Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound                    Elicits Meningeal Venous Permeability in Humans with Early Alzheimer                    Disease

Mehta, Rashi I.; Carpenter, Jeffrey; Mehta, Rupal I.; Haut, Marc W.; Ranjan, Manish; Najib, Umer; Lockman, Paul R.; Wang, Peng; D’Haese, Pierre-François; Rezai, Ali R.

doi:10.1148/radiol.2021200643

Cited by 70 publications

(62 citation statements)

References 20 publications

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“…89 In small case series, transient opening of the BBB by magnetic resonance-guided focused ultrasound was discussed to improve Aβ clearance from the brain without significant side effects. [90][91][92][93][94] After sonication of the hippocampus, contrast enhancement along the course of draining veins in the hippocampus 94 and perivenous enhancement towards the dural venous sinuses 95 were interpreted as glymphatic efflux. 94 The enhanced drainage along veins does not affect CAA, which mainly occurs along arteries.…”

Section: The Wepcast Technique Labels Water By Arterial Spin Labellin...mentioning

confidence: 99%

Dysfunction of the blood–brain barrier in Alzheimer's disease: Evidence from human studies

Kurz

Walker

Rauchmann

et al. 2022

Neuropathology Appl Neurobio

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The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer's disease (AD) and their relation to vascular disease and immunological changes are yet to be fully explored. Amyloid‐β (Aβ) aggregation, vascular damage and altered immune response interact at the blood–brain barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta‐analyses, published in English language from 01/2000 to 07/2021, using the keywords Alzheimer*, amyloid‐β or β‐amyloid or abeta and BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes/macrophages characterise BBB damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD‐specific brain regions. The toxic effects of Aβ and apolipoprotein E (ApoE) are likely to induce a non‐cerebral‐amyloid‐angiopathy‐related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, proinflammatory signalling and cerebral amyloid angiopathy enhance BBB damage. Novel therapeutic approaches for AD, including magnetic resonance‐guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of Aβ along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE‐modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of proinflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of Aβ deposition as a primary versus a secondary event in the complex pathogenesis of AD.

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Section: The Wepcast Technique Labels Water By Arterial Spin Labellin...mentioning

confidence: 99%

Dysfunction of the blood–brain barrier in Alzheimer's disease: Evidence from human studies

Kurz

Walker

Rauchmann

et al. 2022

Neuropathology Appl Neurobio

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“…While many pre-clinical studies have individually demonstrated opening of the BBB/ BTB, very few trials have provided preliminary proof of clinical implementation of this technology. Clinical application of FUS is currently being tested in a few pathologies including primary tumors, Alzheimer's disease, essential tremor, Parkinson's disease and amyotrophic lateral sclerosis [ 72 , 73 , 74 ]. One of first clinical reports of HIFU used the ExAblate 3000 which could reduce acoustic backscatter and beam dispersion due to skull thickness variability [ 75 ].…”

Section: Clinical Impact Of Fus Mediated Bbb/btb Disruptionmentioning

confidence: 99%

“…The BBB opening was immediate and sizeable consisting of about 29% of hippocampus and the BBB closed within 24-h post sonication [ 80 ]. As evident from the basic science studies suggesting immunomodulation, MRI investigation revealed perivenous enhancement during acute BBB opening which persisted even after BBB closure, suggesting a downstream immunological response blood-meningeal barrier in patients with Alzheimer's disease [ 73 ].…”

Section: Clinical Impact Of Fus Mediated Bbb/btb Disruptionmentioning

confidence: 99%

Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery

et al. 2021

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The blood-brain barrier (BBB) is a major anatomical and physiological barrier limiting the passage of drugs into brain. Central nervous system tumors can impair the BBB by changing the tumor microenvironment leading to the formation of a leaky barrier, known as the blood-tumor barrier (BTB). Despite the change in integrity, the BTB remains effective in preventing delivery of chemotherapy into brain tumors. Focused ultrasound is a unique noninvasive technique that can transiently disrupt the BBB and increase accumulation of drugs within targeted areas of the brain. Herein, we summarize the current understanding of different types of targeted ultrasound mediated BBB/BTB disruption techniques. We also discuss influence of the tumor microenvironment on BBB opening, as well as the role of immunological response following disruption. Lastly, we highlight the gaps between evaluation of the parameters governing opening of the BBB/BTB. A deeper understanding of physical opening of the BBB/BTB and the biological effects following disruption can potentially enhance treatment strategies for patients with brain tumors.

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“…Three participants underwent multiple treatment sessions of BBBO targeting the hippocampus and entorhinal cortex. It was found that CE reappeared in the perivenular regions downstream from the targeted sites after BBB closure, supporting that the permeability of the blood–meningeal barrier may last longer, suggesting a perivenular immunological healing response [ 105 ].…”

Section: Clinical Translation Of Bbbomentioning

confidence: 99%

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications

2021

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The blood–brain barrier (BBB) protects the central nervous system (CNS) from invasive pathogens and maintains the homeostasis of the brain. Penetrating the BBB has been a major challenge in the delivery of therapeutic agents for treating CNS diseases. Through a physical acoustic cavitation effect, focused ultrasound (FUS) combined with microbubbles achieves the local detachment of tight junctions of capillary endothelial cells without inducing neuronal damage. The bioavailability of therapeutic agents is increased only in the area targeted by FUS energy. FUS with circulating microbubbles is currently the only method for inducing precise, transient, reversible, and noninvasive BBB opening (BBBO). Over the past decade, FUS-induced BBBO (FUS-BBBO) has been preclinically confirmed to not only enhance the penetration of therapeutic agents in the CNS, but also modulate focal immunity and neuronal activity. Several recent clinical human trials have demonstrated both the feasibility and potential advantages of using FUS-BBBO in diseased patients. The promising results support adding FUS-BBBO as a multimodal therapeutic strategy in modern CNS disease management. This review article explores this technology by describing its physical mechanisms and the preclinical findings, including biological effects, therapeutic concepts, and translational design of human medical devices, and summarizes completed and ongoing clinical trials.

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Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease

Cited by 70 publications

References 20 publications

Dysfunction of the blood–brain barrier in Alzheimer's disease: Evidence from human studies

Dysfunction of the blood–brain barrier in Alzheimer's disease: Evidence from human studies

Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications

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