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

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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.