Treating primary progressive aphasia and elucidating neurodegeneration in the language network using transcranial direct current stimulation

使用经颅直流电刺激治疗原发性进行性失语症并阐明语言网络中的神经退行性变

• 批准号: 10450141
• 负责人: Roy H Hamilton
• 金额: $ 75.16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450141
• 关键词: Address; Advanced Development; Affect; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease patient; Anodes; Anterior; Area; Behavioral; Brain; Brain region; Clinical; Clinical Trials; Cross-Over Studies; Data; Degenerative Disorder; Disease; Disease Progression; Double-Blind Method; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Graph; Image; Individual; Injury; Intervention; Intervention Trial; Investigation; Knowledge; Language; Language Therapy; Left; Location; Measures; Methods; Modeling; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Participant; Pathway Analysis; Patients; Pattern; Performance; Persons; Primary Progressive Aphasia; Production; Property; Quality of life; Randomized; Research; Role; Semantics; Site; Speech; Statistical Data Interpretation; Statistical Models; Syndrome; System; Techniques; Testing; Therapeutic; Variant; Work; behavioral response; cerebral atrophy; clinical phenotype; density; effective therapy; frontal lobe; frontotemporal degeneration; improved; indexing; insight; language impairment; meetings; multimodal data; neurodegenerative dementia; neuroimaging; neuroregulation; noninvasive brain stimulation; novel; predicting response; relating to nervous system; response; statistics; stroke-induced aphasia; treatment effect; treatment trial

PROJECT SUMMARY/ABSTRACT This revised application responds to PAR-18-175: “Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline.” Primary progressive aphasia (PPA), a debilitating condition of language loss affecting many patients with frontotemporal dementia (FTD) and Alzheimer's disease (AD), currently lacks effective treatments. Recent studies suggest that transcranial direct current stimulation (tDCS), a form of noninvasive neuromodulation, may show promise as an intervention for PPA. However, these research efforts are hampered because they do not address important questions about plasticity in the language system, and because they do not fully utilize knowledge regarding the properties of the language network in PPA to guide treatment. This proposal aims to further advance investigation into tDCS as a potential intervention in PPA and to establish which components of the language network in PPA are most capable of tDCS-induced behaviorally relevant plasticity. Our proposal seeks to determine whether neuromodulation therapies in persons with PPA should aim to strengthen connections in the most degenerated regions of the language network or bolster compensatory changes in more intact areas. We will address this knowledge gap by pursuing a randomized, sham-controlled crossover study of high-density tDCS (HD-tDCS) focused over the anterior regions of the left hemisphere language network in participants with two PPA variants that are characterized by decreased word production but which feature different sites of maximal degeneration. This will allow for comparison of stimulation in a region that is degenerated in some subjects but relatively spared in others. Stimulation will be paired with a behavioral language therapy aimed at augmenting tDCS effects in the language system. Our first aim will be to determine how this intervention differentially impacts language performance in subjects with the two PPA variants. We will then use network graph statistical analyses of neuroimaging data to characterize language networks. We will focus on hubs as centers of critical connectivity in networks, and we propose that measuring changes in the ability of regions in the language network to function as hubs (indexed by hub scores) may be a way to describe how neurodegeneration impacts language network functions in PPA. Thus, the second aim of the proposal will explore differences in hub scores across the language network at baseline in our two PPA subtype groups. The third aim of the proposal will extend this approach by examining behaviorally relevant changes in hub scores induced by tDCS. The final aim of the project will integrate and extend prior findings by developing a model that employs clinical phenotypes, patterns of brain atrophy, and hub score data to predict which individuals are most likely to benefit from our stimulation approach. Taken together, this project will advance a potential intervention for a devastating condition associated with neurodegenerative diseases, elucidate network mechanisms of plasticity in these disorders, and develop a potentially generalizable, network-informed approach for predicting response to therapeutic neuromodulation.

项目概要/摘要 此修订后的申请响应 PAR-18-175：“阿尔茨海默病谱的试点临床试验 以及与年龄相关的认知能力下降。”原发性进行性失语症 (PPA)，一种语言衰弱状况 影响许多额颞叶痴呆（FTD）和阿尔茨海默病（AD）患者的损失，目前缺乏 有效的治疗。最近的研究表明，经颅直流电刺激 (tDCS) 是一种 非侵入性神经调节，可能有望作为 PPA 的干预措施。然而，这些研究工作 受到阻碍，因为它们没有解决有关语言系统可塑性的重要问题，并且 因为他们没有充分利用 PPA 中语言网络特性的知识来指导 治疗。该提案旨在进一步推进对 tDCS 作为 PPA 潜在干预措施的研究 确定 PPA 中语言网络的哪些组成部分最有能力进行 tDCS 诱导的行为 相关的可塑性。我们的提案旨在确定神经调节疗法是否适用于 PPA 患者 应旨在加强语言网络最退化区域的联系或支持 更完整区域的补偿性变化。我们将通过随机、 集中于左侧前部区域的高密度 tDCS (HD-tDCS) 的假对照交叉研究 具有两种 PPA 变体的参与者的半球语言网络，其特征是单词减少 生产，但具有不同的最大退化位点。这将允许比较 某个区域的刺激在某些受试者中退化，但在其他受试者中相对幸免。刺激将是 与旨在增强 tDCS 在语言系统中的效果的行为语言疗法相结合。我们的第一个 目的是确定这种干预如何对具有以下特征的受试者的语言表现产生不同的影响： 两个 PPA 变体。然后，我们将使用神经影像数据的网络图统计分析来表征 语言网络。我们将重点关注作为网络关键连接中心的集线器，我们建议 衡量语言网络中区域作为枢纽功能的能力的变化（由枢纽索引 分数）可能是描述神经退行性变如何影响 PPA 中语言网络功能的一种方式。因此， 该提案的第二个目标是探索整个语言网络的中心分数在基线上的差异 在我们的两个 PPA 亚型组中。该提案的第三个目标将通过审查来扩展这种方法 tDCS 引起的中心评分的行为相关变化。该项目的最终目标将整合和 通过开发一个采用临床表型、脑萎缩模式的模型来扩展先前的发现， 中心评分数据来预测哪些人最有可能从我们的刺激方法中受益。采取 该项目将共同推进对与以下疾病相关的破坏性状况的潜在干预： 神经退行性疾病，阐明这些疾病的可塑性网络机制，并开发 潜在可推广的、基于网络的方法，用于预测治疗性神经调节的反应。