BRACE - Raising money for research into dementia

Research into dementia is carried out all over the world but we are lucky in the South West to have a large group of scientists, clinicians and psychologists working in the Bristol area on different aspects of dementia research.

BRACE has no particular strategic approach to the type and scope of projects it will consider for funding except that they should be of the highest scientific quality and address an area of research that would ultimately lead to improvements in diagnosis, treatment or quality of life for sufferers of dementing conditions.

Applications are invited from researchers in the region on a regular basis, as funds allow. Each research project is assessed for suitability by the Trustees Scientific Advisory Committee (SAC) chaired by Professor Brian Pickering. Each project is then sent out for peer review to experts in the field of research of the project. The SAC then makes its recommendations for funding to the Trustees who approve funding.

 

Some of the current project areas that we support are:

 

• The Neurotrophins - balance between life and death Dr Shelley Allen and her group are working to understand the molecular changes underlying Alzheimer's disease, which is a necessary path towards the development of novel therapeutics.  Their BRACE-funded research investigates and identifies changes which occur in the regions of the brain which are affected very early in Alzheimer's disease.
  
  Following the group's work which showed an increase in the enzyme which produces amyloid (beta-secretase) in Alzheimer's disease brain, they are looking at why this enzyme increases and the effects that 'in house' peptide inhibitors have on this enzyme.
  
  In addition they are interested in a small group of 'cholinergic' cells, which connect and communicate with cells in another brain structure, called the hippocampus.  Together these brain areas are crucial for the formation of memories, and it is their degeneration which results in the memory and attention problems associated with Alzheimer's disease.  The cholinergic cells and those of the hippocampus require a protein, called BDNF or brain-derived neurotrophic factor to stay healthy.  Levels of BDNF are much reduced in Alzheimer's brain.  The cholinergic cells also require another protein called nerve growth factor (NGF) for their maintenance.  NGF is present in two forms: proNGF and 'mature' NGF.  These interact with other proteins called 'receptors' on the surface of cholinergic cells.  Mature NGF keeps cholinergic cells alive; whereas evidence suggests that proNGF may lead to cell death.  As there is an increase in proNGF in Alzheimer's disease brain, the group is trying to understand whether a harmful imbalance in proNGF/mature NGF levels is causing early degeneration of the cholinergic cells, and also how this may relate to the changes seen in BDNF levels.
  
  The group is working, not only to understand the basic underlying mechanisms involved, but also to 'redress the balance', and one of their ongoing projects is to produce a drug which will mimic the benefits of NGF and support the cholinergic cells. 
  

   

• Visual attention in Alzheimer's disease and mild cognitive impairment The evidence of robust and significant deficits in many aspects of visual attention-related processing in AD has lead Dr Andrea Tales to consider the possibility that tests of such function may be of use in the search for early markers of this disease. Currently, the clinical diagnosis of Alzheimer's disease (AD) involves neuropsychological tests to assess the integrity of higher order cerebral functions such as memory, cognition, visual perception, language and executive function. However, the onset of AD is insidious and such tests tend to lack the sensitivity and specificity necessary to correctly diagnose the very early stage of the disease. This together with similar shortcomings in relation to assessing disease progression and response to treatment has prompted the search for disease markers based on other aspects of brain processing.
  
  BRACE is funding further work by Andrea Tales and her colleague, Dr Gillian Porter to extend studies in basic visual attention-related processing and the time sequence of information processing which is altered in AD. Further work is planned to determine the use of this as an early disease marker.

   

• Neurifibrillary tangles and TGFß signalling in Alzheimer's disease Dr Katy Chalmers is working with Dr Patrick Kehoe and Professor Seth Love in the Dementia Research Group. Her work is addressing an important area of how functions of the genes that protect the brain are impaired in Alzheimer's disease by the abnormal binding of one particular protein, (Smad3) in abnormal neurons. The TGFß signalling pathway is involved in protecting the brain cells, reducing inflammation and providing a network of molecules which support the brain cells so that they can function. One of the key proteins in the pathway, pSmad3 is found to be sequestered in neurofibrillary tangles, thus potentially preventing it from carrying out its normal functions that would provide protection to brain cells. If this project can show exactly what is taking place, therapies that counteract the binding may be possible, with significant impact on the way Alzheimer's disease is treated. This is at the forefront of international research and the availability of the material from the South West Dementia Brain Bank means that Katy has access to the relevant resources to carry out this project.
  
  

• The role of caveolins in the processing of amyloid precursor protein  Dr Emma Kidd and Dr Rhian Thomas (University of Cardiff).  Evidence is accumulating to suggest that changes in endocytosis may be involved in the pathogenesis of Alzheimer’s disease (AD). Dr Kidd’s group is currently investigating the importance of a number of endocytic proteins involved in clathrin- and non-clathrin-dependent endocytosis in the processing of proteins important for AD. In particular, there is growing evidence to link the caveolin proteins involved in non-clathrin-dependent endocytosis to various aspects of AD, as higher levels have been found in AD brains than in non-AD brains. However, attempts to relate the relevance of this finding to the processing of amyloid precursor protein (APP) have produced conflicting results. This project aims to clarify this situation by investigating the hypothesis that the over-expression of caveolins in cells will increase amyloid-β (Aβ) production with potentially deleterious effects in man. The effects of over-expression or knock down of caveolin proteins in cell lines that constitutively express APP will be investigated. It is anticipated that this project will enhance understanding of the role of caveolins in AD and will also provide important information regarding their effects on APP processing and production of Aβ. Currently it is not clear whether the higher levels of Aβ found in AD lead to the observed increases in caveolins or whether increased levels of caveolin represent an earlier causative stage in the disease process. Ultimately, the results should enhance knowledge of the disease process and highlight future therapeutic targets. 
  
  

• The BCAT proteins and their potential role in the pathogenesis of Alzheimer's disease Dr Myra Conway (University of the West of England) leads a project that aims to decipher how alterations to key metabolic mechanisms in the brain can contribute to the pathogenesis of Alzheimer's disease (AD). An understanding of how these pathways are altered can highlight potential drug targets for the development of new and novel therapies to slow down or prevent the progression of AD.
  
  Through funding from BRACE the role of the branched chain aminotransferase proteins (BCAT) in contributing to the pathogenesis of AD will be investigated. The human branched chain aminotransferase enzymes are strategically located in the axon and nerve terminals of glutamatergic neurons, where they are responsible for the production of 30% of glutamate in the brain.  In health glutamate plays a dominant role in facilitating learning and memory. However, when levels of glutamate rise, as seen in patients with Alzheimer's disease, there is a direct increased in intracellular calcium leading to amplification in cell signalling and oxidative stress, ultimately contributing to Aβ plaque formation and destruction of neuronal integrity and cell death.
  
  Preliminary studies from Dr Conway's group have identified a significant increase in the expression of the BCAT proteins in the brains of patients with AD relative to control patients. As the BCAT proteins contribute to the levels of glutamate in the brain, the group believes that alteration to the expression of BCAT can contribute to glutamate toxicity thus ultimately causing neuronal cell death leading to the progression of AD.
  
  This work is in collaboration with Dr Katy Chalmers, Dr Patrick Kehoe and Professor Seth Love from the Dementia Research Group, which reflects the expertise over a number of disciplines and allows the enrichment and development of new ideas and concepts to support the success of these projects.

• Clinical research project at The BRACE Centre  Dr Liz Coulthard (University of Bristol) In June 2011, a new clinical research initiative started at The BRACE Centre, Frenchay Hospital. Led by Dr Liz Coulthard, it brings together different disciplines and opens up new opportunities for dementia research in the Bristol area.
  
  Several different streams of clinical research are planned focussing on Alzheimer’s disease and other dementias. Each research study involves asking patients and volunteers for their informed consent to take part. At the heart of the research program is a research register where details of willing patients and healthy volunteers are recorded. Using the register, participants are identified as being suitable for a given study. Patients recruited onto the research register and into studies come primarily from the new neurology dementia clinic in the BRACE centre.
  
  Patients are referred to the cognitive neurology and dementia clinic by GPs or other hospital consultants who suspect that they might have some form of dementia. The clinicians then carry out tests to establish what their symptoms mean and, if the cause is dementia, try to establish which form of dementia is involved. Patients attending the clinic are asked if they would like to be entered onto the research register. Much of the research is based in The BRACE Centre ensuring that patients can take part in research in a familiar environment and research and clinical care are closely allied.
  
  Planned research projects will look both at the underlying problems experienced by people who have dementia and also how therapy can be targeted to individual patients. Initial studies are investigating how memory can be affected in dementia. There are several different types of memory including very short term or working memory and longer term memory. We are using computerised cognitive tasks to study the way in which patients retain memory over time and how this could be improved using medication.
  
  Further studies will be based on the preclinical, laboratory-based work of the Dementia Research Group, run by Professor Seth Love and Dr Patrick Kehoe. Their work has demonstrated that blood vessels are affected early in the course of Alzheimer’s disease. Dr Kehoe and Dr Coulthard plan to study the possible beneficial effects of agents that can protect blood vessels and are already used safely to treat high blood pressure. In addition there is the opportunity to help with the early stages of stem research already underway in Bristol and Bath.
  
  In order to measure the effectiveness of treatments, the team is going to perform repeated psychology tests, as well as detailed brain imaging. Repeated volumetric MR imaging of the brain can tell us how much the brain shrinks over time and any benefit of the of the trial drugs on brain volume can be measured. Dr Coulthard is building strong links with the Clinical Research and Imaging Centre (CRIC) in the University of Bristol and the medical physics departments of North Bristol Trust and University Hospital, Bristol, in order to develop high quality image analysis both for clinical and research work.
  
  Over time it is hoped that a portfolio of studies will be developed, each designed to improve understanding and treatment of dementia.

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