Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.

Publication Type	Academic Article
Authors	Rezai A, Ranjan M, D'Haese P, Haut M, Carpenter J, Najib U, Mehta R, Chazen J, Zibly Z, Yates J, Hodder S, Kaplitt M
Journal	Proc Natl Acad Sci U S A
Volume	117
Issue	17
Pagination	9180-9182
Date Published	04/13/2020
ISSN	1091-6490
Keywords	Blood-Brain Barrier, Ultrasonic Therapy
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.
DOI	10.1073/pnas.2002571117
PubMed ID	32284421
PubMed Central ID	PMC7196825