Summary: Researchers report applying ultrasound to the whole brain improves cognitive dysfunction in mouse models of dementia. A clinical trial is currently underway to test the effectiveness in humans with the neurodegenerative disease.
Source: Tohoku University.
Ultrasound waves applied to the whole brain improve cognitive dysfunction in mice with conditions simulating vascular dementia and Alzheimer’s disease. The research, conducted by scientists at Tohoku University in Japan, suggests that this type of therapy may also benefit humans.
The team, led by cardiologist Hiroaki Shimokawa, found that applying low-intensity pulsed ultrasound (LIPUS) to the whole brain of the mice improved blood vessel formation and nerve cell regeneration without having obvious side effects.
“The LIPUS therapy is a non-invasive physiotherapy that could apply to high-risk elderly patients without the need for surgery or anaesthesia, and could be used repeatedly,” says Shimokawa.
Dementia affects about 50 million people worldwide, with 10 million new cases occurring every year. But there are currently no curative treatments available for vascular dementia or Alzheimer’s disease, the most common causes of dementia. Also, the cells lining the brain’s blood vessels are tightly packed, forming a blood-brain barrier that prevents large molecules from crossing into the brain tissue. This limits the types of drugs and cell therapies that could be made available to treat dementia.
Shimokawa and his team had conducted previous studies showing that LIPUS improved blood vessel formation in pigs with myocardial ischemia, a condition where there is reduced blood flow to the heart. Other studies have reported that LIPUS increases the production of proteins involved in nerve cell survival and growth, in addition to a role in promoting nerve regeneration. Focusing LIPUS treatment on a region in the brain called the hippocampus, which is involved in memory, has also been found to improve dementia in mice, but the details of how it does this need to be more fully investigated.
The Tohoku University team wanted to find out if whole-brain rather than focused LIPUS is effective in treating mouse models of dementia, and if it was, what was happening at the molecular levels to achieve this.
They found that cognitive impairment markedly improved in mice with conditions similar to vascular dementia and Alzheimer’s disease when LIPUS was applied to the whole brain three times a day for 20 minutes each time. The mice with vascular dementia received the treatment on the first, third and fifth days following a surgical procedure that limited the brain’s blood supply. The mice with a condition simulating Alzheimer’s disease in humans received 11 LIPUS treatments over a period of three months.
At the molecular level, genes related to the cells lining blood vessels were turned on. Also, there was increased expression of an enzyme involved in blood vessel formation and a protein involved in nerve cell survival and growth.
The researchers conclude that their study, recently published in the journal Brain Stimulation, provides the first experimental evidence that whole-brain LIPUS therapy markedly improves cognitive dysfunctions without serious side effects by enhancing specific cells related to dementia’s pathology.
The first clinical trials to evaluate the effectiveness and safety of the LIPUS treatment are already underway.
Funding: Funding provided by Japan Agency for Medical Research and Development.
Source: Hiroaki Shimokawa – Tohoku University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Hiroaki Shimokawa.
Original Research: Open access research for “Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia – Crucial roles of endothelial nitric oxide synthase” by Kumiko Eguchi, Tomohiko Shindo, Kenta Ito, Tsuyoshi Ogata, Ryo Kurosawa, Yuta Kagaya, Yuto Monma, Sadamitsu Ichijo, Sachie Kasukabe, Satoshi Miyata, Takeo Yoshikawa, Kazuhiko Yanai, Hirofumi Taki, Hiroshi Kanai, Noriko Osumi, and Hiroaki Shimokawa in Brain Stimulation. Published May 21 2018.
Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia – Crucial roles of endothelial nitric oxide synthase
Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer’s disease, AD), and if so, to elucidate the common underlying mechanism(s) involved.
We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain.
In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice.
These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism.