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Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

Authors :
Joseph-Mathurin N
Llibre-Guerra JJ
Li Y
McCullough AA
Hofmann C
Wojtowicz J
Park E
Wang G
Preboske GM
Wang Q
Gordon BA
Chen CD
Flores S
Aggarwal NT
Berman SB
Bird TD
Black SE
Borowski B
Brooks WS
Chhatwal JP
Clarnette R
Cruchaga C
Fagan AM
Farlow M
Fox NC
Gauthier S
Hassenstab J
Hobbs DA
Holdridge KC
Honig LS
Hornbeck RC
Hsiung GR
Jack CR Jr
Jimenez-Velazquez IZ
Jucker M
Klein G
Levin J
Mancini M
Masellis M
McKay NS
Mummery CJ
Ringman JM
Shimada H
Snider BJ
Suzuki K
Wallon D
Xiong C
Yaari R
McDade E
Perrin RJ
Bateman RJ
Salloway SP
Benzinger TLS
Clifford DB
Source :
Annals of neurology [Ann Neurol] 2022 Nov; Vol. 92 (5), pp. 729-744. Date of Electronic Publication: 2022 Oct 13.
Publication Year :
2022

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).<br />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.<br />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 (odds ratio [OR] = 9.1, confidence interval [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 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. 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.<br />Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg 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. ANN NEUROL 2022;92:729-744.<br /> (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Details

Language :
English
ISSN :
1531-8249
Volume :
92
Issue :
5
Database :
MEDLINE
Journal :
Annals of neurology
Publication Type :
Academic Journal
Accession number :
36151869
Full Text :
https://doi.org/10.1002/ana.26511