视网膜光学相干断层扫描测量在 Verubecestat 阿尔茨海默病临床试验中保持不变，但与基线区域脑萎缩相关。

Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer's Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy.

机构信息

Wills Eye Hospital, and Annesley Eye Brain Center, Thomas Jefferson University, Philadelphia, PA, USA.

Merck & Co., Inc., Kenilworth, NJ, USA.

出版信息

J Alzheimers Dis. 2021;79(1):275-287. doi: 10.3233/JAD-200735.

DOI:10.3233/JAD-200735

PMID:33252075

Abstract

BACKGROUND

We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD).

OBJECTIVE

To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy.

METHODS

Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo.

RESULTS

Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant.

CONCLUSION

BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline.

TRIAL REGISTRATION

Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

摘要

背景

我们对阿尔茨海默病（AD）患者中 AβPP 裂解酶（BACE）抑制剂 verubecestat 的临床试验中的视网膜厚度数据进行了探索性分析。

目的

评估：1）BACE 抑制后可能发生的视网膜厚度变化；2）视网膜厚度与脑萎缩之间的可能关联。

方法

在一项为期 78 周的、针对 verubecestat 的随机安慰剂对照临床试验中，使用频域光学相干断层扫描对 1785 例轻中度 AD 患者的视网膜厚度进行了测量。评估 verubecestat 与安慰剂相比在视网膜色素上皮、黄斑网格视网膜神经纤维层、中央眼底视网膜厚度和黄斑网格容积方面的基线变化。进行相关分析以研究黄斑网格视网膜神经纤维层和中央眼底视网膜厚度与基线时脑容积磁共振成像（vMRI）数据之间的潜在关联，以及在接受安慰剂的患者中第 78 周时的基线变化的相关性。

结果

与安慰剂相比，verubecestat 在试验期间并未显著改变视网膜厚度。基线时，黄斑网格视网膜神经纤维层和中央眼底视网膜厚度的平均值与包括整个大脑、海马体和丘脑在内的几个脑区的 vMRI 呈弱但显著相关（Pearson r 值≤0.23，p 值<0.01）。在第 78 周，安慰剂组中视网膜厚度与脑 vMRI 从基线的变化之间的相关性较小，且大多无统计学意义。