, Julie Liss, J. Canedo, Paige Kaplan, J. Sidhpura, G. Madril, Paula Harris, Marvella E. Ford, Nathan D. Price, Carolyn C. Meltzer, Steven M. Schwartz, Stephen Stewart, K. Appledorn, E. Toffler, Alexandra Pitman, Karen L. Herbst, Lucy Frost, Catherine Henderson, Nicolas Couturier, Christopher L. Wolfe, Olivia Graham, James M. Ellison, David G. Harper, B. Forester, Darin E. Olson, S. Kim, M. Wodward, Keith A. Johnson, Marcelo F. Di Carli, Mary J. Malloy, Brittany L. Jordan-Arthur, M. Biber, Maryam M. Gilpatrick, Keith A. Johnson, Amanda L. Stein, Marcelo F. Di Carli, Michael Stanton, Leonard F. M. Scinto, Margaret Scofield, Robert D. Bell, D. Cheng, Vivencio Barrios, Victoria Atkinson, H. R. Sullivan, Manfred Oster, Sherral Devine, Gregory M. Shoukimas, D Rimmer, M. Cincotta, Darrius McMillian, Giuseppina Tramontano, Tom Redling, Kelly Elizabeth Wilder-Willis, E. Sangama, Chris Hinrichs, Karen Tennyson, I. Genkin, R. Thomas Bonk, M. Glassmoyer, Natalia Méndez, E. Capstraw, Joseph Noye, Stephan F. Taylor, David Bernardo, Michael Kelly, David Kudrow, V. Yarema, G. Arreloa, J. Latorre, Tom Newman, Elizabeth Vásquez, Betsy Valdez, Estella S. Hung, Jennifer S. Stevens, C.K.M. Lee, Lisa Brown, Joseph C. Wu, Isabel Cabrera, Grace Gibbon, Sarah Waldman, Stefano Mossa, Anthony Ciabarra, Jangsup Moon, Ea Wha Kang, Mike Slaven, Paul A. Armstrong, Joseph C. Wu, Simone Fani, A Ornelas, Smita Kittur, Caroline Cowley, Jade Chapman, Stephen L. Graziano, Bernard J. Poiesz, Malakh Shrestha, Arthur Colby Sprague, Steven P. Stratton, Jennifer Ellis, B. Bashara, LUKAS BEDNAR, Jason Axt, Brian Hess, K. Ciliberti, Martina Parise, Thomas A. Willis, A. Shreefter, Catherine L. Gallagher, R Macchi, Keisuke Noto, R. Mansen, J. Kleiner, A. S. Kloman, R. Lamoureaux, Mitchell Clionsky, Sarah A. Marshall, Keith R. Edwards, Julia Kittler, E. Grandey, H. Majchrowski, T. Vittone, J. Ramsey-Rosenheim, Keith A. Johnson, D. Cheng, E. Kalinowsky, Andrew Plager, Scott McCauley, S. Steinman, J Steinman, Amy C. Reynolds, H Leland, K. Weslowski, M. Nash, Darin E. Olson, Jacqueline M. Miller, Karin Schindler, Josh Turknett, G. Yarbrough, Charlotte Panter, LaTeshia Thomas-Seaton, Karl Young, Sara P. Myers, L. Vedanarayanan, S. Golson, A. Bruflodt, Leah Craft, Nick Townsend, Y. Houssami, M. Brazeale, S Rozin, David A. Krendel, Patrick Kennedy, A. A. Schiff, M. Williamson, Y. Mohajermilani, A. Cutsuries, Maria Michelli, Carolyn C. Meltzer, S. Brufoldt, Sharon D. Chandler, C. Flemister, M. T. Whiting, David Gbadebo, Stephen L. Mayo, R. A. JACKSON, Nerina Jane Caltabiano, Cooper G. Hazelrig, Austin T. Mudd, J. Itzcovich-Schuster, M. Malamed, Michael D. Schreiber, Robert E. Ettlinger, Marshall Brown, Y. Grosz, L. Resille, William B. Smith, N. Matsoyan, R. Schuster, Emily Rose, Maggie Hayes, Joseph C. Wu, L. Labunsky, D. Svidler, Christopher P. Neal, Veronica Ramirez, Seyed Reza Hosseini, Celine Ossinalde, Janelle M. Haider, Jaron L. Winston, Craig Whitehead, Crystal F. Simpson, Lee D. Eisenberg, Douglas G. Walker, Roderick McColl, M. Plopper, Catherine R. Ayers, Asaf Berkowitz, Monte S. Buchsbaum, Michel Buda, Donna Cary, Jennifer M. Coughlin, Kim Dang, M. Dobrina, Matthew Geriak, T. Hessling, J. Highum, Carl K. Hoh, C. LoCascio, C. Morache, François Nicolas, C. Pirlliman, D. Tecca, Leslie Woods, Marvin Kalafer, Peter Pressman, Meghan Lyman, A. Cummins, A. Wilkening, S. Lombardo, Albert Dobi, A. Geiger, Arthur A. Levin, Carla Lombardo, Steven E. Arnold, M. Lobatz, Anat Blumenfeld, Jan Peter Heinen, Jack M. Rosenberg, Jack Schim, Guillermo F. López Sánchez, Thomas J. Chippendale, C. O’Neill-Conover, Mark Sadoff, A. Wang, E. Soto, B. Frishberg, Gregory Sahagian, A. Tenorio, Laura Hinkle, Inez Y. Oh, Carl K. Hoh, J. Brower, Linnea Banker, Monte S. Buchsbaum, James B. Brewer, M. Lehmer, Helen Vanderswag, David Fontaine, Guerry M. Peavy, Monte S. Buchsbaum, Edmund C. Jenkins, Christina Gigliotti, J. Gonzales, Sara Espinoza, Carl K. Hoh, Aimee Pierce, Junfeng Sun, Elizabeth D. Peña, Ricardo Espinoza, Ayesha Sherzai, Tobia Caccavale, Steven Tam, A.R.M. Wilson, Adrian Preda, Steven G. Potkin, Lawrence Faziola, Danh V. Nguyen, Andrew H. Kemp, Joseph C. Wu, Glenn Ramsey, Rosa Pellicer, N. D. Shah, L. Plon, Jane Upton, D. Hannaford, D. Highurn, Norah Milne, Nancy R. Barbas, Judith L. Heidebrink, Gaurang Shah, Bruno Giordani, Joanne Lord, Jill Rothley, Fung Peng Woon, Kristen Votruba, Christina Cline, Sarah J. Wilson, David W. Hammers, Dominique Powells, Laura S. Michalski, Tarin Coulas, Lindsay Franti, Andrew H. Ford, Molly McFadden, Oscar L. López, Robert A. Sweet, L. Macedonia, Howard Aizenstein, Sarah Berman, Thomas G. Baumgartner, Elizabeth Sarles, William E. Rothfus, Jamie R. Doyle, James M. Mountz, Dawn B. Simpson, Rock Heyman, W. Zachariah, J. Ruszhiewicz, William E. Klunk, Eric McDade, Claire M. Rickard, Kenneth S. Greenberg, David A. Wolk, Sanjay Asthana, Carey E. Gleason, Cindy Carlsson, Steven R. Barczi, Sterling C. Johnson, S. Claiborne Johnston, Padon Mary Sivesind, Zachary Zugin, Tamara S. Markgraf, Bradley Christian, Brigitta U. Mueller, Hanna Blazel, S. Harding, Jeffrey R. Sachs, Mark Wroblewski, M. Gassman, Christopher van Dyck, Rajesh R. Tampi, Rania S Abdel Aziz, G. Friedman, P. Whang, Kristina M. Reech, A Benincasa, S. Wiemers, Martha G. MacAvoy, Thomas Frye, Maria Cristina Vinci, Nicole Barcelos, Jia Hu, M. Corsi, Noriyuki Nishimura, P. Oellette, C. Ryan-Parsch, Jean Lopez, S. Mayeri, Mohsen Shamsi, Stephan F. Taylor, D. Ricitelli, Basel Azar, C. Beltran, R. Chivukulu, P Corréa, Lauren E. Wiznia, D. Cheng, Snigdha Vallabhaneni, Sunita K. Patel, S. Henry, N. Werdiger, J. Cleves-Bayon, Ilse R. Wiechers, Kathryn Paturzo, Harald A. Nygaard, Grace Bowen, T. Brisibe, P. Laborde-Lahoz, A. Wägner, M Nespoli, Shima Asis, Susan P. Good - Neurology 2015 被引用: 152

OBJECTIVE: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using (11)C-Pittsburgh compound B ((11)C-PiB)-PET. METHODS: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an (11)C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. RESULTS: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in (11)C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = -0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = -0.068; p = 0.027; 1.0 mg/kg vs placebo δ = -0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. CONCLUSIONS: The (11)C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.