Opening Blood-Brain Barrier to Deliver Alzheimer's Drug Shows Promise

 Because of your risk of dementia post stroke you'll want your doctor to know about this. So be prepared to train them.

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Opening Blood-Brain Barrier to Deliver Alzheimer's Drug Shows Promise

Focused ultrasound helped aducanumab reduce amyloid-beta levels

by Judy George, Deputy Managing Editor, MedPage Today January 3, 2024

Last Updated January 4, 2024

Aducanumab (Aduhelm) infusions combined with focused ultrasound led to lower cerebral amyloid-beta levels in Alzheimer's disease, a proof-of-concept trial showed.

The investigational treatment involved creating an opening in the blood-brain barrier with MRI-guided focused ultrasound to boost drug delivery.

In each of three participants who received aducanumab infusions, amyloid reduction was greater in brain regions targeted with focused ultrasound than in regions not exposed to focused ultrasound, said Ali Rezai, MD, of West Virginia University Rockefeller Neuroscience Institute in Morgantown, and co-authors in a New England Journal of Medicineopens in a new tab or window brief report.

From baseline to the 26-week assessment, PET scans showed that focused ultrasound combined with aducanumab led to a drop in amyloid levels from 224.2 to 115.2 centiloids in participant 1, from 185.6 to 104.6 centiloids in participant 2, and from 251.5 to 84.9 centiloids in participant 3. Contralateral brain regions that did not have focused ultrasound showed little change in amyloid levels from baseline to 26 weeks.

"We observed an average 32% reduction in SUVR [standardized uptake value ratio] for the three participants combined after 26 weeks in the regions that had received treatment to open the blood-brain barrier and six combination treatments," Rezai and colleagues wrote.

Headaches were the most common adverse events and were mild except for one moderate headache. One participant had two severe adverse events during the focused ultrasound treatment due to discomfort with head and neck positioning; this resolved immediately after the procedure. No amyloid-related imaging abnormalities were seen.

Low-intensity focused ultrasound has reversibly opened the blood-brain barrier in people with Alzheimer's disease or other neurologic disorders, including Parkinson's disease, brain tumors, and amyotrophic lateral sclerosis.

Previous work by Rezai's group showed that focused ultrasound alone -- without a therapeutic agent like aducanumab -- slightly reducedopens in a new tab or window amyloid-beta levels, noted Kullervo Hynynen, PhD, of the University of Toronto in Canada. "The reduction observed in the current trial was numerically greater than in the previous studies," he wrote in an accompanying editorialopens in a new tab or window.

"The blood-brain barrier safeguards the brain from harmful substances while allowing essential nutrients to pass through," Hynynen said. "However, it also impedes the delivery of drugs to the brain."

The three participants were a 77-year-old man (participant 1), a 59-year-old man (participant 2), and a 64-year-old woman (participant 3). All received a diagnosis of Alzheimer's disease within the year before enrollment. None had previously received aducanumab therapy and none carried an APOE4 allele.

For 6 months, participants received monthly intravenous aducanumab, escalated up to 6 mg/kg rather than the on-label doseopens in a new tab or window of 10 mg/kg, as a risk mitigation strategy.

Opening the blood-brain barrier with focused ultrasound started 2 hours after each infusion. The blood-brain barrier closed within 24 to 48 hours after the procedure.

Focused ultrasound was applied to areas with high beta-amyloid in the frontal or temporal lobe or the hippocampus. In the contralateral hemisphere, homologous brain regions that were not exposed to focused ultrasound served as controls.

Participants 1 and 2 had no neurologic, cognitive, or behavioral changes at their last follow-up visit. At day 30 of follow-up, participant 3's cognitive test scores declined, but she showed no neurologic change or change in activity of daily living scores.

These findings are consistent with those of mouse studiesopens in a new tab or window that demonstrated increased penetration of aducanumab when combined with focused ultrasound to open the blood-brain barrier, Rezai and colleagues noted.

"However, our trial did not quantify monoclonal antibody penetration, and therefore enhanced delivery of the monoclonal antibody was not directly shown," they acknowledged.

The study involved small tissue volumes in one side of the brain of only three patients, Hynynen pointed out. Larger trials are needed and expanding treatment to both sides of the brain is crucial to determine efficacy, he observed.

"That all being said, the results spark optimism that this approach to treatment, together with agents that remove [amyloid-beta], could eventually slow the progression of Alzheimer's disease," he wrote.

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study was funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.

Rezai had no disclosures.

Co-authors reported relationships with Insightec, AbbVie, Genentech, Neurocrine Biosciences, Teva Pharmaceuticals USA, and Taylor & Francis Group.

Hynynen is a founder of FUS Instruments and holds patents related to focus ultrasound methods.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowRezai AR, et al "Ultrasound blood–brain barrier opening and aducanumab in Alzheimer's disease" N Engl J Med 2024; DOI: 10.1056/NEJMoa2308719.

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowHynynen K "Sounding out the blood–brain barrier" N Engl J Med 2024; DOI: 10.1056/NEJMe2311358.

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Combined therapy of focused ultrasound and aducanumab induces neurogenesis and decreases of beta-amyloid plaques in a mouse model of Alzheimer’s disease

20 pages for your doctor to apply for preventing your likely Alzheimers and better stroke recovery.

Combined therapy of focused ultrasound and aducanumab induces neurogenesis and decreases of beta-amyloid plaques in a mouse model of Alzheimers disease

Directed by Professor Jin Woo Chang Doctoral Dissertation submitted to the Department of Medicine, the Graduate School of Yonsei University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chanho Kong

Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood–brain barrier opening

 For when our researchers find a drug they need to get across the blood brain barrier. Assuming that our fucking failures of stroke associations  can remember this when researchers need it.

Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood–brain barrier opening

• Seiichi Ohta,
• Emi Kikuchi,
• Ayumu Ishijima,
• Takashi Azuma,
• Ichiro Sakuma &
• Taichi Ito 

Scientific Reports volume 10, Article number: 18220 (2020) Cite this article

• 102 Accesses

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Abstract

The blood–brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.

Introduction

Nanoparticles have attracted global attention in the biomedical field. It has been revealed that their interaction with cells and/or tissues can be tailored through nanoparticle design, such as their size, shape, and surface chemistry¹. Combined with the advances in nanoparticle functionalization methods, this has opened the way for various biomedical applications of nanoparticles, including drug delivery, imaging, and therapies^2,3. However, despite the promise of nanoparticle-based systems, their translation to clinical use remains a challenge, mainly due to the low efficiency of their delivery to target sites^4,5. Various factors have been proposed as hampering nanoparticle delivery, including uptake by the reticuloendothelial system (RES), restricted diffusion in dense extracellular matrix (ECM), resistance by interstitial pressure, and clearance via the renal system^6,7,8.

The brain is one of the most difficult target organs to deliver nanoparticles to because of the existence of the blood–brain barrier (BBB). The BBB is composed of brain endothelial cells attached to a continuous basement membrane and linked together by tight junctions that prevents foreign substances from entering into the brain⁹. Even small molecular drugs can barely cross the BBB, which is a major limitation for the treatment of central nervous system (CNS) diseases, such as Alzheimer’s disease and Parkinson’s disease; diseases whose prevalence is rapidly increasing as societies around the world are aging. In the case of nanoparticles, the restriction of their permeation across the BBB is even more pronounced because of their relatively large size. Although various delivery methods have been attempted, e.g., using receptor-mediated endocytosis^10,11,12, transcytosis^13,14, or transporters^15,16, the efficiency of delivering nanoparticles into the brain is insufficient to fully exploit their therapeutic and diagnostic potential. For example, using transferrin receptor-targeted nanoparticles is one of the most widely used strategies to get nanoparticles across the BBB, but it typically results in < 0.1% delivery efficiency to the brain¹⁰.

Focused ultrasound (FUS) in combination with the administration of microbubbles (MBs) is an emerging technique being investigated to enhance the permeation of therapeutics across the BBB in a noninvasive, localized, and transient manner¹⁷. FUS induces inertial or stable cavitation with MBs that exerts a mechanical force onto capillary walls, leading to a temporary opening of the BBB via the widening of tight junctions^17,18,19. The enhanced delivery of small molecular drugs^20,21, oligonucleotides^22,23, and antibodies^24,25,26 into the brain via FUS-induced BBB opening has been demonstrated in vivo. In addition, clinical trials are now being conducted into the FUS-assisted delivery of small molecular drugs into gliomas^27,28. This technology could provide a promising strategy for improving the efficiency of nanoparticle delivery to the brain, although there are still only a limited number of reports on its application for nanoparticles^{29,30,31,32,33,34}.

To employ FUS-induced BBB opening for nanoparticle delivery, a question that must be addressed is how the size of nanoparticles can affect the enhanced permeation through opened BBB gaps. It is expected that the optimum nanoparticle design for this delivery mechanism would be different from that usually employed for enhanced permeation and retention (EPR)-based delivery strategies for tumors, in which nanoparticles are extravasated from naturally leaky blood vessels¹. However, although some previous studies investigated the effect of the size of nanoparticles, such as liposomes, on this strategy³⁴, the mechanism still needs to be clarified, especially in single to sub-hundred nanometer range. Here, we explored the effect of nanoparticle size on their delivery into the brain assisted by FUS-induced BBB opening, using polyethylene glycol (PEG)-coated gold nanoparticles (AuNPs) of different sizes, 3 to 120 nm, as a model (Fig. 1). An in vitro BBB model capable of FUS exposure was developed to examine the size-dependent permeation behavior of these particles. The size-dependent delivery of AuNPs into the brain was further investigated in vivo via transcranial FUS exposure in mice. Based on the obtained results, a kinetic model was proposed to estimate the optimum nanoparticle size for delivery into the brain assisted by FUS-induced BBB opening.

 

 

New Alzheimer’s Treatment Fully Restores Memory Function

What is YOUR doctor and stroke hospital doing to ensure that this is tested in humans? You will likely need this so you don't want incompetent personnel passing on this because SOMEONE ELSE WILL SOLVE THE PROBLEM.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.

3. A 20% chance in this research.   July 2013.

4. A 2-fold increase in dementia risk in this study    Jan. 2017 

New Alzheimer’s Treatment Fully Restores Memory Function

Australian researchers have come up with a non-invasive ultrasound technology that clears the brain of neurotoxic amyloid plaques - structures that are responsible for memory loss and a decline in cognitive function in Alzheimer’s patients.
If a person has Alzheimer’s disease, it’s usually the result of a build-up of two types of lesions - amyloid plaques, and neurofibrillary tangles. Amyloid plaques sit between the neurons and end up as dense clusters of beta-amyloid molecules, a sticky type of protein that clumps together and forms plaques.
Neurofibrillary tangles are found inside the neurons of the brain, and they’re caused by defective tau proteins that clump up into a thick, insoluble mass. This causes tiny filaments called microtubules to get all twisted, which disrupts the transportation of essential materials such as nutrients and organelles along them, just like when you twist up the vacuum cleaner tube.
As we don’t have any kind of vaccine or preventative measure for Alzheimer’s - a disease that affects 343,000 people in Australia, and 50 million worldwide - it’s been a race to figure out how best to treat it, starting with how to clear the build-up of defective beta-amyloid and tau proteins from a patient’s brain. Now a team from the Queensland Brain Institute (QBI) at the University of Queensland have come up with a pretty promising solution for removing the former.
Publishing in Science Translational Medicine, the team describes the technique as using a particular type of ultrasound called a focused therapeutic ultrasound, which non-invasively beams sound waves into the brain tissue. By oscillating super-fast, these sound waves are able to gently open up the blood-brain barrier, which is a layer that protects the brain against bacteria, and stimulate the brain’s microglial cells to activate. Microglial cells are basically waste-removal cells, so they’re able to clear out the toxic beta-amyloid clumps that are responsible for the worst symptoms of Alzheimer’s.
The team reports fully restoring the memory function of 75 percent of the mice they tested it on, with zero damage to the surrounding brain tissue. They found that the treated mice displayed improved performance in three memory tasks - a maze, a test to get them to recognise new objects, and one to get them to remember the places they should avoid.
"We’re extremely excited by this innovation of treating Alzheimer’s without using drug therapeutics," one of the team, Jürgen Götz, said in a press release. "The word ‘breakthrough’ is often misused, but in this case I think this really does fundamentally change our understanding of how to treat this disease, and I foresee a great future for this approach."
The team says they’re planning on starting trials with higher animal models, such as sheep, and hope to get their human trials underway in 2017. 
You can hear an ABC radio interview with the team here.