Transcranial Blood–Brain Barrier Opening in Alzheimer’s Disease Patients Using a Portable Focused Ultrasound System with Real-Time 2-D Cavitation Mapping

Abstract

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 mm3following 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 (R2=0.74, p=0.1), Tau (R2=0.95, p=0.02), and P-Tau181 (R2=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 by18F-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.

Transcranial Functional Ultrasound Imaging Detects Focused Ultrasound Neuromodulation Induced Hemodynamic Changes in Mouse and Nonhuman Primate BrainsIn Vivo

“…In one case, activation maps matched the predicted focal area of neuromodulation very well. The differences in results could be explained by individual differences in skull properties that might affect fUSI and by small errors in the targeting procedure 64,65 . Interestingly, we were able to identify negatively correlated regions with stimulation-associated decreases in CBV, which could be connected to decreases in neuronal activity 66 .…”

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

“…This disrupts central communication circuits, resulting in impairments in memory, cognition, behavior, sensory and/or motor function [181][182][183]. With increasing age on a global scale, the number of neurodegenerative diseases is constantly growing, with Alzheimer's disease and Parkinson's disease being the most prevalent [184][185][186][187][188].…”