Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer's disease with an implantable ultrasound device

Stéphane Epelbaum, Ninon Burgos, Michael Canney, Dawn Matthews, Marion Houot, Mathieu D Santin, Carole Desseaux, Guillaume Bouchoux, Sebastian Stroer, Cyril Martin, Marie-Odile Habert, Marcel Levy, Aicha Bah, Karine Martin, Benoît Delatour, Maximilien Riche, Bruno Dubois, Lisa Belin, Alexandre Carpentier, Stéphane Epelbaum, Ninon Burgos, Michael Canney, Dawn Matthews, Marion Houot, Mathieu D Santin, Carole Desseaux, Guillaume Bouchoux, Sebastian Stroer, Cyril Martin, Marie-Odile Habert, Marcel Levy, Aicha Bah, Karine Martin, Benoît Delatour, Maximilien Riche, Bruno Dubois, Lisa Belin, Alexandre Carpentier

Abstract

Background: Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer's disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device.

Methods: An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results: A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of - 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial.

Conclusions: These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed.

Trial registration: ClinicalTrials.gov, NCT03119961.

Keywords: Alzheimer’s disease; Amyloid; Blood-brain barrier; Clinical trial; Florbetapir; Magnetic resonance imaging; Position emission tomography; Ultrasound.

Conflict of interest statement

Michael Canney, Carole Desseaux, Guillaume Bouchoux, and Cyril Martin are employees of Carthera and have an ownership interest in the company. Alexandre Carpentier is a paid consultant to Carthera and has an ownership interest in Carthera.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
The SonoCloud-1 is a 1-MHz implantable ultrasound device that is implanted within the skull thickness (extradural) and activated at each treatment cycle by connecting it using a transdermal needle to an external radiofrequency generator. In this study, the SonoCloud-1 was implanted to target and temporarily disrupt the BBB above the left supramarginal gyrus
Fig. 2
Fig. 2
Region of interest (ROI) definition to measure the changes in PET amyloid levels in gray matter targeted by the implant (ROI1) as compared to similar tissue in the opposite (ROI2) and same hemispheres (ROI3)
Fig. 3
Fig. 3
Trial overview
Fig. 4
Fig. 4
PET amyloid (florbetapir) change observed in the region targeted by the SonoCloud-1 device (ROI1). SUVRs referenced to a ROI similar to the target ROI but in the opposite hemisphere (ROI2) showed decreases from the baseline of − 6.6% (SD = 7.2%) at 4 months and − 5.7% (SD = 6.2%) at 8 months
Fig. 5
Fig. 5
FDG PET changes in the target ROI (ROI1) referenced to the whole cerebellum. Overall, a blunting or plateau of decline was observed in the target region referenced to the whole cerebellum after 4 months

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