Tag Archive for: Neuroscience

Prestigious lectureship award for NIHR Cambridge BRC stroke researcher

Congratulations to Dr Nicholas Evans, who has been awarded the prestigious Royal College of Physicians Linacre Lectureship.

The lectureship, which is awarded annually, is presented to a clinical academic under the age of 40 for their translational research in medicine.

Stroke Association Senior Clinical Lecturer and Honorary Consultant Dr Evans will deliver his lecture “Advances in stroke medicine: blood vessels, brains and beyond” at the Royal College of Physicians on Monday 25th March.

Dr Evans said: “The lecture will focus on advances in stroke medicine over the last 20 years and the translational work being done in Cambridge and the region.

“Those advances have been really quite amazing.

“My grandmother had a stroke in the 1990s and she didn’t recover. Now we’re seeing people who have had a thrombectomy following stroke walking out of hospital within days, and they are making excellent physical recoveries.

“My research looks at what happens when carotid arteries (the blood vessels to the brain) fur up – this is atherosclerosis and it’s a major cause of stroke.

“But we need to look more closely at the effects downstream on the brain from this inflammation, this furring up of arteries.

“Understanding this interaction between what’s happening in the blood vessels and brain health may help provide new therapeutic approaches for reducing the effects of stroke.

“Finally I’d like to thank NIHR Cambridge BRC for their huge support to my work and the research of my colleagues in stroke, imaging and cardiovascular medicine.

“They have certainly made a difference.”

  • Every year around 100,000 people in the UK will have a stroke. Stroke is a leading cause of adult disability, and cerebrovascular disease more broadly is a major cause of dementia.
  • “Advances in stroke medicine: blood vessels, brains and beyond” Linacre lecture 2024 is being live-streamed from the Royal College of Physicians and is open to all members (registration free). For more information visit this link.

Top research award for Neuroscience Theme co-lead Prof Hutchinson

Congratulations to our Neuroscience theme TBI (Traumatic Brain Injury) co-lead Professor Peter Hutchinson, who has been awarded the Vilhelm Magnus Medal from the Norwegian Neurosurgical Association in Oslo, following delivery of the prestigious Vilhelm Magnus Lecture.

The award, which is often described as the “Nobel Prize of Neurosurgery”, was given to Prof Hutchinson and his team for their work on TBI, including a number of studies addressing the concept of “Rescuing the Injured Brain.”

It is the latest in a long list of acclaimed work by Prof Hutchinson, who is also Director of the National Institute of Health and Care Research Global Health Research Group on Acquired Brain and Spine Injury, and the National Institute of Health and Care Research Brain Injury Medtech Co-operative.

The photo shows Prof Hutchinson (right) receiving the medal from Professor Tor Ingebrigtsen.

Watch Professor Hutchinson and Neuroscience Theme Lead Professor Chinnery talk about the theme’s research in this short video:

New study recommends replacing skull section after brain bleed treatment

A new trial supported by NIHR Cambridge BRC has found – where possible – surgeons should replace the removed section of the skull following surgery to treat a form of brain bleed. Researchers say the approach will save patients undergoing skull reconstruction further down the line.

NIHR funded and supported the RESCUE-ASDH study. The international randomised trial involved 40 centres in 11 countries and 450 patients took part. The results published at the annual meeting of the American Association of Neurological Surgeons and in the New England Journal of Medicine.

One of the life-threatening results of head injury is acute subdural haematoma – a bleed occurring between the brain and skull. It can lead to the build-up of pressure. These bleeds need surgery to stem the blood flow, remove the blood clot and relieve the pressure.

There are two approaches to such surgery. The first is a decompressive craniectomy – involving leaving a section of the skull out – which can be as large as 13cm in length. This protects the patient from brain swelling, often seen with this injury. Typically the missing skull needs reconstruction. Some treatment centres replace the patient’s own bone several months after surgery. In others, they use a manufactured plate.

The second approach is a craniotomy. The skull section is replaced after the bleed is stemmed and the blood clot removed. This approach prevents the need for a skull reconstruction further down the line.

To date there was little conclusive evidence and no accepted criteria for which approach to use. Researchers at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust launched RESCUE-ASDH to answer this question. Patients were randomly assigned to undergo craniotomy or decompressive craniectomy.

A total of 228 patients underwent craniotomy and 222 decompressive craniectomy. Researchers assessed the outcomes for these patients and their quality of life up to a year after surgery.

Patients in both groups had similar disability-related and quality-of-life outcomes at 12 months post-surgery. There was a trend towards better outcomes with craniotomy.

Around one in four patients (25.6%) in the craniotomy group and one in five (19.9%) in the craniectomy group had a good recovery.

Around one in three patients in both groups (30.2% craniotomy group and 32.2% craniectomy group died within the first 12 months following surgery. 

14.6% of the craniotomy group and 6.9% of the craniectomy group required additional cranial surgery within two weeks after randomisation. However, this was balanced due to fewer people in the first group experienced wound complications (3.9% compared to 12.2%).

The trial’s Chief Investigator Peter Hutchinson, Professor of Neurosurgery at Cambridge, said: “RESCUE-ASDH is the first multicentre study to address a very common clinical question: which technique is optimal for removing an acute subdural haematoma – a craniotomy or a decompressive craniectomy?

 “This was a large trial and the results convincingly show that there is no statistical difference in the 12 month disability-related and quality of life outcomes between the two techniques.”

Co-chief investigator Professor Angelos Kolias, Consultant Neurosurgeon at Cambridge, said: “Based on the trial findings, we recommend that after removing the blood clot, if the bone flap can be replaced without compression of the brain, surgeons should do so, rather than performing a pre-emptive decompressive craniectomy.

 “This approach will save patients from having to undergo a skull reconstruction, which carries the risk of complications and additional healthcare costs, further down the line.”

Professor Andrew Farmer, Director of NIHR’s Health Technology Assessment (HTA) Programme, which funded the study, said: “The findings of this world-leading trial provide important evidence which will improve the way patients with head injuries are treated. 

“High quality, independently funded research like this is vital in providing evidence to improve health and social care practice and treatments. Research is crucial in informing those who plan and provide care.” 

The NIHR Global Health Research Group on Acquired Brain and Spine Injury and the NIHR Clinical Research Network (CRN) supported the study.

The CENTER-TBI project of the European Brain Injury Consortium, and the Royal College of Surgeons of England Clinical Research Initiative supported it too.

Adapted from NIHR release.

Cambridge researcher wins prestigious award for rare eye disease gene replacement therapy research

Neuroscience researcher Professor Patrick Yu-Wai-Man has won the 2023 Ludwig von Sallmann Clinician-Scientist Award from the Association for Research in Vision and Ophthalmology (ARVO) Foundation.

The award was given in recognition of Prof Yu-Wai-Man’s research on gene replacement therapy for Leber hereditary optic neuropathy (LHON).

LHON is a genetic disorder caused by mutations in mitochondrial DNA (mtDNA). Strictly inherited down the maternal line, it is an important cause of inherited blindness in the young adult population. Currently, there are limited treatment options for LHON and most affected individuals will remain within the legal criteria for blindness.

Prof Yu-Wai-Man said: “I have been working in the field of mitochondrial diseases for nearly 25 years and despite the amazing advances made during that period, finding effective treatments has proven challenging.

“Mitochondrial optic neuropathies have led the way and this award is a recognition of the translational breakthroughs seen in recent years, in particular gene replacement therapy for Leber hereditary optic neuropathy.”

Prof Yu-Wai-Man has worked on several studies using a modified version of the MT-ND4 mitochondrial gene packaged into an adeno-associated viral vector (AAV2) that is injected into the eye. Promising results have been obtained for individuals treated within one year of disease onset with a significant and sustained improvement in vision observed during long-term follow-up.

On receiving the Ludwig von Sallmann Clinician-Scientist Award, Prof Yu-Wai-Man said: “It is a great honour and my hope is that this award will highlight the significant unmet needs for individuals affected with mitochondrial optic neuropathies, which result in significant visual impairment in children and young adults.

“We need to attract more research funding and talents into rare genetic eye diseases. Success breeds success and the future certainly looks bright in this field.”

This article is adapted from arvo.org

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

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 University of Cambridge and Imperial College London.

The findings, published today (3 May) in the journal eClinicalMedicine, emerge from the NIHR COVID-19 BioResource. The 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 University 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.

The 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. The 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 University 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.

The 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.

The research was funded by the NIHR BioResource, NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Charitable Trust and supported by the NIHR Cambridge Clinical Research Facility.

Paper 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

Study suggests lithium may decrease risk of developing dementia

Researchers have identified a link which suggests that lithium could decrease the risk of developing dementia, which affects nearly one million people in the UK.

The researchers, from the University of Cambridge and supported by the NIHR Cambridge BRC, conducted a retrospective analysis of the health records of nearly 30,000 patients from Cambridgeshire and Peterborough NHS Foundation Trust. The patients were all over the age of 50 and accessed NHS mental health services between 2005 and 2019.

The analysis suggested that patients who received lithium were less likely to develop dementia than those who did not, although the overall number of patients who received lithium was small.

Their findings, reported in the journal PLoS Medicine, support the possibility that lithium could be a preventative treatment for dementia, and could be progressed to large randomised controlled trials.

Dementia is the leading cause of death in elderly Western populations, but no preventative treatments are currently available: more than 55 million people worldwide have dementia, with Alzheimer’s disease the most common form.

“The number of people with dementia continues to grow, which puts huge pressure on healthcare systems,” said Dr Shanquan Chen from Cambridge’s Department of Psychiatry, the paper’s first author. “It’s been estimated that delaying the onset of dementia by just five years could reduce its prevalence and economic impact by as much as 40 percent.”

Previous studies have proposed lithium as a potential treatment for those who have already been diagnosed with dementia or early cognitive impairment, but it is unclear whether it can delay or even prevent the development of dementia altogether, as these studies have been limited in size.

Lithium is a mood stabiliser usually prescribed for conditions such as bipolar affective disorder and depression. “Bipolar disorder and depression are considered to put people at increased risk of dementia, so we had to make sure to account for this in our analysis,” said Chen.

Chen and his colleagues analysed data from patients who accessed mental health services from Cambridgeshire and Peterborough NHS Foundation Trust between 2005 and 2019. Patients were all over 50 years of age, received at least a one-year follow-up appointment, and had not been previously diagnosed with either mild cognitive impairment or dementia.

Of the 29,618 patients in the study cohort, 548 patients had been treated with lithium and 29,070 had not. Their mean age was just under 74 years, and approximately 40% of patients were male.

For the group that had received lithium, 53, or 9.7%, were diagnosed with dementia. For the group that had not received lithium, 3,244, or 11.2%, were diagnosed with dementia.

After controlling for factors such as smoking, other medications, and other physical and mental illnesses, lithium use was associated with a lower risk of dementia, both for short and long-term users. However, since the overall number of patients receiving lithium was small and this was an observational study, larger clinical trials would be needed to establish lithium as a potential treatment for dementia.

Another limitation of the study was the number of patients who had been diagnosed with bipolar disorder, which is normally associated with an increased risk of dementia. “We expected to find that patients with bipolar disorder were more likely to develop dementia, since that is the most common reason to be prescribed lithium, but our analysis suggested the opposite,” said Chen. “It’s far too early to say for sure, but it’s possible that lithium might reduce the risk of dementia in people with bipolar disorder.”

This paper supports others which have suggested lithium might be helpful in dementia. Further experimental medicine and clinical studies are now needed to see if lithium really is helpful in these conditions.

The research was supported in part by the UK Medical Research Council and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Paper reference:

Shanquan Chen et al. Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study.’
PLoS Medicine (2022). DOI: 10.1371/journal.pmed.1003941

Researchers eye up new gene therapy trial that could reverse hereditary blindness

Restoration of sight from a rare genetic mutation may now become a reality thanks to a prestigious award from the National Institute for Health Research (NIHR) and Moorfields Eye Charity.

NIHR Cambridge Biomedical Research Centre (BRC) researcher and Addenbrooke’s Hospital Honorary Consultant Ophthalmologist, Dr Patrick Yu Wai Man, has received an NIHR Moorfields Eye Charity Advanced Fellowship award from the NIHR, in partnership with Moorfields Eye Charity, to undertake research into inherited optic neuropathies, which are genetic diseases that affect the optic nerve, causing progressive and irreversible blindness.

A major focus of this ambitious research programme will be on Leber Hereditary Optic Neuropathy (LHON), a disease caused by a gene mutation in the mitochondrial genome that triggers rapid loss of vision in mostly young adults.

Dr Yu Wai Man and his team will run a new clinical trial at Addenbrooke’s Hospital in Cambridge and Moorfields Eye Hospital in London, to better understand LHON and whether gene therapy can help restore sight in some people affected with this condition. 

LHON and mitochondrial blindness

LHON is caused by genetic mutations in the mitochondrial genome – a unique piece of circular DNA that we inherit from our mother. As a result, healthy cells in the retina are lost, leading to optic nerve damage and severe loss of vision to the point where the person is registered blind. There are currently limited treated options for LHON.

LHON is classified as a rare disease, yet it is estimated to affect at least 1 in 30,000 people in the UK. Although women and children can be affected, the majority of cases occur in young men between the ages of 15 and 35. Most people are unaware that they carry a LHON mutation until symptoms begin to develop with blurred vision or if a family member is diagnosed with this condition.

The reasons why LHON predominantly affects men and why it starts so abruptly remains a mystery. “Your eyes are the greatest camera you’ll ever own and this disease is a devastating blow to people,” explains Dr Yu Wai Man, pictured right. “You can go from being fit and well and then suddenly, within weeks, your vision deteriorates rapidly, and you are told you can be registered as blind.

Dr Patrick Yu Wai Man

“We know that this disease is hereditary and affects mostly young men. But there are still so many unanswered questions about this condition and we need to find out more in order to identify suitable treatments. Our recent research published in Science Translational Medicine is promising, indicating that patients with LHON who have experienced loss of vision for up to one year can benefit from gene therapy. We now want to focus on people who have had this condition for more than one year and that is the basis of our trial.”

Launching the trial

The trial will use a form of gene therapy (where a healthy version of the gene is inserted into cells of the retina using a harmless virus) in patients who have lost their vision between one to five years (chronic LHON). It will be hosted across two sites at Addenbrooke’s Hospital and Moorfields Eye Hospital.

Dr Yu Wai Man said: “We know the disease quickly kills off healthy cells in the retina and we want to try and bring as many cells as possible from the brink to prevent further sight loss and potentially improve vision. In the pilot phase, we plan to recruit 30 patients who will be split into two equal groups. One group will receive the gene therapy injections in both eyes whereas the second group will not receive the treatment. The patients will then be closely monitored over two years to see if the treatment improves their eyesight. If we are successful, this breakthrough could be life-changing and it will also provide hope to people with visual impairment from other genetic diseases that affect the optic nerve.”

Monitoring disease and patient outcomes

The gene therapy trial is part of a wider research programme aimed at better understanding how the disease progresses over time (natural history) and what factors (biomarkers) predict the visual outcome in the inherited optic neuropathies. Dr Yu Wai Man and his team will make use of the latest technology available within the Cambridge Clinical Vision Lab, which has recently been established and supported by the NIHR Cambridge Clinical Research Facility and funded by the NIHR Cambridge BRC, as part of its advanced therapies initiative.

“The inherited optic neuropathies have a major impact on quality of life that goes beyond loss of vision,” Dr Yu Wai Man explains. “The Cambridge team will also develop a patient-reported outcome measure (PROM) that will allow the lived experiences of patients to be captured. This new tool will provide a more accurate picture of whether someone’s disease is progressing over time and it will be very helpful for future treatment trials when investigating whether a treatment is actually working.”

Setting sights on further research

Dr Yu Wai Man’s innovative research programme on the inherited optic neuropathies will be made possible thanks to funding from the NIHR in joint partnership with Moorfields Eye Charity. Dr Yu Wai Man said: “Without this level of commitment for rare diseases from the NIHR, we wouldn’t be able to conduct this kind of trial to try and save people’s sight.

“As a clinical academic, an NIHR Moorfields Eye Charity Advanced Fellowship award is a fantastic opportunity. This award will allow me to carry out research which I hope will make a difference to patients, and it will give me the opportunity to work with other leading researchers to further develop my skills in conducting translational research.

“My aim is to drive forward a programme of research in genetic conditions that affect the optic nerve. I’m hoping that our work will help pave the way for more gene therapy trials for other eye diseases – sooner rather than later.

“I’m very excited about what we’re going to learn and achieve in the next few years working closely with patient organisations. We may not be able to restore normal sight 100%, but if we could improve vision enough to have a positive impact on someone’s quality of life, that is the most important thing.”

More information about LHON and the clinical trial

  • The most common cause of LHON is the 11778 mitochondrial DNA mutation
  • This genetic defect affects the amount of energy being produced by mitochondria, which are the powerhouses that fuel cell activity in the human body
  • Affected individuals with the 11778 mutation who have lost vision between one and five years will be eligible to take part in this new trial

Find out more information on the NIHR Fellowship Programme

Link between amino acid and a range of common diseases could help predict personal risk

One of the first population-scale studies on how common genetic traits are influenced by variations in the DNA of mitochondria, the powerhouses of human cells, has been completed by scientists at the Wellcome Sanger Institute, the University of Cambridge, EMBL’s European Bioinformatics Institute (EMBL-EBI), and supported by the NIHR Cambridge BRC.

The team identified associations between mtDNA variants and an amino acid, N-formylmethionine (fMet), and effects of fMet on the risk of developing a range of common, late-onset illnesses.

The study, published (on 23 August 2021) in Nature Medicine found that higher fMet levels are associated with increased risk of a wide range of late-onset diseases and all-cause mortality, demonstrating fMet’s potential as a biomarker of ageing and disease risk, as well as the importance of research into mitochondrial DNA variants.

Mitochondria are organelles that are found in the cells of all complex organisms. They perform a number of vital biological functions, including the production of around 90 per cent of the energy that cells need to function. Mitochondria are unique in that they have their own genetic code, knowns as mitochondrial DNA (mtDNA), which is distinct from the DNA contained in the nucleus of every cell in an organism’s body1. mtDNA is passed on from mother to child.

Many common diseases are influenced by mitochondrial damage or disruption, including genetic diseases such as diabetes, heart disease and depression that are influenced by mutations in mtDNA.

Over time, the accumulation of mutations in mtDNA leads to distinct lineages in the population, known as haplogroups, which confer particular traits. Previous research has shown that haplogroup Uk, found in 10 per cent of the European population, is protective against diseases such as Parkinson’s Disease and ischaemic stroke (IS).

In this study, two large-scale datasets were analysed to look for associations between genetic variants in mtDNA and thousands of common molecular traits such as blood cell counts and plasma proteins, in order to understand the molecular mechanisms behind mtDNA associations with diseases.

In the INTERVAL dataset of up to 16,000 participants, the researchers identified significant associations between levels of fMet and mtDNA variants in haplogroups Uk and H32. The team then verified these associations using cellular models. When fMet levels were measured in a cohort of ischaemic stroke patients, they found lower fMet levels compared to those in a healthy control group.

The researchers then analysed data from EPIC-Norfolk, a study that tracked the health of participants over a 20-year period, to ask whether differences in fMet between individuals were associated with a wider-range of late onset diseases. In contrast to ischaemic stroke, higher fMet levels were associated with increased risk of illnesses such as kidney disease and heart failure.

Dr Cai Na, a first author of the study from the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute (EMBL-EBI), said: “We knew that the Uk haplogroup offered some protection against ischaemic stroke and Parkinson’s disease, and our findings suggests that variants in mitochondrial DNA that upregulate N-formylmethionine (fMet) may play a part in this protection. What was surprising is that these same variants are also associated with higher risk of other diseases. While further study of the molecular mechanisms at work is required, fMet does seem to be a promising biomarker that we could use to better predict an individual’s risk of developing a wide range of common diseases.”

Professor Patrick Chinnery, a senior author of the study from the University of Cambridge, said: “When we examined the molecular processes using human cellular models, we found that variants in Haplogroup Uk modulate protein synthesis and degradation in both the mitochondria and cytoplasm, and this affects cellular processes beyond mitochondrial bioenergetics. In the case of ischaemic stroke (IS), our findings suggest part of the protective effect of mtDNA haplogroup Uk may be attributed to reduced protein clearance mediated by fMet.”

Dr Aurora Gomez-Duran, a first author of the study from the University of Cambridge, said: “Our findings reveal the important part that mtDNA variants play in several pathologies, and that they play a deeper role in cellular homeostasis than we previously thought. Due to this, mtDNA should be carefully considered when investigating a diagnosis and delivering a treatment for age-associated diseases”

With only around 6,000 individuals on which to assess around 1,000 molecular traits in this study, other significant associations between mtDNA variants and genetic traits remain hidden for now. The next step will be to scale up this research in order to identify other traits associated with mtDNA variants.

Professor Nicole Soranzo, a senior author of the study from the Wellcome Sanger Institute, said: “Our study highlights the vast potential of large-scale, hypothesis-free research into mitochondrial DNA as a way of better understanding health and disease. N-formylmethionine (fMet) is a promising biomarker that could one day help us to monitor individual disease risk and plan pre-emptive interventions. This study has been a true collaborative effort with data from genome-wide association studies, cell lines and computational analysis combining to offer rich insights into human biology.”

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