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HomeNeuroscienceUltrasound as a potential treatment for Alzheimer's — Australian animal study

Ultrasound as a potential treatment for Alzheimer's — Australian animal study

Ultrasound can overcome some of the detrimental effects of ageing and dementia without the need to cross the blood-brain barrier, Queensland Brain Institute researchers have found in an animal study published in Nature Molecular Psychiatry, reports MedicalBrief.

Professor Jürgen Götzled a multidisciplinary team at QBI's Clem Jones Centre for Ageing Dementia Research, which showed low-intensity ultrasound effectively restored cognition without opening the barrier in mice models.

The findings provide a potential new avenue for the non-invasive technology and will help clinicians tailor medical treatments that consider an individual's disease progression and cognitive decline.

"Historically, we have been using ultrasound and small gas-filled bubbles to open the almost-impenetrable blood-brain barrier and get therapeutics from the bloodstream into the brain," Götz said.

The new research involved a designated control group that received ultrasound without the barrier-opening microbubbles.

"The entire research team was surprised by the remarkable restoration in cognition," he said. "We conclude therapeutic ultrasound is a non-invasive way to enhance cognition in the elderly."

Ageing is associated with impaired cognition and a reduction in the learning induced plasticity of the signalling between neurons called long-term potentiation (LTP).

Dr Daniel Blackmore, senior postdoctoral researcher on the team, said the new research aimed to use ultrasound to restore LTP and improved spatial learning in aged mice.

Götz said the brain was “not particularly accessible”, but ultrasound provided a tool for overcoming challenges like the blood-brain barrier.

“Using ultrasound could enhance cognition independently of clearing amyloid and tau, which form plaques and tangles in people with Alzheimer's disease,” he said. “Microbubbles will continue to be used in combination with ultrasound in ongoing Alzheimer's research.”

About 400,000 people in Australia have dementia and numbers are projected to increase to one million by 2050, with ageing the single biggest risk factor.

Previous research has shown the long-term safety of ultrasound technology and that pathological changes and cognitive deficits could be improved by using ultrasound to treat Alzheimer's disease.

Götz said there were still questions about the differences between normal “physiological” ageing and the “pathological” ageing that happens in Alzheimer's disease.

“We believe there may be some overlap between physiological and pathological ageing in the brain and the potential for this to be corrected with ultrasound is meaningful for those living with Alzheimer's disease,” he said. "We are taking these findings and implementing them in our Alzheimer's research as we go forward to clinical trials."

His research team aims to understand how brain diseases begin and their progression at molecular and cellular levels in the hope of ultimately developing therapies.

 

Study details

Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling 

Authors: Daniel G. Blackmore, Fabrice Turpin, Tishila Palliyaguru, Harrison T. Evans, Antony Chicoteau, Wendy Lee, Matthew Pelekanos, Nghia Nguyen, Jae Song, Robert K. P. Sullivan, Pankaj Sah, Perry F. Bartlett & Jürgen Götz

Published in Nature journal Molecular Psychiatry 27 May 2021

 

Abstract

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood–brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.

 

Introduction

Physiological aging leads to a progressive decline in the functional and cellular constituents of the brain. Whether the age-dependent decline in memory functions can be slowed or even reversed remains to be determined. Here, we explored the neuromodulatory potential of low-frequency therapeutic ultrasound in aged, cognitively impaired C57BL/6 wild-type (WT) mice, building on earlier work that not only demonstrated the long-term safety of this technology, but also that pathological changes and the ensuing cognitive deficits can be ameliorated in Alzheimer’s disease (AD) mouse models.

In these earlier studies, focused ultrasound was delivered through the skull into the brain in a scanning ultrasound (SUS) mode in animals that had received an intravenous injection of microbubbles (MBs: SUS+MB).

As the MBs undergo repetitive cycles of compression and rarefaction in response to ultrasound, the tight junctions of the endothelial cells lining the blood vessels become disrupted, transiently opening the blood–brain barrier (BBB).

 

Result

This, with the activation of vesicular, trans-cytoplasmic transport, allows for the uptake of as yet unidentified blood-borne factors into the brain, which elicit a wide range of therapeutic effects, including the activation of microglia to take up and remove protein aggregates.

 

Molecular Society Journal article – Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling (Open access)

 

See more from MedicalBrief archives:

 

Dutch Health Minister calls for global strategy to deal with dementia

 

Evidence mounts that eye scan may detect early Alzheimer’s

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