Data And Materials Availability
RNA sequencing metadata that support the findings of this study are openly available in the European Genome-Phenome Archive at EGA Accession Number: EGAS00001005944. All other data are presented in the main text or the supplementary materials or can be made available by contacting the corresponding author.
Alzheimers: Ultrasound Safely Delivers Drugs To Damaged Brains Of Mice
Scientists at Queensland Brain Institute find noninvasive technique slows progression of Alzheimers disease in mice
Australian researchers say they have made a promising step in the future treatment of Alzheimers disease after discovering ultrasound can effectively and safely deliver drugs to the damaged brain.
Scientists at the Queensland Brain Institute found the noninvasive technique successfully penetrated the blood-brain barrier to deliver a therapeutic antibody to the brain. This then slowed the progression of Alzheimers disease in mice, according to a study published in the journal Brain.
One of the major challenges inhibiting the treatment of Alzheimers is that the majority of drugs designed to treat the brain disease do not make it into the brain.
Ultrasound safely opens up the blood-brain barrier just a tiny bit and just for short time to let the antibody into the brain and, importantly, into the nerve cells where the damage occurs, said Prof Jurgen Gotz, the lead researcher at QBI.
Alzheimers disease is the most common form of dementia, with the number of dementia cases in Australia expected to rise to 900,000 by 2050.
Using scanning ultrasound technology, researchers at QBI delivered an antibody that specifically binds to a protein called tau implicated in the progression of Alzheimers.
A Sporadic Alzheimer’s Blood
Joanna M. Wasielewska1,2, Juliana C. S. Chaves1, Rebecca L. Johnston3, Laura A. Milton1#, Damián Hernández4, Liyu Chen5, Jae Song5, Wendy Lee5, Gerhard Leinenga5, Rebecca M. Nisbet6, Alice Pébay4,7, Jürgen Götz5, Anthony R. White1,8*, Lotta E. Oikari1 *
1. Cell & Molecular Biology Department, Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute Brisbane, QLD, Australia.2. Faculty of Medicine, The University of Queensland Brisbane, QLD, Australia.3. Genetics & Computational Biology Department, QIMR Berghofer Medical Research Institute Brisbane, QLD, Australia.4. Department of Anatomy and Physiology, The University of Melbourne Parkville, VIC, Australia.5. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland Brisbane, QLD, Australia.6. The Florey Institute of Neuroscience and Mental Health Parkville, VIC, Australia.7. Department of Surgery, Royal Melbourne Hospital, The University of Melbourne Parkville, VIC, Australia.8. School of Biomedical Sciences, Faculty of Medicine, The University of Queensland Brisbane, QLD, Australia.*These authors contributed equally to this work.#Now located at: School of Mechanical, Medical and Process Engineering, Queensland University of Technology Brisbane, QLD, Australia.
Corresponding author: E-mail: Lotta.Oikariedu.au.
Citation:Theranostics
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Cautious Progress For Possible Dementia Treatment
Götz and his researchers studied ultrasound therapy in mice and observed an improvement in memory function and a reversal of dementia symptoms in the mice after treatment. Because brains become more fragile with age, the team made a point of testing the treatment on older mice who were the equivalent of 80-90 in human years. In early 2018, they reported that the ultrasound procedure did not cause damage or increase bleeding in geriatric mice.
The scientists have also tested the process for safety on larger brains, in sheep. Now, theyre planning to conduct a small clinical trial later this year to evaluate the safety of the ultrasound treatment in humans.
If that trial shows that the ultrasound therapy is safe, they can move forward with trials to see if the treatment is effective for humans.
Its too early to know whether this approach will prove safe in humans, but if it does, it could eventually make ultrasound a viable tool for removing plaques and tangles in people with dementia, with or without the addition of immunotherapy agents.
Götz says of the treatment, The treatment is designed as a potential therapy for dementia and targets the toxic protein build-ups that are a hallmark of this condition. Vascular dementia, which doesnt involve toxic protein build-ups, has a different pathology and will thus require different treatment strategies.
Meet Judi Polak Alzheimer’s Patient And Star Of A Clinical Trial Showing Promising Results
by Hallie Levine, AARP, December 11, 2019
WVU Medicine
Judi Polak with members of the team from the Rockefeller Neuroscience Institute at the WVU School of Medicine
En español | Almost 6 million Americans live with Alzheimer’s, a devastating disease for which there is no known cure. Judi Polak, 62, is one of them. She’s also one of the much smaller number of people who’ve signed on to let researchers experiment on their ailing brains in her case, having ultrasound energy beamed into her hippocampus, the brain’s memory center.
Perhaps surprisingly, Judi didn’t think twice about joining the groundbreaking clinical trial, which she describes as part of her active fight against the disease she was diagnosed with four years ago. We all have a lot of inner strength, Judi says of her family . One of our good friends said that the first person to be cured with Alzheimer’s is alive today. That became our mantra and fight song. I choose not to suffer, not to die, but to fight.”
It’s a fitting motto for a woman whose husband describes her as a butterfly on acid. Before Judi’s diagnosis, I’d joke that Judi didn’t just burn the candle on both ends she set fire to the middle, Mark says.
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Take Control of Your Brain Health With Staying Sharp
WVU Medicine
Judi and Mark Polak
One of our good friends said that the first person to be cured with Alzheimer’s is alive today. That became our mantra and fight song. I choose not to suffer, not to die, but to fight.
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Fus+mb Treatment Has Minimal Effects On Apoe3 And Apoe4 Iastrocyte Phenotype
Astrocytes are a critical component of the BBB, but little is known about the effects of FUS+MB on human astrocytes. As astrocyte end-feet are in direct contact with BECs in vivo, it is likely that FUS+MB treatment also impacts astrocytes, however, this has not been extensively investigated. We therefore examined astrocyte responses to FUS+MB within the first 24 h following treatment. We generated induced astrocytes from the same APOE3 and APOE4-carrying human iPSCs that were used for iBEC differentiation . Neural progenitor cells were generated and characterized for nestin and SOX2 expression and then differentiated into iAstrocytes for a minimum of 60 days. iAstrocytes were further matured 7 days before experiments with 10 ng/mL bone morphogenetic protein 4 and ciliary neurotrophic factor as previously described . Matured iAstrocytes were exposed to FUS+MB using the same parameters as for therapeutic antibody delivery in iBEC monocultures, and cell morphology, viability, marker expression and inflammatory responses were examined 1 h and 24 h following treatment.
Figure 4
Generation Of Human Ipsc
Human iPSC lines were generated and characterized as previously described . iPSCs were expanded on human recombinant vitronectin in StemFlexTM medium . iBEC differentiation was performed as previously described by us . Briefly, iPSCs were first cultured for 6 days in an unconditioned medium, followed by 2 days in endothelial serum free medium supplemented with 2 % B-27, 10 M and 20 ng/mL FGF-2, after which generated iBECs were purified on collagen IV and fibronectin coating . To establish a BBB in vitro model for antibody delivery experiments, iBECs were purified in Ø 0.4 m or 3.0 Øm pore polyester or polycarbonate Transwell inserts in mono- or co-cultures with iAstrocytes . Forty-eight hours following iBEC purification , barrier integrity was characterized by measuring TEER using the EVOM3 Volt/Ohmmeter . Passive dextran permeability was measured by culturing iBECs on Ø 0.4 m pore polyester or polycarbonate Transwell inserts and cells were exposed to 0.5 mg/mL fluorescein isothiocyanate -conjugated 3 – 5 kDa dextran for 24h. The top and bottom well fluorescence was measured using a plate reader and clearance volume calculated as previously described .
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A New Treatment Approach
On June 7, the FDA approved the first Alzheimer’s disease drug in nearly two decades. Aducanumab, a drug developed by Biogen, is an antibody designed to targetand reduce amyloid plaques. The drug has already sparked immense enthusiasm and controversy. Proponents say the drug is a much-needed start in the fight against the disease, but others argue that the drug doesn’t substantially improve cognition. They say the approval could open the door to the FDA greenlighting more Alzheimer’s drugs that don’t have a clear benefit, giving false hope to both patients and their families.
Konofagou’s ultrasound approach could potentially boost the effects of drugs like aducanumab. “Our technique can be seamlessly combined with aducanumab in early Alzheimer’s, where it has shown the most promise, to further enhance both its amyloid load reduction and further reduce cognitive deficits while using exactly the same drug regimen otherwise,” she says. For the Columbia team, the goal is to use ultrasound to maximize the effects of aducanumab, as they’ve done with other drugs in animal studies.
But Konofagou’s approach could transcend drug controversies, and even drugs altogether. The big promise of ultrasound is that it could eventually make drugs for Alzheimer’s obsolete.
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Study Design And Participants
This open label, prospective, proof-of-concept, phase I trial was designed to study the safety and feasibility of repeated BBB opening in patients with AD with demonstrated amyloid deposition in the targeted area. To improve safety, the study was divided into two stages, graded by the volume of brain tissue for BBB opening. Moreover, presumed non-eloquent cortex in the right frontal lobe, namely the superior frontal gyrus white matter of the dorsolateral prefrontal cortex , was selected to minimize potential complications in the event of bleeding or mass effect from vasogenic edema. The study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre and Health Canada. This study was registered with ClinicalTrial.gov number NCT02986932, and Health Canada number 195168. Prior to enrollment, all patients and their primary caregivers provided informed consent to the study, and publication of radiologic images.
Table 3 Inclusion and exclusion criteria
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Breakthrough Ultrasound Treatment To Reverse Dementia Moves To Human Trials
An extraordinarily promising new technique using ultrasound to clear the toxic protein clumps thought to cause dementia and Alzheimer’s disease is moving to the first phase of human trials next year. The innovative treatment has proven successful across several animal tests and presents an exciting, drug-free way to potentially battle dementia.
The ultrasound treatment was first developed back in 2015 at the University of Queensland. The initial research was working to find a way to use ultrasound to temporarily open the blood-brain barrier with the goal of helping dementia-battling antibodies better reach their target in the brain. However, early experiments with mice surprisingly revealed the targeted ultrasound waves worked to clear toxic amyloid protein plaques from the brain without any additional therapeutic drugs.
“The ultrasound waves oscillate tremendously quickly, activating microglial cells that digest and remove the amyloid plaques that destroy brain synapses,” explained Jürgen Götz, one of the researchers on the project back in 2015. “The word ‘breakthrough’ is often mis-used, 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 goal, long-term, is to come up with an affordable, portable device, which would help the millions of Alzheimer’s patients in our country and worldwide,” says Götz.
Alzheimer’s Disease Touches A Quarter Of A Million Australians
Alzheimers affects more than two-thirds of dementia patients, and approximately a quarter of a million Australians.
The total number of dementia cases in Australia is expected to rise to 900,000 by 2050.
With an ageing population placing an increasing burden on the health system, an important factor is cost, and other potential drug treatments using antibodies will be expensive, Professor Götz said.
In contrast, this method uses relatively inexpensive ultrasound and microbubble technology which is non-invasive and appears highly effective.
The approach is able to temporarily open the blood-brain barrier, activating mechanisms that clear toxic protein clumps and restoring memory functions.
With our approach the blood-brain barriers opening is only temporary for a few hours, so it quickly restores its protective role, Professor Götz said.
Research has been conducted using mice with an Alzheimers model, with the next step being to scale the research in higher animal models ahead of human clinical trials, which are at least two years away.
This treatment restored memory function to the same level of normal healthy mice, Professor Götz said.
Were also working on seeing whether this method clears toxic protein aggregates in neurodegenerative diseases other than Alzheimers and whether this also restores executive functions, including decision-making and motor control.
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Rna Extraction Cdna Synthesis And Quantitative Real
For RNA collection, cells were rinsed with PBS, exposed to TRIzolTM reagent and scraped off the culture plate using a pipette tip. Total RNA was extracted using the Direct-zol RNA Miniprep Kit according to the manufacturer’s instructions and treated in-column with DNase I. RNA quality and quantity was measured using NanoDropTM Spectrophotometer, after which RNA was converted to cDNA using SensiFASTTM cDNA synthesis kit according to the manufacturer’s instructions. The qPCR run was performed as triplicate for each sample on QuantStudioTM 5 Real-Time PCR system with run conditions as follows: 2 min at 95 °C followed by 40 cycles of 5 s at 95 °C and 30 s at 60 °C. Ct values were normalized to Ct values of 18S endogenous control , which were found to be consistent across cell lines, conditions and timepoints. Ct values were calculated as 2 and presented as Ct multiplied by 106 or as fold change. Primer sequences used in this study are presented in Table S3.
About Ultrasound Treatment For Alzheimer’s Disease
Research shows that the disease affects more women than men, accounting for two-thirds of the total number. In the U.S., around 3.8 million of those documented to have Alzheimer’s disease are women, while 2.4 million are men. The reason for this large gap could be because women tend to live longer than men, and that older age is a major risk factor for the disease.
The recent research by Professor Jürgen Götz and the multidisciplinary team from Clem Jones Centre for Ageing Dementia Research presents a possible breakthrough in how the health care providers and clinicians approach the disease.
Before arriving at these observations, the QBI researchers tested the ultrasound treatment for Alzheimer’s on mice. One group was given low-intensity ultrasound with barrier-opening microbubbles, while the other group was assigned as the control to receive low-intensity ultrasound but without the microbubbles.
The results showed that ultrasound combined with microbubbles can safely get through the blood brain barrier and enhance the delivery of anti-amyloid antibodies to the brain. Such antibodies are used to reduce plaques in the brain and, in effect, improve cognitive capacity.
“Using ultrasound could enhance cognition independently of clearing amyloid and tau, which form plaques and tangles in people with Alzheimer’s disease. Microbubbles will continue to be used in combination with ultrasound in ongoing Alzheimer’s research,” Götz said.
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Scientists Are Harnessing Sound Waves In Hopes Of Treating Alzheimers
Researchers at Columbia University are testing an experimental treatment for Alzheimer’s that uses ultrasound waves and “microbubbles.”
In 2010, a 67-year-old former executive assistant for a Fortune 500 company was diagnosed with mild cognitive impairment. By 2014, her doctors confirmed she had Alzheimer’s disease.
As her disease progressed, she continued to live independently but wasn’t able to drive anymore. Today, she can manage most of her everyday tasks, but her two daughters are considering a live-in caregiver. Despite her condition, the woman may represent a beacon of hope for the approximately 44 million people worldwide living with Alzheimer’s disease. The now 74-year-old is among a small cadre of Alzheimer’s patients who have undergone an experimental ultrasound procedure aimed at slowing cognitive decline.
In November 2020, Elisa Konofagou, a professor of biomedical engineering and director of the Ultrasound and Elasticity Imaging Laboratory at Columbia University, and her team used ultrasound to noninvasively open the woman’s blood-brain barrier. This barrier is a highly selective membrane of cells that prevents toxins and pathogens from entering the brain while allowing vital nutrients to pass through. This regulatory function means the blood-brain barrier filters out most drugs, making treating Alzheimer’s and other brain diseases a challenge.
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Experimental Ultrasound Treatment Targets Alzheimer’s Brain Plaque
Preliminary research in mice raises the possibility that an ultrasound-based treatment might help eliminate plaque buildup in the brain that’s associated with Alzheimer’s disease.
Scientists don’t know whether the approach is feasible for humans, but the research is promising, especially because of how well mice with an Alzheimer’s-like disease fared after treatment, said study lead author Gerhard Leinenga, a graduate student at the University of Queensland in Australia.
“The mice performed better on three tests of their memory,” Leinenga said, noting their performance was similar to that of healthy mice used as controls.
The ultrasound treatment targets brain-clogging material known as amyloid plaque. Scientists suspect plaque is connected to the development of Alzheimer’s disease — a progressive brain disorder — but its exact role is unclear.
“We know that amyloid interferes with the function of neurons and causes brain cells to die, but not everyone with amyloid in their brain will go on to develop Alzheimer’s or another dementia,” said James Hendrix, director of global science initiatives for the Alzheimer’s Association.
Alzheimer’s, the most common type of dementia, causes problems with memory, thinking and behavior.
There are many caveats to the new research.
Hendrix said the research is “intriguing” but “still very preliminary.”
The study appears in the March 11 issue of Science Translational Medicine.