Blood-Brain Barrier Opening in Alzheimer's Disease Patients Using Portable Focused Ultrasound System.

Focused ultrasound (FUS) has recently shown great promise in facilitating blood-brain barrier opening (BBBO) for drug delivery and immunotherapy in Alzheimer's disease. However, FUS-mediated BBBO treatment is currently limited to systems integrated with the MRI or post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we present the outcomes of a phase 1 clinical study with mild to moderate Alzheimer's disease patients (N=6) using a portable neuronavigated FUS system that did not require surgery or an online MRI during treatment. BBBO occurred in 5 out of 6 subjects with the volume of 983±626 mm 3 following a single session of FUS at the right frontal lobe. The outpatient treatment was completed within 34.8±10.7 min. Real-time cavitation monitoring was used to ensure the efficacy and safety of the BBBO procedure. Cavitation doses significantly correlated with the BBBO volume (R2>0.9, p<0.05), demonstrating the portable FUS system's capability of predicting opening volumes. Larger BBBO volumes correlated with increased levels of Alzheimer's disease biomarkers assayed in serum-derived extracellular vesicles, including Aβ42/Aβ40 (R 2 =0.74, p=0.1), Tau (R 2 =0.95, p=0.02), and P-Tau181 (R 2 =0.86, p=0.02), indicating the release of the two hallmark proteins into the bloodstream. Subjects showed a reduced Aβ accumulation rate in the treated frontal lobe region compared to the contralateral, as indicated by 18 F-Florbetapir PET scans. Clinical changes in mini-mental state examination over 6 months were within the expected range of decline. In conclusion, we have shown the safety and feasibility of this low-cost and portable FUS for BBBO in Alzheimer's patients, providing a new avenue for FUS treatment in Alzheimer's disease, with or without drug delivery.