Pub Date : 2024-10-01DOI: 10.1016/S1474-4422(24)00335-1
Christopher R S Belder, Delphine Boche, James A R Nicoll, Zane Jaunmuktane, Henrik Zetterberg, Jonathan M Schott, Frederik Barkhof, Nick C Fox
Progressive cerebral volume loss on MRI is a hallmark of Alzheimer's disease and has been widely used as an outcome measure in clinical trials, with the prediction that disease-modifying treatments would slow loss. However, in trials of anti-amyloid immunotherapy, the participants who received treatment had excess volume loss. Explanations for this observation range from reduction of amyloid β plaque burden and related inflammatory changes through to treatment-induced toxicity. The excess volume changes are characteristic of only those immunotherapies that achieve amyloid β lowering; are compatible with plaque removal; and evidence to date does not suggest an association with harmful effects. Based on the current evidence, we suggest that these changes can be described as amyloid-removal-related pseudo-atrophy. Better understanding of the causes and consequences of these changes is important to enable informed decisions about treatments. Patient-level analyses of data from the trials are urgently needed, along with longitudinal follow-up and neuroimaging data, to determine the long-term trajectory of these volume changes and their clinical correlates. Post-mortem examination of cerebral tissue from treated patients and evaluation of potential correlation with antemortem neuroimaging findings are key priorities.
{"title":"Brain volume change following anti-amyloid β immunotherapy for Alzheimer's disease: amyloid-removal-related pseudo-atrophy.","authors":"Christopher R S Belder, Delphine Boche, James A R Nicoll, Zane Jaunmuktane, Henrik Zetterberg, Jonathan M Schott, Frederik Barkhof, Nick C Fox","doi":"10.1016/S1474-4422(24)00335-1","DOIUrl":"10.1016/S1474-4422(24)00335-1","url":null,"abstract":"<p><p>Progressive cerebral volume loss on MRI is a hallmark of Alzheimer's disease and has been widely used as an outcome measure in clinical trials, with the prediction that disease-modifying treatments would slow loss. However, in trials of anti-amyloid immunotherapy, the participants who received treatment had excess volume loss. Explanations for this observation range from reduction of amyloid β plaque burden and related inflammatory changes through to treatment-induced toxicity. The excess volume changes are characteristic of only those immunotherapies that achieve amyloid β lowering; are compatible with plaque removal; and evidence to date does not suggest an association with harmful effects. Based on the current evidence, we suggest that these changes can be described as amyloid-removal-related pseudo-atrophy. Better understanding of the causes and consequences of these changes is important to enable informed decisions about treatments. Patient-level analyses of data from the trials are urgently needed, along with longitudinal follow-up and neuroimaging data, to determine the long-term trajectory of these volume changes and their clinical correlates. Post-mortem examination of cerebral tissue from treated patients and evaluation of potential correlation with antemortem neuroimaging findings are key priorities.</p>","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 10","pages":"1025-1034"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/S1474-4422(24)00370-3
Bradley T Hyman
{"title":"Amyloid removal and the appearance of brain volume loss.","authors":"Bradley T Hyman","doi":"10.1016/S1474-4422(24)00370-3","DOIUrl":"10.1016/S1474-4422(24)00370-3","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 10","pages":"957-958"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/S1474-4422(24)00320-X
Vinojini Vivekanandam, Iwona Skorupinska, Dipa L Jayaseelan, Emma Matthews, Richard J Barohn, Michael P McDermott, Michael G Hanna
<p><strong>Background: </strong>Non-dystrophic myotonias are skeletal muscle channelopathies caused by ion channel dysfunction. Symptom onset is frequently in the first decade of life, causing disability in a young cohort. Although there is no cure, symptomatic treatments exist. Previous trials provide evidence of the efficacy of mexiletine. More recently, lamotrigine has been shown to be effective. Both treatments have different profiles, including pharmacokinetics and adverse events. This trial aimed to investigate whether lamotrigine is non-inferior to mexiletine to directly inform clinical practice.</p><p><strong>Methods: </strong>We did a randomised, double-blind, crossover, non-inferiority, phase 3 trial at the National Hospital for Neurology and Neurosurgery (London, UK). Participants (aged ≥18 years) who had genetically confirmed symptomatic non-dystrophic myotonia were randomly assigned (1:1), by means of a block randomisation schedule created by a computer program, to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine, with a 7-day washout period in between. Investigators and participants were masked to treatment allocation. The primary outcome measure was the mean interactive voice response (IVR) diary stiffness score (0-9 scale) over the participant's final 2 weeks of diary reporting in each treatment period. Non-inferiority was assessed using a mixed-effects model with a predefined margin of 0·5 and included all randomly assigned participants who contributed at least 7 days of IVR-diary data in either treatment period. The trial is registered at ClinicalTrials.gov, NCT05017155, and EudraCT, 2020-003375-17.</p><p><strong>Findings: </strong>Between Aug 1, 2021, and Dec 12, 2022, of 60 participants were screened (24 females and 36 males) and randomly assigned between Aug 1, 2021 and Dec 12, 2022, to either the mexiletine-lamotrigine sequence (n=30) or the lamotrigine-mexiletine sequence (n=30). 53 participants contributed data to the primary analysis. The mean IVR stiffness score after treatment with mexiletine was 2·54 (95% CI 1·98 to 3·10) versus 2·77 (2·21 to 3·32) with lamotrigine (mean mexiletine-lamotrigine difference -0·23 [95% CI -0·63 to 0·17]). The most common adverse event with both treatments was indigestion-reflux (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine). No serious adverse events were reported.</p><p><strong>Interpretation: </strong>We were unable to conclude that lamotrigine is non-inferior to mexiletine; however, improvements in all outcome measures from baseline were similar between lamotrigine and mexiletine. Lamotrigine is an important treatment consideration in non-dystrophic myotonias alongside mexiletine; we propose a treatment algorithm to guide clinical practice.</p><p><strong>Funding: </strong>Neuromuscular Study Group, Jon Moulton Charity Trust, UCLH BRC Fast Track
背景：非萎缩性肌营养不良症是由离子通道功能障碍引起的骨骼肌通道病。该病通常在患者出生后的头十年发病，导致年轻群体致残。虽然无法治愈，但有对症治疗方法。以前的试验证明了美西律汀的疗效。最近，拉莫三嗪也被证明有效。这两种治疗方法具有不同的特点，包括药代动力学和不良反应。本试验旨在研究拉莫三嗪是否不劣于甲西利定，从而为临床实践提供直接参考：我们在英国国立神经病学和神经外科医院（伦敦）进行了一项随机、双盲、交叉、非劣效性的三期试验。参试者（年龄≥18岁）经基因证实患有症状性非肌营养不良性肌张力障碍，他们通过计算机程序创建的分块随机分配表（1:1）被随机分配到两种药物中，一种是先接受8周的阿西列汀治疗，然后再接受8周的拉莫三嗪治疗，另一种是先接受拉莫三嗪治疗，然后再接受阿西列汀治疗，中间有7天的冲洗期。研究人员和参与者均被蒙蔽，不知道治疗分配。主要结果测量指标是每个治疗期间参与者最后两周的交互式语音应答（IVR）日记僵硬度平均得分（0-9分制）。采用混合效应模型评估非劣效性，预设差值为 0-5，包括所有在任一治疗期提供至少 7 天 IVR 日志数据的随机分配参与者。该试验已在 ClinicalTrials.gov 和 EudraCT 注册，注册号分别为 NCT05017155 和 2020-003375-17：2021年8月1日至2022年12月12日期间，共筛选了60名参与者（24名女性和36名男性），并在2021年8月1日至2022年12月12日期间随机分配到甲西利定-拉莫三嗪序列（30人）或拉莫三嗪-甲西利定序列（30人）。53 名参与者为主要分析提供了数据。使用甲西利定治疗后，IVR僵硬度平均得分为2-54（95% CI 1-98至3-10），而使用拉莫三嗪为2-77（2-21至3-32）（甲西利定-拉莫三嗪平均差异为-0-23 [95% CI -0-63至0-17]）。两种疗法最常见的不良反应都是消化不良-反流（8 名患者，208 个疗程服用甲西利汀；7 名患者，130 个疗程服用拉莫三嗪）。没有严重不良事件的报告：我们无法得出拉莫三嗪不劣于甲西利汀的结论；但是，拉莫三嗪和甲西利汀的所有结果指标与基线相比均有相似的改善。拉莫三嗪是非肌萎缩性肌病治疗的一个重要考虑因素，可与麦西来坦并用；我们提出了一种治疗算法，以指导临床实践：Neuromuscular Study Group、Jon Moulton Charity Trust、UCLH BRC Fast Track Grant。
{"title":"Mexiletine versus lamotrigine in non-dystrophic myotonias: a randomised, double-blind, head-to-head, crossover, non-inferiority, phase 3 trial.","authors":"Vinojini Vivekanandam, Iwona Skorupinska, Dipa L Jayaseelan, Emma Matthews, Richard J Barohn, Michael P McDermott, Michael G Hanna","doi":"10.1016/S1474-4422(24)00320-X","DOIUrl":"10.1016/S1474-4422(24)00320-X","url":null,"abstract":"<p><strong>Background: </strong>Non-dystrophic myotonias are skeletal muscle channelopathies caused by ion channel dysfunction. Symptom onset is frequently in the first decade of life, causing disability in a young cohort. Although there is no cure, symptomatic treatments exist. Previous trials provide evidence of the efficacy of mexiletine. More recently, lamotrigine has been shown to be effective. Both treatments have different profiles, including pharmacokinetics and adverse events. This trial aimed to investigate whether lamotrigine is non-inferior to mexiletine to directly inform clinical practice.</p><p><strong>Methods: </strong>We did a randomised, double-blind, crossover, non-inferiority, phase 3 trial at the National Hospital for Neurology and Neurosurgery (London, UK). Participants (aged ≥18 years) who had genetically confirmed symptomatic non-dystrophic myotonia were randomly assigned (1:1), by means of a block randomisation schedule created by a computer program, to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine, with a 7-day washout period in between. Investigators and participants were masked to treatment allocation. The primary outcome measure was the mean interactive voice response (IVR) diary stiffness score (0-9 scale) over the participant's final 2 weeks of diary reporting in each treatment period. Non-inferiority was assessed using a mixed-effects model with a predefined margin of 0·5 and included all randomly assigned participants who contributed at least 7 days of IVR-diary data in either treatment period. The trial is registered at ClinicalTrials.gov, NCT05017155, and EudraCT, 2020-003375-17.</p><p><strong>Findings: </strong>Between Aug 1, 2021, and Dec 12, 2022, of 60 participants were screened (24 females and 36 males) and randomly assigned between Aug 1, 2021 and Dec 12, 2022, to either the mexiletine-lamotrigine sequence (n=30) or the lamotrigine-mexiletine sequence (n=30). 53 participants contributed data to the primary analysis. The mean IVR stiffness score after treatment with mexiletine was 2·54 (95% CI 1·98 to 3·10) versus 2·77 (2·21 to 3·32) with lamotrigine (mean mexiletine-lamotrigine difference -0·23 [95% CI -0·63 to 0·17]). The most common adverse event with both treatments was indigestion-reflux (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine). No serious adverse events were reported.</p><p><strong>Interpretation: </strong>We were unable to conclude that lamotrigine is non-inferior to mexiletine; however, improvements in all outcome measures from baseline were similar between lamotrigine and mexiletine. Lamotrigine is an important treatment consideration in non-dystrophic myotonias alongside mexiletine; we propose a treatment algorithm to guide clinical practice.</p><p><strong>Funding: </strong>Neuromuscular Study Group, Jon Moulton Charity Trust, UCLH BRC Fast Track","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 10","pages":"1004-1012"},"PeriodicalIF":45.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-22DOI: 10.1016/S1474-4422(24)00364-8
Alfred K Njamnshi, Agustin Ibanez, Gagandeep Singh, Mika Pyykko, Vladimir Hachinski, Harris A Eyre
{"title":"The Yaoundé Declaration.","authors":"Alfred K Njamnshi, Agustin Ibanez, Gagandeep Singh, Mika Pyykko, Vladimir Hachinski, Harris A Eyre","doi":"10.1016/S1474-4422(24)00364-8","DOIUrl":"10.1016/S1474-4422(24)00364-8","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"966-967"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/S1474-4422(24)00336-3
Maria Pia Sormani, Heinz Wiendl
{"title":"Non-inferiority design for trials in multiple sclerosis.","authors":"Maria Pia Sormani, Heinz Wiendl","doi":"10.1016/S1474-4422(24)00336-3","DOIUrl":"10.1016/S1474-4422(24)00336-3","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 10","pages":"970"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/S1474-4422(24)00375-2
Peter Ranscombe
{"title":"On the trail of Edinburgh's neuroscience past and present.","authors":"Peter Ranscombe","doi":"10.1016/S1474-4422(24)00375-2","DOIUrl":"10.1016/S1474-4422(24)00375-2","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 10","pages":"972"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/S1474-4422(24)00359-4
Ray Cavanaugh
{"title":"Christopher Ross: diseases of the brain, not the mind.","authors":"Ray Cavanaugh","doi":"10.1016/S1474-4422(24)00359-4","DOIUrl":"10.1016/S1474-4422(24)00359-4","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 10","pages":"968"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号