Research into lacunar stroke and dementia

A little-known type of stroke could be contributing to dementia. Sarah Brealey hears how Professor Joanna Wardlaw and her colleagues are tackling the problem. 

Professor Joanna Wardlaw 

If you know about stroke, you probably know it’s caused by a failure of blood supply to part of the brain. You might also know that this is caused by a clot blocking the blood flow or a burst blood vessel bleeding into the brain.

But few people have heard of lacunar stroke. This type of stroke affects the small blood vessels – less than a millimetre wide – deep inside the brain. It was described in post-mortem examinations in the 1950s, when ‘lacunae’, or empty spaces, were spotted in the brain. It accounts for about a fifth of strokes – more than 25,000 a year in the UK.

Professor Joanna Wardlaw, Chair of Applied Neuroimaging at the University of Edinburgh, is an expert in brain scanning. Her internationally-recognised research focuses on trying to prevent, diagnose and treat stroke more effectively. She and her team are also finding out more about what causes different types of stroke.

Understanding lacunar stroke 

“For a long time people thought all strokes were due to blood clots or blood vessels bursting,” says Professor Wardlaw. “Only recently have we realised there is a set of strokes caused by problems with small blood vessels. These milder strokes have literally gone under the radar.” Because there has been so little recognition of the problem, our understanding remains poor. This means options for prevention and treatment are limited. Professor Wardlaw is trying to address this.

“Lacunar stroke is not usually too physically disabling, but it might stop people being able to live independently if it affects their memory or decision-making,” says Professor Wardlaw. Sometimes described as ‘small’ strokes, they can happen without the patient noticing. The more they happen, the more likely you are to develop problems with thinking or even dementia. This can be combined with mood disorders, depression or balance issues.

You might think you have slowed down a bit or you’ve been forgetting things, but don’t necessarily spot something sudden

“Some people have symptoms that lead them to go to the doctor and some don’t,” says Professor Wardlaw. “It probably boils down to which part of the brain is affected. If it falls in a part of the brain that controls your hand or leg then you’ll go to the doctor, but if it’s in part of your brain that controls complex decision-making, for example, you might never realise. You might think you have slowed down a bit or you’ve been forgetting things, but don’t necessarily spot something sudden that you would recognise as a problem.”

Even if the patient does seek help, these strokes are sometimes wrongly classified as another type of stroke or as something else entirely. “For many years, people have been looking at scans and calling this problem by different names,” says Professor Wardlaw. “We found there are over 150 different names for what are essentially holes in the brain.” 

She has helped to establish international standards for neuroimaging to reduce this problem. She also wants to see doctors taking a more holistic view, rather than separately treating stroke, memory problems, mood disorders and high blood pressure, which all overlap in lacunar patients. 

Problems with the small blood vessels of the brain contribute to around 40 per cent of dementia cases, affecting an estimated 350,000 sufferers in the UK. “There is a lot going on in the brain that we don’t understand, but treating stroke and dementia as if they are completely different is a bit artificial, and we should look at them together,” says Professor Wardlaw.

An MRI scan, showing the brain

What causes lacunar stroke?

Professor Wardlaw is studying how these strokes are caused, and in particular she’s looking at the lining of blood vessels – the endothelium. It is known to play a role in processes that lead to heart and circulatory disease, but is much less studied in the brain. “The endothelium has been studied a lot by cardiologists,” says Professor Wardlaw. “But it has been rather ignored in connection to stroke and dementia.”

The endothelium works with nerve cells and other cells in the brain. She thinks that when it becomes damaged, messages travelling around your brain slow down or don’t arrive at all.

Causes of lacunar stroke are not fully understood, but probably include the same risk factors as other strokes, including old age, smoking, high cholesterol and high blood pressure. And Professor Wardlaw’s team already have some ideas about treatments.

Future treatments for lacunar stroke

They have been testing two existing drugs, which are known to have effects on the endothelium. The first is isosorbide mononitrate, part of a group of drugs called nitrates, which are used to treat angina. The other is cilostazol, which is used as an antiplatelet drug (although it’s not common in the UK), but may also help improve endothelial function.

With a team in Nottingham and Edinburgh, they ran a pilot study, funded by the Alzheimer’s Society, which has enabled them to plan a larger trial of at least 200 people, funded by £850,000 from the BHF. 

It might be that you could use it as a treatment for people who haven’t had a stroke yet

“We are testing these two drugs individually and together, because they may have increased effects when used together,” says Professor Wardlaw. “The pilot has been really helpful in telling us how to vary the dose, what kind of side effects people might get, and how well people tolerate the drugs.”

The three-year BHF-funded trial will follow people who have had lacunar stroke. “If the theory is correct, we would hope to find they have reduced risk of another stroke of this type, and are less likely to get cognitive impairment,” she says. “We will scan their brains and measure what has changed after one year on the different drugs.”

If the trial is successful, they hope to run larger trials to establish this as a treatment. It could potentially be used for prevention too. “If it works in people who have had symptoms, it seems plausible it would work in people who haven’t had symptoms but are at high risk, perhaps due to family history,” says Professor Wardlaw. “It might be that you could use it as a treatment for people who haven’t had a stroke yet.”

BHF stroke researchProfessor Joanna Wardlaw

This is just one example of the BHF funding research to help people affected by stroke. Many of the risk factors for stroke and heart disease are the same, and we know many of the same processes are behind both conditions. 

We’ve given researchers at the University of Cambridge £1m to search for possible genetic causes of lacunar strokes. Working with researchers worldwide, as part of the International Stroke Genetics Consortium, they will look at the DNA of 5,000 people who have had a lacunar stroke to see which genes could play a role in the disease. Learning which genes can increase your risk of lacunar stroke will shed more light on how the condition works and which medications might be helpful.

We’re currently funding more than a dozen other stroke research projects, including six with the Stroke Association. These include a project in the UK and abroad, run by the University of Glasgow, to see whether a new clot-busting drug is better at treating stroke. A Cambridge-based trial has been looking at whether a ‘polypill’ of three different drugs is more effective at preventing further strokes in people who have already had one.

We’re funding another trial, called RIGHT-2, run by the University of Nottingham, to test if giving GTN (nitrate) patches in the ambulance on the way to hospital can help treat all types of stroke.

We’re also researching atrial fibrillation, a major cause of stroke, as well as several other projects studying causes of stroke.

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