Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J; Li, Yan; McCullough, Austin A; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; ... Dominantly Inherited Alzheimer Network Trials Unit.; + view all Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J; Li, Yan; McCullough, Austin A; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M; Wang, Qing; Gordon, Brian A; Chen, Charles D; Flores, Shaney; Aggarwal, Neelum T; Berman, Sarah B; Bird, Thomas D; Black, Sandra E; Borowski, Bret; Brooks, William S; Chhatwal, Jasmeer P; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M; Farlow, Martin; Fox, Nick C; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A; Holdridge, Karen C; Honig, Lawrence S; Hornbeck, Russ C; Hsiung, Ging-Yuek R; Jack, Clifford R; Jimenez-Velazquez, Ivonne Z; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S; Mummery, Catherine J; Ringman, John M; Shimada, Hiroyuki; Snider, B Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J; Bateman, Randall J; Salloway, Stephen P; Benzinger, Tammie LS; Clifford, David B; Dominantly Inherited Alzheimer Network Trials Unit.; - view fewer (2022) Amyloid-related imaging abnormalities in the DIAN-TU-001 trial of gantenerumab and solanezumab: lessons from a trial in dominantly inherited Alzheimer disease. Annals of Neurology 10.1002/ana.26511. (In press).

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Abstract

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n=52), solanezumab IV (n=50), or placebo (n=40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (OR=9.1, CI[1.2, 412.3]; p=0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR=5.0, CI[1.0, 30.4]; p=0.055), as were individuals with microhemorrhage at baseline (OR=13.7, CI[1.2, 163.2]; p=0.039). No ARIA-E was observed at the initial 225mg/month gantenerumab dose, and most cases were observed at doses >675mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR>0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. This article is protected by copyright. All rights reserved.

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