Question Clinical effects of current therapies for neurodegeneration are limited. Very recently, a novel therapeutic approach has been developed as non-invasive add-on therapy: Transcranial Pulse Stimulation TPS (Beisteiner et al. 2019, Beisteiner & Lozano 2020, Popescu et al. 2021). This presentation intends to give an overview about clinical add-on effects in patients with neurodegenerative disease. Methods TPS applies repeated ultrashort pressure pulses in the ultrasound frequency range. TPS is the first brain stimulation technique which allows precise targeting of deep and superficial areas of grossly changed pathological brains. Clinical effects in patient cohorts with Alzheimer’s Disease, Depression and Parkinson’s disease will be presented. Statistical analyses are based on the CERAD score for documentation of cognitive improvements, BDI-II for documentation of mood improvement and UPDRS for documentation of motor improvements. In all studies, only state-of-the-art treated patients are included. Results In the AD study with 35 patients a significant improvement of CERAD scores was found, lasting 3 months. Improvements correlated with improved functional connectivity values within the Default Mode Network (fMRI data). In the Depression study (18 AD patients with Depression as comorbidity), we found significant improvement in BDI-II after TPS therapy. Functional connectivity (fMRI data) showed a normalization of the FC between the salience network (right anterior insula) and the ventromedial network (left frontal orbital cortex). In the running PD study, preliminary analysis of observational data show significant improvements in UDRS scores in patients with optimized medications. Final PD analyses will be presented. Conclusion First evidence indicates, that Transcranial Pulse Stimulation TPS may show beneficial add-on effects in state-of-the-art treated neurodegeneration. References Popescu T, Pernet C, Beisteiner R. Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: A follow-up study. Alzheimers Dement (N Y). 2021 Feb 25;7(1):e12121. doi: 10.1002/trc2.12121. PMID: 33681449; PMCID: PMC7906128. Beisteiner R, Lozano AM. Transcranial Ultrasound Innovations Ready for Broad Clinical Application. Advanced Science 2020 Oct 27;7(23):2002026. doi: 10.1002/advs.202002026. PMID: 33304757; PMCID: PMC7709976 Beisteiner R, Matt E, Fan C, Baldysiak H, Schönfeld M, Philippi Novak T, Amini A, Aslan T, Reinecke R, Lehrner J, Weber A, Reime U, Goldenstedt C, Marlinghaus E, Hallett M, Lohse-Busch H. Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. Advanced Science 2019 Dec 23;7(3):1902583. doi: 10.1002/advs.201902583. PMID: 32042569; PMCID: PMC7001626.