Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound

Abstract

The blood–brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer’s disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

β-Amyloid Plaque Reduction in the Hippocampus After Focused Ultrasound-Induced Blood–Brain Barrier Opening in Alzheimer’s Disease

“…Six participants (55–73 years of age, five females, one male) completed the trial. For reference, in all 18 treatment sessions (three per participant), parenchymal contrast enhancement was demonstrated at each target with an average opening of 95% of the FUS target volume corresponding to 29% of the overall hippocampus volume and resolved in 24 h indicating opening and closure of BBB ( Figure 3 ) ( Rezai et al, 2020 ). Conventional cerebellar-based PET analysis on the treated hippocampus/EC shows after treatment a change from baseline of −12.44%, −5.78%, −1.83%, −1.70%, 0.11%, and −17.15%, respectively, for participants 1 to 6.…”

“…Participants underwent FUS treatment at either the West Virginia University Rockefeller Neuroscience Institute or Weill Cornell Medical College with 220 kHz ExAblate Neuro Type 2 system (INSIGHTEC) to the hippocampus/EC with concomitant IV microbubble (Definity) injection with a cumulative max dose of 20 μl/kg immediately prior to sonication using a range of power of 4–11.5 W for 90 s. The sonication power and parameters were tailored to each subject to achieve a 50–60% of cavitation thresholds to open the BBB. FUS targets were selected either in the left or right hippocampus/EC, based on individual anatomy and β-amyloid plaque distribution ( Rezai et al, 2020 ) ( Figure 1 ). In this study, we use 18 F-Florbetaben as the PET β-amyloid imaging agent ( Rowe et al, 2008 ) to facilitate the clinical evaluation and provide an objective measure of the FUS treatment on the β-amyloid plaque burden.…”

“…Previously, it was reported that low-intensity MR-guided focused ultrasound (FUS) can open the BBB in the frontal lobe in patients with Alzheimer’s disease ( Lipsman et al, 2018 ). Recently, we demonstrated that FUS can safely and reversibly open a large portion (average 29%) of the hippocampus and entorhinal cortex (EC) BBB in patients with early AD ( Rezai et al, 2020 ). Animal studies have shown that FUS BBB opening reduced β-amyloid plaque and improved memory ( Burgess et al, 2014 ).…”

ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma

“…With the expanding role of nuclear medicine in FUS therapy [46], our findings lend credence to the utility of noninvasive techniques such as immuno-PET imaging for the design and monitoring of FUS immunotherapy paradigms. PET imaging has already been demonstrated to serve as a powerful tool for gaining robust insights into the mechanisms underlying FUS BBB disruption [22,47]. The workflow established within this study reiterates the tremendous and yet untapped potential of molecular imaging as an adjunct to FUS-mediated therapeutic paradigms [46].…”

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

“…The limited brain delivery and penetration was addressed employing MRIg-FUS, which has been shown to enhance the deposition of different drugs in various organs [57][58][59] while being well tolerated by animals [60][61][62][63] and humans [64,65]. Moreover, MRIg-FUS showed therapeutic efficacy per se on phosphorylated Tau and amyloid plaques [66,67].…”