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Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease

BACKGROUND: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer’s disease (AD) in a proof-of-concept trial. METHODS: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10–20 inclusive] with po...

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Autores principales: Cummings, Jeffrey L., Zhong, Kate, Kinney, Jefferson W., Heaney, Chelcie, Moll-Tudla, Joanne, Joshi, Abhinay, Pontecorvo, Michael, Devous, Michael, Tang, Anne, Bena, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731943/
https://www.ncbi.nlm.nih.gov/pubmed/26822146
http://dx.doi.org/10.1186/s13195-016-0173-2
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author Cummings, Jeffrey L.
Zhong, Kate
Kinney, Jefferson W.
Heaney, Chelcie
Moll-Tudla, Joanne
Joshi, Abhinay
Pontecorvo, Michael
Devous, Michael
Tang, Anne
Bena, James
author_facet Cummings, Jeffrey L.
Zhong, Kate
Kinney, Jefferson W.
Heaney, Chelcie
Moll-Tudla, Joanne
Joshi, Abhinay
Pontecorvo, Michael
Devous, Michael
Tang, Anne
Bena, James
author_sort Cummings, Jeffrey L.
collection PubMed
description BACKGROUND: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer’s disease (AD) in a proof-of-concept trial. METHODS: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10–20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer’s Disease Assessment Scale–Cognitive subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ(1–40) and Aβ(1–42) measurements were collected as biomarker outcomes. RESULTS: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ(1–42) and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. CONCLUSIONS: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ(1–42) in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0173-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-47319432016-01-30 Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease Cummings, Jeffrey L. Zhong, Kate Kinney, Jefferson W. Heaney, Chelcie Moll-Tudla, Joanne Joshi, Abhinay Pontecorvo, Michael Devous, Michael Tang, Anne Bena, James Alzheimers Res Ther Research BACKGROUND: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer’s disease (AD) in a proof-of-concept trial. METHODS: Twenty patients with AD [Mini Mental State Examination (MMSE) score 10–20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer’s Disease Assessment Scale–Cognitive subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ(1–40) and Aβ(1–42) measurements were collected as biomarker outcomes. RESULTS: There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ(1–42) and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. CONCLUSIONS: The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ(1–42) in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0173-2) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-29 /pmc/articles/PMC4731943/ /pubmed/26822146 http://dx.doi.org/10.1186/s13195-016-0173-2 Text en © Cummings et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Cummings, Jeffrey L.
Zhong, Kate
Kinney, Jefferson W.
Heaney, Chelcie
Moll-Tudla, Joanne
Joshi, Abhinay
Pontecorvo, Michael
Devous, Michael
Tang, Anne
Bena, James
Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease
title Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease
title_full Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease
title_fullStr Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease
title_full_unstemmed Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease
title_short Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease
title_sort double-blind, placebo-controlled, proof-of-concept trial of bexarotene xin moderate alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731943/
https://www.ncbi.nlm.nih.gov/pubmed/26822146
http://dx.doi.org/10.1186/s13195-016-0173-2
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