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

原发性进行性失语症（PPA）是一种与阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD）相关的语言丧失的衰弱性病症，影响许多额颞叶痴呆（FTD）和阿尔茨海默病（AD）患者，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沉重的障碍之一是命名障碍，患者无法获得物体的名称，表现为单词查找困难。经颅直流电刺激（tDCS），一种非侵入性神经调节的形式，显示出作为PPA患者命名障碍的干预措施的前景。然而，将这种新的治疗方法引入临床实践的努力受到了该患者人群中先前tDCS研究的适度规模和范围的阻碍，这阻碍了建立明确，可靠的临床证据来支持tDCS在临床环境中的广泛使用。为了解决这一差距，该提案旨在进行世界上第一个在PPA中进行tDCS治疗的良好动力，多中心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，宾夕法尼亚大学和Baycrest Health Sciences的研究团队之间的合作，这些研究团队共同产生了100%的已发表的关于PPA中tDCS的北美研究和80%的国际研究。在总共120例PPA患者的队列中，我们将采用随机、双盲、受试者内、交叉设计，类似于之前在每个参与研究中心采用的试验。在重点关注语言能力和MRI成像的基线行为测试后，PPA受试者将在两周内接受10次每日一次的tDCS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治疗）或假（安慰剂）tDCS与NASP配对。参与者将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，然后在干预结束后3个月重复测试和大脑成像。然后，参与者将转换研究组，并以相同的时间间隔接受干预，测试和成像。我们还将对60名神经系统健康的老年人进行基线行为测试和神经成像（无治疗），以与PPA受试者在语言表现和脑成像方面进行比较。随后的分析将确定是否tDCS在左额叶语言区配对命名治疗的结果在口头和书面命名的持续改善，还将确定预测tDCS对命名性能的影响的临床，神经，生物，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的双语人口，我们将特别关注双语作为可能影响结果的人口特征。总的来说，这项有影响力的试验将提供迄今为止最可靠的答案，即tDCS是否能有效治疗PPA中的命名缺陷，并将帮助该领域确定最适合这种有希望的AD/ADRD干预的患者。

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.