β-Amyloid Plaque Reduction in the Hippocampus After Focused Ultrasound-Induced Blood-Brain Barrier Opening in Alzheimer's Disease.

Pierre-François D’Haese,Peng Wang,Sally Hodder,Marc W Haut,Alexander Song,Michael Kaplitt,Ali R Rezai,Rashi I Mehta,Manish Ranjan,Umer Najib,J Levi Chazen,Daniel Claassen,Jeffrey Carpenter,Gerard Dieb

doi:10.3389/fnhum.2020.593672

Abstract

The blood–brain barrier (BBB) limits therapeutic delivery in Alzheimer’s disease (AD) and other neurological disorders. Animal models have demonstrated safe BBB opening and reduction in β-amyloid plaque with focused ultrasound (FUS). We recently demonstrated the feasibility, safety, and reversibility of FUS-induced BBB opening in the hippocampus and entorhinal cortex in six participants with early AD. We now report the effect of BBB opening with FUS treatment on β-amyloid plaque. Six participants underwent 18F-Florbetaben PET scan at baseline and 1 week after the completion of the third FUS treatment (60 days interval). PET analysis comparing the hippocampus and entorhinal cortex in the treated and untreated hemispheres revealed a decrease in the ratio of 18F-Florbetaben ligand binding. The standard uptake value ratios (SUVr) reduction ranged from 2.7% to 10% with an average of 5.05% (±2.76) suggesting a decrease in β-amyloid plaque.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia with progressive memory and cognitive decline
We report the effect of focused ultrasound (FUS) treatment in the hippocampus and entorhinal cortex (EC) on β-amyloid plaque in six participants
In all 18 treatment sessions, parenchymal contrast enhancement was demonstrated at each target with an average opening of 95% of the FUS target volume corresponding to 29% of the overall hippocampus volume and resolved in 24 h indicating opening and closure of blood–brain barrierFUS-Induced β-Amyloid Reduction (BBB) (Figure 3) (Rezai et al, 2020)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia with progressive memory and cognitive decline. The absence of any effective treatment for AD has led to experimental studies of immunotherapy targeting the amyloid-beta plaque and other novel therapeutics (Cummings et al, 2019). It was reported that low-intensity MR-guided focused ultrasound (FUS) can open the BBB in the frontal lobe in patients with Alzheimer’s disease (Lipsman et al, 2018). We demonstrated that FUS can safely and reversibly open a large portion (average 29%) of the hippocampus and entorhinal cortex (EC) BBB in patients with early AD (Rezai et al, 2020). Animal studies have shown that FUS BBB opening reduced βamyloid plaque and improved memory (Burgess et al, 2014). We report the effect of FUS treatment in the hippocampus and EC on β-amyloid plaque in six participants

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