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

Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9180-9182. doi: 10.1073/pnas.2002571117. Epub 2020 Apr 13.


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.

Keywords: Alzheimer’s disease; focused ultrasound; hippocampus.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / metabolism
  • Biological Transport
  • Blood-Brain Barrier / diagnostic imaging*
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / physiology
  • Brain / physiology
  • Drug Delivery Systems / methods
  • Female
  • Hippocampus / metabolism
  • Humans
  • Male
  • Microbubbles
  • Middle Aged
  • Ultrasonic Therapy / methods*
  • Ultrasonic Waves
  • Ultrasonography