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

Abstract

AbstractBackgroundFocused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer’s disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigated FUS system with integrated real-time 2D microbubble cavitation mapping.MethodsA phase 1 clinical study with mild to moderate AD patients (N=6) underwent a single session of microbubble-mediated FUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the FUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through18F-Florbetapir PET.ResultsBBBO was achieved in 5 out of 6 subjects with an average volume of 983±626 mm3following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8±10.7 min. Cavitation dose significantly correlated with the BBBO volume (R2>0.9,N=4), demonstrating the portable FUS system’s capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42/Aβ40 (R2=0.74), Tau (R2=0.95), and P-Tau181 (R2=0.86), assayed in serum-derived EVs sampled 3 days after FUS (N=5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the harmonic cavitation dose (R2>0.9,N=3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS.ConclusionSafety and feasibility of this cost-efficient and portable FUS for BBBO in AD patients were demonstrated with real-time mapping correlating with BBBO volume and a reduction in pathology, as well as serum detection of the AD proteins, Aβ and tau. Our study suggest the potential for accessible FUS treatment in AD, with or without drug delivery.