Extracellular vesicle response following focused ultrasound-mediated blood–brain barrier opening for the detection of Alzheimer’s pathology

Abstract

Focused ultrasound (FUS), in conjunction with systemically administered microbubbles, has been shown to induce transient and non-invasive blood–brain barrier opening (BBBO). Originally developed as a method of improving targeted drug delivery, FUS-BBBO has recently been proposed as a means of amplifying detection of disease biomarkers in the bloodstream. We hereby describe a method that can detect extracellular vesicles (EVs) after BBB opening in Alzheimer’s disease (AD) mice and patients. BBBO is shown to enhance the release of EVs with disease-specific cargo to the bloodstream when targeting amyloid affected regions and shown to be more sensitive than cell free DNA. In this presentation, we will describe the overall methodology and quantify the concentration and content of EVs isolated from the serum of mice following drug-free FUS-BBBO in both mice and patients. In AD mice and patients, an average EV concentration increase of 164% and 100% 1 h after FUS-BBBO containing both amyloid and tau was, respectively, found compared to 0% under sham conditions and highly correlated with BBBO volume. Whole genome RNA sequencing and mass spectrometry protein identification demonstrated inflammatory and proliferation gene upregulation. These findings highlight the potential of FUS-BBBO to increase EV serum concentration towards early AD detection.