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Clinical Trial
. 2018 Jul 25;9(1):2336.
doi: 10.1038/s41467-018-04529-6.

Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound

Nir Lipsman  1   2   3 , Ying Meng  4   5 , Allison J Bethune  5   6 , Yuexi Huang  7 , Benjamin Lam  5   8 , Mario Masellis  5   8 , Nathan Herrmann  5   9 , Chinthaka Heyn  7   10 , Isabelle Aubert  5   7   11 , Alexandre Boutet  10 , Gwenn S Smith  12 , Kullervo Hynynen  7   13   14 , Sandra E Black  5   8
Affiliations
Clinical Trial

Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound

Nir Lipsman et al. Nat Commun. .

Abstract

Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer's disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer's disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer's disease.

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Conflict of interest statement

N.L. (chair), K.H., and S.E.B. have received an honorarium for serving on an expert steering committee on focused ultrasound in AD. K.H. is an inventor on intellectual property owned by Brigham and Women’s hospital in Boston and Sunnybrook Research Institute in Toronto related to intracranial focused ultrasound technology. Y.M., A.J.B., Y.H., B.L., M.M., N.H., C.H., I.A., A.B., and G.S.S. declare no competing interests.

Figures

Fig. 1
Fig. 1
Overview of the study. Flow chart illustrates the study design and overview of patients screened and enrolled in the study
Fig. 2
Fig. 2
MRI demonstration of blood–brain barrier opening and closure. Axial T1-weighted gadolinium MR images of patient 5 at a baseline, b immediately after stage 2 sonication and blood–brain barrier (BBB) opening, and c at 24 h after procedure. Contrast extravasation within the 10 × 10 × 7 mm3 sonicated volume in the right frontal lobe is seen immediately after the procedure, demonstrating increased BBB permeability. At 24 h after the procedure, there is no significant extravasation of contrast in the area, suggesting BBB closure
Fig. 3
Fig. 3
[18F]-Florbetaben uptake on PET before and after treatment. Standardized uptake value ratio images (SUVr) in the corresponding axial planes for [18F]-Florbetaben PET scans at a baseline and b approximately 1 week after sonication. c Gadolinium extravasation on T1-weighted MR images immediately after the blood–brain barrier disruption procedure demonstrates the targeted region
See this image and copyright information in PMC

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