Lay Summaries for all the studies supported by BRAIN UK in 2016.
Lay Summary not available.
Project Status: Active
Tuberous Sclerosis Complex (TSC). TSC is a genetic disease which causes multiple tumours within the body. Heart, brain, kidney, skin and lung can be affected. Subependymal giant cell astrocytoma (SEGA) are benign tumours. These grow slowly but constantly in brains of the patients. In children they are one of the more common causes of complications associated with the disease. This leads to brain swelling (increased intracranial pressure) and all associated risks. The treatment of the tumour usually means surgery or medication with so-called mTOR-inhibitors. These are specific types of medications targeting the mTOR complex which is the main affected protein complex in TSC. However, little is known about how these tumours grow and why some of them are more responsive to medication than others. Therefore, we use a battery of modern techniques to gain insights in the development of these tumours and unravel novel therapy strategies.
Project Status: Active
Neurolupus is a serious brain disease which affects most patients who suffer from the autoimmune disease systemic lupus erythematosus (SLE). It can be very disabling, the cause is not known and treatment options are limited. We want to understand the molecular basis of this condition so we can develop effective markers of the disease and effective treatments. We want to study how the innate immune system, which usually protects the body from viral attack, might “accidentally” damage the brain in neurolupus. We will be looking in neurolupus brains to identify activation of innate immune pathways to try and find drug targets.
Project Status: Active
Traumatic brain injury (TBI) causes unexplained brain disease, which gets worse over time (called degeneration). This contributes to 5-10% of all dementia cases. This is a problem because we don’t have a way of defining this degenerative disease after a brain injury as a separate disease. Also, we don’t know how this degeneration happens. So we want to develop the criteria to diagnose this disorder and see how it is related to other degenerative brain diseases such as Alzheimers.
We also want to look at the chemical make up of TBI and the genetic footprint in cases of degeneration in the brain after a TBI. We particularly want to look at the time scale and how inflammation may add to the degeneration. If we do this this could change our understanding of long-term exposure to TBI as well as opening up new ways of developing treatments for TBI.
To do this we want to bring together the international research community to develop collective intelligence and to work collaboratively. We will use a combination of face to face and advanced digital pathology ‘round microscope’ techniques to enable us to review case material quickly and to validate criteria. In time this archive will be available for the wider research community.
Project Status: Active
In this disease degeneration of nerve cells takes place in parts of the brain, which are essential for maintaining fundamental functions such as sleep, respiration and movement. This is due to the accumulation of a protein, called tau in the form of insoluble filaments within nerve cells and their processes of specific brain and spinal cord areas. Interestingly in individuals with this disease an antibody can be identified in the blood, which is produced by the affected individual’s immune system (autoantibody) against a protein, called IgLON5, present on the surface of nerve cells.
Our project aims to establish the neuropathological diagnostic criteria of this novel, devastating neurological disease. At the UCL Institute of Neurology two such cases has so far been identified to have the post-mortem findings of anti-IgLON5 antibody-related tauopathy. We would like to use these two cases for this research.
Several neuropathologists working in three different European neuroscience centres met in September 2015 and agreed on the details of this project. The experts agreed using unified criteria for the neuropathological study and the comparison of the six cases, which are currently available in the three European centres.
We expect that this project will allow us to propose neuropathological diagnostic criteria of this novel disease, which can be validated in the future. We wish to publicise our findings for the wider neuropathologist community in the form of a scientific paper.
Project Status: Active
A proportion of strokes with bleeding into the brain (so-called haemorrhages or haematomas) are caused by the deposition of an aggregated protein called amyloid-beta in the walls of the blood vessels, which makes them brittle, and prone to rupture and bleed. The vast majority of such amyloid-beta deposition occurs without known cause and a smaller proportion is caused by genetic risk factors and can be predicted to some degree. However, in addition there is a distinct possibility that amyloid-beta deposition can be transmitted through medical procedures. Such transmission is extremely rare and has so far been shown only in patients who had received medical treatments containing human-derived tissue.
Here, we want to investigate if similar changes can also be found in patients who underwent surgical or neurosurgical procedures in the distant past. This would raise the concern that amyloid-beta pathology may also be transmitted through contaminated surgical instruments. Identification of potential sources of contamination are important for adequate risk assessment and evaluation of the methods used for surgical instrument decontamination and thus will have a significant impact on public health.
Project Status: Active
Background:
Despite recent treatment advances ‘high-risk’ paediatric brain tumours (HR-PBTs) remain the leading cause of deaths from cancer in childhood. Advances in biological understanding, and their translation into effective therapies, will be essential to improve outcomes for these children, and coordinated national/international strategies will be required to achieve this.
The INSTINCT programme brings together UCL Institute of Child Health, Newcastle University Northern Institute for Cancer Research and the Institute of Cancer Research, each of which already play international leading roles in paediatric brain tumour research.
What does INSTINCT aim to achieve?
INSTINCT specifically aims to bridge the gap between biological discovery and clinical practice through using state-of–the-art biological investigations to improve the outlook for children with HR-PBTs.
BRAIN UK will support and facilitate the use of archival hospital brain tumour samples for molecular sequencing.
Through co-ordinated research and clinical networks between our centres, our research will:
Project Status: Active
Lumbosacral spinal lipomas (LSL) are part of the spectrum of spina bifida. In “open” spina bifida the developing spinal cord does not close properly and is not covered with skin. LSLs also form when the spinal cord does not form properly, however, the skin does form over the defect, so LSLs are considered to be “closed” spina bifida. Folate supplements early in pregnancy reduces the risk of open spina bifida but not LSLs - this suggests there is a very different underlying mechanism.
Recent assessment of LSL tissue samples show that although they are called lipomas (this normally refers to a collection of fat cells), in reality there is a diverse range of different cell types present. This has led us to propose a mechanism by which LSLs might develop. There is a group of cells that form with the developing spinal cord called neural crest cells. Recent research has shown that neural crest cells are capable of forming a wide range of different cell types including the fat cells found in LSLs.
In this study we will assess archived samples taken from children at time of surgical resection of their LSLs. We will assess these samples to see if there are any markers of neural crest cells present. If there are this will help guide further research, help us develop a model and hopefully find a way to prevent this disease.
Project status: Active
Epilepsy is a common neurological condition where patients have recurrent seizures. A small number of patients can have many seizures in a day and may require brain surgery to control them.
The “mechanistic target of rapamycin” (mTOR) pathway is a vital cellular pathway. It is involved in many cellular functions, including cell growth and excitability in brain cells. Its overactivity may be responsible for making individuals prone to have epilepsy.
There is suggestion of increased activity of mTOR pathway in brain tissue of individuals who had brain surgery to control their epilepsy. We would like to evaluate if this overactive mTOR pathway is present in a wider variety of patients who need brain surgery for managing their seizures.
A group of medications known as mTOR inhibitors, such as Sirolimus (rapamycin) and Everolimus, have been effective in reducing seizures in animal models as well as clinical trials in conditions such as Tuberous sclerosis. Individuals with Tuberous sclerosis commonly have epilepsy, with high burden of seizures.
If the study suggests that the brain tissues of patients with difficult to control epilepsy have overactive mTOR pathway, it is likely we would be able to test if mTOR inhibitors can be used to manage these cases.
Project Status: Active
Motor neuron disease (MND) is a progressive neurodegenerative disorder that destroys motor neurons, the cells that carry the signal for muscle movement such as speaking, walking, breathing, and swallowing. There are different types of motor neurons which can be grouped depending on whether they are carrying signals around the brain and spine (upper motor neurons) or from the spine to the muscles (lower motor neurons). They can be further grouped depending on whether they are signalling fast acting or quickly fatiguing movements. Certain groups of neurons are affected differently during the course of motor neuron disease. The most significant degeneration (decline) of neurons in MND occurs within the spinal cord, however there is also moderate loss of upper motor neurons in the brain and spine.
We are particularly interested in upper motor neuron vulnerability. To investigate this, we will look for proteins that characterise neuron subtypes in conjunction with proteins that charcterise the disease effects, to identify whether particular neurons are more likely to collect disease-related proteins.
Project Status: Active
Malignant peripheral nerve sheath tumours (MPNST) can occur at numerous sites in the body and form within the outer layer of nerves. MPNSTs are associated with poor patient survival and are more common in a group of patients with a genetic condition called Neurofibromatosis type 1. These patients are missing an important protein, Neurofibromin 1, which normally prevents tumour growth along nerves. When Neurofibromin 1 is absent, it leads to an increase or decrease in many other proteins, helping the tumour to grow and survive. We are interested in finding new treatments for patients who have an MPNST that is missing Neurofibromin 1. We will look at a number of proteins that are increased in other tumours and determine if they are increased in MPNST tumours. If they are, we will use a drug to stop these proteins from working and see if there are any changes in tumour growth. In the future these drugs could be used to treat patients instead of invasive surgery and they may be able to improve patient survival.
Project Status: Active
Spinal muscular atrophy (SMA) is severely debilitating and ultimately life-limiting conditions that selectively affect motor neurons, the nerve cells that control our voluntary muscles. People affected by motor neuron diseases lose the ability to walk, move, talk, and finally breathe. Currently, there is no cure or therapy to treat these devastating diseases effectively, as the precise mechanisms that cause motor neuron diseases are still poorly understood. The aim of our research therefore is to identify key disease mechanisms and targets to accelerate the development of much-needed treatments for motor neuron diseases.
This research project is based on our compelling results that links nerve cell injury to damage in the molecule that carries the genetic information (DNA) in all the cells. The studies proposed will use a multidisciplinary approach to explore the exact role of the gene causing Spinal muscular atrophy in DNA damage. Using experimental models and human tissue, these studies should create significant insights into the mechanisms behind motor neuron injury and identify key targets and new strategies for the development of effective treatments for motor neuron diseases. Moreover, these insights should also benefit and improve outcomes for other related and currently untreatable disorders caused by the damage and loss of nerve cells.
Project Status: Active
During the development of Alzheimer’s disease, proteins build up in the brain to form structures called 'plaques' and 'tangles'. This leads to the loss of connections between nerve cells, and eventually to the death of nerve cells and loss of brain tissue. This means that gradually, over time, more parts of the brain are damaged. As this happens, more symptoms develop. They also become more severe.
Gum disease is caused by specific types of bacteria that coat teeth and cause gums to bleed. The coating is called a “biofilm”. Research demonstrates a cause and effect relationship between gum disease and worsening memory as dental treatment for gum disease in Alzheimer’s disease patients appears to improve memory. However, the relevance of this observation remains to be fully investigated.
A novel concept in which, bacterial infections of the brain have resulted in the cause of Alzheimer’s disease is being suggested. This hypothesis proposes the ‘plaques’ of Alzheimer’s disease as a biofilm containing multiple types of bacteria living together harmoniously. Our interest in this project comes from our expertise in the oral-infection model of Alzheimer’s disease and from two recent research articles that focused on non-oral bacterial biofilm found within the plaques. Since bacteria responsible for causing gum disease are found in late-onset Alzheimer’s disease brains; there is a high possibility that they are likely to be found in the plaque biofilm as well. We propose to explore this novel concept further to identify specific oral bacteria and their contribution to AD plaques in archival tissue specimens from Syphilis with Alzheimer’s disease diagnosis cases, as this disease is caused by bacteria from the same ‘family’.
Project Status: Closed
Neonatal Hypoxic Ischaemic Encephalopathy (HIE) is a significant worldwide problem that affects 1.3 to 1.7 per 1000 live births in UK. It occurs in babies who have been starved of oxygen around the time of birth and is associated with a high risk of brain injury and long-term neurological and neurodevelopmental problems. Body cooling treatment, where the body temperature is decreased from 37oC to 33.5oC for 72 hours, has dramatically improved the survival of the HIE babies without major side-effects. However, in the long-term, these children developed a number of neurological problems impacting on their daily life. It is thought that this is due to abnormal behaviour of the microglia during this time of oxygen starvation. Microglia is a brain cell which is an integral part of the immune system in the brain. Several studies suggest that the increased survival rates is driven by blocking this microglia. However, it has been observed in animal studies that microglia are an important component of the brain development in normal conditions. Therefore we hypothesize that the cooling treatment causes microglia to behave in a way that leads to brain development malfunction.
To explore this hypothesis, we will perform a study on post-mortem brain tissue investigating microglia and brain dysfunction.
Project status: Active
Changes in our DNA are often found in cancer. In the hospital laboratory we can set up tests to look for these changes, to help diagnose and treat cancer. In a brain cancer called glioma, we need to find some better tests to help with getting the diagnosis right. We want to try a new method called ‘digital PCR’ that should help us give a more accurate way of looking for a mutation in the gene IDH1, which is very common in this cancer. We will compare the method with the way the test is done now, looking at cells down a microscope, to see if we can get a better test. We also want to add in some ‘DNA sequencing’ to try and pick up rarer IDH mutations that can be found in glioma; currently our hospital can’t offer this extra service. These extra tests will mean we can help the doctors to make a more accurate diagnosis of the disease. This should in turn make sure the patients get the most appropriate treatment.
Project Status: Active
Epilepsy is the fourth most common neurological disorder, and in the U.K. approximately 1 in 30 people develop it as some stage in their life. Drug resistant epilepsy can have serious implications on quality of life and increase risk of memory loss, mood difficulties and death, observed in patients with frequent untreated seizures [1]. Our research investigates the significance of densities of ectopic (abnormal) neurons in the white matter of three lobes of the brain: temporal, parietal and frontal. Ectopic neurons in the white matter of these lobes are noted in variable number in normal and epilepsy patients. It is not clear what is the normal or abnormal density of these ectopic neurons. Therefore, we look to compare the density of these neurons between epilepsy patients and normal. Autopsy brain samples of patients who died of sudden unexplained death in epilepsy (SUDEP) and non-epileptic samples will be used. Temporal, parietal and frontal lobe slides will be gathered from two populations (non-epileptic and SUDEP patients) from patients autopsied. Results will be documented and matched with the clinical history of the patient. Our research hopes to enhance the understanding of the pathogenesis of epilepsy and ultimately provide improved management strategies.
1. http://www.epilepsy.com/learn/types-epilepsy-syndromes/temporal-lobe-epilepsy
Project status: Active
The diagnosis of a high-grade glioma (a type of brain tumour) in a child has a dismal prognosis ranging from a 2 year survival of <10 – 30% depending on where the tumour is located within the brain. However, a small group of tumours that occur in infants tend to have a better prognosis than those occurring in older children. And we want to try and find out why. There is a great need to study the molecular biology of these tumours to better understand how they grow, develop and identify potential targets for treatment. We are gathering samples of different brain tumours from children who are aged less than 4 years old. We are using microscopes to assess the different features of the tumour cells, and we are performing various molecular experiments and tests on these samples to try and find the different genetic abnormalities that occur within the cancer cells. Once these are identified, we can try and design different drugs that can be used to try and stop the cancer from growing and help to improve the survival of the children diagnosed with these tumours.
Project Status: Active
Primary central nervous system lymphoma (PCNSL) is a rare cancer with a generally poor outcome and with very limited therapeutic choices resulting in a short patient survival (the median overall survival ranges from 2 to 4 years). Despite intensive research activities, our understanding of the disease remains obscure; moreover, most of the data has emerged from relatively small studies. In this project we will investigate the origin of tumour cells in a relatively large cohort of PCNSL and correlate the results to clinical data and the frequency of mutations of different genes involved in development of PCNSL. We will use different modern molecular and immunohistochemical techniques. Our research will lead to better understanding of PCNSL, and ultimately will allow us to offer novel prognostic biomarkers and potential therapeutic targets to the patients.
Project Status: Active