Time saved in activities of daily living and whole-brain volume: Post hoc analysis of a randomized feasibility trial of gamma oscillation treatment in participants with mild or moderate Alzheimer's disease

IF 6.8 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-06-11 DOI:10.1002/trc2.70118

Ralph Kern, Benjamin Haaland, Jessie Nicodemus-Johnson, Samuel Dickson, Matthew Morgan, Joshua R. Christensen, Marwan N. Sabbagh, Lily Lee, Mihaly Hajós, Julia Riddle, Chandran V. Seshagiri, Christian Howell, Craig Mallinckrodt, Suzanne Hendrix

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引用次数: 0

Abstract

INTRODUCTION

Gamma oscillations in the brain are necessary for normal cognitive function, sensory processing, and memory consolidation, and are reduced in Alzheimer's disease (AD). In a 6 month, randomized, feasibility trial in participants with mild-to-moderate AD (OVERTURE [NCT03556280], n = 76), a non-invasive method for sensory-evoked brain gamma oscillations outperformed sham on the secondary outcomes of slowing decline on the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) functional scale, magnetic resonance imaging measures of whole brain volume and the Mini-Mental State Examination (MMSE) cognitive outcome, despite not showing statistical significance on the primary outcome (Mild and Moderate Alzheimer's Disease Composite [MADCOMS]), a composite cognitive-functional score. In this post hoc analysis of OVERTURE, we evaluated the effects of investigational sensory-evoked gamma oscillation treatment in terms of time saved, as an estimate of slowing in disease progression, on ADCS-ADL, MMSE, and whole-brain volume.

METHODS

Disease trajectories based on the ADCS-ADL, MMSE, and whole-brain volume changes from baseline within each treatment group were constructed using mixed-effects models. Horizontal projection from active to sham arm yielded time saved from baseline at each visit. Data from the open label extension (OLE) phase of the OVERTURE study have also been used to analyze the time-saving effect of active treatment in an extended period.

RESULTS

Compared to sham, time savings of 4.83, 4.59, and 4.09 months over 6 months of active treatment on ADCS-ADL, MMSE, and whole-brain atrophy were observed in the randomized controlled trial phase. When including the OLE phase, time savings of 8.66, 10.00, and 7.48 months over 14.64, 15.98, and 13.46 months of active treatment on ADCS-ADL, MMSE, and whole-brain atrophy were observed relative to the sham group.

DISCUSSION

These findings suggest that further exploration of the effect of evoked gamma oscillations in participants with mild-to-moderate AD, as well as the evaluation of treatment effects using time saved, is merited.

Highlights

Evoked gamma oscillation slows functional loss and brain atrophy in Alzheimer's disease.
Slowing of functional and cognitive decline and brain atrophy worsening can be expressed as time saved.
Evoked gamma oscillation saves 4.83 months of progression in activities of daily living, 4.59 months of progression in Mini-Mental State Examination, and 4.09 months of decline in whole-brain volume over 6 months.

Abstract Image

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日常生活活动节省的时间和全脑容量：对轻度或中度阿尔茨海默病参与者进行伽马振荡治疗的随机可行性试验的事后分析

大脑中的伽马振荡对于正常的认知功能、感觉处理和记忆巩固是必要的，并且在阿尔茨海默病（AD）中减少。在一项针对轻中度AD患者的为期6个月的随机可行性试验（OVERTURE [NCT03556280], n = 76）中，感觉诱发脑γ振荡的非侵入性方法在阿尔茨海默病日常生活活动合作研究（ADCS-ADL）功能量表、全脑容量磁共振成像测量和迷你精神状态检查（MMSE）认知结果减缓衰退的次要结果上优于假手术。尽管在主要结局（轻度和中度阿尔茨海默病复合[MADCOMS]），复合认知功能评分方面没有显示出统计学意义。在这项对OVERTURE的事后分析中，我们评估了实验性感觉诱发伽马振荡治疗在ADCS-ADL、MMSE和全脑容量方面节省的时间，作为疾病进展减缓的估计。方法使用混合效应模型构建基于每个治疗组ADCS-ADL、MMSE和全脑容量从基线变化的疾病轨迹。从活动臂到假臂的水平投影使每次就诊的时间比基线节省。来自OVERTURE研究开放标签扩展（OLE）阶段的数据也被用于分析延长时间内积极治疗的节省时间效果。结果：与假手术相比，在随机对照试验阶段，积极治疗ADCS-ADL、MMSE和全脑萎缩6个月后，分别节省4.83、4.59和4.09个月的时间。当包括OLE期时，与假手术组相比，积极治疗ADCS-ADL、MMSE和全脑萎缩的时间分别节省了8.66、10.00和7.48个月，分别为14.64、15.98和13.46个月。这些发现表明，值得进一步探索诱发伽马振荡对轻度至中度AD患者的影响，以及使用节省的时间来评估治疗效果。诱发伽马振荡减缓阿尔茨海默病的功能丧失和脑萎缩。功能和认知衰退的减缓以及脑萎缩的恶化可以用节省的时间来表示。诱发伽马振荡在6个月内使日常生活活动进展减少4.83个月，精神状态小检查进展减少4.59个月，全脑容量减少4.09个月。

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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.