scholarly journals Extensive frontal focused ultrasound mediated blood–brain barrier opening for the treatment of Alzheimer’s disease: a proof-of-concept study

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
So Hee Park ◽  
Kyoungwon Baik ◽  
Seun Jeon ◽  
Won Seok Chang ◽  
Byoung Seok Ye ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Lobe ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Standardized Uptake Value ◽  
Brain Barrier ◽  
Cortical Region ◽  
Blood Brain ◽  
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Abstract Background Focused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies, but this is rarely reported in clinical studies. This study was conducted to evaluate the safety, feasibility and potential benefits of repeated extensive BBB opening. Methods In this open-label, prospective study, six patients with Alzheimer’s disease (AD) were enrolled at Severance Hospital in Korea between August 2020 and September 2020. Five of them completed the study. FUS-mediated BBB opening, targeting the bilateral frontal lobe regions over 20 cm3, was performed twice at three-month intervals. Magnetic resonance imaging, 18F-Florbetaben (FBB) positron emission tomography, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI) and comprehensive neuropsychological tests were performed before and after the procedures. Results FUS targeted a mean volume of 21.1 ± 2.7 cm3 and BBB opening was confirmed at 95.7% ± 9.4% of the targeted volume. The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease, which was statistically significant, compared to the pre-procedure value (− 1.6%, 0.986 vs1.002, P = 0.043). The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline (2.2 ± 3.0 vs 8.6 ± 6.0, P = 0.042), but recovered after 3 months (5.2 ± 5.8 vs 8.6 ± 6.0, P = 0.89). No adverse effects were observed. Conclusions The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. In addition, the BBB opening is potentially beneficial for amyloid removal in AD patients.

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

2020 ◽  
Vol 117 (17) ◽  
pp. 9180-9182 ◽  
Author(s):  
Ali R. Rezai ◽  
Manish Ranjan ◽  
Pierre-François D’Haese ◽  
Marc W. Haut ◽  
Jeffrey Carpenter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Therapeutic Delivery ◽  
Blood Brain ◽  
Initial Clinical Trial ◽  
Clinical Trial Results ◽  
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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.

scholarly journals Vasculotide restores the blood-brain barrier after focused ultrasound-induced permeability in a mouse model of Alzheimer's disease

2021 ◽  
Vol 18 (2) ◽  
pp. 482-493
Author(s):  
Madelaine Lynch ◽  
Stefan Heinen ◽  
Kelly Markham-Coultes ◽  
Meaghan O'Reilly ◽  
Paul Van Slyke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Blood Brain ◽  
Model Of Alzheimer’S Disease

scholarly journals Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound

2021 ◽  
Author(s):  
Ramon Vilar ◽  
Tiffany G Chan ◽  
Carmen Ruehl ◽  
Sophie Morse ◽  
Michelle Simon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Complexes ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Amyloid Β ◽  
Binding Mode ◽  
Brain Barrier ◽  
Amyloid Β Peptide ◽  
Blood Brain

One of the key hallmarks of Alzheimer’s disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt...

scholarly journals Blood-Brain Barrier Opening in Alzheimer's Disease Using MR-guided Focused Ultrasound

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Ying Meng ◽  
Zahra Shirzadi ◽  
Bradley MacIntosh ◽  
Chris Heyn ◽  
Gwen S Smith ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Amyloid Deposition ◽  
Brain Barrier ◽  
Therapeutic Delivery ◽  
Blood Brain ◽  
Bbb Permeability

Abstract INTRODUCTION The blood-brain barrier (BBB) represents a significant restriction to therapeutic delivery to the central nervous system. Several techniques are available to circumvent the BBB, however focused ultrasound does so noninvasively and under image-guidance. MR-guided focused ultrasound (MRgFUS) in combination with intravenous microbubbles has been shown in animal models to transiently open the BBB, enhance biological therapeutics, and lead to greater reductions in Alzheimer disease (AD) pathology. Leveraging this preclinical data, we test, for the first time, whether MRgFUS induced increase in BBB permeability is safe, feasible, and repeatable in patients with early-to-moderate AD. METHODS Five patients with AD (mean age 66.2, mean MMSE 22.6) were recruited to this phase I open-label study. Two MRgFUS procedures targeting the right dorsolateral prefrontal cortex were performed 1-mo apart. [18F]-florbetaben PET was used to confirm amyloid deposition at the target site before the procedure. Patients were followed for 3 mo. Safety was assessed by the number and quality of adverse events. Feasibility was qualitatively assessed by gadolinium contrast extravasation in the target immediately and 1-d postprocedure. Resting state functional MRIs (rs-fMRIs) and [18F]-florbetaben PET were additionally acquired as exploratory measures. RESULTS Immediate gadolinium extravasation after MRgFUS demonstrated increased BBB permeability. This resolved the morning after. BBB open was uniform and achievable on all occasions. Opening the BBB did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at 3 mo compared to baseline. [18F]-florbetaben PET analysis suggested no group-wise changes in amyloid deposition at the target postsonication. There was a significant temporary decrease in functional connectivity in the ipsilateral frontoparietal network, with no additional long-term changes in frontoparietal or default mode network. CONCLUSION Our results provide the basis for the next investigation of MRgFUS as a potential novel treatment and therapeutic delivery strategy for patients with Alzheimer's disease. Exploratory analysis of advanced imaging further suggests ultrasound is capable of noninvasive neuromodulation.

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