The long war to defeat dementia

The long war to defeat dementia
PHOTO: The Straits Times

Two decades ago, only 3 per cent of Singaporeans aged 65 or more had dementia, the severe form of mental deterioration associated with old age. According to a recent Institute of Mental Health study, however, the prevalence of dementia has now risen to 10 per cent of people aged 60 or above.

To date, there is no cure for the condition but a University of Queensland study just published in the journal Science Translational Medicine reports on a non-invasive ultrasound technique that the Australian scientists claim "restores memory" in mice genetically modified to develop an Alzheimer's-like condition.

In humans, Alzheimer's disease is the commonest cause of dementia. Throughout the Alzheimer brain, plaque can be found on the outside of dying brain cells, which are called neurons. This plaque, formed from a protein called amyloid, accumulates in synapses, the spaces between neurons.

Because neurons connect to one another across synapses, affected neurons can no longer interconnect and eventually die, leading to the cognitive decline and memory loss that so tragically characterise dementia.

The Australian scientists reported using just ultrasound to remove the amyloid plaque found in the brains of their Alzheimer mice. No drugs were used.

If true, this would be a major development since the difficulty in trying to treat any form of brain disease with drugs is that most drugs cannot be delivered into the brain because of the blood-brain barrier - the membrane around the brain that prevents bugs (and drugs) in the blood from getting inside the brain.

That protective membrane comprises a network of specialised blood capillaries that total about 20 sq m. This network is a broad, continuous, one-cell-thick filter that tightly regulates what can enter or exit the brain.

Only nano-size particles can penetrate it, and a nanometre (nm) is one billionth of a metre. For instance, a water molecule is 0.25nm in diameter, so it can enter the brain. Only small-molecule drugs such as L-dopa used to treat Parkinson's disease can pass through this barrier.

Unfortunately, most brain conditions cannot be treated with small-molecule drugs. But in the new study, this was not a consideration since no drug was used. Instead, ultrasound was used to disrupt the barrier.

This property of ultrasound waves has been known since 1956. The difference today is that, using MRI brain scans to guide accurately where to focus an ultrasound beam, scientists working on animals can disrupt the blood-brain barrier at precise spots. But how do ultrasound waves open up the barrier? The mechanism probably involves microscopic air bubbles found within human tissues. The energy of ultrasound waves causes the bubbles to vibrate, so they start expanding and contracting.

These oscillations cause microscopic eddies to develop in the surrounding tissue fluid, which then begins to flow or stream around.

This "micro-streaming" moves the micro-bubbles around, resulting in shear stresses on cell membranes, whose weakest points are channels penetrating them to connect the outside with the inside of a cell. These channels become stretched by the shear stresses, allowing small molecules to enter and exit brain cells more easily.

In rat models, ultrasound has been used in other studies to disrupt that barrier so that amyloid antibodies can be delivered into the brain to attack the amyloid plaque. Some cognitive deficits in these rat models of early Alzheimer's have been reversed. What was different in the present study was that no drugs were used. Instead, repeated scanning with ultrasound to the brain opened the barrier temporarily for a few hours by way of causing that micro-streaming.

The micro-streaming was boosted by an injection of micro-bubbles made of the inert gas xenon wrapped in an oil shell. This concoction was given before the rat brains were treated with focused ultrasound beams.

One may ask why even open up the barrier if they were not trying to get a drug into the brain. The scientists postulate that ultrasound has yet another effect, of activating scavenger cells that digest amyloid. The broken-down amyloid then gets washed out of the brain through the stretched channels in cell membranes.

In 75 per cent of their Alzheimer mice, amyloid was cleared and memory functions were found to have been restored. So this is an exciting development that holds out the possibility that ultrasound may one day be used to clear the brain of amyloid and perhaps improve cognitive function in Alzheimer's patients.

The researchers claim that their technique "really does fundamentally change our understanding of how to treat this disease". However, compared to mice, the human brain is much bigger and the human skull is much thicker. This means that ultrasound waves with energy levels much higher may be needed in humans. However, such waves can raise the temperature in target areas to more than 70 deg C, which can cook human tissues.

Although such ultrasound machines are unproven in safety and effectiveness, some doctors have gone ahead to use them to treat dementia. Of course, if these machines were calibrated well and operated accordingly, the dangers could be minimised. However, so much is unknown about the technology's biological effects that there are still no international standards to calibrate them for human use.

In August 2009, the Singapore Medical Council censured and fined a Singapore doctor for using just such an untested machine to treat a dementia patient. In February 2010, the doctor appealed and won on a technicality, so the court emphasised that it was not declaring the therapeutic use of ultrasound to be safe. Five years on, this has not changed. Further tests in larger animals are needed before human clinical trials can start.

Much of the Alzheimer's disease research is still focused on drug therapies. Recently, a firm called Biogen based in Durham, North Carolina, claimed that a drug it was testing in small trials was able to slow cognitive decline. But experience suggests that in this field, one must take initial reports like this one with a big pinch of salt. Keep your fingers crossed.

•This is the fifth of a six-part series on new scientific findings about the brain.


This article was first published on Aug 15, 2015.
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