Ultrasound improves cognitive function in Alzheimer's disease and is expected to change the design of treatment trials

Editor's Choice: Researchers at the University of Queensland have found that targeting amyloid plaques in the brain is not necessary for ultrasound to improve cognitive abilities in people with neurodegenerative diseases. This finding challenges the conventional wisdom in Alzheimer's disease research that targeting and clearing amyloid plaques is essential for improving cognitive performance.

Alzheimer's disease (AD) accounts for 80% of all dementia cases. The most important histopathological feature is that two key molecules, amyloid-β (Aβ) and tau, form insoluble aggregates that develop into microscopic brain lesions called β plaques and tau-containing neurofibrillary tangles. Aβ and tau dysfunction is thought to initiate and drive the degenerative processes of Alzheimer's disease, leading to progressive impairment of memory, reasoning, and social skills. As amyloid plaques build up in the brain, blocking communication between brain cells, leading to memory loss and other symptoms of Alzheimer's disease, the general view in the treatment of Alzheimer's disease (AD) is that cognitive improvement must target the reduction of amyloid plaque pathology.

High-intensity ultrasound is used as a focused, incision-free, FDA-approved surgical tool that can be used to ablate brain tissue to treat conditions such as essential tremor and parkinson's disease tremens. Low-intensity ultrasound as a neuromodulation and/or blood-brain barrier (BBB) opening tool is being studied in a variety of animal and human study participants. The low-intensity ultrasonic thermal effect is essentially negligible. Considering the blood-brain barrier and the difficulty of developing brain therapeutic drugs, exploring alternative treatment strategies for low-intensity focused ultrasound (FUS) is a research hotspot.

In simple terms, the ultrasonic-induced mechanical effects can be divided into acoustic radiation forces and cavitation forces. When ultrasound local delivery interacts with intravenous microbubbles (FUS+MB), cavitation is enhanced—it opens the blood-brain barrier, leading to uptake of bloodborne factors, some of which have therapeutic effects. Several research groups have found that the use of FUS+MB and SUS+MB to treat and scan the whole brain can reduce the risk of AD in mouse models (e.g., APP23 mice, transgenic mice routinely used to mimic Alzheimer's disease and other dementias, K670N/M671L pathogenic mutations expressed in human amyloid precursor protein (APP) and familial AD cases, with Aβ plaque formation and memory impairment) - amyloid plaque load without the need for concomitant injections of exogenous drugs, as well as improved memory function. After treatment, it was found that Aβ was absorbed and cleared by microglia. This powerful Aβ clearance is thought to be responsible for improving memory function.

The cavitation effect is largely absent with ultrasound alone, and only mechanical forces are used for neuromodulation. SUSonly treatment alone is not sufficient to clear Aβ. Given that low-intensity ultrasound is increasingly being explored as a new treatment option for AD patients, researchers at the University of Queensland have explored the effects of two frequencies: 1 MHz (SUSonly HighF) and 286 kHz (SUSonlyLowF) on a mouse model of APP23 AD – 286 kHz is a frequency in the (210-650 kHz) range, where transcranial human FUS+MB treatments are typically performed since at 1 At MHz, the attenuation and distortion of the human skull is too high to achieve safe and effective biological effects.

The results suggest that repetitive scanning ultrasound (SUS) treatment at a frequency of 1 MHz is sufficient to improve memory deficits in the APP23 AD mouse model without reducing amyloid-β (Aβ) burden. Unlike previous studies that showed that the opening of the blood-brain barrier (BBB) resulted in Aβ clearance, the blood-brain barrier did not open without the use of microvesicles. Quantitative SWATH proteomics and functional magnetic resonance imaging showed that ultrasound induced long-term functional changes associated with memory improvement. Interestingly, the treatment at a higher frequency (1 MHz) is more effective than the frequency range (286 kHz) currently explored in clinical trials in AD patients.

The data suggest that the frequency-dependent biological effects of ultrasound and cognitive improvement are not necessarily associated with Aβ clearance, i.e., contrary to the popular belief that Aβ pathology (other than tau) drives the degenerative process and that improvement in cognitive function requires a reduction in Aβ, this study found that memory improvement in AD mice occurred in the absence of Aβ reduction. Targeting amyloid plaques in the brain is not necessary for ultrasound to improve cognition in patients with neurodegenerative diseases. This has important implications for the design of trials for the treatment of Alzheimer's disease. The article was published in the journal Molecular Psychiatry.

The authors also investigated whether ultrasound therapy can modulate these dysfunctional brain networks in the long term, and whether it can be used as an alternative treatment for AD. Correlation analysis between quantitative proteomics, rsfMRI, and behavioral testing has shown that SUSonly alone, especially at 1 MHz, causes long-term structural and functional changes in neurons and their connections. The study also suggests that current clinical trials may not be using optimal ultrasound parameters, and the data provide new insights into ultrasound treatment optimization.

* High-frequency SUS improves spatial memory performance

* In the absence of a reduction in amyloid plaques and Aβ levels, memory function is improved

* Ultrasound treatment alters the proteome of APP23 mice in a frequency-dependent manner

* Ultrasound improves brain network connectivity, as measured by magnetic resonance imaging

* Ultrasound has an effect on brain microstructures

Dr Gerhard Leinenga of the Queensland Brain Institute at the University of Queensland said the findings challenged conventional wisdom in Alzheimer's disease research that targeting and clearing amyloid plaques is essential to improve cognitive performance. Previous studies have focused on opening the blood-brain barrier with microbubbles, activating microglia in the brain and clearing amyloid plaques. "But we used ultrasound scans alone on mouse models and observed significant memory enhancement. Ultrasound without microbubbles can cause lasting cognitive changes in the brain and is associated with improved memory. Ultrasound itself has a direct effect on neurons, increasing plasticity and improving brain networks. We believe that ultrasound increases the brain's plasticity or resilience to plaques, although it does not unambiguously clear them. ”

Professor Götz says the study has also revealed that the effectiveness of ultrasound therapy depends on the frequency of use. "We tested two different frequencies of ultrasound and found that higher frequencies showed better results compared to those currently explored in clinical trials in patients with Alzheimer's disease. ”

The researchers hope to incorporate these findings into Professor Götz's groundbreaking study – a safety trial using non-invasive ultrasound for the treatment of Alzheimer's disease. "By understanding the underlying mechanisms of ultrasound therapy, we can tailor treatment strategies to maximize the cognitive abilities of patients," said Dr. Leinenga. "This approach represents an important step forward in personalized, effective treatment of neurodegenerative diseases. ”

来源：Molecular Psychiatry

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