BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain
BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain
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DOI：
10.1093/brain/awaa332
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发表时间：
2020-12-01
期刊：
影响因子：
14.5
通讯作者：
Egan, Michael F.
中科院分区：
文献类型：
--
作者：
Sur, Cyrille;Kost, James;Egan, Michael F.
在第三阶段的EPOCH试验(ClinicalTrials.gov；NCT01739348)中，BACE抑制剂verubecestat的治疗未能改善轻至中度阿尔茨海默病患者的认知能力，但与78周后MRI评估的海马体体积缩小有关。本探索性分析的目的是：(I)通过评估不同大脑区域的体积MRI变化的时间进程来表征verubecestat对脑体积的影响；以及(Ii)通过评估verubecestat与淀粉样蛋白、神经退行性变和认知的指标的关系，了解verubecestat可能导致海马区(和其他大脑区域)体积损失的机制。受试者年龄在55-85岁之间，可能患有阿尔茨海默病痴呆症，迷你精神状态检查得分分别为15分和0.27分。治疗78周时，Verubecestat组和安慰剂组的脑脊液神经丝轻链水平变化无显著差异(Verubecestat组分别增加7.2和14.6pg/ml，安慰剂组分别增加19.7pg/ml，P=0.1)。在78周时，包括安慰剂在内的所有组的体积MRI改变与认知功能下降之间存在中等程度的相关性(例如，r=-0.45~-0.55，P
In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score >= 15 and 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values >= 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P