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Cited by 4Extracellular vesicles in diseaseUltrasound and Hyperthermia ApplicationsBarrier Structure and Function Studies

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Response of Serum-Isolated Extracellular Vesicles to Focused Ultrasound-Mediated Blood-Brain Barrier Opening

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Kline-Schoder, Alina R., Tsitsos, Fotios N., Batts, Alec J., DiBenedetto, Melody R., Liu, Keyu, Bae, Sua, Konofagou, Elisa E.·2025·Ultrasound in Medicine & Biology
DOI 10.1016/j.ultrasmedbio.2025.04.019PMC PMC12229771
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Abstract

Objective To characterize the response of extracellular vesicles (EV) in the serum of mice and Alzheimer's disease (AD) patients following focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening (FUS-BBBO) as a means to improve liquid biopsy. Methods Blood was collected from C57BL/6 mice before, and one hour after FUS-BBBO, and from AD patients before, one hour after, and three days after FUS-BBBO. EVs were isolated from serum using the Exoquick precipitation solution and their concentration was quantified using nanoparticle tracking analysis. The transcriptomic and proteomic content of EVs from mice was assessed using RNA sequencing and mass spectrometry protein analysis respectively. Additionally, the release of EVs in mice was inhibited using the GW4869 drug to assess the role of EVs in the restoration of the BBB. Finally, the biomarker content of EVs in AD patients was detected using a Luminex multiplex assay. Results We observed a 164±85% (95% confidence interval: 78.998 - 249.202) increase in murine EV concentration one hour after treatment, as well as an increase in EV RNA associated with FUS-BBBO neuroimmunotherapy. Inhibition of EVs reduced the inflammatory response and BBBO volume in mice. Patient EV concentration also increased one hour after treatment and was dependent on the volume of BBB opening three days post-treatment. Furthermore, EV isolation was found to significantly enhance (p<0.05) the detection of FUS-BBBO-induced amplification of AD and CNS biomarkers such as GFAP, beta-amyloid 42 and phosphorylated tau 181, exhibiting on average a 1.2 times higher log-fold change in biomarker levels in isolated EVs compared to total serum. Conclusion Overall, we hereby present the first evidence of altered murine and AD patient EV concentration and content in response to FUS-BBBO, providing evidence of EVs' role within FUS-BBBO neuroimmunotherapy as well as their utility in improving FUS-BBBO biomarker amplification. Our results pave the way for clinical applications of EV-based liquid biopsy in patients with neurodegenerative diseases following FUS-BBBO, as a way of noninvasively monitoring disease progression.

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Metadata

Authors
Kline-Schoder, A. R., Tsitsos, F. N., Batts, A. J., DiBenedetto, M. R., Liu, K., Bae, S., & Konofagou, E. E.
Affiliations
  • Columbia University (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Konofagou, Elisa E.
ORCID
Venue
Ultrasound in Medicine & Biology
Publisher
Elsevier BV
Published
2025-08
Volume
51
Issue
8
Pages
1316-1325
ISSN
0301-5629 (ISSN-L)
DOI
10.1016/j.ultrasmedbio.2025.04.019
PMC
PMC12229771
OpenAlex
W4410889508
Cited by
4
References
42
Citations by year
2026: 4
FWCI
0.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Ultrasound in Medicine & Biology (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute on Aging (R56AG038961)
  • National Institute of Biomedical Imaging and Bioengineering (R01EB009041)
  • National Institutes of Health
  • Focused Ultrasound Foundation
  • Alexander S Onassis Public Benefit Foundation (F ZT 072-1/2023-2024)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
extracellular vesicles, focused ultrasound, blood-brain barrier opening, Alzheimer's disease, liquid biopsy, serum biomarkers, glial fibrillary acidic protein, amyloid-beta 42, phosphorylated tau 181, GW4869, neuroinflammation, non-invasive disease monitoring

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