Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound

Lipsman, Nir; Meng, Ying; Bethune, Allison; Huang, Yuexi; Lam, Benjamin; Masellis, Mario; Herrmann, Nathan; Heyn, Chinthaka; Aubert, Isabelle; Boutet, Alexandre; Smith, Gwenn S.; Hynynen, Kullervo; Black, Sandra E.

doi:10.1038/s41467-018-04529-6

Cited by 696 publications

(630 citation statements)

References 38 publications

Supporting

Mentioning

576

Contrasting

Unclassified

Order By: Relevance

“…Follow up studies might also control for blood brain barrier opening, [23] although our energy levels render it unlikely, that this occurred in our subjects. The simulations, laboratory, and in vivo animal measurements also indicate broad safety margins according to the current state of acquired data.…”

Section: Resultsmentioning

confidence: 95%

See 1 more Smart Citation

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease—A New Navigated Focal Brain Therapy

et al. 2019

View full text Add to dashboard Cite

Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies.

show abstract

Section: Resultsmentioning

confidence: 95%

“…The application of ultrasound for brain therapy has become a hot topic as it bears the potential for providing a new class of semi-invasive (ablation [20][21][22] or blood brain barrier opening [23] ), or noninvasive (brain stimulation) brain therapies. However, Adv.…”

Section: Resultsmentioning

confidence: 99%

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease—A New Navigated Focal Brain Therapy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The mechanism of PRGFRaÀinduced BBB disruption is not understood, but intriguingly, the expression of Pdgfra is largely restricted to perivascular fibroblasts among the different cell types of the NVU [17]. An alternative approach is based on focused ultrasound, which may transiently open BBB to release toxic Ab from AD patients [177]. As discussed above, pericytes are important for the constriction of capillaries and reduced CBF observed in the post-stroke situation [39,40].…”

Section: Toward Therapy Developmentmentioning

confidence: 99%

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

View full text Add to dashboard Cite

Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non-existing. It is an emerging notion that neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes-important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood-brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.

show abstract

“…For clinical imaging using DEFINITY as a contrast agent, 20 μL/kg is the maximal dose recommended by the manufacturer [40], which has been shown to successfully increase BBB permeability following FUS in rodents [39, 41]. The first clinical trial in AD patients used DEFINITY at a dose of 4 μL/kg for FUS-mediated BBB opening in humans [16]. Using a clinical imaging dose of DEFINITY microbubbles for FUS-mediated BBB permeability, McMahon et al reported no acute inflammatory response, hemorrhage, or edema following treatment.…”

Section: Notesmentioning

confidence: 99%

“…1). Focused ultrasound, combined with microbubbles and guided by magnetic resonance imaging (MRI), has been applied to open the BBB in a safe, noninvasive, and reversible manner in targeted areas ofbrain in animal models [15] and, most recently, in AD patients [16]. MRI-guided FUS (MRIgFUS)-mediated delivery of rAAVs to targeted areas of the brain and spinal cord can be achieved with systemic doses which are up to 100 times lower than those conventionally used with rAAVs capable of crossing the BBB [11, 15, 17–20].…”

Section: Introductionmentioning

confidence: 99%

MRI-Guided Focused Ultrasound for Targeted Delivery of rAAV to the Brain

Noroozian

Xhima

Huang

et al. 2019

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

Recombinant adeno-associated viral (rAAV) vectors are a promising tool for therapeutic gene delivery to the brain. However, the delivery of rAAVs across the blood-brain barrier (BBB) and entry into the brain remains a major challenge for rAAV-based gene therapy. To circumvent this limitation, transcranial MRI-guided focused ultrasound (MRIgFUS) combined with intravenously injected microbubbles has been used to transiently and reversibly increase BBB permeability in targeted brain regions. Systemic administration of rAAVs at the time of sonication with focused ultrasound (FUS) facilitates the passage of rAAVs through the BBB and into the brain parenchyma. We and others have demonstrated that FUS-mediated rAAV delivery to the brain results in efficient transduction and transgene expression in vivo. Using this approach, the dose of intravenously injected rAAV variants that can cross the BBB can be reduced by 100 times, achieving significant transgene expression in the brain parenchyma with reduced peripheral transduction. Moreover, this strategy can be used to deliver rAAV variants that do not cross the BBB from the blood to selected brain regions. Here, we provide a detailed protocol for FUS-induced BBB permeability for targeted rAAV delivery to the brain of adult mice and rats.

show abstract

Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound

Cited by 696 publications

References 38 publications

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease—A New Navigated Focal Brain Therapy

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease—A New Navigated Focal Brain Therapy

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

MRI-Guided Focused Ultrasound for Targeted Delivery of rAAV to the Brain

Contact Info

Product

Resources

About