Ultra-fast brain scanning for Alzheimer’s

The method is based on a special brain scanning technique called MREG-BOLD and has been shown to detect Alzheimer’s in experiments on both animals and humans.

‘We hope this method will make it possible to diagnose Alzheimer’s 10–20 years earlier than usual, in people in their 40s, and well before they start to show signs of the disease,’ explain Professor Maiken Nedergaard from the University of Copenhagen in Denmark and Professor Vesa Kiviniemi from the University of Oulu in Finland.

The two professors head a research team funded by the Danish Lundbeck Foundation, which is refining, testing and evaluating the new method.

Alzheimer’s rarely sets in until patients are well on in life, but numbers are rising throughout the Western world, mainly due to increasing longevity. According to the scientists, if the new method can diagnose the condition decades before it manifests itself in the form of cognitive problems, it could change the Alzheimer’s agenda in several ways.

‘At the moment, actual treatment isn’t really possible. By the time we diagnose Alzheimer’s, the condition is already so far advanced, and the patient’s brain so degraded, that death is inevitable. But if we can diagnose it at a very early stage when the damage is still limited, it should be easier to develop treatments that prevent the disease from progressing unchecked – or maybe even stop it altogether,’ says Professor Nedergaard.

The brain’s dishwasher

Humans and other mammals have a biological system often referred to as the “brain’s dishwasher”. Doctors call it the glymphatic system. It is this system – this “dishwasher” – that cleans the mammalian brain, getting rid of harmful waste products such as degraded proteins, usually while we sleep.

In highly simplistic terms, this is how the “dishwasher” works: during the sleep phase, the brain opens its internal gates, doors and connecting pathways and lets cerebrospinal fluid (CSF) flow through. Later, when this fluid is sluiced out of the brain via the nerves and lymphatic vessels, the waste products are flushed out along with it.

This process, which had never been described before, was the main theme of a much-publicised research article in Science in 2013. It was written by a group of neuroscientists headed by Maiken Nedergaard. The dishwasher theory has been the central theme of her research ever since.

The glymphatic system is driven in part by the pulse, which stems from the pumping movements of the heart, but presumably also by the breath and muscle contractions in the arteries. Ever since it was introduced in Science, a key question has been

whether it is possible to analyse the driving forces behind the dishwasher and their relation to brain disorders. In other words, to find out more about if – and if so, how – different brain disorders affect the glymphatic system. Because if it’s possible to source such information from the realm of sleep, it may be possible to use it to diagnose various brain diseases, including Alzheimer’s.

‘Maiken Nedergaard and I have been working on in-depth answers to that question,’ says Professor Kiviniemi, a specialist in brain scanning techniques. ‘It turns out that speed plays a crucial role; in this case, the very rapid brain scanning speed achieved by the MREG-BOLD technique. And a key feature of the method is that it’s easy to do the scans without contrast fluid,’ she adds.

The idea that high scanning speeds provide more detail isn’t necessarily obvious. For example, if you are hurtling along the motorway at 150km/h, there’s a limit to how much of the landscape you actually take in as you race through it.

But when it comes to the driving forces behind the brain’s dishwasher, it’s slightly different,’ she continues.

‘If you try to use more traditional brain-scanning techniques to picture the drivers behind the glymphatic system, you get – roughly speaking – a mixed signal on your screen. It’s not particularly informative – you can’t tell the different driving forces apart because they sort of run into each other – nor can you tell the difference between the effects of the pulse and breath, for example. But when you turn the scanning speed up by about 20, as we do with MREG-BOLD, something happens. The mixed signal suddenly becomes several separate signals, each representing one of the driving forces behind the system. And at this point, we can start thinking in terms of diagnostic pathways.’

MREG-BOLD scanning is so fast it produces ten complete images of the brain per second. As it takes about 10 minutes, that makes a total of 6,000 complete brain scans.

One of the things that analyses of this huge amount of data reveal is how the effects of the pulse on the glymphatic system change in Alzheimer’s patients.

The Danish-Finnish research team first demonstrated this in experiments on mice genetically engineered to contract Alzheimer’s. They then went on to confirm it in a patient study. At the University Hospital in Oulu, scientists measured the effects of the pulse on the glymphatic systems of a group of patients aged 60+, all of whom had been diagnosed with Alzheimer’s but were not yet showing pronounced symptoms of the neurodegenerative disorder. The results were then compared with similar measurements in a group of their peers who did not have Alzheimer’s.

The result was clear. The findings for the Alzheimer’s patients corresponded with the results observed in the mice – that the disease sabotages the function of the pulse as a driving force in the glymphatic system. This usually happens in the regions of the brain most affected by Alzheimer’s, such as in and around the hippocampus, and the effect can be so pronounced that the pulse literally runs backwards.

It is a very serious situation,’ Kiviniemi explains, ‘because it puts a great deal of stress on the glymphatic system. And it can also mean that waste products the brain needs to get rid of are flushed back into it instead, including harmful beta-amyloid proteins formed by Alzheimer’s disease.’

 

Further experiments

Although the new method of analysis has proven capable of detecting Alzheimer’s in both mice and humans by using high-speed scanning of the glymphatic system, evidence is still lacking that the method is capable of detecting the disease decades before it causes symptoms in the patient.

Obtaining such documentation is difficult for obvious reasons, Nedergaard explains. ‘Waiting 10–20 years to see if a person who showed signs of Alzheimer’s in an MREG-BOLD analysis in their mid-40s develops the disease in later life is far from optimal. And we just don’t have the time for it, given the increasing number of Alzheimer’s patients. We need to try other approaches.’

The plan is to seek funding to conduct a very big MREG-BOLD analysis of a large number of middle-aged people with a particular hereditary variant of Alzheimer’s in their family. About 3% of patients have this genetic variant and will definitely develop the disease sooner or later.

‘If we can confirm that people with this genetic variant suffer problems in their glymphatic system as early as their mid-40s, we can conduct various experiments to improve fluid transport in the brain. In other words, we could improve their capacity to purge the brain of various unwanted substances – such as amyloid – and thus reduce the risk of them developing dementia,’ Nedergaard explains.

One method would be to give the participants different antibodies designed to purge harmful proteins. If that has a positive effect, it will show up when new scans are made of the efficiency of the fluid transport in the patients’ brains.