Lying on a vibrating mattress while taking nitric oxide pills has shown promise for boosting the brain’s waste-disposal system. It caused the brain’s blood vessels to swell and constrict more strongly, which enhanced the glymphatic system’s clearance of a protein that accumulates during Alzheimer’s disease.
Other experiments into boosting the glymphatic system have involved ultrasound, pink noise and even intermittently inhaling high doses of carbon dioxide. “It’s important to come at this from as many angles as possible, to increase the chance of this translating to the clinic and benefitting patients,” says Christopher Brown at the University of Southampton, UK, who wasn’t involved in the latest research.
But risky experimental approaches like taking nitric oxide and inhaling carbon dioxide shouldn’t be tried at home, says Vesa Kiviniemi at the University of Oulu in Finland. Regarding the latest experiment, which he led, Kiviniemi points out that “nitric oxide can reduce blood pressure, and if one happens to have low blood pressure to begin with, taking a pill might lead to loss of consciousness”.
Prior studies in mice have shown that vibrating the body activates a motion-sensitive protein called Piezo1, which is found in muscle cells in the walls of the brain’s blood vessels. This causes the vessels to dilate and constrict more strongly, which helps push waste fluid from brain cells through the glymphatic system, a network of channels that surrounds blood vessels in the brain and transports waste for disposal elsewhere in the body.
Other research has shown that nitric oxide, which is naturally produced in the brain, also dilates its blood vessels. This seems to make the surrounding glymphatic channels narrower, putting more pressure on the waste fluid so it exits the brain more quickly, says Kiviniemi.
Combining these approaches, Kiviniemi and his colleagues recruited 29 adults who hadn’t been diagnosed with Alzheimer’s disease or any other cognitive issues. The participants took a pill that dissolves when under the tongue, releasing nitric oxide. They then lay on a mattress that caused their bodies to gently vibrate for 40 minutes, taking another pill halfway through.
Blood samples revealed that their levels of a type of protein called beta-amyloid 42 increased by 35 per cent, on average, after the intervention. This protein, which usually helps neurons signal and connect to each other, misfolds and form clumps in Alzheimer’s disease. “The treatment seemed to enhance the glymphatic system’s ability to clear beta-amyloid from the brain to the blood,” says Kiviniemi.
“A 35 per cent increase in circulating beta-amyloid 42 is a substantial and very interesting acute effect,” says Tuomas Lilius at the University of Helsinki, who wasn’t involved in the work. “It is certainly possible it could become biologically, and eventually clinically, relevant.”
Side effects were mild and minimal, with six of the participants experiencing issues such as nausea and headache. However, this could partly be due to the expectation of an effect from the nitric oxide pills. The researchers hope to overcome this in future work by including placebo pills.
Brain scans suggest the treatment enhanced the flow of fluid along glymphatic channels, probably by widening the brain’s blood vessels and making them pump more strongly, says Kiviniemi.
But other mechanisms could also be at play, says Christopher Brown at the University of Southampton, UK. For instance, this intervention may slow the breakdown of beta-amyloid 42 by the liver, leading to higher amounts in the bloodstream, he says. Future studies could get around this by injecting markers into cerebrospinal fluid, which moves through the glymphatic system, to more directly measure its flow, says Brown.
Additional experiments by Kiviniemi and his colleagues tested either only the mattress vibrations or only the nitric oxide pills on the same participants, at least a week before or after they underwent the combined approach. Based on brain scans, these solo interventions seemed to have less than half the effect on the glymphatic system than when they were combined.
The researchers now hope to trial the combined approach in 60 people with mild cognitive impairment or Alzheimer’s disease next year, which could produce results in the following two years.
If that goes well, they hope to conduct a trial where a similar group of people has the treatment regularly for several months, rather than as a one-off intervention. This should be long enough to detect any improvements in cognitive abilities, like memory and problem-solving, says Kiviniemi.