Glymphatics Visualization after Focused Ultrasound‐Induced Blood–Brain Barrier Opening in Humans

Meng, Ying; Abrahão, Agessandro; Heyn, Chinthaka; Bethune, Allison; Huang, Yuexi; Pople, Christopher B; Aubert, Isabelle; Hamani, Clement; Zinman, Lorne; Hynynen, Kullervo; Black, Sandra E.; Lipsman, Nir

doi:10.1002/ana.25604

Cited by 93 publications

(69 citation statements)

References 22 publications

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“…An experimental study using regular FLAIR imaging, which temporarily opened the blood-brain barrier with focused ultrasound (FUS) showed that the amount of GBCA leakage into the subarachnoid space after intravenous injection was increased by FUS. 18 According to the previous report, the leakage around the cortical veins after intravenous injection of GBCA is limited to the perivascular space around the cortical veins at 5 min after intravenous injection, after which it spreads into the surrounding the subarachnoid space. 1 Furthermore, images in which the perivascular space around the cortical veins is directly connected to the meningeal lymphatic vessels near the SSS have been shown.…”

Section: Discussionmentioning

confidence: 97%

Confirmation of Age-dependence in the Leakage of Contrast Medium around the Cortical Veins into Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agent

et al. 2020

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It has been reported previously that intravenously administered gadolinium-based contrast agent (GBCA) leaks into the subarachnoid space around the cortical veins at 4 h after injection in all old people over 37 years, but not in younger people up to 37 years of age in 3D-real IR images. The purpose of this study was to investigate whether there was a strict threshold of 37 years of age for the leakage of the GBCA into the subarachnoid space. Methods: The subjects included 190 patients, that were scanned for 3D-real IR images at 4 hours after intravenous injection of GBCA as a diagnostic test for endolymphatic hydrops. The patient's age ranged from 14 to 81 years. Two experienced neuroradiologists evaluated the images to determine whether the GBCA leakage around the cortical veins was positive or negative. Any discrepancies between the two observers were discussed and a consensus was obtained. A Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were used to compare the positive and the negative group and to set the age cutoff value for the prediction of GBCA leakage. Results: The GBCA leakage around the cortical veins was negative in 35 patients and positive in 155 patients. The average age was 33 ± 11 years in the negative group, and 55 ± 12 years in the positive group (P < 0.01). In the ROC analysis for the age and leakage of the GBCA, an area under the curve was 0.905 and the cutoff age was 37.317 years (sensitivity of 0.942 and specificity of 0.771). Conclusion: Intravenously administered GBCA leaks into the subarachnoid space around the cortical veins in most patients over 37 years of age. However, it should be noted that it can be found occasionally in patients under 37 years of age.

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Section: Discussionmentioning

confidence: 97%

Confirmation of Age-dependence in the Leakage of Contrast Medium around the Cortical Veins into Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agent

et al. 2020

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“…Our results highlight the conformal capacity of FUS to safely and repeatedly open the BBB in the hippocampus, with spatial precision and no off-target BBB opening. FUS-mediated BBB opening in preclinical models has been found to promote amyloid-beta clearance, delivery of endogenous antibodies, activation of microglia (8,12), and potential modulation of the glymphatic system (13). The significance with respect to human translation of amyloid reduction observed in animal models with FUS-mediated BBB disruption is unknown.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound

Rezai

Ranjan

D’Haese

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

244

151

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The blood–brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer’s disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

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“…Several groups have shown that CSF flows between the BM and astrocyte endfeet of arteries and capillaries, with arteriole pulsations driving bulk fluid flow through the parenchyma, although others have argued about the extent of bulk flow (Abbott et al, 2018; Hladky and Barrand, 2019). This “glymphatic” system helps to clear interstitial solutes such as amyloid via paravenous drainage pathways (Iliff et al, 2012; Xie et al, 2013; Mestre et al, 2018) and has been visualized in human patients via magnetic resonance imaging (MRI; Meng et al, 2019; Fultz et al, 2019). Expression of water channel aquaporin-4 in astrocyte endfeet has been reported to play a critical role in the movement of CSF into the parenchyma (Haj-Yasein et al, 2011; Iliff et al, 2012; Mestre et al, 2018).…”

Section: The Nvumentioning

confidence: 99%

The blood–brain barrier in health and disease: Important unanswered questions

Profaci

Munji

Pulido

et al. 2020

Journal of Experimental Medicine

471

358

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The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control the movement of ions, molecules, and cells between the blood and the parenchyma. This “blood–brain barrier” is initiated during angiogenesis via signals from the surrounding neural environment, and its integrity remains vital for homeostasis and neural protection throughout life. Blood–brain barrier dysfunction contributes to pathology in a range of neurological conditions including multiple sclerosis, stroke, and epilepsy, and has also been implicated in neurodegenerative diseases such as Alzheimer’s disease. This review will discuss current knowledge and key unanswered questions regarding the blood–brain barrier in health and disease.

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Glymphatics Visualization after Focused Ultrasound‐Induced Blood–Brain Barrier Opening in Humans

Cited by 93 publications

References 22 publications

Confirmation of Age-dependence in the Leakage of Contrast Medium around the Cortical Veins into Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agent

Confirmation of Age-dependence in the Leakage of Contrast Medium around the Cortical Veins into Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agent

Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound

The blood–brain barrier in health and disease: Important unanswered questions

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