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

Ali R. Rezai*, Manish Ranjan, Pierre François D’Haese, Marc W. Haut, Jeffrey Carpenter, Umer Najib, Rashi I. Mehta, J. Levi Chazen, Zion Zibly, Jennifer R. Yates, Sally L. Hodder, Michael Kaplitt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)9180-9182
Number of pages3
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number17
DOIs
StatePublished - 28 Apr 2020
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • Focused ultrasound
  • Hippocampus

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