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Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab

2018; Lippincott Williams & Wilkins; Volume: 90; Issue: 10 Linguagem: Inglês

10.1212/wnl.0000000000005060

1526-632X

Enchi Liu, Dai Wang, Reisa A. Sperling, Stephen Salloway, Nick C. Fox, Kaj Blennow, Philip Scheltens, Mark E. Schmidt, Johannes Streffer, Gerald Novak, Steve Einstein, Kevin Booth, Nzeera Ketter, H. Robert Brashear, SY Chair, Reisa A. Sperling, Murray A. Raskind, Marwan N. Sabbagh, Lawrence S. Honig, Anton P. Porsteinsson, Steven H. Ferris, David Weisman, Martha McCartney, N. Iqbal, D. Dietrich, Tasha Miller, J. Hermann-Gertz, Edward Zimmerman, Concetta Forchetti, G.M. Dempsey, Prakash G. Ettigi, A. Jacobson, Aristeidis Zacharis, Joshua R. Shua‐Haim, Varun Mehra, S. Markind, Drago Žagar, J N Thompson, Gus Alva, William Fuller, Jennifer M. Rodd, S. van der Steen, Pierre N. Tariot, Marwan N. Sabbagh, Rachelle S. Doody, L. Severa, P. Green, Robert A. Stern, W. McElveen, Mark Brody, Guillermo Marshall, David L. Seiden, Andrew Frank, Stephen Salloway, Fiona Kinney, Robert E. Litman, Joseph Soufer, Lanny Edelsohn, Michael D. Lesem, Charles Bernick, Reinhart Kluge, Victor Biton, Maria DeSantis, X. Wang, G.A. USHER, Christophe Morin, Omid Omidvar, Lawrence S. Honig, C. Martin Curtis, Jonathan D. Licht, David G. Coffey, C. Anderson, M. Nash, Mark S. Stein, Marcel Germain, V. Nair, Carol F. Lippa, J. Beyer, Barbora Richardson, Nicole M. Moore, Thomas R. Vidic, J. Igleburger, Allan I. Levey, Keith R. Edwards, D. Steiner, Fuju Chang, Julie M. Long, Raymond Scott Turner, Jeffrey Apter, B. Barnhart, M. Nash, Raymond Schwartz, Rhonna Shatz, A. Robillard, Ángeles García, Cary J. Kohlenberg, Benjamin Matthews, H. Chehrenama, Jered C. Garrison, Raj S. Shiwach, D. Jennings, Suzanne Gazda, A.A. Davtian, Jessica K. Booker, Barry W. Rovner, J. B. Goldenberg, Arjun Raj, Paul B. Rosenberg, F. Watkins, John C. L. Ingram, Howard Chertkow, Kashinath Yadalam, Jerachmiel Applebaum, Michael J. Biunno, Alireza Minagar, Dan Rujescu, Simran Randhawa, Eric Dinnerstein, David A. Margolin, Neill R. Graff‐Radford, David S. Knopman, Piero Antuono, Kerri Wilks, M.D. Du Preez, Thorsten Lichtenstein, F. Barkhuizen, Adly Thebaud, Julie Liss, Jacobo Mintzer, Peter Dal‐Bianco, Richard J. Schmidt, Stefan M. Gold, Mildred V. Farmer, Marc Agronin, Bruce Kohrman, Andrea Bozoki, J. Kapper, D. Winegarner, James English, Hillel Grossman, Nunzio Pomara, Daniel L. Murman, Lorraine Spikol, Sumit Malhotra, M. Biber, John A. Burkholder, Giuseppina Tramontano, Jay R. Harris, Richard Holub, David Kudrow, Wanda Honeycutt, Sarah Waldman, Smita Kittur, Lawrence Stein, G Gérard, S. Cohen, L. Goldstick, Di‐Yen Chueh, Frederick W. Schaerf, Ziad Nasreddine, Jennifer L. Ellis, M. Nash, Richard Shubin, M. Gywnn, Juliet N. Barker, Julie Wendt, Marek M. Mesulam, Martin Sadowski, Joseph Quinn, Jessica S. Mikszewski, Michael Tuchman, C. Michael Foley, Michael Borrie, Steven E. Arnold, Roxanne Rousseau, Nader Oskooilar, Daniel Grosz, C. Mel Wilcox, J. Kwentus, Cyril Sadowsky, Michael S. Mega, Walter G. Carlini, Rakesh Ranjan, M. Bowman, Amil Chakraburtty, John Nardandrea, Brendan Sloan, Brian R. Ott, John Stoukides, A. Keegan, I Bettinger, George T. Grossberg, Jerome Goldstein, J. Itzcovich-Schuster, Jaron L. Winston, Rebecca Feldman, M. Plopper, G. Ferencz, Tom Ala, Nick G. Vatakis, L. Montoya, M.E.E. van Rossen, Mike Stedman, S. Pasternak, Scott Losk, S. Cohen, Phillip C. Ginsberg, Bernard Ng, WY Au, Douglas Dolnak, G. Tunell, Giorgio Marotta, John F. Ervin, Marvin Kalafer, Paul R. Solomon, Jeffrey Ross, C. Scharre, M. Lobatz, Richard C. Hubbard, A. Lerner, Geoffrey L. Ahern, D. Patry, Charles DeCarli, J. Grill, Adam Boxer, James Brewer, Adrian Preda, James A. Mastrianni, Jeffrey M. Burns, Gregory A. Jicha, Paul Fishman, A. Chopra, Nancy R. Barbas, C. J. B. Ford, Oscar L. López, Anton P. Porsteinsson, A. David Smith, Alexander P. Auchus, R. Rosenberg, Gerhard W. Eschweiler, Matthias W. Riepe, Christine A. F. Von Arnim, Edward Zamrini, Steven T. DeKosky, W. Pendelbury, S. Asthana, David Hart, Murray A. Raskind, Daniel Träder, James Dougherty, Donna F. Vine, David B. Carr, Joseph Tornabene, Ron Keren, Christopher van Dyck,

Neuroinflammation and Neurodegeneration Mechanisms

To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns.Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed.A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Aβ42 in APOE ε4 noncarrier ARIA-E vs non-ARIA-E groups (bapineuzumab non-ARIA-E p = 0.027; placebo non-ARIA-E p = 0.012). At week 71, bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p-tau) (all comparisons p < 0.01), and total tau (t-tau) (all comparisons p < 0.025), and greater hippocampal volume reduction and ventricular enlargement (all p < 0.05). Greater reduction in CSF Aβ40 concentrations was observed for ARIA-E versus both non-ARIA-E groups (bapineuzumab/placebo non-ARIA-E p = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Aβ42.Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.