在使用 bapineuzumab 的 3 期随机临床试验中，ARIA-E 参与者的生物标志物模式。

Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab.

机构信息

From Janssen Research & Development, LLC (E.L.), La Jolla, CA; Janssen Research & Development, LLC (D.W., G.N., S.E.), Titusville, NJ; Brigham and Women's Hospital (R.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Brown University (S.S.), Providence, RI; UCL Institute of Neurology (N.C.F.), London, UK; Clinical Neurochemistry Lab, Department of Neuroscience and Physiology (K.B.), The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; VUMC (P.S.), Amsterdam, the Netherlands; Janssen Pharmaceuticals (M.E.S., J.S.), NV, Beerse, Belgium; Reference Center for Biological Markers of Dementia (BIODEM) (J.S.), Institute Born-Bunge, University of Antwerp, Belgium; Pfizer, Inc. (K.B.), Collegeville, PA; and Janssen Research & Development, LLC (N.K., H.R.B.), Fremont, CA.

出版信息

Neurology. 2018 Mar 6;90(10):e877-e886. doi: 10.1212/WNL.0000000000005060. Epub 2018 Feb 2.

DOI:10.1212/WNL.0000000000005060

PMID:29429971

Abstract

OBJECTIVE

To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns.

METHODS

Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed.

RESULTS

A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Aβ in ε4 noncarrier ARIA-E vs non-ARIA-E groups (bapineuzumab non-ARIA-E = 0.027; placebo non-ARIA-E = 0.012). At week 71, bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p-tau) (all comparisons < 0.01), and total tau (t-tau) (all comparisons < 0.025), and greater hippocampal volume reduction and ventricular enlargement (all < 0.05). Greater reduction in CSF Aβ concentrations was observed for ARIA-E versus both non-ARIA-E groups (bapineuzumab/placebo non-ARIA-E = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Aβ.

CONCLUSIONS

Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.

摘要

目的

评估 bapineuzumab 临床试验中观察到的伴有水肿/渗出的淀粉样蛋白相关影像异常（ARIA-E）是否与特定的生物标志物模式相关。

方法

bapineuzumab 是一种抗β-淀粉样蛋白单克隆抗体，用于评估轻度至中度阿尔茨海默病患者。评估了淀粉样蛋白 PET 成像、CSF 生物标志物或容积 MRI（vMRI）。

结果

共有 1512 名参与者接受了一项或多项生物标志物评估；154 名参与者出现了偶发性 ARIA-E。在基线时，通过 PET 评估脑淀粉样蛋白负荷、大多数 vMRI 测量值或 CSF 生物标志物，ARIA-E 与非 ARIA-E 参与者之间没有差异，除了在非 ε4 携带者 ARIA-E 组中 CSF Aβ 基线值较低（bapineuzumab 非 ARIA-E 组=0.027；安慰剂非 ARIA-E 组=0.012）。在第 71 周时，与非 ARIA-E 组相比，bapineuzumab 治疗的 ARIA-E 参与者的脑淀粉样蛋白 PET 减少更多，CSF 磷酸化 tau（p-tau）（所有比较均<0.01）和总 tau（t-tau）（所有比较均<0.025）减少更多，以及海马体积减少和脑室扩大（均<0.05）更多。与非 ARIA-E 组相比，ARIA-E 组 CSF Aβ 浓度的降低更明显（bapineuzumab/安慰剂非 ARIA-E 组=0.015/0.049）。在第 71 周时，未观察到各组在全脑容积或 CSF Aβ 变化方面存在差异。

结论

基线生物标志物在很大程度上不能预测发生 ARIA-E 的风险。ARIA-E 与几个生物标志物的纵向显著变化相关，淀粉样蛋白 PET 和 CSF p-tau 和 t-tau 浓度的降低更大，矛盾的是海马体积的减少和脑室的扩大更大，这表明 bapineuzumab 治疗病例中的 ARIA-E 可能与大脑中 Aβ 的流出增加和影响下游发病过程有关。