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Importance: Given the increasing prevalence of dementia and the limited treatment options available, ultrasound neuromodulation could serve as a novel add-on therapy to standard treatments for Alzheimer disease (AD). As ultrasound neuromodulation is still in its early stages, further research is essential to fully explore its potential in treating brain disorders. Objective: To evaluate clinical and functional imaging effects of transcranial pulse stimulation (TPS) in patients with AD. Design, Setting, and Participants: A randomized, double-blind, sham-controlled, crossover clinical trial was conducted at the Medical University of Vienna between January 1, 2017, and July 27, 2022. Sixty patients with clinically diagnosed AD receiving state-of-the-art treatment were randomly allocated to treatment sequence groups verum-sham (first cycle verum, second cycle sham, n = 30) and sham-verum (n = 30). Data analysis was performed from July 28, 2022, to September 5, 2024. Intervention: Each participant received 6 verum and 6 sham TPS sessions (6000 pulses, 0.20 mJ/mm2, 5 Hz) to frontoparietal brain areas. Main Outcomes and Measures: Neuropsychological tests, including the primary outcome Consortium to Establish a Registry for Alzheimer's Disease (CERAD) corrected total score (CTS), were performed at baseline and 1 week, 1 month, and 3 months following the stimulations in each cycle. Primary and secondary outcomes, including functional magnetic resonance imaging and Beck Depression Inventory-II, were analyzed by intention-to-treat analysis and, for sensitivity, by per protocol analysis. Results: For the intention-to-treat analysis, 60 patients between ages 51 and 82 years (mean SD, 70.65 8.16 years; 30 females; 30 males) were included. The CERAD CTS increased by a mean (SD) of 2.22 (6.87) points in the verum condition from 70.93 (14.27) points at baseline to 73.15 (14.90) 3 months after stimulation, while the mean (SD) score in the sham condition increased by 1.00 (6.82) point vs baseline from 71.68 (13.62] at baseline to 72.68 (14.48) 3 months after stimulation. Primary data analysis of the condition × session interaction was not significant (P = .68; partial η2 ηp2 = 0.01), but its interaction with age was P = .003; ηp2 = 0.08, followed by post hoc analyses of age subsamples. Although several patients older than 70 years benefited from verum TPS, only the younger subgroup (≤70 years) showed significantly higher CTS increases for verum in all poststimulation sessions (condition × session: P = .005; ηp2 = 0.16). At 3 months after stimulation, for example, a mean (SD) 3.91 (7.86)-point increase was found for verum TPS in the younger patients, but a mean (SD) CTS decrease of 1.83 (5.80) was observed for sham. Memory-associated brain activation was significantly higher after verum TPS in the precuneus, visual, and frontal areas, while resting state functional connectivity was significantly upregulated in the dorsal attention network. In the per protocol sample, a significant reduction of the Beck Depression Inventory-II scores 3 months following verum TPS was found (verum baseline: 7.27 5.87; verum 3 months after stimulation: 5.27 5.27; sham baseline: 6.70 5.65; sham 3 months after stimulation: 6.22 4.40; P = .008; ηp2 = 0.23). During both verum and sham conditions, the most common observed adverse symptom was depression; no major neuropathologic change was detected in the patients by detailed neuroradiologic assessments. Conclusions and Relevance: In this randomized clinical trial of TPS in patients with AD, a 2-week verum treatment improved cognitive scores in the younger subgroup, ameliorated depressive symptoms, and induced upregulation of functional brain activation and connectivity. These findings suggest TPS may be a safe and promising add-on therapy for patients with AD receiving state-of-the-art treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT03770182.
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