Blood–brain barrier opening of the default mode network in Alzheimer’s disease with magnetic resonance-guided focused ultrasound-Reference-Cited by-同舟云学术

Blood–brain barrier opening of the default mode network in Alzheimer’s disease with magnetic resonance-guided focused ultrasound

Published:2023-01-25 Issue:3 Volume:146 Page:865-872
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Meng Ying¹²^ORCID,Goubran Maged²³⁴,Rabin Jennifer S²³⁵⁶^ORCID,McSweeney Melissa²,Ottoy Julie²^ORCID,Pople Christopher B²,Huang Yuexi²,Storace Alexandra²,Ozzoude Miracle²,Bethune Allison²,Lam Benjamin²³⁶,Swardfager Walter²³⁷,Heyn Chinthaka²⁸,Abrahao Agessandro²³⁶^ORCID,Davidson Benjamin¹²,Hamani Clement¹²³,Aubert Isabelle²³⁹^ORCID,Zetterberg Henrik¹⁰¹¹¹²¹³^ORCID,Ashton Nicholas J¹⁰¹⁴¹⁵¹⁶,Karikari Thomas K¹⁰¹⁷^ORCID,Blennow Kaj¹⁰¹¹,Black Sandra E²³⁶,Hynynen Kullervo²⁴,Lipsman Nir¹²³

Affiliation:

1. Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON M4N 3M5 , Canada

2. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON M4N 3M5 , Canada

3. Hurvitz Brain Sciences Research Program, Harquail Centre for Neuromodulation, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON M4N 3M5 , Canada

4. Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7 , Canada

5. Rehabilitation Sciences Institute, University of Toronto , Toronto, ON M5G 1V7 , Canada

6. Department of Medicine (Neurology), Sunnybrook Health Sciences Centre and University of Toronto , Toronto, ON M4N 3M5 , Canada

7. Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8 , Canada

8. Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON M4N 3M5 , Canada

9. Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, ON M5S 1A8 , Canada

10. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at The University of Gothenburg , 405 30 Mölndal , Sweden

11. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , 413 45 Mölndal , Sweden

12. Department of Neurodegenerative Disease, UCL Institute of Neurology , London WC1N 3BG , UK

13. UK Dementia Research Institute at UCL , London W1T 7NF , UK

14. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg , 405 30 Gothenburg , Sweden

15. King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute , London SE5 9RX , UK

16. NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation , London SE5 8AF , UK

17. Department of Psychiatry, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15213 , USA

Abstract

Abstract The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Funder

Weston Brain Institute

Focused Ultrasound Foundation

Harquail Centre for Neuromodulation

Sunnybrook Foundation

Swedish Research Council

Swedish Alzheimer Foundation

European Research Council

Swedish State Support for Clinical Research

Alzheimer Drug Discovery Foundation

UCL

Canadian Institute of Health Research