Phase II clinical trial of transcranial direct current stimulation in the treatment of primary progressive aphasia

原发性进行性失语(PPA)是一种与阿尔茨海默病(AD)和阿尔茨海默病相关痴呆(AD/ADRD)相关的语言丧失的衰弱状态，影响着许多额颞部痴呆(FTD)和阿尔茨海默病(AD)患者，但缺乏有效的治疗方法。与AD/ADRD的这种表现相关的最常见和最繁重的损害之一是失范，即无法获得物体的名称，患者将其视为查找单词的困难。经颅直流电刺激(TDC)是一种非侵入性神经调节方式，有望成为PPA患者异常的干预手段。然而，将这种新的治疗方法引入临床实践的努力受到了以前在这一患者群体中进行的tDCs研究的适度规模和范围的阻碍，这阻碍了建立明确、有力的临床证据来支持tDCs在临床上的广泛使用。为了弥补这一差距，这项提案旨在进行世界上第一个动力良好的、多站点的PPA的tDCs治疗的2期临床试验。为了实现这一目标，目前的项目巩固了约翰·霍普金斯大学、宾夕法尼亚大学和贝克雷斯特健康科学公司的研究团队之间的合作，这三个研究团队共同完成了北美PPA中关于tDC的100%已发表研究和国际上80%的研究。在总共120名PPA患者的队列中，我们将采用随机、双盲、受试者内、交叉设计，类似于先前在每个贡献站点所采用的试验。在专注于语言能力和MRI成像的基线行为测试之后，患有PPA的受试者将在两周内接受为期10天的tDC与命名和拼写治疗(NASP；一种针对口头和书面命名产生的行为语言疗法)的配对治疗，或假(安慰剂)tDC与NASP配对。参与者在干预结束时再次接受行为测试和成像，一个月后接受行为测试，然后在干预结束3个月后重复测试和脑成像。然后，参与者将交换研究手臂，并在相同的时间间隔接受干预、测试和成像。我们还将对60名神经学健康的老年人进行基线行为测试和神经成像(无需治疗)，以与PPA受试者在语言表现和脑成像方面进行比较。随后的分析将确定左侧额叶语言区的tdcs与命名治疗相结合是否会导致口头和书面命名的持续改善，并将确定预测tdcs对命名成绩影响的临床、神经、生物学、认知和人口统计学特征。由于我们有独特的机会研究加拿大以双语为主的人口，我们将特别关注双语作为一种可能影响结果的人口特征。总体而言，这项有效的试验将提供迄今为止最可靠的答案，即tDCs是否有效地治疗PPA中的命名缺陷，并将帮助现场确定最适合AD/ADRD这一有前景的干预措施的患者。

Primary progressive aphasia (PPA), a debilitating condition of language loss associated with Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) affecting many patients with frontotemporal dementia (FTD) and Alzheimer’s disease (AD), lacks effective treatments. One of the most common and burdensome impairments associated with this manifestation of AD/ADRD is anomia, the inability to access the names of objects, experienced by patients as word-finding difficulty. Transcranial direct current stimulation (tDCS), a form of noninvasive neuromodulation, shows promise as an intervention for anomia in persons with PPA. However, efforts to introduce this novel treatment approach into clinical practice are hampered by the modest size and scope of prior tDCS studies in this patient population, which prevents establishment of clear, robust clinical evidence to support the widespread use of tDCS in clinical contexts. To address this gap, this proposal aims to conduct the world’s first well-powered, multi-site Phase 2 clinical trial of tDCS therapy in PPA. In order to accomplish this goal, the current project solidifies a collaboration between research teams at Johns Hopkins, University of Pennsylvania, and Baycrest Health Sciences, which have collectively produced 100% of the published studies on tDCS in PPA in North America and 80% of the studies internationally. In a total cohort of 120 patients with PPA, we will employ a randomized, double-blind, within-subject, cross-over design similar to trials that have been previously employed at each of the contributing sites. Following baseline behavioral testing focused on language abilities and MRI imaging, subjects with PPA will receive 10 daily sessions over two weeks of either tDCS paired with NAming and SPelling treatment (NASP; a behavioral language therapy targeting both oral and written naming production) or sham (placebo) tDCS paired with NASP. Participants will undergo behavioral testing and imaging again at the end of the intervention, receive behavioral testing a month later, and then repeat testing and brain imaging 3 months after the end of the intervention. Participants will then switch study arms and receive the intervention, testing, and imaging at the same intervals. We will also conduct baseline behavioral testing and neuroimaging (with no treatment) on 60 neurologically healthy older adults for comparison to PPA subjects with respect to language performance and brain imaging. Subsequent analyses will determine whether tDCS over the left frontal language areas paired with naming treatment results in persistent improvement in oral and written naming, and will also identify the clinical, neural, biological, cognitive, and demographic characteristics that predict tDCS effects on naming performance. Owing to our unique opportunity to study a largely bilingual population in Canada, we will focus specific attention on bilingualism as a demographic feature that may influence outcomes. Overall, this impactful trial will provide the most reliable answer to date as to whether tDCS is effective for treating naming deficits in PPA and will help the field to identify patients best suited for this promising intervention in AD/ADRD.