Long-Term Therapy With Transcranial Magnetic Stimulation in Primary Progressive Aphasia: A Randomized Clinical Trial.

Importance: Primary progressive aphasia (PPA) is a neurodegenerative clinical syndrome with no effective treatment. Objective: To evaluate the efficacy, safety, and adherence of transcranial magnetic stimulation (TMS) plus language therapy in participants with PPA over 6 months. Design, Setting, and Participants: This prospective, double-blind parallel-design randomized clinical trial was performed in Spain between December 2021 and July 2024. Participants meeting criteria for PPA and with a Clinical Dementia Rating of 0 to 1 (in which scores range from 0 to 3, with higher scores indicating greater severity of dementia symptoms) were eligible. Interventions: Participants were randomized 2:1 to active-TMS (intermittent theta-burst TMS protocol) vs sham-TMS therapy for 6 months, immediately followed by evidence-based language intervention for treating PPA, stratified by PPA variants (nonfluent/agrammatic, semantic, and logopenic). Main Outcomes and Measures: The main outcome was the standardized uptake value ratio in a large brain region encompassing most of the left hemisphere, assessed at baseline and at 6 months (immediately following the intervention) and measured by 18F-fludeoxyglucose-positron emission tomography. Secondary outcomes included results from the Mini Linguistic State Examination, confrontation naming, words per minute derived from a spontaneous speech task, the Interview for Deterioration in Daily Living Activities in Dementia, and the Neuropsychiatric Inventory. Secondary outcomes were assessed at baseline, 3 months, and 6 months. Safety and adherence were also evaluated. Results: Among 78 participants who were screened for the study, 63 were enrolled (mean [SD] age, 71.8 [8.4] years; 42 females [66.7%]); of these, 42 were randomized to the active-TMS group and 21 were randomized to the sham-TMS group. The primary outcome measure was positive; the adjusted mean of the standardized uptake value ratio at 6 months was higher in the active group than in the sham group (0.78 [95% CI, 0.77-0.79] vs 0.77 [95% CI, 0.75-0.78]; P = .046). Active TMS was associated with improvement in the mean adjusted difference for all of the secondary outcomes at 6 months (Mini Linguistic State Examination: 7.71 [95% CI, 3.06-12.35], confrontation naming: 23.81 [95% CI, 11.85-35.77], Interview for Deterioration in Daily Living Activities in Dementia: -5.39 [95% CI, -10.73 to -0.05], and Neuropsychiatric Inventory: -4.25 [95% CI, -8.37 to -0.14]), except for words per minute results (3.41 [95% CI, -8.86 to 15.68]). There were no significant differences in the number of adverse events. Adherence was complete in 58 of 63 participants (92.1%). Conclusions and Relevance: In this randomized clinical trial including participants with PPA, intermittent theta-burst TMS over the left dorsolateral prefrontal cortex during a 6-month interval was associated with less decline in regional brain metabolism and improvement in language abilities, functional independence, and neuropsychiatric symptoms. These findings suggest that TMS combined with evidence-based language intervention in participants with PPA promotes greater functional outcomes and slower progression compared with language therapy alone. Trial Registration: ClinicalTrials.gov Identifier: NCT05842473.