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Comparative Research Budgets (charity and government resources) for the four major diseases in the UK
Research Budget (government and charity)
£ per Sufferer per Year
NB The cost of caring for someone with Alzheimer's disease is more than double that of caring for someone with one of the three other major diseases in the UK.
A recent report in the journal Nature describes an experiment that demonstrates a link between caspase-12, an enzyme that plays a key role in cell death, and the neurotoxic substance, b-amyloid, which many scientists believe is central to the ways in which the brain becomes damaged in AD. Brain tissue in which caspase-12 activity was prevented showed reduced neurotoxic effects of b-amyloid. Therefore, the scientists from Harvard Medical School have suggested that blockade of caspase-12 activity may be a potential therapy in Alzheimer’s disease.
A team at New York University has reported in The Lancet that they have a discovered a chemical that in mice will make the prion which is thought to be responsible for Creuztfeld-Jacob Disease harmless. The so-called beta sheet breaker peptides cause the proteins to refold from the faulty shape associated with CJD back to their normal configuration. They hope that it will be possible to extrapolate some of their findings from CJD to Alzheimer’s disease, which is their main target, by looking at whether it is possible to do something similar with the beta-amyloid protein. However, it is still not definitely known whether beta-amyloid is a cause of Alzheimer’s disease or just a symptom, and therefore whether this would have any effect.
Report on our first Major Grant
which was won, after an open competition, by a combined group in Cambridge from the Laboratory of Molecular Biology, Centre for Brain Repair and The Babraham Institute. We are grateful for the support of The Freemasons’ Grand Charity with this grant.
One of the most exciting recent findings in dementia research has been the involvement of certain key genes in the pathogenesis of dementing conditions, including Alzheimer’s disease and Lewy Body dementias. In its work funded by the Trust, the Cambridge group are exploiting molecular genetics methods, in which copies of the harmful genes such as those for abnormal human tau and amyloid precursor protein (associated particularly with Alzheimer’s) and alpha-synuclein (associated particularly with Lewy Body dementias) can be inserted into small numbers of transgenic mice – which can then be studied for signs of the human diseases.
The programme benefits significantly from being able to assess, in detail, the effects of having these harmful genes at the molecular, neural and behavioural levels. This multi-disiciplinary approach means that they can address key issues as regards how having these genes affect the mice, particularly: i) the extent to which inheriting these genetic mutations shows up as deficits in behaviour or cognition; ii) the extent to which the progression of these deficits seem to match the pathological changes that appear in the brains of the animals as they age (because some people who have massive changes in their brains on scans only have mild symptoms of dementia, and we have no idea why); iii) whether the pathology in the brains of these mice can be consistently reproduced so that they can form a model which can then be used to design and test therapies to arrest the disease in humans.
Work is progressing very well, and the group is about to take on a PhD student to help with the project.
The next major project we will fund will look specifically at early diagnosis and early intervention to slow the progress of the disease.
US Clinical trials of metrifonate, an acetylcholinesterase inhibitor similar to Aricept and Exelon (drugs which slow down the breakdown of the vital brain chemical acetylcholine) have been put on hold after the makers, Bayer AG, found a side effect of muscle weakness in 20 out of the 3000 patients taking it, with a few of them requiring help with breathing. Metrifonate is said to control psychiatric and behavioural disturbances as will as helping to slow loss of memory in AD, and has been in use for years as a treatment for schistosomiasis, a parasitic disorder. Bayer AG are investigating.
New types of anti-psychotic drugs such as Risperdal with far fewer side effects, are now being use to help control aggression in Alzheimer's patients. Risperdal is given in low doses and doesn't seem to sedate or cause further confusion.
Individuals suffering from Down's Syndrome are in later life at very high risk of Alzheimer's disease. Down's Syndrome is caused by a mutation leading to a duplicate copy of chromosome 21. This is the chromosome on which one of the amyloid genes is located - responsible for producing amyloid protein, part of the pathology of Alzheimer's disease. Doctors in the US are trying a small study with Aricept, one of the drugs believed to slow the cognitive decline in AD sufferers for a period of time, to see whether this can benefit the cognition of consenting Down's Syndrome individuals. So far results have been encouraging.
Nitrendipine, the anti-hypertensive drug which was shown in a European study to halve the risk of stroke, is being proposed as an anti-dementia drug. Those who took part in the study were tested for dementia after five years - 21 had developed dementia in the control group as opposed to 11 in the group of those receiving the drug.
Pfizer is working on a drug known as NGD97-1 to try to reverse memory loss, which has begun clinical trials in Europe. NGD97-1 is thought to block a chemical transmitter in the brain that reduces the ability to form a memory. Rats with induced memory deficits were able to find their way twice as quickly round a maze after having the drug as those with memory deficits who did not. It is hoped that the drug may help those with mild to moderate AD, although memory loss is only one aspect of the condition.
Phytopharm, a small botanic biotech group, hopes to start human trials this year on its drug P58, which appears to reverse age-related memory loss in aged rats, allowing them to remember a maze more easily. It hopes that eventually P58, "derived from an Asian plant", may provide a treatment for Alzheimer's disease.
The Irish American Elan Pharmaceuticals has reported in the respected Nature journal that its AN-1792 vaccine protects laboratory mice from developing the amyloid plaques in the brain that are part of the pathology of Alzheimer’s disease. In addition, Elan says that a second experiment on mice which already showed the symptoms of the disease did not continue to worsen as would normally have been expected. It is still not known whether the plaques are actually a cause or an effect of the disease , and this still leaves the question of the other major pathology, the Tau protein "tangles", which some scientists think are more important. The research, whatever the outcome, is extremely valuable as another step in understanding the biology of this highly complex disorder. Elan plans to start human testing later this year, and if this works, they will go to clinical trials. Delaying the average onset of Alzheimer’s disease by just five years would reduce the number of cases by half because people would die from other causes.
Amgen Inc and Guildford Pharmaceuticals Inc have started human testing of a drug which aims to regenerate damaged nerve cells in the brain in Parkinson’s disease. This is only the second human study of a new class of drugs called neuroimmunophilins, which may have implications for Alzheimer’s disease. Years of testing lie ahead.
American researchers have isolated stem (non-specific) cells in the brain which can grow into nerve cells while continuing to reproduce, something until recently thought to be impossible. This would mean that scientists could grow nerve cells for transplantation. In addition, work on mice revealed that neurones themselves can divide (though very slowly), contrary to accepted wisdom, and that "a challenging environment [learning new things] for elderly mice promoted brain cell growth (neurogenesis)". This occurs in the hippocampus, as well as other areas, which is responsible for memory and learning, and the research could be of benefit in AD.
Additional research is looking at using nose drops to deliver Nerve Growth Factor (NGF) directly to the brain to see if it will allow brain cells to regenerate.
The discovery by London-based molecular biologists, Gillian Bates and Stephen Davies, of a key event in Huntington's disease (HD) has intensified research with the hope of finding a cure or therapy in the next ten years. Huntington's disease, like Alzheimer's disease, is a neurodegenarative disorder, and the research being done may have implications for AD. In HD, symptoms appear in middle age, with jerky movements, loss of memory and concentration, depression and mood swings. The gene for HD was discovered in 1993, and work with transgenic mice showed that it produced an abnormal protein which them "clumped" in brain cells. Work is being done in a number of scientific disciplines - chemicals to stop the "clumping", gene therapy, and looking for a way to delay the onset of the disease.
Watching AD patients make tea has allowed Sussex researchers to conclude that patients in familiar surroundings retain their ability to do tasks much longer as they can still pick up cues from where things are. As they often lose the ability to describe how to do the task, verbal tests to determine competence can sometimes lead to the assumption that they can no longer be independent.
American researchers have discovered an enzyme called Pin 1 in the brains of Alzheimer’s patients. This is a crucial component of other cells to allow them to divide, but it was an unexpected finding in brain cells. Pin 1 latches onto Tau protein which forms "tangles" – because the enzyme is responsible for getting cells back to normal after they divide – or it could be that Pin 1 is triggering them to form – because the enzyme readies cells for division by changing their shape. Whatever the outcome, the research will be valuable at looking at possible treatments. This work follows from research at the Oxford Network centre two years ago that identified abnormal expression of proteins involved in cell division in nerve cells in Alzheimer’s Disease.
A study in the Proceeding of the National Academy of Sciences suggests that the ability of stem cells (non-specific cells) to transform themselves might be useful in Alzheimer’s disease. Stem cells transplanted into the brains of mice spread and changed into the type of cell they needed by the brain.
Researchers in Nottingham have discovered how presenilin, a protein associated with familial early onset AD, is processed in the brain and how its levels are controlled, leading to hope of a better understanding of the mechanism of the disease.
Edinburgh scientists are doing a long-term study into the effect of stress – and the hormones this produces – on the part of the brain responsible for memory, the hippocampus. They will ask volunteers in their sixties to undertake intellectual tasks and give them MRI scans every 18 months to see if there is a link between stress and an increase in shrinkage in the hippocampus.
A recent report to the government on closing the gap between rich and poor on health recommends adding folate to flour as folic acid helps to prevent spina bifida and may be beneficial in preventing heart disease. Work by the Oxford team headed by the Chairman of ART's Scientific Advisory Board, Professor David Smith, leads them to believe that the risks for Alzheimer's disease may be the same as those for heart disease and other vascular disorders, so regular exercise and a good diet might be important.
Increased accuracy of diagnosis and an ageing population means that deaths recorded as being from Alzheimer's disease have increased twenty-fold in the last 15 years, the Office of National Statistics says, and it believes that death rates "greatly underestimate the burden of the diseases", as some studies indicate that possibly only a quarter of patients diagnosed with dementia have that recorded as the underlying cause of death. This means that it is still difficult to calculate the full cost to society.
9,000 preserved brains of those who were diagnosed at death as suffering from Alzheimer's disease are being examined to see that none of them died from Creutzfeldt-Jakob disease (CJD), a new variant of which, it is believed, may be caused by eating meat infected with BSE, and which has many similar symptoms.
World Alzheimer’s Disease Day, 21 September 2000
Hormones, Memory decline and Alzheimer’s disease
Dr. Eva Hogervorst, Oxford Project To Investigate Memory and Ageing,
Radcliffe Infirmary, Woodstock Road OX2 6HE, United Kingdom
Alzheimer’s disease is characterised by memory loss and other cognitive deficits and affects about 1 in 5 people aged over 80. The risk of developing Alzheimer’s disease is twice as low in men compared with women. It is possible that there are protective mechanisms in men. For instance, elderly men have higher levels of sex hormones, such as estrogens, than elderly women. After the menopause, levels of estrogens are very low in women. Animal studies have shown that estrogens can possibly have protective effects in the brain.
The abrupt decline in estrogens after the menopause is not necessarily accompanied by an abrupt decline in memory. However, it is possible that increasing estrogen levels with hormone replacement therapy could protect the ageing brain. Previous short experiments have shown that in healthy ageing women, hormone replacement therapy has small positive effects that include better memory functions. It is difficult to investigate long term effects in the population as women who choose to start using hormone replacement therapy are often healthier than women who do not; which could also protect them against memory decline. It is therefore currently unclear whether hormone replacement therapy can protect against the development of Alzheimer’s disease. Two large studies in the U.K. and the U.S.A. each including over 22.000 elderly women are currently underway to investigate this and should present their results in 2010 and 2006. Three large studies this year showed that in women already affected by Alzheimer’s disease, hormone replacement therapy does not slow down progression of the disease.
E. Hogervorst, J. Williams, M. Budge, W. Riedel & J. Jolles (In press) The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: A meta-analysis. Neuroscience (published by Elsevier)
This is a review of the studies done of the effect of hormone replacement therapy on cognitive function in healthy and demented women
A study published in the journal Neurology suggests that AD patients wander off not because they forget where they are going - a result of damage to the part of the brain responsible for memory - but because they are unable to sense direction and motion properly, due to damage in a different part of the brain. 6 out of 11 patients could not identify the direction of movement of a "snowflake" pattern on a screen, though all of the control volunteers could do so. These six also found it more difficult to perform a navigational test along a simple path, giving rise to the hope that there might be a way in the future to do a simple test to identify those with AD who are more likely to wander off.
A is for Aberdeen
- the start of a report on Centres participating in The Alzheimer's Research Trust Research Centre Network. Click here for more.
Professor Claude Wischik, the Network Centre Director at Aberdeen, is the recently appointed Professor of Psychiatric Geratology at the University and was formerly a Senior Research Fellow in Cambridge. He states, "The newly-established Network is an important step towards developing an effective new Alzheimer's disease research force in Aberdeen which will hopefully have the capacity to impact internationally in the field.
There are tremendous possibilities in Aberdeen to combine a powerful molecular research environment at the institute of Medical Sciences with sophisticated brain imaging technologies and also with clinical and health economic studies at the Aberdeen Royal Infirmary and Royal Cornhill Hospital. This is a winning combination."
Prof Wischik and his team have leading-edge technology which they hope to develop over a 5-year time scale into a preventative treatment for AD. A full development programme will require an investment of £2 million. Prof Wischik believes that dementia care in the Grampian region alone costs the health service £84 million per annum.
C is for Cambridge
(a Member of The Alzheimer's Research Trust Network). Click here for more.
(Network funding for each of the eight Members is approximately £12,000 per year to facilitate the exchange of information about research between scientists around the country via Network Co-ordinators and Network Administrators)
John Hodges, the Network Co-ordinator at Cambridge, is Professor of Behavioural Neurology at the MRC Cognition and Brain Sciences Unit and the University of Cambridge. He is Chairman of the British Neuropsychiatric Association and the World Federation of Neurology: Research Group on Aphasia and Cognitive Disorders. The Cambridge Network draws together researchers at Addenbrooke's Hospital, the MRC Cognition and Brain Sciences Unit, the MRC Laboratory for Molecular Biology, The Institute of Public Health, The Babraham Institute, The Brain Repair Centre and renowned departments of the University of Cambridge.
The groups comprising the Cambridge part of the Network have interests in the characterisation of Alzheimer's disease (AD) in its early stages, imaging techniques, neuropsychiatry, neuropsychology, clinical genetics, epidemiological studies of AD and basic biology. Frontotemporal dementia (Pick's Disease) is also a topic of major interest. Those from Cambridge who are participating in the Network have a phenomenal combined publishing record of more than 250 papers per year, greatly contributing to new information on the disease. Major discoveries made in recent years at Cambridge include:
C is for Cardiff
(a Member of the Alzheimer’s Research Trust Network). Click here for more.
Prof. Mike Owen, Head of Department of Psychological Medicine at the University of Wales College of Medicine and Art Network Co-ordinator in Cardiff, leads a team involved in searching for genes associated with late onset of Alzheimer’s disease (AD). The search for genes associated with early onset AD has been successful in isolating a number of genes which have helped in understanding the disease process, but early onset disease has a clear inheritance pattern which makes the associated genes relatively easy to find. Late onset AD is much more complicated and likely to be caused by both inherited and non-inherited factors, which makes studying its genetics more difficult. Prof. Owen and his team have a wealth of expertise in mapping disease genes in such complex disorders, and are applying their expertise to late onset AD with funding from ART and the Medical Research Council.
The Cardiff Group in collaboration with John Hardy (Mayo Clinic, Jacksonville, USA) and Alison Goate (Washington University, St Louis, USA) is currently completing a study of 600 pairs of siblings where both have late-onset AD, in order to locate the genes responsible for conferring susceptibility to the disorder. They have been studying the particular genes which could possibly be involved in the disorder and have identified a variation, or polymorphism, in a gene called DCPI, whose product is the angiontensin-converting enzyme (ACE), which seems to predispose people to develop AD. This enzyme is known for be important in body water balance, but was examined as a candidate gene for AD because of its know association with longevity.
Further studies are now essential to define the relationship of this gene to AD and to examine its possible role in the course of the disease. The ART network has funded a PhD studentship to carry out this work. Berwyn Lloyd will start work in Cardiff in Sept1999, with Dr Lesley Jones, Dr Julie Williams and Prof. Owen initially refining the genetic association with AD by looking at other variants in the gene and subsequently carrying out functional studies of the enzyme cells to examine the effect of genetic variations on activity on the enzyme. Berwyn graduated from the School of Biosciences at the University of Cardiff this summer, and has already had a year’s laboratory experience in many of the techniques required in the project as he undertook a 12 month practical placement during his four year undergraduate training.
As well as providing information about the association of AD and ACE, this project provides a good opportunity for a student to gain a wide variety of technical skills. Importantly, it also provides a blueprint for the analysis of other genes which prove to be associated with AD.
D is for Dundee
D is for Dundee - a Member of the Alzheimer’s Research Trust Network. (Network funding for each of the eight Members is approximately £12,000 per year to facilitate the exchange of information about research between scientists around the country via Network Co-ordinators and Network Administrators)
The Dundee Network centre is co-ordinated by Dr. Kieran Breen, Senior Lecturer from the Department of Pharmacology and Neuroscience at the University of Dundee, Ninewells Hospital and Medical School. Dr. Breen’s current research interests include the biochemical analysis of AD pathology - particularly the function and processing of the amyloid ß precursor protein. In collaboration with Dr. David Balfour, Reader in the Department of Pharmacology & Neuroscience, Dr. Breen has recruited a PhD student from Malta who will investigate both the behavioural and biochemical effects of nicotine on memory and behaviour.
The Dundee Network centre comprises 20 researchers and clinicians whose interests include the biomedical, behavioural and clinical aspects of Alzheimer’s disease.
Other research interests of those affiliated with the Dundee Network centre include:
The role of anti-oxidants in nerve cell survival
The relationship between lipid metabolism, inflammation and AD
Involvement in clinical research projects such as antipsychotic drug trials in AD.
The subjective experience of dementia and the implications for care and treatment.
Language and memory in Alzheimer’s disease.
a feasibility study into the possible applications of communication and information technology to assist people with dementia, such as memory aids, multi-media reminiscence experiences, information organisers for carers, and further ideas suggested by experts and carers.
Since Dundee became part of Alzheimer’s Research Trust Network, other activities have included:
Two public lectures at which five Alzheimer’s researchers and clinicians combined efforts to educate the lay public about current developments in Alzheimer’s research in Dundee and internationally and also about how these research efforts are currently incorporated into clinical practice. A similar lecture is planned as part of Brain Awareness Week (13 – 19 March 2000).
Co-hosting a workshop on ‘The Social and Medical Aspects of Dementia – Bridging the Gap’ with funds from the Scottish Hospital Endowments Research Trust (SHERT) in collaboration with the Centre for Social Research on Dementia, University of Stirling. The workshop brought together a diverse group of professionals including carers, old age psychiatrists, social workers, policy makers, GPs, and biomedical and social researchers from the Tayside area. Recommendations from the meeting will serve as a basis for future AD research.
a web site for the Dundee Network that includes information about the research conducted in Dundee, the Alzheimer’s Research Trust, and Alzheimer’s disease in general.
a monthly newsletter to the members of the Centre that contains information about research grants and events that relate to Alzheimer’s disease.
L is for London
(a Member of The Alzheimer's Research Trust Network)
(Network funding for each of the eight Members is currently £12,000 per year to facilitate the exchange of information about research between scientists around the country via Network Co-ordinators and Network Administrators)
The London Network centre is led by Professor Martin Rossor and focuses on the younger onset dementias. The group of more than 30 researchers provides a multidisciplinary approach ranging from collaborative work on the genetics of young onset dementia through to the emotional impact on carers of the frontotemporal dementias. A Cognitive Disorders Clinic provides a tertiary referral service for unusual and early onset dementias. A telephone advisory service was set up to provide information to patients, families, carers and all professionals involved in the management of this complex group of disorders. The CANDID (Counselling ANd Diagnosis In Dementia) Service was awarded the BUPA and Patient Association Award for Patient Communication in 1999.
A long-standing interest has been the study of familial dementias. Many of the degenerative dementias can occur as an early onset autosomal dominant disorder with clinical features that are similar to those without a prominent family history. These families provide the opportunity to locate the genes responsible for the disease and this has had a major impact on our understanding of the pathophysiology of familial Alzheimer's disease. The group in collaboration with John Hardy were the first to identify a disease mutation in the amyloid precursor protein gene that can cause Alzheimer's disease. Similar genetic studies in the familial non-Alzheimer dementias causing frontotemporal degeneration have identified mutations in the tau gene. However, it is clear that the genetic factors that influence the apparent sporadic cases are much more complex, as discussed by Professor Owen (C is for Cardiff).
The familial cases also offer an ideal opportunity for solving a number of clinical problems of early diagnosis. Since the disorders are autosomal dominant, 50% of children of an affected parent are likely to develop the disease which often starts at a relatively constant age within a family. Thus one can enter individuals into a study at a presymptomatic stage and follow them through the development of the very earliest abnormalities to established disease. Such research can be very demanding upon individuals who are already aware of their potential risk.
The group uses neuropsychological measures of language, perception and memory; biochemical measures and neuroimaging. It has focused on magnetic resonance imaging which can give very detailed structural information. Dr Nicholas Fox, MRC Clinician Scientist, has developed a technique for positionally matching volume images which are then directly superimposed or registered. This can provide a very precise measure of the amount of tissue lost. Using this the group has been able to demonstrate a clinical phase of tissue loss in Alzheimer's disease which recedes symptoms by a number of years. It has also explored environmental and genetic factors which may influence the rate of progression as measured by tissue loss.
To take some of the imaging research forward the ART have funded a PhD studentship for Rachael Scahill. Rachael obtained her Zoology degree from Oxford University and then did her MSc in Scientific Computing before joining the group in 1998.