The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease

IF 4.9 Q1 CLINICAL NEUROLOGY Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2024-10-11 DOI:10.1002/trc2.70004

Arnold Bakker, Nisha Rani, Richard Mohs, Michela Gallagher

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Abstract

Introduction

Hippocampal hyperactivity is a hallmark of prodromal Alzheimer's disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended-release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI study was a 78-week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR-SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non-carriers over the 78-week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non-carriers who completed the 78-week protocol.

Methods

Structural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were analyzed for plasma biomarkers.

Results

Treatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR-SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration.

Discussion

The HOPE4MCI study showed that APOE ε4 non-carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non-carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR-SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non-carriers treated with AGB101 before a clinical diagnosis of dementia.

Highlights

AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non-carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD).
Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline.
Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain.
AGB101 treatment reduces neurodegeneration in APOE ε4 non-carriers with MCI due to AD.

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HOPE4MCI 研究：AGB101 治疗可延缓 APOE ε4 非携带者因阿尔茨海默病导致的轻度认知障碍的内叶皮质萎缩进展速度

引言海马活动亢进是阿尔茨海默病（AD）前驱期的一个特征，可预测失忆性轻度认知障碍（aMCI）患者的病情发展。AGB101 是左乙拉西坦的缓释制剂，其剂量范围曾被证实可使海马活动恢复正常并改善 aMCI 患者的认知能力。HOPE4MCI 研究是一项为期 78 周的试验，旨在评估注意力缺失所致 MCI 的进展情况。正如 Mohs 等人报告的那样，在为期 78 周的研究中，载脂蛋白 E（APOE）ε4 非携带者的临床痴呆评级方框总分（CDR-SB）下降了 40%，而对携带者的影响微乎其微。我们在此报告一项探索性分析，分析 AGB101 对完成 78 周方案的 44 名 APOE ε4 非携带者的神经影像学和生物标志物测量的影响。方法使用海马亚区自动分割软件分析基线和 78 周后获得的结构性磁共振成像扫描，该软件提供了与 AD 进展相关的内侧颞叶关键结构的体积测量值。在研究的第 78 周收集的血样用于分析血浆生物标志物。结果与安慰剂相比，AGB101 能显著减少左侧内侧皮层 (ERC) 的萎缩。萎缩程度的减轻与 78 周内 CDR-SB 评分下降较少以及神经变性标志物神经丝蛋白轻链（NfL）降低有关。讨论 HOPE4MCI 研究表明，APOE ε4 非携带者接受 AGB101 治疗的疗效比携带者好得多。我们在此报告，APOE ε4 非携带者接受 AGB101 治疗 78 周后，左侧 ERC 萎缩明显减少。萎缩的减少与 CDR-SB 和血浆 NfL 的变化密切相关，而血浆 NfL 表明大脑神经变性。这些探索性分析表明，APOE ε4非携带者在临床诊断出痴呆症之前接受AGB101治疗可减少神经变性。研究亮点：AGB101能减缓因阿尔茨海默病（AD）导致轻度认知障碍（MCI）的载脂蛋白E（APOE）ε4非携带者的内侧皮层（ERC）萎缩。 AGB101 可延缓 ERC 萎缩，从而减少临床痴呆症评分总和（Clinical Dementia Rating Sum of Boxes）的下降。 AGB101可减缓ERC萎缩，这与神经丝轻链降低有关。 AGB101治疗可减少APOE ε4非携带者因AD引起的MCI的神经退行性变。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.