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Neurology. 2018 Mar 6;90(10):e877-e886. doi: 10.1212/WNL.0000000000005060. Epub 2018 Feb 2.

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

Collaborators (241)

Chair SS, Sperling R, Raskind M, Sabbagh M, Honig L, Porsteinsson A, Ferris S, Weisman D, McCartney M, Iqbal N, Dietrich D, Miller T, Hermann-Gertz J, Zimmerman E, Forchetti C, Dempsey GM, Ettigi P, Jacobson A, Zacharis A, Shua-Haim J, Mehra V, Markind S, Zagar D, Thompson J, Alva G, Fuller W, Rodd J, Steen S, Tariot P, Sabbagh M, Doody R, Severa L, Green P, Stern R, McElveen W, Brody M, Marshall G, Seiden D, Frank A, Salloway S, Kinney F, Litman R, Soufer J, Edelsohn L, Lesem M, Bernick C, Kluge R, Biton V, DeSantis M, Wang X, Usher G, Morin C, Omidvar O, Honig L, Curtis C, Licht J, Coffey D, Anderson C, Nash M, Stein M, Germain M, Nair V, Lippa C, Beyer J, Richardson B, Moore N, Vidic T, Igleburger J, Levey A, Edwards K, Steiner D, Chang F, Long J Jr, Turner R, Apter J, Barnhart B, Nash M, Schwartz R, Shatz R, Robillard A, Garcia A, Kohlenberg C, Matthews B, Chehrenama H, Garrison J 3rd, Shiwach R, Jennings D, Gazda S, Davtian A, Booker J, Rovner B, Goldenberg J, Raj A, Rosenberg P, Watkins F, Ingram J, Chertkow H, Yadalam K, Applebaum J, Biunno M, Minagar A, Rujescu D, Randhawa S, Dinnerstein E, Margolin D, Graff-Radford N, Knopman D, Antuono P, Wilks K, Du Preez M, Lichtenstein T, Barkhuizen F, Thebaud A, Liss J, Mintzer J, Dal-Bianco P, Schmidt R, Gold S, Farmer M, Agronin M, Kohrman B, Bozoki A, Kapper J Jr, Winegarner D, English J, Grossman H, Pomara N, Murman D, Spikol L, Malhotra S, Biber M, Burkholder J, Tramontano G, Harris J, Holub R, Kudrow D, Honeycutt W, Waldman S, Kittur S, Stein L, Gerard G, Cohen S, Goldstick L, Chueh D, Schaerf F, Nasreddine Z, Ellis J, Nash M, Shubin R, Gywnn M, Barker J 2nd, Wendt J, Mesulam M, Sadowski M, Quinn J, Mikszewski J, Tuchman M, Foley C, Borrie M, Arnold S, Rousseau R, Oskooilar N, Grosz D, Wilcox C, Kwentus J, Sadowsky C, Mega M, Carlini W, Ranjan R, Bowman M, Chakraburtty A, Nardandrea J, Sloan B, Ott B, Stoukides J, Keegan A, Bettinger I, Grossberg G, Goldstein J, Itzcovich-Schuster J, Winston J, Feldman R, Plopper M, Ferencz G, Ala T, Vatakis N, Montoya L, Rossen M, Stedman M, Pasternak S, Losk S, Cohen S, Ginsberg P, Ng B, Au W, Dolnak D, Tunell G, Marotta G, Ervin J, Kalafer M, Solomon P, Ross J, Scharre C, Lobatz M, Hubbard R, Lerner A, Ahern G, Patry D, DeCarli C, Grill J, Boxer A, Brewer J, Preda A, Mastrianni J, Burns J, Jicha G, Fishman P, Chopra A, Barbas N, Ford C, Lopez O, Porsteinsson A, Smith A, Auchus A, Rosenberg R, Eschweiler G, Riepe M, von Arnim C, Zamrini E, Dekosky S, Pendelbury W, Asthana S, Hart D, Raskind M, Trader D, Dougherty J Jr, Vine D, Carr D, Tornabene J, Keren R, van Dyck C.

Author information

1
From Janssen Research & Development, LLC (E.L.), La Jolla, CA; Janssen Research & Development, LLC (D.W., G.N., S.E.), Titusville, NJ; Brigham and Women's Hospital (R.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Brown University (S.S.), Providence, RI; UCL Institute of Neurology (N.C.F.), London, UK; Clinical Neurochemistry Lab, Department of Neuroscience and Physiology (K.B.), The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; VUMC (P.S.), Amsterdam, the Netherlands; Janssen Pharmaceuticals (M.E.S., J.S.), NV, Beerse, Belgium; Reference Center for Biological Markers of Dementia (BIODEM) (J.S.), Institute Born-Bunge, University of Antwerp, Belgium; Pfizer, Inc. (K.B.), Collegeville, PA; and Janssen Research & Development, LLC (N.K., H.R.B.), Fremont, CA. Enchi.liu@prothena.com.
2
From Janssen Research & Development, LLC (E.L.), La Jolla, CA; Janssen Research & Development, LLC (D.W., G.N., S.E.), Titusville, NJ; Brigham and Women's Hospital (R.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Brown University (S.S.), Providence, RI; UCL Institute of Neurology (N.C.F.), London, UK; Clinical Neurochemistry Lab, Department of Neuroscience and Physiology (K.B.), The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; VUMC (P.S.), Amsterdam, the Netherlands; Janssen Pharmaceuticals (M.E.S., J.S.), NV, Beerse, Belgium; Reference Center for Biological Markers of Dementia (BIODEM) (J.S.), Institute Born-Bunge, University of Antwerp, Belgium; Pfizer, Inc. (K.B.), Collegeville, PA; and Janssen Research & Development, LLC (N.K., H.R.B.), Fremont, CA.

Abstract

OBJECTIVE:

To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

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