Arnold Bakker, Nisha Rani, Richard Mohs, Michela Gallagher
{"title":"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","authors":"Arnold Bakker, Nisha Rani, Richard Mohs, Michela Gallagher","doi":"10.1002/trc2.70004","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Introduction</h3>\n \n <p>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 (<i>APOE</i>) 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 <i>APOE</i> ε4 non-carriers who completed the 78-week protocol.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Discussion</h3>\n \n <p>The HOPE4MCI study showed that <i>APOE</i> 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 <i>APOE</i> 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 <i>APOE</i> ε4 non-carriers treated with AGB101 before a clinical diagnosis of dementia.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (<i>APOE</i>) ε4 non-carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD).</li>\n \n <li>Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline.</li>\n \n <li>Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain.</li>\n \n <li>AGB101 treatment reduces neurodegeneration in <i>APOE</i> ε4 non-carriers with MCI due to AD.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70004","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"Arnold Bakker, Nisha Rani, Richard Mohs, Michela Gallagher\",\"doi\":\"10.1002/trc2.70004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Introduction</h3>\\n \\n <p>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 (<i>APOE</i>) 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 <i>APOE</i> ε4 non-carriers who completed the 78-week protocol.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Discussion</h3>\\n \\n <p>The HOPE4MCI study showed that <i>APOE</i> 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 <i>APOE</i> 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 <i>APOE</i> ε4 non-carriers treated with AGB101 before a clinical diagnosis of dementia.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (<i>APOE</i>) ε4 non-carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD).</li>\\n \\n <li>Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline.</li>\\n \\n <li>Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain.</li>\\n \\n <li>AGB101 treatment reduces neurodegeneration in <i>APOE</i> ε4 non-carriers with MCI due to AD.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":53225,\"journal\":{\"name\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"volume\":\"10 4\",\"pages\":\"\"},\"PeriodicalIF\":4.9000,\"publicationDate\":\"2024-10-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70004\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70004\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70004","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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
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.
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.
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