Cummings Jeffrey L, Zhong Kate, Kinney Jefferson W, Heaney Chelcie, Moll-Tudla Joanne, Joshi Abhinay, Pontecorvo Michael, Devous Michael, Tang Anne, Bena James
Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue, Las Vegas, NV, 89106, USA.
Department of Psychology, University of Nevada, Las Vegas, NV, USA.
Alzheimers Res Ther. 2016 Jan 29;8:4. doi: 10.1186/s13195-016-0173-2.
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.
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 Aβ1-40 and Aβ1-42 measurements were collected as biomarker outcomes.
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 Aβ1-42 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.
The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1-42 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.
ClinicalTrials.gov identifier NCT01782742 . Registered 29 January 2013.
在一项概念验证试验中，我们评估了维甲酸X受体（RXR）激动剂贝沙罗汀对阿尔茨海默病（AD）患者经淀粉样蛋白成像测定的脑淀粉样蛋白的影响。
20例经氟代硼吡咯扫描呈阳性的AD患者[简易精神状态检查表（MMSE）评分在10至20分（含）之间]被随机分为两组，分别接受300毫克贝沙罗汀或安慰剂治疗4周。淀粉样蛋白成像结果为主要结局指标。进行了全人群分析以及按基因型[载脂蛋白Eε4（ApoE4）携带者和非携带者]进行的预先设定分析。次要结局指标包括阿尔茨海默病评估量表认知分量表评分、阿尔茨海默病协作研究日常生活活动量表评分、MMSE评分、临床痴呆评定量表评分以及神经精神科问卷评分。收集血清淀粉样蛋白-β（Aβ）肽序列Aβ1-40和Aβ1-42的测量值作为生物标志物结局指标。
当将所有患者纳入分析时，综合或区域淀粉样蛋白负荷没有变化。在六个区域测量中的五个测量中，ApoE4非携带者的综合测量显示脑淀粉样蛋白显著减少。在ApoE4携带者中未观察到淀粉样蛋白负荷的变化。在ApoE4非携带者中（而非携带者中），血清Aβ1-42升高与脑淀粉样蛋白减少之间存在显著关联。接受贝沙罗汀治疗的患者血清甘油三酯显著升高。任何临床指标均未出现一致变化。
该试验的主要结局为阴性。数据表明，贝沙罗汀可降低ApoE4非携带者的脑淀粉样蛋白水平并升高血清Aβ1-42。甘油三酯升高可能代表心血管风险，且贝沙罗汀不应在研究环境之外使用。RXR激动剂作为AD治疗方法值得进一步研究。
ClinicalTrials.gov标识符NCT01782742。于2013年1月29日注册。
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