Cambridge begins world-first COVID-19 vaccine booster study

Researchers in Cambridge have welcomed their first participants in a new UK study to understand the effects of a ‘booster’ dose of a COVID-19 vaccine.

The Cov-Boost study, a world-first clinical trial, offers individuals a chance to have a third dose of COVID-19 vaccine to see whether such a booster dose can better protect against the virus.

This Government-funded trial, led by the University of Southampton, has now opened a site at the National institute for Health Research (NIHR) Cambridge Clinical Research Facility at Cambridge University Hospitals (CUH).   

It is the first study in the world to provide vital data on the impact of a third dose on patients’ immune responses.

It will give scientists from around the world and the experts behind the UK’s COVID-19 vaccination programme a better idea of how effective a booster of each vaccine is in protecting the individual from the virus.

The trial will look at seven different COVID-19 vaccines (including the Pfizer/BioNTech, and Valneva vaccines) as potential boosters, given at least 10 to 12 weeks after a second dose as part of the ongoing vaccination programme. One booster will be provided to each participant and could be a different brand to the one they were originally vaccinated with.

Researchers at the NIHR Cambridge Clinical Research Facility will see more than 180 participants from the Cambridgeshire area take part. Volunteers will be aged 30 years or older and will have already received their full COVID-19 immunisation.

On arrival, participants will be fully informed about the study. If they agree to take part they will be randomly allocated to receive one of several different COVID-19 vaccines or a placebo vaccine. After the booster, the study will monitor any reaction and also measure the immune response to vaccination over the next year.

Professor Krishna Chatterjee, Director of the NIHR Clinical Research Facility in Cambridge, who is leading the trial at CUH, said on the day of opening:

“We are delighted to support this study here in Cambridge. We have conducted trials of several COVID-19 vaccine studies over the last year. It’s an exciting opportunity to now work on a study to determine the effects of a third ‘booster’ dose of vaccines and I want to thank both the trial participants and our staff who are helping with this important research.”

All the data will be analysed with initial results expected in September. This will help inform decisions by the Joint Committee on Vaccination and Immunisation (JCVI) on any potential booster programme from autumn this year, ensuring the country’s most vulnerable are given the strongest possible protection over the winter period.

Volunteering for COVID-19 vaccine clinical trials

People wishing to volunteer to support clinical trials can sign up for information on Covid-19 vaccine trials with the NHS COVID-19 Vaccine Research Registry, developed in partnership with NHS Digital. It is helping large numbers of people to be recruited into trials, meaning more effective vaccines for coronavirus can be found as soon as possible.

The service was commissioned as part of the UK Government’s Vaccine Taskforce in conjunction with the NIHR and the Northern Ireland, Scottish and Welsh Governments. Anyone living in the UK can sign up online to take part in the trials through the NHS, giving permission for researchers to contact you if they think you’re a good fit.  Once you sign up, you can withdraw at any time and request that your details be removed from the COVID-19 Vaccine Research Registry.  The process takes about 5 minutes to complete

A single gene could be the reason why some of us carry an extra 30 pounds of fat

Could a gene be the key why some of us carry extra fat? New research has found that one in every 340 people might carry a mutation in a single gene that makes them more likely to have a greater weight from early childhood and, by 18 years of age, they could be up to 30 pounds heavier with the excess weight likely to be mostly fat. 

The study supported by the NIHR Cambridge BRC was led by scientists at the MRC Metabolic Diseases Unit which is part of the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge and the MRC Integrative Epidemiology Unit at the University of Bristol has been published in Nature Medicine.

It has been known for a long time that obesity tends to run in families, but it was not until about 20 years ago that scientists started to discover that changes in specific genes can have very large effects on our weight even from early childhood.

One of these genes, the Melanocortin 4 Receptor (MC4R), makes a protein that is produced in the brain where it sends signals to our appetite centres, telling them how much fat we have stored. When the MC4R gene does not work properly, our brains think we have lower fat stores than we do, signalling that we are starving and need to eat.

The research team found that around one in every 340 people may carry a disruptive mutation at MC4R. People who carry these mutations were more likely to have a greater weight from early childhood and, by 18 years of age, they were on average 17 kg (37 lbs or 2.5 stone) heavier, with the majority of this excess weight likely to be fat.

These results were found by studying the MC4R gene in a random sample of around 6,000 participants born in Bristol in 1990-91, who were recruited to Children of the 90s, a health study based at the University of Bristol. This is a unique UK study that recruited approximately 80 percent of the births occurring in a specific region of the South West and which has continued to follow participants. As the Children of the 90s study managed to recruit such a high percentage of mothers during pregnancy, it is one of the most representative and comprehensive studies of its kind.

The authors examined the MC4R gene in all 6,000 people and, whenever a mutation was found, went on to study its functional effects in the laboratory. This meticulous approach has provided the best estimates so far of the frequency and impact of MC4R mutations on people’s weight and body fat. Based on the frequency of mutations in this study, it is possible that around 200,000 people in the UK could carry a substantial amount of additional fat because of mutations in MC4R.

Professor Sir Stephen O’Rahilly, from the University of Cambridge and is theme lead for metabolism, endocrinology and bone research is one of the authors of the study, said: “Parents of obese children are often blamed for poor parenting and not all children obtain appropriate professional help. Our findings show that weight gain in childhood due to a single gene disorder is not uncommon. This should encourage a more compassionate and rational approach to overweight children and their families – including genetic analysis in all seriously obese children.”

Dr Kaitlin Wade, from the University of Bristol’s MRC Integrative Epidemiology Unit and an author on the paper, added: “Work like this is really made possible as a result of the amazing properties presented by a study like Children of the 90s. Having biological samples for sequencing and rich life course data within a representative population sample is critical to allow new understanding and deep characterisation of important biological genetic effects like these.”

Professor Nic Timpson, Children of the 90s’ Principal Investigator, and also one of the study’s authors, explained: “This work helps to recalibrate our understanding of the frequency and functional impact of rare MC4R mutations and will help to shape the future management of this important health factor – we extend our thanks to the participants of the Children of the 90s.”

Though the MC4R gene is a striking example, this is only one gene of many that affect our weight and there are likely to be further examples that emerge as genetic sequencing becomes more common.

In the longer term, knowledge of the brain pathways controlled by MC4R should help in the design of drugs that bypass the signalling blockade and help restore people to a healthy weight.

Paper reference
Wade KH et al. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort. 
Nature Medicine; 27 May 2021

World-first covid-19 vaccine booster study launches in Eastern region

Volunteers from the East of England will soon be able to receive a third ‘booster’ COVID-19 vaccine through a new Government-funded clinical trial launching this week, the Health Secretary has announced.

The Cov-Boost study will be run at NIHR Cambridge Clinical Research Facility at Cambridge University Hospitals NHS Foundation Trust (CUH) and is being led by University Hospital Southampton NHS Foundation Trust. It will be the first study in the world to provide vital data on the impact of a third dose on patients’ immune responses.

It will give scientists from around the world and the experts behind the UK’s COVID-19 vaccination programme a better idea of how effective a booster of each vaccine is in protecting the individual from the virus.

The trial will look at seven different COVID-19 vaccines (including the Oxford/AstraZeneca, Pfizer/BioNTech, and Moderna vaccines) as potential boosters, given at least 10 to 12 weeks after a second dose as part of the ongoing vaccination programme. One booster will be provided to each volunteer and could be a different brand to the one they were originally vaccinated with.

Anyone interested in participating can find out more by signing up to the NHS COVID-19 Vaccine Research Registry. Participants will be adults aged 30 years or older and will include those immunised early on in the vaccination programme – for example, adults aged 75 and over or health and care workers.

All the trial sites are working on ways of including people in research from a wide variety of backgrounds and individuals from ethnic minorities are encouraged to apply.

The initial results, expected in September, will help inform decisions by the Joint Committee on Vaccination and Immunisation (JCVI) on any potential booster programme from autumn this year, ensuring the country’s most vulnerable are given the strongest possible protection over the winter period.

Prof. Krishna Chatterjee, Director of NIHR Clinical Research Facility in Cambridge (pictured right), who will be leading the trial at CUH, said: 

“Following the exemplary work our Cambridgeshire teams have already carried out to find effective vaccines for COVID-19, we are excited to now be able to offer the chance to take part in this next, vital study to people in the region. We hope as many volunteers as possible who are over the age of 30 and who’ve already received two doses of a vaccine will join us in this important research.”

Dr Helen Macdonald, Chief Operating Officer for the NIHR’s Clinical Research Network in the Eastern region, said:

“The launch of this clinical trial, testing the effects of a third dose of COVID-19 vaccine, offers a chance to reflect on how far our UK research community has come over the past year. Our NIHR colleagues have been instrumental in the progress that’s been made, but we couldn’t have reached this point without the people who volunteer to help by taking part in research. We hope as many people as possible will take the opportunity to help support this research too.”

Rt Hon Matt Hancock MP, Health and Social Care Secretary, said:

“We will do everything we can to future-proof this country from pandemics and other threats to our health security, and the data from this world-first clinical trial will help shape the plans for our booster programme later this year.

“I urge everyone who has had both doses of a COVID-19 vaccine, and is eligible, to sign up for this study and play a part in protecting the most vulnerable people in this country and around the world for months and years to come.”

Volunteering for COVID-19 vaccine clinical trials

People wishing to volunteer to support clinical trials can sign up for information on Covid-19 vaccine trials with the NHS Covid-19 Vaccine Research Registry, developed in partnership with NHS Digital. It is helping large numbers of people to be recruited into trials, meaning more effective vaccines for coronavirus can be found as soon as possible.

The service was commissioned as part of the UK Government’s Vaccine Taskforce in conjunction with the National Institute for Health Research (NIHR) and the Northern Ireland, Scottish and Welsh Governments.

Anyone living in the UK can sign up online to take part in the trials through the NHS, giving permission for researchers to contact you if they think you’re a good fit.  Once you sign up, you can withdraw at any time and request that your details be removed from the COVID-19 Vaccine Research Registry.  The process takes about 5 minutes to complete.

IBD BioResource – Celebrating 5 years of its contribution to Crohn’s and Colitis research

May 2021 is an important milestone for the National Institute for Health Research (NIHR) IBD BioResource as it marks their fifth year of helping to transform the research landscape in Crohn’s disease and ulcerative colitis (collectively known as Inflammatory Bowel Disease or IBD) – and what better way to celebrate this anniversary than World IBD Day held on 19 May.

What is the NIHR IBD BioResource?

The team support research by connecting leading IBD clinicians and researchers with people living with IBD. The concept is simple: NIHR IBD BioResource participating hospitals enrol patients with Crohn’s disease and ulcerative colitis via a national research platform. This enables patients to participate in future research studies which helps accelerate research into IBD.

The NIHR IBD BioResource launched in January 2016 and rolled out nationally in May 2016. The Cambridge-led research initiative is now open in over 100 NHS hospitals across the UK and has almost 35,000 patients with Crohn’s disease and ulcerative colitis taking part.

What is IBD and why is research needed in this area?

Inflammatory Bowel Disease (IBD) is a term used to describe two conditions, Crohn’s disease and ulcerative colitis, which together affect around 500,000 people in the UK. It is a life-long disease with no known cure and what causes it remains unclear.

People with the condition often find themselves in severe pain and suffer with abdominal cramps, recurring diarrhoea, bloating, weight loss and fatigue. The medical treatments do not always work for some people, and currently there is no way to predict which patients will most likely benefit from which treatment option, or who will develop side-effects. In some cases, where treatments don’t work or complications of IBD develop, patients will need to undergo surgery to remove parts of their bowel.

Following in the footsteps of the UK IBD Genetics Consortium and as part of the NIHR BioResource, the NIHR IBD BioResource was developed in Cambridge five years ago. It was created to drive the genetic discoveries of IBD into functional and clinical translation and develop better treatments for the disease. It also aimed to provide people who are diagnosed with the condition the opportunity to participate in research.

Taking part in the NIHR IBD BioResource for both patients and clinical teams is easy:

• Patients are recruited through clinical attendance at participating hospitals
• Patients that consent provide a small blood sample and complete a health and lifestyle questionnaire, while allowing access to their health records
• Analyses are carried out on the DNA extracted from the blood sample to determine the genetic makeup of these samples

Enrolled patients become members of the NIHR BioResource. Samples and collected data from the recruited patients form the basis of the IBD BioResource panel which is accessible to all researchers from science to industry through a simple application process. Patients can be selected on specific criteria and invited to participate in studies to research IBD and other conditions. Future participation may involve giving another blood or stool sample, completing a questionnaire or participating in a clinical trial.

Range of studies facilitated by NIHR IBD BioResource include:

• analysis of existing genetics and clinical data; recall studies of patients selected by genotype for functional genomics
• running surveys of the impact of certain aspects of IBD on quality of life
• recall studies to develop early diagnostic tests
• recruitment to commercial drugs trials
• access to existing banked serum samples
• assessing the contribution of viral infection to IBD pathogenesis
• aiding recruitment to observational studies and intervention studies

The NIHR IBD BioResource wanted to make it easier for patients to take part in research, and for researchers to find the right patients for their studies – matching the right patients to the right research is one of the slowest parts of medical research. Since the launch of NIHR IBD BioResource, IBD research for both patients and researchers has gone from strength to strength.

Miles Parkes explains: “IBD affects large numbers of people and its causes are not currently well understood. Research is important both to help us better understand these causes, in the hope that preventative strategies become possible in the future, and to help us move on from a ‘one size fits all’ approach to treatment and medication, to something more tailored to the individual. The NIHR IBD BioResource allows us to tackle both questions – to help researchers to create better, more personalised treatments and improve our knowledge of the disease.”

To date, the team have received 50 research applications to access the NIHR IBD BioResource panel. 17 of these studies have requested access to data only and 33 were interested in data, samples and recalling patients. Five of these studies have now been completed and published.

While COVID has slowed some elements of research, the NIHR BioResource has proudly continued supporting vital applications throughout the pandemic and facilitated important studies looking at the impact of IBD drug therapies and COVID-19 infection. Details about all current and active studies can be found here.

The NIHR IBD BioResource – a success story for all involved!

Future of the NIHR IBD BioResource and IBD research

The trials and tribulations of recruiting a large cohort of patients while facing unforeseen challenges such as the COVID-19 pandemic, has taught the NIHR IBD BioResource some important lessons and enabled us to develop better processes. For example, the team are currently exploring ways to enable ‘e-consent’ and remote recruitment (e.g. outside hospital) into the study.

The success of NIHR IBD BioResource remains unprecedented and has led to a flourishing partnership with the Health Data Research Hub for IBD or ‘Gut Reaction’.

Gut Reaction aims to build on the high-quality health data already held in the NIHR IBD BioResource by combining it with ‘real-world’ data from participating NHS hospitals and the UK IBD Registry. This will allow researchers to use powerful pooled data to support important research into IBD. 

The team now plan to create a Paediatric IBD BioResource. This will mean they can offer research to children and young people with IBD. The Paediatric arm of IBD BioResource will be led by Professor Holm Uhlig at Oxford and under the umbrella of the NIHR/IBD BioResource. Watch this space!

As part of World IBD Day, the team are ever grateful for all the IBD patients who take part in research, both in the UK and worldwide. They wish to thank their funders: The National Institute for Health Research (NIHR), the Medical Research Council, the Wellcome Trust, Open Targets, Crohn’s & Colitis UK, the Helmsley Charitable Trust and our Industry partners.

Cambridge clinical researchers elected Fellows of the Royal Society

Congratulations to Sadaf Farooqi, Professor of Metabolism and Medicine at the NIHR Cambridge BRC and to David Rowitch, Professor and theme lead for paediatric research at the NIHR Cambridge BRC, who have been elected as Royal Society Fellows.

The Royal Society elects scientists, engineers and technologists from the UK and the Commonwealth on the basis of excellence in science. The Society’s fundamental purpose is to encourage the development and use of science to benefit humanity.

Professor Sadaf Farooqi was elected in recognition of her research into obesity and how the body controls weight.

Professor Farooqi discovered how the hormone leptin and the brain’s melanocortin system regulates appetite and weight and that genetic mutations can cause severe obesity in some people.

Discoveries by her team have directly led to diagnostic testing for genetic obesity syndromes world-wide and provided life-saving treatments for some people.

Professor Farooqi said: “As a Clinician and Scientist, I am absolutely delighted to be elected as a Fellow of the Royal Society. This prestigious honour recognises the work of many team members past and present, our network of collaborators and the patients and families who played a vital role in this research”.

Professor David Rowitch’s work on glial cells (cells in the nervous system) found they provide much more than ‘the glue’ to support to the nervous system but they also protect neuron cells (nerve cells which send and receive signals from your brain).

He found their function is critical to support the spinal cord and that they also might play a part in the development of the brain and neurodegenerative illnesses, which is one of the reasons why he has been given this top award.

Professor Rowitch said: “It is a great honour to be elected to the Fellowship of the Royal Society, joining many of my esteemed Cambridge, and other scientific, colleagues.”

Ability of multi-drug resistant infection to evolve within cystic fibrosis patients highlights need for rapid treatment

Scientists have been able to track how a multi-drug resistant organism is able to evolve and spread widely among cystic fibrosis patients – showing that it can evolve rapidly within an individual during chronic infection. The researchers say their findings highlight the need to treat patients with Mycobacterium abscessus infection immediately, counter to current medical practice.

Around one in 2,500 children in the UK is born with cystic fibrosis, a hereditary condition that causes the lungs to become clogged up with thick, sticky mucus. The condition tends to decrease life expectancy among patients.

In recent years, M. abscessus, a species of multi-drug resistant bacteria, has emerged as a significant global threat to individuals with cystic fibrosis and other lung diseases. It can cause a severe pneumonia leading to accelerated inflammatory damage to the lungs, and may prevent safe lung transplantation. It is also extremely difficult to treat – fewer than one in three cases is treated successfully.

In a study published today in Science, a team led by scientists at the University of Cambridge examined whole genome data for 1,173 clinical M. abscessus samples taken from 526 patients to study how the organism has evolved – and continues to evolve. The samples were obtained from cystic fibrosis clinics in the UK, as well as centres in Europe, the USA and Australia.

The team found two key processes that play an important part in the organism’s evolution. The first is known as horizontal gene transfer – a process whereby the bacteria pick up genes or sections of DNA from other bacteria in the environment. Unlike classical evolution, which is a slow, incremental process, horizontal gene transfer can lead to big jumps in the pathogen’s evolution, potentially allowing it to become suddenly much more virulent.

The second process is within-host evolution. As a consequence of the shape of the lung, multiple versions of the bacteria can evolve in parallel – and the longer the infection exists, the more opportunities they have to evolve, with the fittest variants eventually winning out. Similar phenomena have been seen in the evolution of new SARS-CoV-2 variants in immunocompromised patients.

Professor Andres Floto, joint senior author from the Centre for AI in Medicine (CCAIM) and the Department of Medicine at the University of Cambridge and the Cambridge Centre for Lung Infection at Royal Papworth Hospital, said: “What you end up with is parallel evolution in different parts of an individual’s lung. This offers bacteria the opportunity for multiple rolls of the dice until they find the most successful mutations. The net result is a very effective way of generating adaptations to the host and increasing virulence. 

“This suggests that you might need to treat the infection as soon as it is identified. At the moment, because the drugs can cause unpleasant side effects and have to be administered over a long period of time – often as long as 18 months – doctors usually wait to see if the bacteria cause illness before treating the infection. But what this does is give the bug plenty of time to evolve repeatedly, potentially making it more difficult to treat.”

Professor Floto and colleagues have previously advocated routine surveillance of cystic fibrosis patients to check for asymptomatic infection. This would involve patients submitting sputum samples three or four times a year to check for the presence of M. abscessus infection. Such surveillance is carried out routinely in many centres in the UK.

Using mathematical models, the team have been able to step backwards through the organism’s evolution in a single individual and recreate its trajectory, looking for key mutations in each organism in each part of the lung. By comparing samples from multiple patients, they were then able to identify the key set of genes that enabled this organism to change into a potentially deadly pathogen.

These adaptations can occur very quickly, but the team found that their ability to transmit between patients was constrained: paradoxically, those mutations that allowed the organism to become a more successful pathogen within the patient also reduced its ability to survive on external surfaces and in the air – the key mechanisms by which it is thought to transmit between people. 

Potentially one of the most important genetic changes witnessed by the team was one that contributed towards M. abscessus becoming resistant to nitric oxide, a compound naturally produced by the human immune system. The team will shortly begin a clinical trial aimed at boosting nitric oxide in patients’ lung by using inhaled acidified nitrite, which they hope would become a novel treatment for the devastating infection.

Examining the DNA taken from patient samples is also important in helping understand routes of transmission. Such techniques are used routinely in Cambridge hospitals to map the spread of infections such as MRSA and C. difficile – and more recently, SARS-CoV-2. Insights into the spread of M. abscessus helped inform the design of the new Royal Papworth Hospital building, opened in 2019, which has a state-of-the-art ventilation system to prevent transmission. The team recently published a study showing that this ventilation system was highly effective at reducing the amount of bacteria in the air.

Professor Julian Parkhill, joint senior author from the Department of Veterinary Medicine at the University of Cambridge, added: “M. abscessus can be a very challenging infection to treat and can be very dangerous to people living with cystic fibrosis, but we hope insights from our research will help us reduce the risk of transmission, stop the bug evolving further, and potentially prevent the emergence of new pathogenic variants.”

The team have used their research to develop insights into the evolution of M. tuberculosis – the pathogen that causes TB about 5,000 years ago. In a similar way to M. abscessus, M. tuberculosis likely started life as an environmental organism, acquired genes by horizontal transfer that made particular clones more virulent, and then evolved through multiple rounds of within-host evolution. While M. abscessus is currently stopped at this evolutionary point, M. tuberculosis evolved further to be able to jump directly from one person to another.  

Dr Lucy Allen, Director of Research at the Cystic Fibrosis Trust, said: “This exciting research brings real hope of better ways to treat lung infections that are resistant to other drugs. Our co-funded Innovation Hub with the University of Cambridge really shows the power of bringing together world-leading expertise to tackle a health priority identified by people with cystic fibrosis. We’re expecting to see further impressive results in the future coming from our joint partnership.”

The study was funded by the Wellcome Trust, Cystic Fibrosis Trust, NIHR Cambridge Biomedical Research Centre and The Botnar Foundation

Paper reference
Bryant, JM et al. Stepwise pathogenic evolution of Mycobacterium abscessus. Science; 30 Apr 2021

Stress does not lead to loss of self-control in eating disorders, study finds

A unique residential study has concluded that, contrary to perceived wisdom, people with eating disorders do not lose self-control – leading to binge-eating – in response to stress.

People who experience bulimia nervosa and a subset of those affected by anorexia nervosa share certain key symptoms, namely recurrent binge-eating and compensatory behaviours, such as vomiting. The two disorders are largely differentiated by body mass index (BMI): adults affected by anorexia nervosa tend to have BMI of less than 18.5 kg/m². More than 1.6 million people in the UK are thought to have an eating disorder, three-quarters of whom are women.

One prominent theory of binge-eating is that it is a result of stress, which causes individuals to experience difficulties with self-control. However, until now, this theory has not been directly tested in patients.

To examine this theory, researchers at the University of Cambridge working with clinicians at Cambridgeshire and Peterborough NHS Foundation Trust invited 85 women – 22 with anorexia nervosa, 33 with bulimia nervosa and 30 healthy controls – to attend a two-day stay at Wellcome Trust-MRC Institute of Metabolic Science Translational Research Facility (TRF). The facility, which includes an Eating Behaviour Unit, is designed so that a volunteer’s diet and environment can be strictly controlled and their metabolic status studied in detail during a residential status. The setting is intended to be as naturalistic as possible.

During their stay, each morning the women would receive controlled meals provided by a metabolic nutritionist. The women then underwent a fasting period during which they were taken to the next door Wolfson Brain Imaging Centre, where they performed tasks while their brain activity was monitored using a functional MRI scanner.

The tasks involved stopping the progression of a bar rising up a computer screen by pressing a key. The main task involved stopping the moving bar as it reached the middle line. On a minority of trials, stop-signals were presented, where the moving bar stopped automatically before reaching the middle line; participants were instructed to withhold their response in the event of a stop-signal.

The women then performed a task, aimed at raising their stress levels. The women were asked to carry out a series of mental arithmetic tests while receiving mild but unpredictable electric shocks, and were told that if they failed to meet the performance criterion, their data would be dismissed from the study. They were given feedback throughout the task, such as ‘Your performance is below average’.

The women then repeated the stop-signal task again. Once the task had been completed – but while the volunteers might still be expected to be in a heightened state of stress – they returned to the Eating Behaviour Unit, where they were offered an ‘all you can eat’ buffet in its relaxing lounge and were told they could eat as much or as little as they would like.

On the second day of their study, the volunteers carried out the same tasks, but without the added stress of unpleasant electric shocks and pressure to perform. (For some participants, the order of the days was reversed.)

Dr Margaret Westwater, who led the research while a PhD student at Cambridge’s Department of Psychiatry, said: “The idea was to see what happened when these women were stressed. Did it affect key regions of the brain important for self-control, and did that in turn lead to increases in food intake? What we found surprised us and goes counter to the prevailing theory.”

The team found that even when they were not stressed, those women with bulimia nervosa performed worse on the main task, where they had to stop the rising bar as it reached the middle bar – but this was not the case for those women affected by anorexia nervosa. This impairment occurred alongside increased activity in a region in the prefrontal cortex, which the team say could mean these particular women were unable to recruit some other regions the brain required to perform the task optimally.

Interestingly – and contrary to the theory – stress did not affect the actual performance in any way for either of the patient groups or the controls. However, the patient groups showed some differences in brain activity when they were stressed – and this activity differed between women with anorexia and those with bulimia.

While the researchers observed that the patients in general ate less in the buffet than the controls, the amount that they ate did not differ between the stress and control days. However, activity levels in two key brain regions were associated with the amount of calories consumed in all three groups, suggesting that these regions are important for dietary control.

Dr Westwater added: “Even though these two eating disorders are similar in many respects, there are clear differences at the level of the brain. In particular, women with bulimia seem to have a problem with pre-emptively slowing down in response to changes in their environment, which we think might lead them to make hasty decisions, leaving them vulnerable to binge-eating in some way.

“The theory suggests that these women should have eaten more when they were stressed, but that’s actually not what we found. Clearly, when we’re thinking about eating behaviour in these disorders, we need to take a more nuanced approach.”

In findings published last year, the team took blood samples from the women as they performed their tasks, to look at metabolic markers that are important for our sense of feeling hungry or feeling full. They found that levels of these hormones are affected by stress.

Under stress, patients with anorexia nervosa had an increase in ghrelin, a hormone that tells us when we are hungry. They also had an increase in peptide tyrosine tyrosine (PYY), a satiety hormone. In other words, when they are stressed, people with anorexia nervosa produce more of the hunger hormone, but contradictorily also more of a hormone that should tell them that they are full, so their bodies are sending them confusing signals about what to do around food.

The situation with bulimia nervosa was again different: while the team saw no differences in levels of ghrelin or PYY, they did see lower levels of cortisol, the ‘stress hormone’, than in healthy volunteers. In times of acute stress, people who are chronically stressed or are experiencing depression are known to show this paradoxical low cortisol phenomenon.

Professor Paul Fletcher, joint senior author at the Department of Psychiatry, said: “It’s clear from our work that the relationship between stress and binge-eating is very complicated. It’s about the environment around us, our psychological state and how our body signals to us that we’re hungry or not.

“If we can get a better understanding of the mechanisms behind how our gut shapes those higher order cognitive processes related to self-control or decision-making, we may be in a better position to help those women affected by these extremely debilitating illnesses. To do this, we need to take a much more integrated approach to studying these illnesses. That’s where facilities such as Cambridge’s new Translational Research Facility can play a vital role, allowing us to monitor within a relatively naturalistic environment factors such as an individual’s behaviour, hormone levels and, brain activity.”

The research was funded by the Bernard Wolfe Health Neuroscience Fund, Wellcome, the NIH-Oxford-Cambridge Scholars Program and the Cambridge Trust. Further support was provided by the NIHR Cambridge Biomedical Research Centre.

Paper Reference

Westwater, ML, et al. Prefrontal responses during proactive and reactive inhibition are differentially impacted by stress in anorexia and bulimia nervosa.
Neuro; 12 April 2021; DOI: 10.1523/JNEUROSCI.2853-20.2021

Placenta is dumping ground for genetic defects

In the first study of the genomic architecture of the human placenta, scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators have confirmed that the normal structure of the placenta is different to any other human organ and resembles that of a tumour, harbouring many of the same genetic mutations found in childhood cancers.

The study funded by Wellcome and NIHR Cambridge BRC and published in Nature, found evidence to support the theory of the placenta as a ‘dumping ground’ for genetic defects, whereas the fetus corrects or avoids these errors. The findings provide a clear rationale for studying the association between genetic aberrations and birth outcomes, in order to better understand problems such as premature birth and stillbirth.

In the earliest days of pregnancy, the fertilized egg implants into the wall of the uterus and begins dividing from one cell into many. Cells differentiate into various types of cell and some of them will form the placenta. Around week ten of pregnancy, the placenta begins to access the mother’s circulation, obtaining oxygen and nutrients for the fetus, removing waste products and regulating crucial hormones*.

It has long been known that the placenta is different from other human organs. In one to two per cent of pregnancies, some placental cells have a different number of chromosomes to cells in the fetus – a genetic flaw that could be fatal to the fetus, but with which the placenta can often function reasonably normally.

Despite this genetic robustness, problems with the placenta are a major cause of harm to the mother and unborn child, such as growth restriction or even stillbirths. 

This new study is the first high-resolution survey of the genomic architecture of the human placenta. Scientists at the Wellcome Sanger Institute and the University of Cambridge conducted whole genome sequencing of 86 biopsies and 106 microdissections from 42 placentas, with samples taken from different areas of each organ.

The team discovered that each one of these biopsies was a genetically distinct ‘clonal expansion’ – a cell population descended from a single common ancestor – a clear parallel between the formation of the human placenta and the development of a cancer.

Analysis also identified specific patterns of mutation that are commonly found in childhood cancers, such as neuroblastoma and rhabdomyosarcoma, with an even higher number of these mutations in the placenta than in the cancers themselves.

Professor Steve Charnock-Jones, a senior author of the study from the University of Cambridge, said: “Our study confirms for the first time that the placenta is organised differently to every other human organ, and in fact resembles a patchwork of tumours. The rates and patterns of genetic mutations were also incredibly high compared to other healthy human tissues.”

The team used phylogenetic analysis to retrace the evolution of cell lineages from the first cell divisions of the fertilised egg and found evidence supporting the theory of the placenta tolerating major genetic flaws.

In one biopsy, the researchers observed three copies of chromosome 10 in each cell, two from the mother and one from the father, instead of the usual one copy from each parent. But other biopsies from the same placenta and from the fetus carried two copies of chromosome 10, both from the mother. A chromosomal copy number error such as this in any other tissue would be a major genetic flaw.

Professor Gordon Smith, a senior author of the study from the University of Cambridge, said: “It was fascinating to observe how such a serious genetic flaw as a chromosomal copy number error was ironed out by the baby but not by the placenta. This error would have been present in the fertilized egg. Yet derivative cell populations, and most importantly those that went on to form the child, had the correct number of copies of chromosome 10, whereas parts of the placenta failed to make this correction. The placenta also provided a clue that the baby had inherited both copies of the chromosome from one parent, which can itself be associated with problems.”

Now that the link between genetic aberrations in the placenta and birth outcomes has been established, further studies using larger sample sizes could help to uncover the causes of complications and diseases that arise during pregnancy.

Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute, said: “The placenta is akin to the ‘wild west’ of the human genome, completely different in its structure from any other healthy human tissue. It helps to protect us from flaws in our genetic code, but equally there remains a high burden of disease associated with the placenta. Our findings provide a rationale for studying the association between genetic aberrations in the placenta and birth outcomes at the high resolution we deployed and at massive scale.”

Paper reference:

Tim H. H. Coorens, Thomas R. W. Oliver and Rashesh Sanghvi et al. (2021). Somatic mutations reveal widespread mosaicism and mutagenesis in human placentas. Nature. DOI: https://doi.org/10.1038/s41586-021-03345-1

Diphtheria risks becoming ‘major global threat’ again as it evolves resistance to antimicrobials

Diphtheria – a relatively easily-preventable infection – is evolving to become resistant to a number of classes of antibiotics and in future could lead to vaccine escape, warn an international team of researchers from the UK and India.

The researchers, led by scientists at the University of Cambridge, say that the impact of COVID-19 on diphtheria vaccination schedules, coupled with a rise in the number of infections, risk the disease once more becoming a major global threat.

Diphtheria is a highly contagious infection that can affect the nose and throat, and sometimes the skin. If left untreated it can prove fatal. In the UK and other high-income countries, babies are vaccinated against infection. However, in low- and middle-income countries, the disease can still cause sporadic infections or outbreaks in unvaccinated and partially-vaccinated communities.

The number of diphtheria cases reported globally has being increasing gradually. In 2018, there were 16,651 reported cases, more than double the yearly average for 1996–2017 (8,105 cases).

Diphtheria is primarily caused by the bacterium Corynebacterium diphtheriae and is mainly spread by coughs and sneezes, or through close contact with someone who is infected. In most cases, the bacteria cause acute infections, driven by the diphtheria toxin – the key target of the vaccine. However, non-toxigenic C. diphtheria can also cause disease, often in the form of systemic infections.

In a study published in Nature Communications,  an international team of researchers from the UK and India used genomics to map infections, including a subset from India, where over half of the globally reported cases occurred in 2018.

By analysing the genomes of 61 bacteria isolated from patients and combining these with 441 publicly available genomes, the researchers were able to build a phylogenetic tree – a genetic ‘family tree’ – to see how the infections are related and understand how they spread. They also used this information to assess the presence of antimicrobial resistance (AMR) genes and assess toxin variation.

The researchers found clusters to genetically-similar bacteria isolated from multiple continents, most commonly Asia and Europe. This indicates that C. diphtheriae has been established in the human population for at least over a century, spreading across the globe as populations migrated.

The main disease-causing component of C. diphtheriae is the diphtheria toxin, which is encoded by the tox gene. It is this component that is targeted by vaccines. In total, the researchers found 18 different variants of the tox gene, of which several had the potential to change the structure of the toxin.

Professor Gordon Dougan from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) said: ““The diphtheria vaccine is designed to neutralise the toxin, so any genetic variants that change the toxin’s structure could have an impact on how effective the vaccine is. While our data doesn’t suggest the currently used vaccine will be ineffective, the fact that we are seeing an ever-increasing diversity of tox variants suggests that the vaccine, and treatments that target the toxin, need to be appraised on a regular basis.”

Diphtheria infections can usually be treated with a number of classes of antibiotic. While C. diphtheriae resistant to antibiotics have been reported, the extent of such resistance remains largely unknown.

When the team looked for genes that might confer some degree of resistance to antimicrobials, they found that the average number of AMR genes per genome was increasing each decade. Genomes of bacteria isolated from infections from the most recent decade (2010-19) showed the highest average number of AMR genes per genome, almost four times as many on average than in the next highest decade, the 1990s.

Robert Will, a PhD student at CITIID and the study’s first author, said: “The C. diphtheriae genome is complex and incredibly diverse. It’s acquiring resistance to antibiotics that are not even clinically used in the treatment of diphtheria. There must be other factors at play, such as asymptomatic infection and exposure to a plethora of antibiotics meant for treating other diseases.”

Erythromycin and penicillin are the traditionally recommended antibiotics of choice for treating confirmed cases of early-stage diphtheria, though there are several different classes of antibiotics available to treat the infection. The team identified variants resistant to six of these classes in isolates from the 2010s, higher than in any other decades.

Dr Pankaj Bhatnagar from the World Health Organization country office for India said: “AMR has rarely been considered as a major problem in the treatment of diphtheria, but in some parts of the world, the bacterial genomes are acquiring resistance to numerous classes of antibiotics. There are likely to be a number of reasons to this, including exposure of the bacteria to antibiotics in their environment or in asymptomatic patients being treated against other infections.”

The researchers say that COVID-19 has had a negative impact on childhood vaccination schedules worldwide and comes at a time when reported case numbers are rising, with 2018 showing the highest incidence in 22 years.

Dr Ankur Mutreja from CITIID, who led the study, said: “It’s more important than ever that we understand how diphtheria is evolving and spreading. Genome sequencing gives us a powerful tool for observing this in real time, allowing public health agencies to take action before it’s too late.

“We mustn’t take our eye off the ball with diphtheria, otherwise we risk it becoming a major global threat again, potentially in a modified, better adapted, form.”

The research was funded primarily by the Medical Research Council, with additional support from the NIHR Cambridge Biomedical Research Centre.

Paper Reference

Will, RC et al. Spatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheria.
Nat Comms; 8 Mar 2021; DOI: 10.1038/s41467-021-21870-5

Celebrating International Women’s Day

Today marks International Women’s Day, this year’s theme is ‘choose to challenge’, to call out gender bias and inequality.

Hear from two women who work in research at the NIHR Cambridge Biomedical Research Centre and have explained why it is important for more women to be involved in research and science.

Find out more about International Women’s Day.

Maura Malpetti – Post-doctorial research associate

Beth Vincent – Patient and Public Involvement Coordinator

Genomics study identifies routes of transmission of coronavirus in care homes

Genomic surveillance – using information about genetic differences between virus samples – can help identify how SARS-CoV-2 spreads in care home settings, whose residents are at particular risk.

Care homes are at high risk of experiencing outbreaks of COVID-19, the disease caused by SARS-CoV-2. Older people and those affected by heart disease, respiratory disease and type 2 diabetes – all of which increase with age – are at greatest risk of severe disease and even death, making the care home population especially vulnerable.

Care homes are known to be high-risk settings for infectious diseases, owing to a combination of the underlying vulnerability of residents who are often frail and elderly, the shared living environment with multiple communal spaces, and the high number of contacts between residents, staff and visitors in an enclosed space.

In research published in eLife, a team led by scientists at the University of Cambridge and Wellcome Sanger Institute used a combination of genome sequencing and detailed epidemiological information to examine the impact of COVID-19 on care homes and to look at how the virus spreads in these settings.

SARS-CoV-2 is an RNA virus and as such its genetic code is prone to errors each time it replicates. It is currently estimated that the virus mutates at a rate of 2.5 nucleotides (the A, C, G and U of its genetic code) per month. Reading – or ‘sequencing’ – the genetic code of the virus can provide valuable information on its biology and transmission. It allows researchers to create ‘family trees’ – known as phylogenetic trees – that show how samples relate to each other.

Scientists and clinicians in Cambridge have pioneered the use of genome sequencing and epidemiological information to trace outbreaks and transmission networks in hospitals and community-based healthcare settings, helping inform infection control measures and break the chains of transmission. Since March 2020, they have been applying this method to SARS-CoV-2 as part of the COVID-19 Genomics UK (COG-UK) Consortium.

In this new study, researchers analysed samples collected from 6,600 patients between 26 February and 10 May 2020 and tested at the Public Health England (PHE) Laboratory in Cambridge. Out of all the cases, 1,167 (18%) were care home residents from 337 care homes, 193 of which were residential homes and 144 nursing homes, the majority in the East of England. The median age of care home residents was 86 years.

While the median number of cases per care home was two, the ten care homes with the largest number of cases accounted for 164 cases. There was a slight trend for nursing homes to have more cases per home than residential homes, with a median of three cases.

Compared with non-care home residents admitted to hospital with COVID-19, hospitalised care home residents were less likely to be admitted to intensive care units (less than 7% versus 21%) and more likely to die (47% versus 20%).

The researchers also explored links between care homes and hospitals. 68% of care home residents were admitted to hospital during the study period. 57% were admitted with COVID-19, 6% of cases had suspected hospital-acquired infection, and 33% were discharged from hospital within 7 days of a positive test. These findings highlight the ample opportunities for SARS-CoV-2 transmission between hospital and care home settings.

When the researchers examined the viral sequences, they found that for several of the care homes with the highest number of cases, all of the cases clustered closely together on a phylogenetic tree with either identical genomes or just one base pair difference. This was consistent with a single outbreak spreading within the care home.

By contrast, for several other care homes, cases were distributed across the phylogenetic tree, with more widespread genetic differences, suggesting that each of these cases was independent and not related to a shared transmission source.

“Older people, particularly those in care homes who may be frail, are at particular risk from COVID-19, so it’s essential we do all that we can to protect them,” said Dr Estée Török, an Honorary Consultant at Addenbrooke’s Hospital, Cambridge University Hospitals (CUH), and an Honorary Senior Visiting Fellow at the University of Cambridge.

“Preventing the introduction of new infections into care homes should be a key priority to limit outbreaks, alongside infection control efforts to limit transmission within care homes, including once an outbreak has been identified.”

The team found two clusters that were linked to healthcare workers. One of these involved care home residents, a carer from that home and another from an unknown care home, paramedics and people living with them. The second involved several care home residents and acute medical staff at Cambridge University Hospitals NHS Foundation Trust who cared for at least one of the residents. It was not possible to say where these clusters originated from and how the virus spread.

“Using this technique of ‘genomic surveillance’ can help institutions such as care homes and hospitals better understand the transmission networks that allow the spread of COVID-19,” added Dr William Hamilton from the University of Cambridge and CUH. “This can then inform infection control measures, helping ensure that these places are as safe as possible for residents, patients, staff and visitors.”

The absolute number of diagnosed COVID-19 cases from care home residents declined more slowly in April than for non-care home residents, increasing the proportion of cases from care homes and contributing to the slow rate of decline in total case numbers during April and early May 2020.

“Our data suggest that care home transmission was more resistant to lockdown measures than non-care home settings. This may reflect the underlying vulnerability of the care home population, and the infection control challenges of nursing multiple residents who may also share communal living spaces,” said Gerry Tonkin-Hill from the Wellcome Sanger Institute.

The team found no new viral lineages from outside the UK, which may reflect the success of travel restrictions in limiting new viral introductions into the general population during the first epidemic wave and lockdown period.

This work was funded by COG-UK, Wellcome, the Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre.

Paper reference

Hamilton, W et al.
COVID-19 infection dynamics in care homes in the East of England: a retrospective genomic epidemiology study. eLife; 2 March 2021; DIO: 10.7554/eLife.64618

Single dose of Pfizer BioNTech vaccine reduces asymptomatic infections and potential for SARS-CoV-2 transmission

New data from Addenbrooke’s Hospital in Cambridge suggests that a single dose of the Pfizer BioNTech vaccine can reduce by 75% the number of asymptomatic SARS-CoV-2 infections. This implies that the vaccine could significantly reduce the risk of transmission of the virus from people who are asymptomatic, as well as protecting others from getting ill.

The study by a team at Cambridge University Hospitals NHS Foundation Trust (CUH) and the University of Cambridge analysed results from thousands of COVID-19 tests carried out each week as part its screening programmes on hospital staff who showed no signs of infection.

Vaccination for health care workers on the CUH site began on 8 December 2020, with mass vaccination from 8 January 2021. During a two-week period between 18 and 31 January 2021, the team screened similar numbers of vaccinated and unvaccinated staff using around 4,400 PCR tests per week. 

The results were then separated out to identify unvaccinated staff, and staff who had been vaccinated more than 12 days prior to testing (when protection against symptomatic infection is thought to occur). The study, which is yet to be peer-reviewed, found that 26 out of 3,252 (0·80%) tests from unvaccinated healthcare workers were positive. This compared to 13 out of 3,535 (0.37%) tests from healthcare workers less than 12 days post-vaccination and 4 out of 1,989 (0·20%) tests from healthcare workers at 12 days or more post-vaccination.

This suggests a four-fold decrease in the risk of asymptomatic COVID-19 infection amongst healthcare workers who have been vaccinated for more than 12 days (75 percent protection). The level of asymptomatic infection was also halved in those vaccinated for less than 12 days.

Dr Mike Weekes, an infectious disease specialist at CUH and the University of Cambridge’s Department of Medicine, who led the study, said:  “This is great news – the Pfizer vaccine not only provides protection against becoming ill from SARS-CoV-2 but also helps prevent infection, reducing the potential for the virus to be passed on to others.

“This will be welcome news as we begin to plot a roadmap out of the lockdown, but we have to remember that the vaccine doesn’t give complete protection for everyone. We still need social distancing, masks, hand hygiene and regular testing until the pandemic is under much better control.” 

Dr Nick Jones, first author on the study and an infectious diseases/microbiology registrar at CUH, said: “Our findings show a dramatic reduction in the rate of positive screening tests among asymptomatic healthcare workers after a single dose of the Pfizer-BioNTech vaccine. This is fantastic news for both hospital staff and patients, who can be reassured that the current mass vaccination strategy is protecting against asymptomatic carriage of the virus in addition to symptomatic disease, thereby making hospitals even safer places to be.”

Giles Wright, programme director for the CUH Vaccination Hub said:  “Throughout the pandemic so far, we have taken a systematic approach to keeping our staff safe and well. The huge efforts of all those involved in the testing, tracing and vaccination programmes at CUH are making the plan a reality. We are very encouraged by the findings of our research. It gives further hope for the near future.”

When the team included symptomatic healthcare workers, their analyses showed similar reductions. 56 out of 3,282 (1·71%) unvaccinated healthcare workers tested positive. This compared to 8 out of 1,997 (0·40%) healthcare workers at 12 or more days post-vaccination, a 4·3-fold reduction.

The researchers have released their data ahead of peer review because of the urgent need to share information relating to the pandemic.

This work was supported by Wellcome, the Medical Research Council, NHS Blood & Transplant, Addenbrooke’s Charitable Trust and the NIHR Cambridge Biomedical Research Centre.

Paper reference:
Jones, NK et al. 
Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection. 24 Feb 2020; DOI: 10.22541/au.161420511.12987747/v1

Can a tapeworm drug boost protection from Covid-19 for high-risk kidney patients?

UK researchers are launching a clinical trial to investigate if the drug niclosamide, usually used to treat tapeworms, can prevent Covid-19 infection in vulnerable, high-risk kidney patients and reduce the number of people who become seriously ill or die from it.

If the charity and industry-funded trial is successful, it may pave the way for a new treatment to prevent or alleviate the impact of Covid-19 in people on dialysis, people who have had a kidney transplant, and people with auto-immune diseases affecting the kidneys such as vasculitis who require treatment to suppress their immune system. The treatment will last up to nine months.

Led by scientists from the Cambridge University Hospitals NHS Trust, University of Cambridge, and supported by the NIHR Cambridge Biomedical Research Centre, will see a randomised trial for patients to receive either a placebo (or dummy) drug, or UNI911 (niclosamide) as a nasal spray, both provided by the manufacturer UNION therapeutics, in addition to all their usual treatments. The trial plans to expand to other UK healthcare centres and aims to recruit at least 1,500 kidney patients.

Usually used to treat intestinal worms and taken as a tablet, niclosamide has shown real promise in the lab. Early tests revealed niclosamide could stop SARS-CoV-2 multiplying and entering cells of the upper airways.

Niclosamide has been re-formulated into a nasal spray so it can be delivered directly to the lining of the nasal cavity, like a hayfever spray. In the trial, people will take one puff up each nostril twice a day, as this is the part of the body where the virus can take hold. This ‘local’ drug delivery is likely to reduce the chances of people experiencing any side effects.

The news comes as the coronavirus vaccine is being rolled out across the country but amid concerns over virus mutations and limited data regarding the effectiveness and durability of vaccine response in kidney patients. Participants can receive the vaccine and still take part in this trial, which will identify whether niclosamide can protect people from the virus either on its own, or in combination with any of the vaccines currently available.

Dr Rona Smith, senior research associate at the University of Cambridge and honorary consultant nephrologist at Addenbrooke’s Hospital, who is leading the UK study, said: “It is vital that we find a way to protect patients on haemodialysis and other high-risk kidney patients from catching SARS-CoV-2 and developing Covid-19. If they get it, they are more likely to fall seriously ill or die, and we need to find a way to change that.”

She continues: “A number of existing trials are searching for an effective Covid-19 preventative treatment, but patients with impaired kidney function are largely excluded, despite being so vulnerable to the disease. Patients should have the vaccine wherever possible, which will give them a level of protection against the virus.”

She explains: “But we believe testing niclosamide is particularly important for people who are immunosuppressed and have kidney disease, because their immune responses to vaccines can sometimes be less effective. While the vaccine will offer a level of protection, niclosamide may provide further protection against Covid-19 that doesn’t rely on the immune system mounting a response.”

She adds: “If successful, our innovative trial could mean that the treatment becomes available to kidney patients more widely within months. It would mean they could receive their regular life-saving dialysis or take their immunosuppressant drugs without additional worry. And if it’s successful it could even be rolled out more widely – and benefit more vulnerable people.”

Professor Jeremy Hughes, kidney doctor and chair of trustees at Kidney Research UK, one of the charities funding the trial, said: “We must do everything we can to protect kidney patients, who are at serious risk from Covid-19. Sadly, one in five kidney patients receiving dialysis in hospital or who have a kidney transplant and tested positive for the virus died within four weeks. Many of those on dialysis are having to put themselves at risk and attend their renal unit for life-saving dialysis treatment several times each week. And those who have had a kidney transplant must continue taking their immunosuppressant drugs, despite these making them more susceptible to infection. In the UK alone, round 64,000 people receive dialysis treatment or have had a kidney transplant – that’s enough people to fill the O2 stadium three times over.”

He continues: “The vaccine roll-out can’t come fast enough – kidney patients should have the vaccine, as soon as they are offered it. We hope this trial will add an extra layer of protection for kidney patients in the future. It could even reveal a way to prevent Covid-19 in other vulnerable people.”

He explains: “This trial shows why funding research into kidney disease is so important right now. Committing funds to this trial was a challenge for Kidney Research UK. Like so many other charities, our income this year has been badly impacted, and has dropped by 50% but the PROTECT trial, and the patients it aims to help, could not wait. We are delighted to be partnering with others to make this crucial research a reality. Kidney patients need our work to continue, now more than ever.”

The trial, led by the Cambridge University Hospitals NHS Trust and the University of Cambridge, involves researchers and patients from across the UK. It is funded by LifeArc, Kidney Research UK, the Addenbrooke’s Charitable Trust and UNION therapeutics and is supported by the NIHR Cambridge Biomedical Research Centre. UNION therapeutics is supplying the drug.

LifeArc has made £10 million available to develop new therapeutics to support the global effort against Covid-19. “Repurposing already available drugs or those in the late stage of development offers the fastest route to bring benefit to patients at this critical time,” said LifeArc CEO, Melanie Lee.

Could repairing damaged donor livers be the key to increasing life-saving transplants?

Researchers in Cambridge have found a way to grow ‘mini bile ducts’ in a lab-setting to repair damaged livers. This new technique could potentially help treat patients whose own livers are not functioning correctly.     

Bile ducts act as the liver’s waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 per cent of children’s liver transplantations with no alternative treatments.

Even after a liver transplant, bile duct disease can still occur. The disease can return in up to a third of patients after transplantation. Duct damage associated with transplantation is the second most common cause of a graft loss after rejection.

Currently there is shortage of liver donors. According to the NHS, the average waiting time for a liver transplant for adults in the UK is 135 days and children 73 days. However, when a liver is found it may be unsuitable for transplant. Many end up not being used due to a number of reasons such as the organ sustaining damage whilst being held in cold storage outside the body. This means only a limited number of patients can benefit from a transplant.

With the shortage of livers and bile duct diseases, researchers needed to find an alternative treatment to see if the liver could instead be repaired and found that cell-based therapies may be the key.

Supported by the NIHR Cambridge BRC, Cambridge researchers developed a way to restore damaged bile ducts in donated livers in the laboratory.

Using a recently developed ‘perfusion system’, researchers have been able to show for the first time that is it possible to transplant biliary cells grown in the lab known as cholangiocytes organoids – in the bile duct that act as a barrier between the bile and other tissues – into damaged human livers to repair them.  

The research team used a technique known as single-cell RNA sequencing to learn more about the individual cells lining the biliary tree. They found that although duct cells differ, biliary cells from the gallbladder, which are usually spared by bile duct diseases, could be converted into the cells of the bile ducts and replace and repair the damaged ones.

They grew cholangiocytes from the gallbladder using a technology known as ‘organoids’ – small groups of cells that mimic the organ’s function – in the lab. And using the perfusion system, the researchers injected these organoids into a damaged donor liver.

The team were able to demonstrate that the transplanted organoids engrafted and repaired the bile ducts, allowing the liver to function correctly. This new technique has shown that a cell-based therapy could help restore damaged donor livers and may have the potential to fix a patient’s own liver. 

This is the first time that a procedure of this kind has been used on human donor organs. It could also increase the number of livers that are considered suitable for organ transplantation and ultimately save more lives.

Paper reference
Sampaziotis, F et al. Cholangiocyte organoids can repair bile ducts after transplantation in human liver.
Science; 18 Feb 2021

Pfizer BioNTech vaccine likely to be effective against B1.1.7 strain of SARS-CoV-2

The Pfizer BioNTech vaccine BNT162b2 is likely to be effective against the B1.1.7 variant of SARS-CoV-2, even though its efficacy is modestly affected, say scientists at the University of Cambridge. However, when the E484K mutation – first seen in the South African variant – is added, it substantially increases the amount of antibody required to prevent infection.

The preliminary data, which have yet to be to peer-reviewed and relate to only a small number of patients, also suggest that a significant proportion of over-eighty olds may not be sufficiently protected against infection until they have received their second dose of the vaccine.

As the SARS-CoV-2 virus replicates and spreads, errors in its genetic code can lead to changes in the virus. Towards the end of 2020, the Cambridge-led COVID-19 Genomics UK (COG-UK) Consortium identified a variant of the virus (now known as B1.1.7) which includes important changes that change the structure of the Spike protein, including the ΔH69/ΔV70 and Δ144/145 amino acid deletions and N501Y, A570D and P681H mutations. Researchers at Cambridge/COG-UK now report seeing a number of virus sequences that also include the E484K mutation, first seen in the South African variant.

The emergence of the B1.1.7 strain has led to strict lockdown measures in the UK because of concerns over its transmissibility. There is particular concern that these changes might enable the virus to ‘escape’ the newly-developed vaccines, which typically target the Spike protein.

The UK has begun rolling out two vaccines – the Pfizer BioNTech vaccine and the Oxford AstraZeneca vaccine. The efficacy of the vaccines can be boosted by a second dose; however, in order to reach as large a number of people as possible in a short amount of time, the government has concentrated on delivering a first dose to as many individuals as possible by giving the second dose at 12 weeks, rather than three.

Researchers at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, working in collaboration with the NIHR Covid-19 BioResource, used blood samples from 26 individuals who had received their first dose of the Pfizer vaccine three weeks previously, to extract serum, which contains antibodies raised in response to the vaccine. The age range of the volunteers was 29 to 89 years.

Working under secure conditions, the team created a synthetic version of the SARS-CoV-2 virus, known as a pseudovirus. When they tested the individuals’ sera against this pseudovirus, they found that all but seven of the individuals had levels of antibodies sufficiently high to neutralise the virus – that is, to protect against infection.

When the team added all eight Spike protein mutations found in B1.1.7 to the pseudovirus, they found that the efficacy of the vaccine was affected by the B1.1.7 mutations, which required higher concentrations of antibody in the sera to neutralise the virus. Although there was a wide range of variation between individuals, on average B1.1.7 required around a two-fold increase in the concentration of serum antibody.

However, when the E484K mutation was added, substantially higher levels of antibody were required – on average this mutation required an almost ten-fold increase in the concentration of serum antibody for neutralisation when compared to the strain circulating prior to B.1.1.7.

Professor Ravi Gupta from CITIID, who led the study, said: “Our findings suggest that the Pfizer BioNTech vaccine is likely to offer similar protection against B1.1.7 as it does against the previous strain of SARS-CoV-2. Although we found a reduction in the ability of antibodies to neutralise the virus, given the number of antibodies produced following vaccination, this should still only have a relatively modest effect and people should still be protected.

“Of particular concern, though, is the emergence of the E484K mutation, which so far has only been seen in a relatively small number of individuals. Our work suggests the vaccine is likely to be less effective when dealing with this mutation.

“B1.1.7 will continue to acquire mutations seen in the other variants of concern, so we need to plan for the next generation of vaccines to have modifications to account for new variants. We also need to scale up vaccines as fast and as broadly as possible to get transmission down globally.”

The seven individuals who were unable to neutralise the virus after the first dose were all aged over 80 years old. This accounts for almost half of the 15 individuals in this age group. However, at a follow-up visit after these individuals had received their second dose (given at three weeks), they were all able to neutralise the virus.

Dr Dami Collier, the main co-investigator on the studies, added: “Our data suggest that a significant proportion of people aged over eighty may not have developed protective neutralising antibodies against infection three weeks after their first dose of the vaccine. But it’s reassuring to see that after two doses, serum from every individual was able to neutralise the virus.”

The researchers have released their data ahead of peer review because of the urgent need to share information relating to the pandemic, and particularly the new UK variant.

The research was supported by Wellcome, the Medical Research Council, the Bill and Melinda Gates Foundation and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Paper reference

SARS-CoV-2 B.1.1.7 escape from mRNA vaccine-elicited neutralizing antibodies

Age-related heterogeneity in immune responses to SARS-CoV-2 following BNT162b2 vaccination

DNA test can quickly identify pneumonia in patients with severe COVID-19, aiding faster treatment

Researchers have developed a DNA test to quickly identify secondary infections in COVID-19 patients, who have double the risk of developing pneumonia while on ventilation than non-COVID-19 patients.

For patients with the most severe forms of COVID-19, mechanical ventilation is often the only way to keep them alive, as doctors use anti-inflammatory therapies to treat their inflamed lungs. However, these patients are susceptible to further infections from bacteria and fungi that they may acquire while in hospital – so called ‘ventilator-associated pneumonia’.

Now, a team of scientists and doctors at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, led by Professor Gordon Dougan, Dr Vilas Navapurkar and Dr Andrew Conway Morris, have developed a simple DNA test to quickly identify these infections and target antibiotic treatment as needed.

The test, developed at Addenbrooke’s hospital in collaboration with Public Health England, gives doctors the information they need to start treatment within hours rather than days, fine-tuning treatment as required and reducing the inappropriate use of antibiotics. This approach, based on higher throughput DNA testing, is being rolled out at Cambridge University Hospitals and offers a route towards better treatments for infection more generally. The results are reported in the journal Critical Care.

Patients who need mechanical ventilation are at significant risk of developing secondary pneumonia while they are in intensive care. These infections are often caused by antibiotic-resistant bacteria, and are hard to diagnose and need targeted treatment.

“Early on in the pandemic we noticed that COVID-19 patients appeared to be particularly at risk of developing secondary pneumonia, and started using a rapid diagnostic test that we had developed for just such a situation,” said co-author Dr Andrew Conway Morris from Cambridge’s Department of Medicine and an intensive care consultant. “Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit.”

COVID-19 patients are thought to be at increased risk of infection for several reasons. Due to the amount of lung damage, these severe COVID-19 cases tend to spend more time on a ventilator than patients without COVID-19. In addition, many of these patients also have a poorly-regulated immune system, where the immune cells damage the organs, but also have impaired anti-microbial functions, increasing the risk of infection.

Normally, confirming a pneumonia diagnosis is challenging, as bacterial samples from patients need to be cultured and grown in a lab, which is time-consuming. The Cambridge test takes an alternative approach by detecting the DNA of different pathogens, which allows for faster and more accurate testing.

The test uses multiple polymerase chain reaction (PCR) which detects the DNA of the bacteria and can be done in around four hours, meaning there is no need to wait for the bacteria to grow. “Often, patients have already started to receive antobiotics before the bacteria have had time to grow in the lab,” said Morris. “This means that results from cultures are often negative, whereas PCR doesn’t need viable bacteria to detect – making this a more accurate test.”

The test – which was developed with Dr Martin Curran, a specialist in PCR diagnostics from Public Health England’s Cambridge laboratory – runs multiple PCR reactions in parallel, and can simultaneously pick up 52 different pathogens, which often infect the lungs of patients in intensive care. At the same time, it can also test for antibiotic resistance.

“We found that although patients with COVID-19 were more likely to develop secondary pneumonia, the bacteria that caused these infections were similar to those in ICU patients without COVID-19,” said lead author Mailis Maes, also from the Department of Medicine. “This means that standard antibiotic protocols can be applied to COVID-19 patients.”

This is one of the first times that this technology has been used in routine clinical practice and has now been approved by the hospital. The researchers anticipate that similar approaches would benefit patients if used more broadly.

This study was funded by the National Institute for Health Research Cambridge Biomedical Research Centre.

Paper reference

Mailis Maes et al. Ventilator-associated pneumonia in critically ill patients with COVID-19.
Critical Care (2021). DOI: 10.1186/s13054-021-03460-5

Mindfulness can improve mental health and wellbeing – but unlikely to work for everyone

Mindfulness courses can reduce anxiety, depression and stress and increase mental wellbeing within most but not all non-clinical settings, say a team of researchers at the University of Cambridge. They also found that mindfulness may be no better than other practices aimed at improving mental health and wellbeing.

Mindfulness is typically defined as ‘the awareness that emerges through paying attention on purpose, in the present moment, and nonjudgmentally to the unfolding of experience moment by moment’. It has become increasingly popular in recent years as a way of increasing wellbeing and reducing stress levels.

In the UK, the National Health Service offers therapies based on mindfulness to help treat mental health issues such as depression and suicidal thoughts. However, the majority of people who practice mindfulness learn their skills in community settings such as universities, workplaces, or private courses. Mindfulness-based programmes are frequently promoted as the go-to universal tool to reduce stress and increase wellbeing, accessible to anyone, anywhere.

Many randomised controlled trials (RCTs) have been conducted around the world to assess whether in-person mindfulness training can improve mental health and wellbeing, but the results are often varied. In a report published today in PLOS Medicine, a team of researchers from the Department of Psychiatry at the University of Cambridge led a systematic review and meta-analysis to examine the published data from the RCTs. This approach allows them to bring together existing – and often contradictory or under-powered – studies to provide more robust conclusions.

The team identified 136 RCTs on mindfulness training for mental health promotion in community settings. These trials included 11,605 participants aged 18 to 73 years from 29 countries, more than three-quarters (77%) of whom were women.

The researchers found that in most community settings, compared with doing nothing, mindfulness reduces anxiety, depression and stress, and increases wellbeing. However, the data suggested that in more than one in 20 trials settings, mindfulness-based programmes may not improve anxiety and depression.

Dr Julieta Galante from the Department of Psychiatry at the University of Cambridge, the report’s first author, said: “For the average person and setting, practising mindfulness appears to be better than doing nothing for improving our mental health, particularly when it comes to depression, anxiety and psychological distress – but we shouldn’t assume that it works for everyone, everywhere.

“Mindfulness training in the community needs to be implemented with care. Community mindfulness courses should be just one option among others, and the range of effects should be researched as courses are implemented in new settings. The courses that work best may be those aimed at people who are most stressed or in stressful situations, for example health workers, as they appear to see the biggest benefit.”

The researchers caution that RCTs in this field tended to be of poor quality, so the combined results may not represent the true effects. For example, many participants stopped attending mindfulness courses and were not asked why, so they are not represented in the results. When the researchers repeated the analyses including only the higher quality studies, mindfulness only showed effects on stress, not on wellbeing, depression or anxiety.

When compared against other ‘feel good’ practices such as exercise, mindfulness fared neither better nor worse. Professor Peter Jones, also from Cambridge’s Department of Psychiatry, and senior author, said: “While mindfulness is often better than taking no action, we found that there may be other effective ways of improving our mental health and wellbeing, such as exercise. In many cases, these may prove to be more suitable alternatives if they are more effective, culturally more acceptable or are more feasible or cost effective to implement. The good news is that there are now more options.”

The researchers say that the variability in the success of different mindfulness-based programmes identified among the RCTs may be down to a number of reasons, including how, where and by whom they are implemented as well as at whom they are targeted. The techniques and frameworks taught in mindfulness have rich and diverse backgrounds, from early Buddhist psychology and meditation through to cognitive neuroscience and participatory medicine – the interplay between all of these different factors can be expected to influence how effective a programme is.

The number of online mindfulness courses has increased rapidly, accelerated further by the COVID-19 pandemic. Although this review has not looked at online courses, studies suggest that these may be as effective as their offline counterparts, despite most lacking interactions with teacher and peers.

Dr Galante added: “If the effects of online mindfulness courses vary as widely according to the setting as their offline counterparts, then the lack of human support they offer could cause potential problems. We need more research before we can be confident about their effectiveness and safety.”

The research was funded by the National Institute for Health Research (NIHR) Applied Research Collaboration East of England and NIHR Cambridge Biomedical Research Centre, with additional support from the Cambridgeshire & Peterborough NHS Foundation Trust, Medical Research Council, Wellcome and the Spanish Ministry of Education, Culture and Sport.

Paper reference

Galante, J et al. Mindfulness-based programmes for mental health promotion in adults in non-clinical settings: A systematic review and meta-analysis of randomised controlled trials. 
PLOS Medicine; 11 Jan 2021; DOI: 10.1371/journal.pmed.1003481

Dexamethasone should be avoided in patients with chronic subdural haematoma

A commonly-used treatment for chronic subdural haematoma – the build-up of ‘old’ blood in the space between the brain and the skull, usually as a result of minor head injury – could lead to a worse outcome than receiving no medication, suggests new research from the University of Cambridge.

Chronic subdural haematoma is one of the most common neurological disorders and mainly affects older people. People affected often have headaches, deteriorating memory, confusion, balance problems or limb weakness. Surgery to drain the liquid collection is effective with the majority of patients improving.

A commonly used steroid, dexamethasone, has been used alongside surgery or instead of it since the 1970s. However, consensus has been lacking regarding the use of dexamethasone, especially since no high-quality studies confirming its effectiveness had been conducted until now.

With funding from the UK National Institute Health Research, a group of doctors and researchers from 23 neurosurgical units in the United Kingdom enrolled 748 patients with chronic subdural haematoma in the “Dexamethasone in Chronic Subdural Haematoma (Dex-CSDH)” randomised trial. A total of 375 patients were randomised to receive a two-week tapering course of dexamethasone and were compared with 373 patients randomised to an identical matching placebo.

The results of the study, published today (16 December) in the New England Journal of Medicine, show that patients who received dexamethasone had a lower chance of favourable recovery at six months compared to patients who received placebo. More specifically, the vast majority of patients in both groups had an operation to drain the haematoma and had experienced significant functional improvement at six months compared to their initial admission to hospital.

Fewer patients in the dexamethasone group required repeat surgery for a recurrent haematoma compared to patients in the placebo group. However, 84% of patients who received dexamethasone had recovered well at 6 months compared to 90% of patients who received placebo.

Peter Hutchinson, Professor of Neurosurgery at the University of Cambridge and the trial’s Chief Investigator, said: “Chronic subdural haematoma has been steadily increasing in frequency over the past decades. Patients affected are often frail and have other co-existing medical conditions. Since the 1970s, dexamethasone has been used as a drug alongside or instead of surgery with a few studies reporting good results.

“Our trial sought to determine if dexamethasone should be offered routinely to all patients with chronic subdural haematoma or if its use should be abandoned. Based on our findings, we believe that dexamethasone should not be used in patients with chronic subdural haematoma anymore.”

Angelos Kolias, Lecturer of Neurosurgery at the University of Cambridge and the trial’s Co-chief Investigator, added: “The results of the study were surprising given that dexamethasone seemed to help reduce the number of repeat surgeries. However, this simply reinforces the importance of conducting high-quality trials with patient-reported outcomes as the main outcomes of interest”.

Ellie Edlmann, the trial’s research fellow, currently a Clinical Lecturer at the University of Plymouth, concluded: “Credit is due to all doctors and researchers from across the NHS who worked tirelessly in order to enrol all eligible patients in the trial; in particular, the role of trainee neurosurgeons, members of the British Neurosurgical Trainee Research Collaborative, needs to be highlighted. We sincerely thank all patients and their carers, as without their altruistic participation, this trial would not have been possible.”

The trial was funded by the National Institute for Health Research (NIHR), with further support from the NIHR Cambridge Biomedical Research Centre, the NIHR Brain Injury MedTech Co-operative, the Royal College of Surgeons of England, and the Rosetrees Trust.

Paper reference

Hutchinson, PJ et al. Trial of Dexamethasone for Chronic Subdural Hematoma. 
NEJM; 16 Dec 2020; DOI: 10.1056/NEJMoa2020473

Symptoms of depression linked to increased risk of heart disease and stroke

People who experience symptoms of depression are more likely to go on to develop heart disease or suffer a stroke than those who report good mental health, according to research part-funded by the British Heart Foundation and published today (15 December) in JAMA.

Researchers at the University of Cambridge analysed the health records of over half a million people, with no prior history of heart and circulatory disease, who were enrolled to two different studies: UK Biobank (2006-2010) and the Emerging Risk Factor Collaboration (ERFC; 1960-2008).

Upon joining the studies, participants were given a score based on questionnaires assessing their mood and any symptoms of depression that they had experienced over the previous one to two weeks. These scores were divided into five groups based on increasing severity of symptoms.

Now, over 10 years later, researchers have found that those in the highest scoring group, and with most severe symptoms of depression, were more likely to have since developed heart disease or to have had a stroke, compared to people with the lowest scores.

In the UK Biobank cohort of 401,219 participants, there were 21 cases of heart disease per 1000 people across 10 years in those with the highest scoring group vs 14 cases of heart disease per 1000 people in the lowest scoring group. There were 15 strokes per 1000 people over 10 years in those in the highest scoring group and 10 strokes per 1000 people in those with the lowest scores.

This means an extra seven cases of heart disease and five strokes per 10,000 people would be expected in one year for those with higher symptoms of depression. Similar results were found in the ERFC cohort of 162,036 people from 21 different studies across Europe and North America ^[1].

The higher risk for heart disease and stroke existed even after risk factors for heart and circulatory diseases, such as age, sex, smoking status, history of diabetes, blood pressure, body mass index, and cholesterol levels, were accounted for.

The researchers point out that symptoms of depression were only measured when each individual joined the study. This means the scores don’t necessarily reflect a person’s feelings across the entire time they were part of the study.

Professor Emanuele Di Angelantonio, BHF-funded researcher at the University of Cambridge, said: “This is the largest evidence to date that feelings related to depression are associated with a person’s chance of having heart disease or stroke in the future.

“The observed higher risk is small in magnitude and these results are just one piece of the puzzle. We now need to do more research to understand whether these observed associations are causal and the possible biology behind this link.”

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said: “Our mental and physical health go hand-in-hand. It’s clear from this research that our hearts and minds are more connected than we previously thought. By exploring this link further, we may find new ways of helping to improve our heart health.

“However, it is important to stress that the increased risk is modest and observed over a long period of time. It should not alarm those currently experiencing low mood or feelings of depression about their immediate heart health.”

This study was also supported by the National Institute for Health Research (NIHR) and Health Data Research UK (HDRUK).

Paper reference

Emanuele Di Angelantonio, MD, et al; Association Between Depressive Symptoms and Incident Cardiovascular Diseases
JAMA

Apathy could predict onset of dementia years before other symptoms

Apathy – a lack of interest or motivation – could predict the onset of some forms of dementia many years before symptoms start, offering a ‘window of opportunity’ to treat the disease at an early stage, according to new research from a team of scientists led by Professor James Rowe at the University of Cambridge.

Frontotemporal dementia is a significant cause of dementia among younger people. It is often diagnosed between the ages of 45 and 65. It changes behaviour, language and personality, leading to impulsivity, socially inappropriate behaviour, and repetitive or compulsive behaviours.

A common feature of frontotemporal dementia is apathy, with a loss of motivation, initiative and interest in things. It is not depression, or laziness, but it can be mistaken for them. Brain scanning studies have shown that in people with frontotemporal dementia it is caused by shrinkage in special parts at the front of the brain – and the more severe the shrinkage, the worse the apathy. But, apathy can begin decades before other symptoms, and be a sign of problems to come.

“Apathy is one of the most common symptoms in patients with frontotemporal dementia. It is linked to functional decline, decreased quality of life, loss of independence and poorer survival,” said Maura Malpetti, a cognitive scientist at the Department of Clinical Neurosciences, University of Cambridge.

“The more we discover about the earliest effects of frontotemporal dementia, when people still feel well in themselves, the better we can treat symptoms and delay or even prevent the dementia.”

Frontotemporal dementia can be genetic. About a third of patients have a family history of the condition. The new discovery about the importance of early apathy comes from the Genetic Frontotemporal dementia Initiative (GENFI), a collaboration between scientists across Europe and Canada. Over 1,000 people are taking part in GENFI, from families where there is a genetic cause of Frontotemporal dementia. 

Now, in a study published today (15 December) in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, Professor Rowe and colleagues have shown how apathy predicts cognitive decline even before the dementia symptoms emerge. 

The new study involved 304 healthy people who carry a faulty gene that causes frontotemporal dementia, and 296 of their relatives who have normal genes. The participants were followed over several years. None had dementia, and most people in the study did not know whether they carry a faulty gene or not. The researchers looked for changes in apathy, memory tests and MRI scans of the brain. 

“By studying people over time, rather than just taking a snapshot, we revealed how even subtle changes in apathy predicted a change in cognition, but not the other way around,” explained Malpetti, the study’s first author. “We also saw local brain shrinkage in areas that support motivation and initiative, many years before the expected onset of symptoms.”

People with the genetic mutations had more apathy than other members of their family, which over two years increased much more than in people with normal genetics.  The apathy predicted cognitive decline, and this accelerated as they approached the estimated age of onset of symptoms.

Professor Rogier Kievit from the Donders Institute, Radboud University Medical Center at Nijmegen and MRC Cognition and Brain Sciences Unit at Cambridge,  said: “Apathy progresses much faster for those individuals who we know are at greater risk of developing frontotemporal dementia, and this is linked to greater atrophy in the brain. At the start, even though the participants with a genetic mutation felt well and had no symptoms, they were showing greater levels of apathy. The amount of apathy predicted cognitive problems in the years ahead.”

“From other research, we know that in patients with frontotemporal dementia, apathy is a bad sign in terms of independent living and survival. Here we show its importance in the decades before symptoms begin,” said Professor James Rowe from the Department of Clinical Neurosciences, joint senior author. 

Professor Rowe said the study highlights the importance of investigating why someone has apathy. “There are many reasons why someone feels apathetic. It may well be an easy to treat medical condition, such as low levels of thyroid hormone, or a psychiatric illness such as depression. But doctors need to keep in mind the possibility of apathy heralding a dementia, and increasing the chance of dementia if left unaddressed, particularly if someone has a family history of dementia.

“Treating dementia is a challenge, but the sooner we can diagnose the disease, the greater our window of opportunity to try and intervene and slow or stop its progress.”

The research was largely funded by the Medical Research Council, Wellcome, and the National Institute for Health Research Cambridge Biomedical Research Centre.

Paper reference

Malpetti, M et al. Apathy in pre-symptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes. 
Alzheimer’s & Dementia; 14 Dec 2020; DOI: 10.1002/alz.12252