Natural aging and Alzheimer’s disease pathology increase susceptibility to focused ultrasound-induced blood–brain barrier opening

Abstract

Focused Ultrasound (FUS) paired with systemically-injected microbubbles (μB) is capable of transiently opening the blood–brain barrier (BBBO) for noninvasive and targeted drug delivery to the brain. FUS-BBBO is also capable of modulating the neuroimmune system, further qualifying its therapeutic potential for neurodegenerative diseases like Alzheimer’s disease (AD). Natural aging and AD impose significant strain on the brain and particularly the BBB, modifying its structure and subsequently, its functionality. The emerging focus on treating neurodegenerative diseases with FUS-BBBO necessitates an investigation into the extent that age and AD affect the BBB’s response to FUS. FUS-BBBO was performed with a 1.5-MHz, geometrically focused transducer operated at 450 kPa and paired with a bolus microbubble injection of 8 × 10 8 μB/mL. Here we quantify the BBBO, BBB closing (BBBC) timeline, and BBB permeability (BBBP) following FUS-BBBO in male mice with and without AD pathology, aged 10 weeks, one year, or two years. The data presented herein indicates that natural aging and AD pathology may increase initial BBBO volume by up to 34.4% and 40.7% respectively, extend BBBC timeline by up to 1.3 and 1.5 days respectively, and increase BBBP as measured by average K trans values up to 80% and 86.1% respectively in male mice. This characterization of the BBB response to FUS-BBBO with age and AD further clarifies the nature and extent of the functional impact of these factors and may offer new considerations for planning FUS-BBBO interventions in aged and AD populations.