̽��ֱ�� of Cambridge - NIHR Bioresource

Over 20,000 people join search for new dementia treatments

cjb250 — Tue, 14 May 2024 09:00:00 +0000

Using the resource, scientists have already been able to show for the first time that two important bodily mechanisms – inflammation and metabolism – play a role in the decline in brain function as we age.

By 2050, approximately 139 million people are expected to be living with dementia worldwide. In the UK, in 2022, UK Prime Minister launched the Dame Barbara Windsor Dementia Mission, part of the government’s commitment to double increase research funding for dementia.

Although there has been recent progress developing drugs that slow down progression of the disease, the two leading treatments only have a small effect, and the vast majority of new approaches that work in animal studies fail when it comes to patient clinical trials.

One explanation for these failures is that the drugs are tested in people who already have memory loss – and by this point, it may be too late to stop or reverse the disease. Hence, there is an urgent need to understand what is going on before people develop symptoms at the very early stages of disease, and to test new treatments before people come to their doctor with cognitive problems. This approach requires a large cohort of participants willing to be recalled for clinical and experimental studies of cognitive decline.

Today, writing in the journal Nature Medicine, scientists led by the ̽��ֱ�� of Cambridge in partnership with the Alzheimer’s Society report how they have recruited 21,000 people aged 17-85 to the Genes and Cognition Cohort within the National Institute for Health and Care Research (NIHR) BioResource.

̽��ֱ��NIHR BioResource was established in 2007 to recruit volunteers keen to engage in experimental medicine and clinical trials across the whole of medicine. Approximately half of its participants are recruited to disease specific cohorts, but the other half are from the general public, and detailed information about their genetics and their physical makeup has been collected. They have all given their consent to be contacted about future research studies.

For the Genes and Cognition Cohort, researchers used a combination of cognitive tests and genetic data, combined with other health data and demographic information, to enable the first at-scale study of cognitive changes. This will allow the team to recruit participants for studies of cognitive decline and new treatments for this.

For example, a pharmaceutical company with a promising new drug candidate to slow the cognitive decline could recruit people through the BioResource based on their profile and invite them to join in the clinical trial. Having a baseline measurement for their cognitive performance will allow scientists to observe whether the drug slows their expected cognitive decline.

Professor Patrick Chinnery from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge and co-Chair of the NIHR BioResource, who has led the project, said: “We’ve created a resource that is unmatched anywhere else in the world, recruiting people who are not showing any signs of dementia rather than people already having symptoms. It will allow us to match individuals to particular studies and speed up the development of much-needed new drugs to treat dementia.

“We know that over time our cognitive function decreases, so we’ve plotted out the expected trajectory of various different cognitive functions over our volunteers’ life course according to their genetic risk. We’ve also asked the question, ‘What are the genetic mechanisms that predispose you to slow or fast cognitive decline as you age?’.”

Using the research, the team have identified two mechanisms that appear to affect cognition as we age and could serve as potential targets to slow down cognitive decline and thereby delay the onset of dementia. ̽��ֱ��first of these is inflammation, with immune cells specific to the brain and central nervous system – known as microglia – causing gradual deterioration of the brain and hence its ability to perform key cognitive functions. ̽��ֱ��second mechanism relates to metabolism – in particular, how carbohydrates are broken down in the brain to release energy.

Professor Chinnery added: “Cognitive decline is a natural process, but when it drops below a particular threshold, that’s when there’s a problem – that is when we would diagnose dementia. Anything that slows that decline will delay when we drop below that threshold. If you could put off the onset of dementia from 65 to 75 or even 85, it would make a huge difference at an individual and at a population level.”

Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said: “This exciting study, funded by Alzheimer’s Society, is an important step in helping us to better understand how the diseases that cause dementia begin, and will aid in the development of new treatments that target the early stages of these diseases.

“ ̽��ֱ��data, from over 20,000 volunteers, helps us to better understand the connection between participants’ genes and cognitive decline and allows for further ground-breaking analysis in future.

“One in three people born in the UK today will go on to develop dementia in their lifetime but research will beat dementia. We need to make it a reality sooner through more funding, partnership working and people taking part in dementia research.”

For further information about how you can join the BioResource and contribute to studies like this one and many others, please visit bioresource.nihr.ac.uk.

̽��ֱ��research was carried out in collaboration with the Medical Research Council Biostatistics Unit and was supported by the Alzheimer’s Society and the NIHR BioResource. ̽��ֱ��researchers were also supported by Wellcome and the Medical Research Council.

Reference
Rahman, MS et al. Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition Cohort participants. Nat Med; 14 May 2024; DOI: 10.1038/s41591-024-02960-5

More than 20,000 volunteers have been recruited to a resource aimed at speeding up the development of much-needed dementia drugs. ̽��ֱ��cohort will enable scientists in universities and industry to involve healthy individuals who may be at increased risk of dementia in clinical trials to test whether new drugs can slow the decline in various brain functions including memory and delay the onset of dementia.

We’ve created a resource that is unmatched anywhere else in the world, recruiting people who are not showing any signs of dementia rather than people already having symptoms

Patrick Chinnery

Halfpoint Images (Getty Images)

Smiling elderly woman speaking to a healthcare worker

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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CamFest Speaker Spotlight: Dr Anna Moore

zs332 — Tue, 26 Mar 2024 13:42:26 +0000

Assistant Professor of Child Psychiatry at the ̽��ֱ�� of Cambridge and programme lead, Dr Anna Moore, discusses the NIHR BioResource’s national childhood health research programme, D-CYPHR. ̽��ֱ��groundbreaking programme is a world first and aims to be the largest ever DNA research programme involving children aged 0-15.

Low iron levels resulting from infection could be key trigger of long COVID

cjb250 — Mon, 04 Mar 2024 10:00:41 +0000

̽��ֱ��discovery not only points to possible ways to prevent or treat the condition, but could help explain why symptoms similar to those of long COVID are also commonly seen in a number of post-viral conditions and chronic inflammation.

Although estimates are highly variable, as many as three in 10 people infected with SARS-CoV-2 could go on to develop long COVID, with symptoms including fatigue, shortness of breath, muscle aches and problems with memory and concentration (‘brain fog’). An estimated 1.9 million people in the UK alone were experiencing self-reported long COVID as of March 2023, according to the Office of National Statistics.

Shortly after the start of the COVID-19 pandemic, researchers at the ̽��ֱ�� of Cambridge began recruiting people who had tested positive for the virus to the COVID-19 cohort of the National Institute for Health and Care Research (NIHR) BioResource. These included asymptomatic healthcare staff identified via routine screening through to patients admitted to Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, some to its intensive care unit.

Over the course of a year, participants provided blood samples, allowing researchers to monitor changes in the blood post-infection. As it became clear that a significant number of patients would go on to have symptoms that persisted – long COVID – researchers were able to track back through these samples to see whether any changes in the blood correlated with their later condition.

In findings published in Nature Immunology, researchers at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), ̽��ֱ�� of Cambridge, together with colleagues at Oxford, analysed blood samples from 214 individuals. Approximately 45% of those questioned about their recovery reported symptoms of long COVID between three and ten months later.

Professor Ken Smith, who was Director of CITIID at the time of the study and will take up a position as Director of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, in April, said: “Having recruited a group of people with SARS-CoV-2 early in the pandemic, analysis of several blood samples and clinical information collected over a 12 month period after infection has proved invaluable in giving us important and unexpected insights into why, for some unlucky individuals, initial SARS-CoV-2 infection is followed by months of persistent symptoms.”

̽��ֱ��team discovered that ongoing inflammation – a natural part of the immune response to infection – and low iron levels in blood, contributing to anaemia and disrupting healthy red blood cell production, could be seen as early as two weeks post COVID-19 in those individuals reporting long COVID many months later.

Early iron dysregulation was detectable in the long COVID group independent of age, sex, or initial COVID-19 severity, suggesting a possible impact on recovery even in those who were at low risk for severe COVID-19, or who did not require hospitalisation or oxygen therapy when sick.

Dr Aimee Hanson, who worked on the study while at the ̽��ֱ�� of Cambridge, and is now at the ̽��ֱ�� of Bristol, said: “Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later.

“Although we saw evidence that the body was trying to rectify low iron availability and the resulting anaemia by producing more red blood cells, it was not doing a particularly good job of it in the face of ongoing inflammation.”

Interestingly, although iron dysregulation was more profound during and following severe COVID-19, those who went on to develop long COVID after a milder course of acute COVID-19 showed similar patterns in the blood. ̽��ֱ��most pronounced association with long COVID was how quickly inflammation, iron levels and regulation returned to normal following SARS-CoV-2 infection – though symptoms tended to continue long after iron levels had recovered.

Co-author Professor Hal Drakesmith, from the MRC Weatherall Institute of Molecular Medicine at the ̽��ֱ�� of Oxford, said iron dysregulation is a common consequence of inflammation and is a natural response to infection.

“When the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It’s an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert.

“However, if this goes on for a long time, there is less iron for red blood cells, so oxygen is transported less efficiently affecting metabolism and energy production, and for white blood cells, which need iron to work properly. ̽��ֱ��protective mechanism ends up becoming a problem.”

̽��ֱ��findings may help explain why symptoms such as fatigue and exercise intolerance are common in long COVID, as well as in several other post-viral syndromes with lasting symptoms.

̽��ֱ��researchers say the study points to potential ways of preventing or reducing the impact of long COVID by rectifying iron dysregulation in early COVID-19 to prevent adverse long-term health outcomes.

One approach might be controlling the extreme inflammation as early as possible, before it impacts on iron regulation. Another approach might involve iron supplementation; however as Dr Hanson pointed out, this may not be straightforward.

“It isn't necessarily the case that individuals don't have enough iron in their body, it's just that it’s trapped in the wrong place,” she said. “What we need is a way to remobilise the iron and pull it back into the bloodstream, where it becomes more useful to the red blood cells.”

̽��ֱ��research also supports ‘accidental’ findings from other studies, including the IRONMAN study, which was looking at whether iron supplements benefited patients with heart failure – the study was disrupted due to the COVID-19 pandemic, but preliminary findings suggest that trial participants were less likely to develop severe adverse effects from COVID-19. Similar effects have been observed among people living with the blood disorder beta-thalassemia, which can cause individuals to produce too much iron in their blood.

̽��ֱ��research was funded by Wellcome, the Medical Research Council, NIHR and European Union Horizon 2020 Programme.

Reference
Hanson, AL et al. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nat Imm; 1 March 2024; DOI: 10.1038/s41590-024-01754-8

Problems with iron levels in the blood and the body’s ability to regulate this important nutrient as a result of SARS-CoV-2 infection could be a key trigger for long COVID, new research has discovered.

Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later

Aimee Hanson

Malachi Cowie

A man sitting on a couch holding his head in his hands

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Largest ever DNA and health research programme for children and young people launches

Anonymous — Tue, 25 Jul 2023 00:00:22 +0000

̽��ֱ��National Institute for Health and Care Research (NIHR) BioResource’s D-CYPHR – the DNA, Children and Young People’s Health Resource – will play a key role in pioneering new treatments and creating better care for children and the adults they will become – everything from improving understanding of mental health to combatting heart disease. ̽��ֱ��programme is led by NIHR BioResource in partnership with the NHS, Anna Freud and the ̽��ֱ�� of Cambridge.

Many serious health conditions start in the first two decades of life, with over 1.7 million children in England alone suffering from long-term health conditions. However, most health research is carried out with adults, meaning we are not only missing important opportunities to understand how disease starts, develops and its causes, but are limited in developing new treatments.

Dr Anna Moore, ̽��ֱ�� of Cambridge, clinical lead for D-CYPHR, said: “Today we are at the beginning of the most tremendous opportunity which will transform our understanding of genetics for children's health: a moment where families can help much needed health research from home. This will boost all the amazing research happening across the UK.”

̽��ֱ��ground-breaking new programme is open to any child and young person aged 0 to 15 in the UK, to create the biggest health initiative of its kind in this country and a world first – a new national childhood DNA health resource for research from birth through adolescence.

Supporting the programme’s launch, Dr Xand van Tulleken, BBC presenter, urged parents and their children to get involved: “We urgently need research projects that support children’s health and we need children to volunteer to help! Children are amazing – I’m constantly astounded by their bravery in stepping up for causes they believe in. Today, we’re offering the chance to be a hero for healthcare – just by spitting in a tube.

“D-CYPHR will help future children, and it will help all of us in our adult lives. ̽��ֱ��ambition and scope of the D-CYPHR project is awe inspiring and it relies on these incredible volunteers to make amazing discoveries from which all of us, children and adults, will benefit.”

Research has shown the power that understanding genetics can have on outcomes for a range of conditions and illness, from improvements to how diabetes is treated in children, to the national roll-out of whole genome sequencing for babies and children in intensive care. Understanding genetics is vital in helping to understand and treat illness.

D-CYPHR aims to support this, while also mapping development in children and young people. ̽��ֱ��environment and experiences while growing up work together with genetics to affect development, and the likelihood of getting diseases. ̽��ֱ��more we can understand about this, the more treatments can be developed, and tailored to individuals. It even opens up the opportunity for earlier identification of problems, and in the future, we hope to be able to avoid some illnesses, like heart disease and type II diabetes.

Dr Anna Moore continued: “We’ve carefully designed and piloted the programme alongside children, schools and families over two years. This has been very important as this project will also be a way to address inequality in health research – health research needs to benefit everyone, and so we need children and young people from all backgrounds to get involved.

“Each sample joins a resource with thousands of others showing how environment and genetics affect health. ̽��ֱ��potential of D-CYPHR is therefore massive. We’re excited to unlock these secrets together with the young heroes that are agreeing to help us.”

Joining D-CYPHR is simple. Each young person, with parental consent, donates a saliva sample and answers a health and lifestyle questionnaire. ̽��ֱ��information and sample are depersonalised and joins the resource. By studying thousands of DNA samples together with health information, scientists can begin to see the big picture of how our genes and our environment influence our health.

In a world first, the new D-CYPHR programme will support research into any health conditions that begin in or have their origins in childhood – not just a specific condition or age group. This will include mental health conditions, diabetes, heart conditions, rare diseases, immune conditions and many more. It will also help us understand childhood development and what sets the foundations for a healthy life.

Professor Lucy Chappell, Chief Executive of the NIHR commented: "We’ve seen that genetics can help us unlock our understanding of diseases. Now we want to build on that knowledge by ensuring that our children and young people can access the power of genetics to transform diagnosis and treatment through this research. This exciting new project will help us develop an understanding of their genetics in a way that is more detailed and focused than ever before.”

Secretary of State for Health and Social Care, Steve Barclay said: “This pioneering genetic research programme is an exciting opportunity to advance our understanding of the causes of diseases and how they develop from childhood through to adulthood.

“By focusing on the DNA of children and young people we’ll be able to track how genetics affect a child’s development and build a picture of what might impact on their future health. As a result we’ll be able to develop more effective, bespoke treatments and even explore potential preventative measures for a wide range of conditions, including mental health issues and heart disease.”

Find out how you can take part on the D-CYPHR website

Adapted from an NIHR press release

Cambridge researchers are helping launch a nationwide study for children and young people to unlock the power of our DNA.

Today we are at the beginning of the most tremendous opportunity which will transform our understanding of genetics for children's health

Anna Moore

Anna Samoylova

Children playing tug of war

Suzie, mother of a D-CYPHR participant from Salisbury

“I saw my daughter, Sophie's, journey from a very unwell newborn to a vibrant and active seven-year-old, enjoying life to the fullest. She’s now thriving and loves reading, baking, riding, and drama, which brings immense joy to her and our family. But in her early days, she faced significant health challenges. ̽��ֱ��cause of these episodes was unknown, leaving us puzzled and seeking medical answers. Some of these questions remain unanswered, and as a doctor, I know this can happen.

“If by taking part in D-CYPHR, and expanding medical knowledge, then someone else in a similar position gets a better understanding of a cause and so the right treatment, then it’s completely worth it. D-CYPHR is an opportunity for us to support research that might give answers to other parents in our situation, as well as create better treatments for millions of people.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Obesity accelerates loss of COVID-19 vaccination immunity, study finds

ta385 — Thu, 11 May 2023 14:59:00 +0000

Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalisation and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. ̽��ֱ��reasons for this have, however, remained unclear.

This study, published in the journal Nature Medicine, shows that the ability of antibodies to neutralise the virus declines faster in vaccinated people who have obesity. ̽��ֱ��findings have important implications for vaccine prioritisation policies around the world.

During the pandemic, people with obesity were more likely to be hospitalised, require ventilators and to die from COVID-19. In this study, supported by the NIHR Bioresource and funded by UKRI, the researchers set out to investigate how far two of the most extensively used vaccines protect people with obesity compared to those with a normal weight, over time.

A team from the ̽��ֱ�� of Edinburgh, led by Prof Sir Aziz Sheikh, looked at real-time data tracking the health of 3.5 million people in the Scottish population as part of the EAVE II study. They looked at hospitalisation and mortality from COVID-19 in adults who received two doses of COVID-19 vaccine (either Pfizer-BioNTech BNT162b2 mRNA or AstraZeneca ChAdOx1).

They found that people with severe obesity (a BMI greater than 40 kg/m2) had a 76% higher risk of severe COVID-19 outcomes, compared to those with a normal BMI. A modest increase in risk was also seen in people with obesity (30-39.9kg/m2), which affects a quarter of the UK population, and those who were underweight. ‘Break-through infections’ after the second vaccine dose also led to hospitalisation and death sooner (from 10 weeks) among people with severe obesity, and among people with obesity (after 15 weeks), than among individuals with normal weight (after 20 weeks).

Prof Sir Aziz Sheikh said: “Our findings demonstrate that protection gained through COVID-19 vaccination drops off faster for people with severe obesity than those with a normal body mass index. Using large-scale data assets such as the EAVE II Platform in Scotland have enabled us to generate important and timely insights that enable improvements to the delivery of COVID-19 vaccine schedules in a post-pandemic UK.”

̽��ֱ�� ̽��ֱ�� of Cambridge team – jointly led by Dr James Thaventhiran, from the MRC Toxicology Unit and Prof Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science – studied people with severe obesity attending the Obesity clinic at Addenbrooke’s Hospital in Cambridge, and compared the number and function of immune cells in their blood to those of people of normal weight.

They studied people six months after their second vaccine dose and then looked at the response to a third 'booster' vaccine dose over time. ̽��ֱ��Cambridge researchers found that six months after a second vaccine dose, people with severe obesity had similar levels of antibodies to the COVID-19 virus as those with a normal weight.

But the ability of those antibodies to work efficiently to fight against the virus (known as ‘neutralisation capacity’) was reduced in people with obesity. 55% of individuals with severe obesity were found to have unquantifiable or undetectable ‘neutralising capacity’ compared to 12% of people with normal BMI.

“This study further emphasises that obesity alters the vaccine response and also impacts on the risk of infection,” said Dr Agatha van der Klaauw from the Wellcome-MRC Institute of Metabolic Science and first author of the paper. “We urgently need to understand how to restore immune function and minimise these health risks.”

̽��ֱ��researchers found that antibodies produced by people with severe obesity were less effective at neutralising the SARS-CoV-2 virus, potentially because the antibodies were not able to bind to the virus with the same strength.

When given a third (booster) dose of a COVID-19 vaccine, the ability of the antibodies to neutralise the virus was restored in both the normal weight and severely obese groups. But the researchers found that immunity again declined more rapidly in people with severe obesity, putting them at greater risk of infection with time.

Dr James Thaventhiran, a Group Leader from the MRC Toxicology Unit in Cambridge and co-lead author of the SCORPIO study said: “It is promising to see that booster vaccines restore the effectiveness of antibodies for people with severe obesity, but it is concerning that their levels decrease more quickly, after just 15 weeks. This shows that the vaccines work as well in people with obesity, but the protection doesn’t last as long.”

Prof Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science and co-lead author of the SCORPIO study said: “More frequent booster doses are likely to be needed to maintain protection against COVID-19 in people with obesity. Because of the high prevalence of obesity across the globe, this poses a major challenge for health services”.

Reference

A A van der Klaauw et al., ‘Accelerated waning of the humoral response to COVID-19 vaccines in obesity’, Nature Medicine (2023). DOI: 10.1038/s41591-023-02343-2

̽��ֱ��protection offered by COVID-19 vaccination declines more rapidly in people with severe obesity than in those with normal weight, scientists at the Universities of Cambridge and Edinburgh have found. ̽��ֱ��study suggests that people with obesity are likely to need more frequent booster doses to maintain their immunity.

This poses a major challenge for health services

Sadaf Farooqi

Steven Cornfield

Patient receiving a COVID-19 vaccination in their arm

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Cognitive impairment from severe COVID-19 equivalent to 20 years of ageing, study finds

cjb250 — Tue, 03 May 2022 07:00:18 +0000

̽��ֱ��findings, published in the journal eClinicalMedicine, emerge from the NIHR COVID-19 BioResource. ̽��ֱ��results of the study suggest the effects are still detectable more than six months after the acute illness, and that any recovery is at best gradual.

There is growing evidence that COVID-19 can cause lasting cognitive and mental health problems, with recovered patients reporting symptoms including fatigue, ‘brain fog’, problems recalling words, sleep disturbances, anxiety and even post-traumatic stress disorder (PTSD) months after infection. In the UK, a study found that around one in seven individuals surveyed reported having symptoms that included cognitive difficulties 12 weeks after a positive COVID-19 test.

While even mild cases can lead to persistent cognitive symptoms, between a third and three-quarters of hospitalised patients report still suffering cognitive symptoms three to six months later.

To explore this link in greater detail, researchers analysed data from 46 individuals who received in-hospital care, on the ward or intensive care unit, for COVID-19 at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust. 16 patients were put on mechanical ventilation during their stay in hospital. All the patients were admitted between March and July 2020 and were recruited to the NIHR COVID-19 BioResource.

̽��ֱ��individuals underwent detailed computerised cognitive tests an average of six months after their acute illness using the Cognitron platform, which measures different aspects of mental faculties such as memory, attention and reasoning. Scales measuring anxiety, depression and post-traumatic stress disorder were also assessed. Their data were compared against matched controls.

This is the first time that such rigorous assessment and comparison has been carried out in relation to the after effects of severe COVID-19.

COVID-19 survivors were less accurate and with slower response times than the matched control population – and these deficits were still detectable when the patients were following up six months later. ̽��ֱ��effects were strongest for those who required mechanical ventilation. By comparing the patients to 66,008 members of the general public, the researchers estimate that the magnitude of cognitive loss is similar on average to that sustained with 20 years ageing, between 50 and 70 years of age, and that this is equivalent to losing 10 IQ points.

Survivors scored particularly poorly on tasks such as verbal analogical reasoning, a finding that supports the commonly-reported problem of difficulty finding words. They also showed slower processing speeds, which aligns with previous observations post COVID-19 of decreased brain glucose consumption within the frontoparietal network of the brain, responsible for attention, complex problem-solving and working memory, among other functions.

Professor David Menon from the Division of Anaesthesia at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine ageing, but the patterns we saw – the cognitive 'fingerprint' of COVID-19 – was distinct from all of these.”

While it is now well established that people who have recovered from severe COVID-19 illness can have a broad spectrum of symptoms of poor mental health – depression, anxiety, post-traumatic stress, low motivation, fatigue, low mood, and disturbed sleep – the team found that acute illness severity was better at predicting the cognitive deficits.

̽��ֱ��patients’ scores and reaction times began to improve over time, but the researchers say that any recovery in cognitive faculties was at best gradual and likely to be influenced by a number of factors including illness severity and its neurological or psychological impacts.

Professor Menon added: “We followed some patients up as late as ten months after their acute infection, so were able to see a very slow improvement. While this was not statistically significant, it is at least heading in the right direction, but it is very possible that some of these individuals will never fully recover.”

There are several factors that could cause the cognitive deficits, say the researchers. Direct viral infection is possible, but unlikely to be a major cause; instead, it is more likely that a combination of factors contribute, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds. However, emerging evidence suggests that the most important mechanism may be damage caused by the body’s own inflammatory response and immune system.

While this study looked at hospitalised cases, the team say that even those patients not sick enough to be admitted may also have tell-tale signs of mild impairment.

Professor Adam Hampshire from the Department of Brain Sciences at Imperial College London, the study’s first author, said: “Around 40,000 people have been through intensive care with COVID-19 in England alone and many more will have been very sick, but not admitted to hospital. This means there is a large number of people out there still experiencing problems with cognition many months later. We urgently need to look at what can be done to help these people.”

Professor Menon and Professor Ed Bullmore from Cambridge’s Department of Psychiatry are co-leading working groups as part of the COVID-19 Clinical Neuroscience Study (COVID-CNS) that aim to identify biomarkers that relate to neurological impairments as a result of COVID-19, and the neuroimaging changes that are associated with these.

̽��ֱ��research was funded by the NIHR BioResource, NIHR Cambridge Biomedical Research Centre and the Addenbrooke’s Charitable Trust, with support from the NIHR Cambridge Clinical Research Facility.

Reference
Hampshire, A et al. Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort. eClinicalMedicine; 28 Apr 2022; DOI: 10.1016/j.eclinm.2022.101417

Cognitive impairment as a result of severe COVID-19 is similar to that sustained between 50 and 70 years of age and is the equivalent to losing 10 IQ points, say a team of scientists from the ̽��ֱ�� of Cambridge and Imperial College London.

Cognitive impairment is common to a wide range of neurological disorders, but the patterns we saw – the cognitive 'fingerprint' of COVID-19 – was distinct from all of these

David Menon

RUBEN BONILLA GONZALO

Senior woman wearing face mask lying on hospital bed

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Likelihood of severe and ‘long’ COVID may be established very early on following infection

cjb250 — Mon, 18 Jan 2021 12:39:36 +0000

Among the key findings, which have not yet been peer-reviewed, are:

Individuals who have asymptomatic or mild disease show a robust immune response early on during infection.
Patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset.
Persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID’.

̽��ֱ��immune response associated with COVID-19 is complex. Most people who get infected by SARS-CoV-2 mount a successful antiviral response, resulting in few if any symptoms. In a minority of patients, however, there is evidence that the immune system over-reacts, leading to a flood of immune cells (a ‘cytokine storm’) and to chronic inflammation and damage to multiple organs, often resulting in death.

To better understand the relationship between the immune response and COVID-19 symptoms, scientists at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource. These individuals range from asymptomatic healthcare workers in whom the virus was detected on routine screening, through to patients requiring assisted ventilation. ̽��ֱ��team take blood samples from patients over several months, as well as continuing to measure their symptoms.

In research published today, the team analysed samples from 207 COVID-19 patients with a range of disease severities taken at regular interviews over three months following the onset of symptoms. They compared the samples against those taken from 45 healthy controls.

Because of the urgent need to share information relating to the pandemic, the researchers have published their report on MedRXiv. It has not yet been peer-reviewed.

Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “ ̽��ֱ��NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease? And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”

Listen to Professor Ken Smith discuss the findings with the Naked Scientists

̽��ֱ��team found evidence of an early, robust adaptive immune response in those infected individuals whose disease was asymptomatic or mildly symptomatic. An adaptive immune response is where the immune system identifies an infection and then produces T cells, B cells and antibodies specific to the virus to fight back. These individuals produced the immune components in larger numbers than patients with more severe COVID-19 managed, and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these individuals of systemic inflammation that can lead to damage in multiple organs.

In patients requiring admission to hospital, the early adaptive immune response was delayed, and profound abnormalities in a number of white cell subsets were present. Also present in the first blood sample taken from these patients was evidence of increased inflammation, something not seen in those with asymptomatic or mild disease. This suggests that an abnormal inflammatory component to the immune response is present even around the time of diagnosis in individuals who progress to severe disease.

̽��ֱ��team found that key molecular signatures produced in response to inflammation were present in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.

Dr Paul Lyons, senior co-author, also from CITIID, said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms. This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”

̽��ֱ��researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.

̽��ֱ��study also provides clues to the biology underlying cases of ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.

̽��ֱ��team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection, and these problems resolved themselves very differently depending on the type of immune cell. Some recover as systemic inflammation itself resolves, while others recover even in the face of persistent systemic inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long COVID. For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity. ̽��ֱ��more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “ ̽��ֱ��NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”

̽��ֱ��research was supported by CVC Capital Partners, the Evelyn Trust, UK Research & Innovation COVID Immunology Consortium, Addenbrooke’s Charitable Trust, the NIHR Cambridge Biomedical Research Centre and Wellcome.

Reference
Bergamaschi, L et al. Early immune pathology and persistent dysregulation characterise severe COVID-19. MedRXiV; 15 Jan 2021; DOI: 10.1101/2021.01.11.20248765

New research provides important insights into the role played by the immune system in preventing – and in some cases increasing the severity of – COVID-19 symptoms in patients. It also finds clues to why some people experience ‘long COVID’.

Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms

Paul Lyons

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SARS-CoV-2 virus particles are shown emerging from the surface of cells cultured in the lab

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Remdesivir likely to be highly effective antiviral against SARS-CoV-2 for some patients

cjb250 — Mon, 14 Dec 2020 10:00:18 +0000

̽��ֱ��response to the COVID-19 pandemic has been hampered by the lack of effective antiviral drugs against SARS-CoV-2, the coronavirus that causes the disease. Scientists had pinned hope on the drug remdesivir, originally developed to treat hepatitis C and subsequently tested against Ebola. However, results from large clinical trials have been inconclusive, and in early October the World Health Organization (WHO) announced that the drug did not significantly reduce mortality rates. ̽��ֱ��question is more complicated, however, and a clinical team have now used a different approach to determine the effects of the drug on COVID-19 in a closely monitored patient.

Dr James Thaventhiran from the MRC Toxicology Unit at the ̽��ֱ�� of Cambridge said: “There have been different studies supporting or questioning remdesivir’s effectiveness, but some of those conducted during the first wave of infection may not be optimal for assessing its antiviral properties.

“Mortality is due to a combination of factors, likely including unchecked viral replication and, importantly, the response of the immune system. A clinical trial that looks only at remdesivir’s impact on mortality will have difficulty distinguishing between these two factors. This limits our ability to ask the simple question: how good is remdesivir as an antiviral?”

To answer this question, a team led by scientists at the ̽��ֱ�� of Cambridge and Barts Health NHS Trust examined the case of a 31 year old man with XLA, a rare genetic condition that affects the body's ability to produce antibodies and hence fight infection.

̽��ֱ��patient’s illness began with fever, cough, nausea and vomiting, and on day 19 he tested positive for SARS-CoV-2. His symptoms persisted and on day 30 he was admitted to hospital, where he was given supplemental oxygen due to breathing difficulties.

Unusually, his fever and inflammation of the lungs persisted for longer than 30 days, but without causing severe breathing problems or spreading to other organs. ̽��ֱ��researchers say this may have been due to his inability to produce antibodies – although antibodies fight infection, they can also cause damage to the body and even lead to severe disease.

At first, the patient was treated with hydroxychloroquine and azithromycin, which had little effect, and the treatments were stopped on day 34. ̽��ֱ��patient then commenced a ten-day course of remdesivir. Within 36 hours, his fever and shortness of breath had improved and his nausea and vomiting ceased. Rising oxygen saturation allowed him to be taken off supplemental oxygen.

This dramatic clinical response was accompanied by a progressive decrease in levels of C-reactive protein (CRP), a substance produced by the liver in response to inflammation. At the same time, doctors saw an increase in the number of his immune cells known as lymphocytes, and chest scans showed that his lung inflammation was clearing. ̽��ֱ��patient was discharged on day 43.

A week after discharge, the patient’s fever, shortness of breath and nausea returned. He was readmitted to hospital on day 54 and given supplemental oxygen. He again tested positive for SARS-CoV-2, was found to have lung inflammation, and his CRP levels had increased and his lymphocyte count fallen.

On day 61, the patient began treatment with a further ten-day course of remdesivir. Once again, his symptoms improved rapidly, his fever dropped and he was taken off supplemental oxygen. His CRP and lymphocyte count normalised. Following additional treatment with convalescent plasma on days 69 and 70, he was discharged three days later and is no longer symptomatic.

̽��ֱ��team found that the patient’s virus levels fell progressively during his first course of remdesivir, corresponding with the improvement in his symptoms. His virus levels increased again, as did his symptoms, when the first course of the treatment ceased, but the effect of the second course of remdesivir was even more rapid and complete. By day 64, he was no longer testing positive for the coronavirus.

̽��ֱ��patient’s inability to clear his infection without antiviral medication is very likely to be due to his lack of antibodies, say the researchers. However, there are other immune cells that contribute to fighting infection, including those known as CD8+ T cells. ̽��ֱ��team observed that the patient was able to produce CD8+ T cells that responded to the ‘spike protein’ on the surface of the virus – spike proteins give the virus its characteristic crown profile (hence the name coronavirus). While insufficient to clear the infection spontaneously, this likely contributed to the clearance of virus during the second course of remdesivir.

Dr Nicholas Matheson from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) at the ̽��ֱ�� of Cambridge added: “Our patient’s unusual condition gave us a rare insight into the effectiveness of remdesivir as a treatment for coronavirus infection. ̽��ֱ��dramatic response to the drug – on repeated challenge – suggests that it can be a highly effective treatment, at least for some patients.”

̽��ֱ��team further suspect that remdesivir is likely to be most beneficial when administered early in infection, before the virus is able to trigger a potentially catastrophic immune response. They say that the course of their patient’s disease also underscores the important – but often conflicting – roles that antibodies play in protecting us from infection.

“ ̽��ֱ��fact that our patient was unable to fight off the disease without treatment suggests that antibodies contribute to the control of SARS-CoV-2,” explained Dr Matthew Buckland from the Department of Clinical Immunology, Barts Health, London. “But this lack of antibodies may also have prevented his COVID-19 from becoming life-threatening, because he had no antibodies to trigger a damaging immune response.

“All of this suggests that treatments will need to be tailored for individual patients, depending on their underlying condition – for example, whether it is the virus that is causing the symptoms, or the immune response. ̽��ֱ��extended viral monitoring in our study was clinically necessary because in April 2020 we didn’t know if this drug would be effective. Adopting this approach more widely could further clarify how best to use remdesivir for clinical benefit.”

̽��ֱ��research was supported by the Medical Research Council, the NIHR Bioresource, NHS Blood and Transplant, Wellcome and the European Union’s Horizon 2020 programme.

Reference
Buckland, MS et al. Successful treatment of COVID-19 with remdesivir in the absence of humoral immunity, a case report. Nat Comms; 14 Dec 2020; DOI: 10.1038/s41467-020-19761-2

̽��ֱ��drug remdesivir is likely to be a highly effective antiviral against SARS-CoV-2, according to a new study by a team of UK scientists. Writing in Nature Communications, the researchers describe giving the drug to a patient with COVID-19 and a rare immune disorder, and observing a dramatic improvement in his symptoms and the disappearance of the virus.

Our patient’s unusual condition gave us a rare insight into the effectiveness of remdesivir as a treatment for coronavirus infection

Nicholas Matheson

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Creative rendition of SARS-COV-2 virus particles

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