Enchi Liu1, Dai Wang2, Reisa Sperling2, Stephen Salloway2, Nick C Fox2, Kaj Blennow2, Philip Scheltens2, Mark E Schmidt2, Johannes Streffer2, Gerald Novak2, Steve Einstein2, Kevin Booth2, Nzeera Ketter2, H Robert Brashear2. 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.
RCT Entities:
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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