Predictors of 6-month clinical change in primary progressive aphasia following language therapy and transcranial magnetic stimulation

Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by progressive language impairment. Available treatments and information on factors associated with clinical change and treatment response remain limited. This study is a post-hoc analysis of a randomized controlled trial and aimed to identify baseline demographic, cognitive, and neuroimaging factors associated with clinical change in a subanalysis of a double-blind, randomized, parallel clinical trial of transcranial magnetic stimulation (TMS) and language therapy in PPA. Fifty-seven patients diagnosed with PPA received six months of lexical retrieval treatment, 40 with active TMS and 17 with sham TMS. All participants underwent comprehensive cognitive and language assessments before treatment and were evaluated using the Mini Linguistic State Examination (MLSE), naming task, words per minute, the Interview for Deterioration in Daily Living Activities in Dementia (IDDD), the Neuropsychiatric Inventory (NPI), and fluorodeoxyglucose positron emission tomography (FDG-PET) scans before and after treatment. Predictors of clinical change were analyzed using least absolute shrinkage and selection operator (LASSO) and Elastic Net regression models, and unsupervised k-means clustering was applied to identify response profiles. Models for MLSE (LASSO: R2=0.52; Elastic Net: R2=0.57), naming (LASSO: R2=0.42; Elastic Net: R2=0.41), IDDD (LASSO: R2=0.46; Elastic Net: R2=0.58), and NPI (LASSO: R2=0.81; Elastic Net: R2=0.77) demonstrated good predictive accuracy. TMS treatment consistently emerged as the strongest predictor of clinical improvement across all outcomes. Higher metabolism in several brain regions (left hippocampus, posterior cingulate, and orbitofrontal cortex) predicted greater clinical improvement. Cluster analysis identified two subgroups: responders and non-responders, with 77.5% of patients receiving active TMS in the responder cluster, and 82.4% of the sham group in the non-responder cluster. Among patients receiving active TMS, a positive effect was associated with the non-fluent and semantic variants and with better cognitive performance in non-language domains. In conclusion, TMS treatment emerged as the main factor associated with clinical improvement on cognitive-linguistic and functional measures. Better cognitive performance and preserved brain metabolism in key regions were linked to more favorable clinical outcomes. These findings underscore the potential of TMS in combination with language therapy, and pave the way for precision medicine approaches in PPA, emphasizing the need to identify individual profiles that predict optimal treatment response.