학술논문
Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound
Document Type
Author
Meng, Y.; Goubran, M.; Rabin, J. S.; McSweeney, M.; Ottoy, J.; Pople, C. B.; Huang, Y. X.; Storace, A.; Ozzoude, M.; Bethune, A.; Lam, B.; Swardfager, W.; Heyn, C.; Abrahao, A.; Davidson, B.; Hamani, C.; Aubert, I.; Zetterberg, Henrik, 1973; Ashton, Nicholas J.; Karikari, Thomas; Blennow, Kaj, 1958; Black, S. E.; Hynynen, K.; Lipsman, N.
Source
Brain. 146(3):865-872
Subject
Language
English
ISSN
0006-8950
Abstract
In an open-label single-arm trial, Meng et al. investigate the feasibility and tolerability of opening the blood-brain barrier in the default mode network with MR-guided focused ultrasound in patients with Alzheimer's disease. The study intervention led to local amyloid reduction on PET imaging, but no change in disease-specific markers in plasma or CSF. 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 (NCT04118764) 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 F-18-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-beta 42/40 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.