̽��ֱ�� of Cambridge - Hugh Markus

Epilepsy drug could help prevent stroke in people with ‘furred’ arteries

cjb250 — Mon, 04 Apr 2022 07:45:01 +0000

A drug used to treat epilepsy patients could help prevent stroke in people whose arteries show signs of atherosclerosis – furring of the arteries – scientists will tell audiences at the Cambridge Festival.

New genetic clues point to new treatments for ‘silent’ stroke

cjb250 — Thu, 25 Mar 2021 23:30:09 +0000

Researchers discovered changes to 12 genetic regions in the DNA of people who have had a lacunar stroke – a type of stroke caused by weakening of the small blood vessels deep within the brain. Over time, damage to the blood vessels and subsequent interruption to blood flow can lead to long-term disability, causing difficulty with thinking, memory, walking and ultimately dementia.

There are few proven drugs to prevent or treat lacunar strokes. ̽��ֱ��blood vessels affected are less than a millimetre wide and a lacunar stroke can strike without the person knowing. It’s not usually until someone has had a number of these strokes and starts to see signs of dementia that they realise something is wrong.

To date, only one genetic fault has been associated with lacunar strokes. However, after over a decade of research, Professor Hugh Markus and his team at the ̽��ֱ�� of Cambridge working with researchers from around the world now believe their genetic breakthrough holds the key to finding much-needed treatments for lacunar stroke and vascular dementia.

In research funded by the British Heart Foundation, the team scanned and compared the genetic code of 7,338 patients who had a lacunar stroke with 254,798 people who had not. Participants were recruited from across Europe, United States, South America and Australia after they attended hospital and had an MRI or CT brain scan.

They discovered that many of the 12 genetic regions linked to lacunar strokes were involved in maintaining the neurovascular unit – the part of the brain that separates the blood vessels from the brain and ensures that nerves function normally. These genetic changes are thought to make the small blood vessels ‘leakier’, causing toxic substances to enter the brain, and meaning that messages travelling around the brain slow down or don’t arrive at all.

̽��ֱ��team now plan to test whether new treatments can correct these abnormalities on brain cells in the lab. They hope to begin human clinical trials in the next ten years.

̽��ֱ��study also highlighted that high blood pressure, type 2 diabetes and a history of smoking are causally associated with an increased risk of lacunar stroke, identifying things that we can immediately tackle.

Professor Hugh Markus, leader of the study and neurologist at the ̽��ֱ�� of Cambridge, said: “These small and often silent lacunar strokes have gone under the radar for a long time, and so we haven’t been able treat patients as well as we’d like to. Although small, their consequences for patients can be enormous. They cause a quarter of all strokes and they are the type of stroke which is most likely to lead to vascular dementia.

“We now plan to use this new genetic blueprint as a springboard to develop much needed treatments to prevent lacunar strokes from occurring in the first place and to help stave off dementia.”

Dr Matthew Traylor, first author of the study at Queen Mary ̽��ֱ�� of London, said: “Genetics offers one of the few ways we can discover completely new insights into what causes a disease such as lacunar stroke. It is only by better understanding of what causes the disease that we will be able to develop better treatments.”

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said:

“This is the most extensive genetic search to date which truly gets to grips with what cause lacunar strokes. These findings are a significant leap forward and we now have a much greater understanding of the genetics and biology behind what causes the small blood vessels deep in the brain to become diseased.

“Lacunar strokes affect around 35,000 people in the UK each year. This research provides real hope that we can prevent and treat this devastating type of stroke much better in the

Reference

Traylor, M et al. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurology; 26 Mar 2021.

Adapted from a press release by the British Heart Foundation

Scientists have identified new genetic clues in people who have had small and often apparently ‘silent’ strokes that are difficult to treat and a major cause of vascular dementia, according to research led by the ̽��ֱ�� of Cambridge and published in ̽��ֱ��Lancet Neurology.

These small and often silent lacunar strokes have gone under the radar for a long time, and so we haven’t been able treat patients as well as we’d like to. Although small, their consequences for patients can be enormous

Hugh Markus

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Elderly man's hands

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Age and pre-existing conditions increase risk of stroke among COVID-19 patients

cjb250 — Wed, 28 Oct 2020 15:34:55 +0000

COVID-19 has become a global pandemic, affecting millions of people worldwide. In many cases, the symptoms include fever, persistent dry cough and breathing difficulties, and can lead to low blood oxygen. However, the infection can cause disease in other organs, including the brain, and in more severe cases can lead to stroke and brain haemorrhage.

A team of researchers at the Stroke Research Group, ̽��ֱ�� of Cambridge, carried out a systematic review and meta-analysis of published research into the link between COVID-19 and stroke. This approach allows researchers to bring together existing – and often contradictory or under-powered – studies to provide more robust conclusions.

In total, the researchers analysed 61 studies, covering more than 100,000 patients admitted to hospital with COVID-19. ̽��ֱ��results of their study are published in the International Journal of Stroke.

̽��ֱ��researchers found that stroke occurred in 14 out of every 1,000 cases. ̽��ֱ��most common manifestation was acute ischemic stroke, which occurred in just over 12 out of every 1,000 cases. Brain haemorrhage was less common, occurring in 1.6 out of every 1,000 cases. Most patients had been admitted with COVID-19 symptoms, with stroke occurring a few days later.

Age was a risk factor, with COVID-19 patients who developed stroke being on average (median) 4.8 years older than those who did not. COVID-19 patients who experienced a stroke were on average (median) six years younger than non-COVID-19 stroke patients. There was no sex difference and no significant difference in rates of smokers versus non-smokers.

Pre-existing conditions also increased the risk of stroke. Patients with high blood pressure were more likely to experience stroke than patients with normal blood pressure, while both diabetes and coronary artery disease also increased risk. Patients who had a more severe infection with SARSCoV2 – the coronavirus that causes COVID-19 – were also more likely to have a stroke.

̽��ֱ��researchers found that COVID-19-associated strokes often followed a characteristic pattern, with stroke caused by blockage of a large cerebral artery, and brain imaging showing strokes in more than one cerebral arterial territory. They argue that this pattern suggests cerebral thrombosis and/or thromboembolism are important factors in causing stroke in COVID-19. COVID-19-associated strokes were also more severe and had a high mortality.

An important question is whether COVID-19 increases the risk of stroke or whether the association is merely a result of COVID-19 infection being widespread in the community.

“ ̽��ֱ��picture is complicated,” explained Dr Stefania Nannoni from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, the study’s first author. “For example, a number COVID-19 patients are already likely to be at increased risk of stroke, and other factors, such as the mental stress of COVID-19, may contribute to stroke risk.

“On the other hand, we see evidence that COVID-19 may trigger – or at least be a risk factor for – stroke, in some cases. Firstly, SARSCoV2 more so than other coronaviruses – and significantly more so than seasonal flu – appears to be associated with stroke. Secondly, we see a particular pattern of stroke in individuals with COVID-19, which suggests a causal relationship in at least a proportion of patients.”

̽��ֱ��researchers say there may be several possible mechanisms behind the link between COVID-19 and stroke. One mechanism might be that the virus triggers an inflammatory response that causes thickening of the blood, increasing the risk of thrombosis and stroke. Another relates to ACE2 – a protein ‘receptor’ on the surface of cells that SARS-CoV-2 uses to break into the cell. This receptor is commonly found on cells in the lungs, heart, kidneys, and in the lining of blood vessels – if the virus invades the lining of blood vessels, it could cause inflammation, constricting the blood vessels and restricting blood flow.

A third possible mechanism is the immune system over-reacting to infection, with subsequent excessive release of proteins known as cytokine. This so-called ‘cytokine storm’ could then cause brain damage.

̽��ֱ��team say their results may have important clinical implications.

“Even though the incidence of stroke among COVID-19 patients is relatively low, the scale of the pandemic means that many thousands of people could potentially be affected worldwide,” said Professor Hugh Markus, who leads the Stroke Research Group at Cambridge.

“Clinicians will need to look out for signs and symptoms of stroke, particularly among those groups who are at particular risk, while bearing in mind that the profile of an at-risk patient is younger than might be expected.”

While the majority of strokes occurred after a few days of COVID-19 symptoms onset, neurological symptoms represented the reason for hospital admission in more than one third of people with COVID-19 and stroke.

Dr Nannoni added: “Given that patients admitted to hospital with symptoms of stroke might have mild COVID-19-related respiratory symptoms, or be completely asymptomatic, we recommend that all patients admitted with stroke be treated as potential COVID-19 cases until the results of screening in the hospital are negative.”

̽��ֱ��research was supported by the Medical Research Council, the National Institute for Health Research (NIHR), the NIHR Cambridge Biomedical Research and the British Heart Foundation.

Reference
Nannoni S, de Groot R, Bell S, Markus HS. Stroke in COVID-19: a systematic review and meta-analysis. Int J Stroke; 26 Oct 2020; DOI: 10.1177/1747493020972922. Epub ahead of print. PMID: 33103610.

Fourteen out of every 1,000 COVID-19 patients admitted to hospital experience a stroke, a rate that is even higher in older patients and those with severe infection and pre-existing vascular conditions, according to a report published this week.

Even though the incidence of stroke among COVID-19 patients is relatively low, the scale of the pandemic means that many thousands of people could potentially be affected worldwide

Hugh Markus

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Brain inflammation stroke

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A healthy lifestyle cuts stroke risk, irrespective of genetic risk

cjb250 — Wed, 24 Oct 2018 23:11:23 +0000

Stroke is a complex disease caused by both genetic and environmental factors, including diet and lifestyle. But could adhering to a healthy lifestyle offset the effect of genetics on stroke risk?

An international team led by researchers at the ̽��ֱ�� of Cambridge decided to find out by investigating whether a genetic risk score for stroke is associated with actual ("incident") stroke in a large population of British adults.

They developed a genetic risk score based on 90 gene variants known to be associated with stroke from 306,473 white men and women in the UK Biobank - a database of biological information from half a million British adults.

Participants were aged between 40 and 73 years and had no history of stroke or heart attack. Adherence to a healthy lifestyle was based on four factors: non-smoker, diet rich in fruit, vegetables and fish, not overweight or obese (body mass index less than 30), and regular physical exercise.

Hospital and death records were then used to identify stroke events over an average follow-up of seven years.

Across all categories of genetic risk and lifestyle, the risk of stroke was higher in men than women.

Risk of stroke was 35% higher among those at high genetic risk compared with those at low genetic risk, irrespective of lifestyle.

However, an unfavourable lifestyle was associated with a 66% increased risk of stroke compared with a favourable lifestyle, and this increased risk was present within any genetic risk category.

A high genetic risk combined with an unfavourable lifestyle profile was associated with a more than twofold increased risk of stroke compared with a low genetic risk and a favourable lifestyle.

These findings highlight the benefit for entire populations of adhering to a healthy lifestyle, independent of genetic risk, say the researchers. Among the lifestyle factors, the most significant associations were seen for smoking and being overweight or obese.

This is an observational study, so no firm conclusions can be drawn about cause and effect, and the researchers acknowledge several limitations, such as the narrow range of lifestyle factors, and that the results may not apply more generally because the study was restricted to people of European descent.

However, the large sample size enabled study of the combination of genetic risk and lifestyle in detail. As such, the researchers conclude that their findings highlight the potential of lifestyle interventions to reduce risk of stroke across entire populations, even in those at high genetic risk of stroke.

Professor Hugh Markus from the Department of Clinical Neurosciences at ̽��ֱ�� of Cambridge says: “This drives home just how important a healthy lifestyle is for all of us, even those without an obvious genetic predisposition. Some people are at an added disadvantage if ‘bad’ genes put them at a higher risk of stroke, but even so they can still benefit from not smoking and from having a healthy diet.”

̽��ֱ��research was funded by the British Heart Foundation and the NIHR Cambridge Biomedical Research Centre.

Adapted from a press release by ̽��ֱ��BMJ.

Reference
Rutten-Jacobs, LCA, et al. Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: follow-up study of 306,473 UK Biobank participants. BMJ; 25 Oct 2018; DOI: 10.1136/bmj.k4168

People at high genetic risk of stroke can still reduce their chance of having a stroke by sticking to a healthy lifestyle, in particular stopping smoking and not being overweight, finds a study in ̽��ֱ��BMJ today.

This drives home just how important a healthy lifestyle is for all of us, even those without an obvious genetic predisposition

Hugh Markus

U.S. Department of Agriculture

Healthy diet

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Genetics study adds further evidence that education reduces risk of Alzheimer’s disease

cjb250 — Thu, 07 Dec 2017 00:01:01 +0000

Alzheimer’s disease is the leading cause of dementia. Its chief hallmark is the build of ‘plaques’ and ‘tangles’ of misshapen proteins, which lead to the gradual death of brain cells. People affected by Alzheimer’s experience memory and communication problems, disorientation, changes in behaviour and progressive loss of independence.

̽��ֱ��causes of Alzheimer’s are largely unknown, and attempts to develop drug treatments to halt or reverse its effects have been disappointing. This has led to increasing interest in whether it is possible to reduce the number of cases of Alzheimer’s disease by tackling common risk factors that can be modified. In fact, research from the Cambridge Institute of Public Health has shown that the incidence of Alzheimer’s is falling in the UK, probably due to improvements in education, and smoking reduction and better diet and exercise.

“Many studies have shown that certain risk factors are more common in people with Alzheimer’s disease, but determining whether these factors actually cause Alzheimer’s is more difficult,” says Professor Hugh Markus from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge.

“For example, many studies have shown that the more years spent in full time education, the lower the risk of Alzheimer’s. But it is difficult to unravel whether this is an effect of education improving brain function, or whether it’s the case that people who are more educated tend to come from more wealthy backgrounds and therefore have a reduction in other risk factors that cause Alzheimer’s disease.”

Professor Markus led a study to unpick these factors using a technique known as ‘Mendelian randomisation’. This involves looking at an individual’s DNA and comparing genes associated with environmental risk factors – for example, genes linked to educational attainment or to smoking – and seeing which of these genes are also associated with Alzheimer’s disease. If a gene is associated with both, then it provides strong evidence that this risk factor really does cause the disease.

As part of a project known as CoSTREAM, researchers studied genetic variants that increase the risk of a variety of different environmental risk factors to see if these were more common in 17,000 patients with Alzheimer’s disease. They found the strongest association with genetic variants that predict higher educational attainment.

“This provides further strong evidence that education is associated with a reduced risk of Alzheimer’s disease,” says first author Dr Susanna Larsson, now based at the Karolinska Institute, Sweden. “It suggests that improving education could have a significant effect on reducing the number of people who suffer from this devastating disease.”

Exactly how education might reduce the risk of Alzheimer’s is uncertain. Previous studies have shown that the same amount of damage in the brain is associated with less severe and less frequent Alzheimer’s in people who have received more education. One possible explanation is the idea of ‘cognitive reserve’ – the ability to recruit alternative brain networks or to use brain structures or networks not normally used to compensate for brain ageing. Evidence suggests that education helps improve brain wiring and networks and hence could increase this reserve.

̽��ֱ��researchers also looked at other environmental risk factors, including smoking, vitamin D, and alcohol and coffee consumption. However, their results proved inconclusive. This may be because genes that predispose to smoking, for example, have only a very small effect on behaviour, they say.

̽��ֱ��study was supported by the European Union’s Horizon 2020 Research and Innovation Programme.

Reference
Larsson, SC et al. Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis. BMJ; 7 Dec 2017; DOI: 10.1136/bmj.j5375

̽��ֱ��theory that education protects against Alzheimer’s disease has been given further weight by new research from the ̽��ֱ�� of Cambridge, funded by the European Union. ̽��ֱ��study is published today in ̽��ֱ��BMJ.

Many studies have shown that certain risk factors are more common in people with Alzheimer’s disease, but determining whether these factors actually cause Alzheimer’s is more difficult

Hugh Markus

Cambridge ̽��ֱ��

Darwin Lecture Series

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̽��ֱ��Academy of Medical Sciences announces new Fellows for 2017

cjb250 — Mon, 08 May 2017 09:00:39 +0000

̽��ֱ��Fellows have been elected for their contribution to biomedical and health research, the generation of new knowledge in medical sciences and its translation into benefits to society.

This year's elected Fellows have expertise that spans women’s health, immunology, public health and infectious disease among many other fields.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences said: “As we elect new Fellows each year, the Academy continues to grow as a unique and productive hub of the best minds in UK medical science. Our expanding and evolving Fellowship allows the Academy to play a vital role in tackling the major health challenges facing society today and in the future.

“ ̽��ֱ��election of these 46 exceptional biomedical and health researchers is a well-deserved honour. Each newly elected Fellow has made an outstanding impact in the community, contributing to the development of better healthcare - from fundamental scientific understanding to the prevention, diagnosis and treatment of disease. I am delighted to welcome them to the Academy and greatly look forward to working with them all in the future.”

̽��ֱ��newly elected Fellows include Professor Giovanna Mallucci, whose research is pioneering new treatments for dementia and who was recently announced as one of the five associate directors of the UK Dementia Research Institute.

Professor Giovanna Mallucci said: “Election to the Fellowship is a great honour and distinction, internationally recognised, and I am delighted and proud to be awarded it. This is a tremendous achievement in any medical research career: a milestone in a scientific and personal journey. It is a real privilege to join this this community of distinguished, inspirational and luminary leaders in the medical sciences.”

Four of Cambridge’s Fellows are cancer specialists, including CRUK Cambridge Centre Director Professor Richard Gilbertson.

Professor Gilbertson said: “I am deeply honoured to have received this recognition of our work and feel privileged to join such a wonderful organisation dedicated to promoting excellence in medical science, ultimately for the good of patients. This honour belongs to my many postdocs, PhD students, technicians and wonderful collaborators who over the years who have worked with me to pursue fantastic science. ̽��ֱ��cadre of scientists elected from Cambridge also reflects the vibrant cancer research community in our city and the terrific support of the clinical school.”

̽��ֱ�� ̽��ֱ�� of Cambridge Fellows elected in 2017 are:

Professor Sheila Bird OBE FRSE, Visiting Senior Fellow, MRC Biostatistics Unit, ̽��ֱ�� of Cambridge School of Clinical Medicine and Institute of Public Health and Visiting Professor at Department of Mathematics and Statistics, Strathclyde ̽��ֱ��
Dr Jason Carroll, Senior Group Leader, Cancer Research UK Cambridge Institute, ̽��ֱ�� of Cambridge
Professor Richard Gilbertson, Li Ka Shing Chair of Oncology, Head of Department of Oncology, Director, Cancer Research UK Cambridge Centre, ̽��ֱ�� of Cambridge
Professor Gregory Hannon, Royal Society Wolfson Research Professor of Molecular Cancer Biology, ̽��ֱ�� of Cambridge
Dr Roman Hovorka, Director of Research, WT-MRC Institute of Metabolic Science, ̽��ֱ�� of Cambridge
Professor Arthur Kaser, ̽��ֱ�� Chair of Gastroenterology, Honorary Consultant Physician, ̽��ֱ�� of Cambridge
Professor Giovanna Mallucci, van Geest Professor of Clinical Neurosciences, Clinical Neurosciences, ̽��ֱ�� of Cambridge; Associate Director UK Dementia Research Institute at ̽��ֱ�� of Cambridge; Programme Leader and Head of Neurobiology, MRC Toxicology Unit, ̽��ֱ�� of Leicester
Professor Hugh Markus, Professor of Stroke Medicine, Clinical Neurosciences, ̽��ֱ�� of Cambridge
Professor Christine J. Watson, Professor of Cell and Cancer Biology, ̽��ֱ�� of Cambridge

In addition, two Fellows were elected from the MRC Laboratory of Molecular Biology and Wellcome Trust Sanger Institute:

Dr Anne Bertolotti, Programme Leader, MRC Laboratory of Molecular Biology
Dr Matthew Hurles, Senior Group Leader, Human Genetics, Wellcome Trust Sanger Institute

̽��ֱ��new Fellows will be formally admitted to the Academy at a ceremony on 28 June 2017.

Nine researchers from the ̽��ֱ�� of Cambridge are among 46 world leading UK researchers who have been elected to the prestigious Fellowship of the Academy of Medical Sciences.

Academy of Medical Sciences

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