Broad repetitive transcranial magnetic stimulation (rTMS) of the precuneus in Alzheimer's disease: A rationale and study design

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-03-10 DOI:10.1002/trc2.70043

Michael K. Leuchter, Hanadi A. Oughli, Kelly A. Durbin, Nicholas J. Jackson, David Elashoff, Timothy S. Chang, Juliana Corlier, Doan Ngo, Cole Matthews, Darice Wong, Brent L. Fogel, Gal Bitan, Andrew F. Leuchter, Keith Vossel, Nanthia Suthana

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引用次数: 0

Abstract

INTRODUCTION

Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent contributor to the clinical progression of Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. Here, we present the rationale and design of a study using off-the-shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process.

METHODS

We will conduct a two-stage trial of large-coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimer's Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily focused on determining short-term efficacy for memory. The first stage will involve 5 to 10 participants receiving open-label active treatment to refine the protocol. The following second stage will consist of a 1:1 randomized, double-blind, sham-controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open-label active treatment will be offered as an extension to the sham group after unblinding. Outcomes will focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography, neuroimaging, and blood biomarkers to demonstrate the feasibility of collection and explore preliminary changes in these measures.

RESULTS

We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement.

DISCUSSION

Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability.

Highlights

Induction-to-maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising treatment for Alzheimer's disease (AD), though recent methods require intensive personalization.
We propose here a trial design of precuneus rTMS in mild-to-early-moderate AD dementia using exclusively off-the-shelf equipment and protocol modifications to reduce participant burden.
Our two novel modifications from prior work are (1) using a larger rTMS coil, and (2) consolidating the induction phase of treatment.
This trial focuses primarily on tolerability and feasibility while exploring clinical measures of efficacy and biomarkers of target engagement.
Our trial is registered at ClinicalTrials.gov NCT06597942.

Abstract Image

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广泛重复经颅磁刺激（rTMS）治疗阿尔茨海默病的楔前叶：理论基础和研究设计

脑网络功能障碍，特别是在默认模式网络（DMN）内，是阿尔茨海默病（AD）临床进展的一个越来越明显的因素。重复经颅磁刺激（rTMS）可以靶向关键的DMN枢纽，维持信号功能，延迟或改善AD的临床结果。在这里，我们提出了一项研究的基本原理和设计，使用现成的设备和最新的临床证据来扩展之前的rTMS工作，并减轻参与者在这个过程中的负担。方法：我们将在54名轻度至中度阿尔茨海默氏临床综合征患者中开展一项针对胼胝体前叶（受AD影响的DMN的关键中枢）的大线圈rTMS两阶段试验，主要是确定其耐受性和可行性，其次是确定其对记忆的短期疗效。第一阶段将有5至10名参与者接受开放标签积极治疗，以完善方案。接下来的第二阶段将包括一个1:1随机、双盲、假对照的临床试验，以研究可行性和耐受性，同时探索目标参与和短期记忆效果。参与者将在5周的时间内接受16次rTMS脑刺激。在解盲后，假手术组将接受一个完整的开放标签积极治疗。结果将关注完成率和不良事件，以证明可行性和耐受性。进一步的探索性结果将包括神经心理学评估、脑电图、神经成像和血液生物标志物，以证明收集的可行性，并探索这些措施的初步变化。结果：我们预期这种治疗是可行的、可耐受的，并可能显示出目标接触和临床改善的证据。如果我们在可行性和耐受性方面取得预期的积极结果，这将证明未来的工作重点是临床疗效和生物标志物参与的明确证明，以及增强可推广性和可扩展性。尽管最近的方法需要高度个性化，但通过对胼胝体前叶的诱导-维持重复性经颅磁刺激（rTMS）治疗阿尔茨海默病（AD）是一种很有前景的治疗方法。我们在此提出一项针对轻度至早期中度阿尔茨海默氏痴呆的楔前叶颞叶刺激试验设计，使用完全现成的设备和方案修改，以减轻参与者的负担。我们对先前工作的两个新改进是：(1)使用更大的rTMS线圈，(2)巩固诱导阶段的治疗。该试验主要关注耐受性和可行性，同时探索临床疗效和目标接触的生物标志物。我们的试验注册在ClinicalTrials.gov网站NCT06597942。

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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.