Microsoft word - what_are_the_future_developments_of_alzheimer's_disease_research1 final.docx
WHAT ARE THE POSSIBLE FUTURE DEVELOPMENTS
OF ALZHEIMER’S DISEASE RESEARCH?
Alzheimer’s disease (AD) is mainly caused by tangles and plaques in the brain. AD research since the late 1970s has developed from discovering the gene ApoE4 in the 1990s to possible drugs today and the importance of AD research in terms of economic and medical costs in the UK. Preventative measures can be used in lifestyle or by therapeutic means e.g. AriceptTM or Ebixa®. Theories, possible cures, possible causes of AD and current research is detailed here i.e. NSAID therapy, use of stems cells, curing cerebral emboli, tau hyper-phosphorylation, stimulating the production of alpha-secretase, use of Seliligene and Vitamin E, Gingko Biloba, oestrogen therapy and the current research of a possible vaccine. The application details that the possible use of a vaccine, stem cell therapy and the Src family Tyrosine inhibitor is promising in the future of AD research. The moral and ethical issues are also considered from the AD patient’s perspective. It is the new research that will be responsible for developing the possible ‘cure’ of AD.
Alzheimer’s disease (AD) is a neuropsychiatric disease where there is an increased growth of tangles and plaques formed in the brain. Tangles are insoluble polypeptides made up of the tau protein which forms weak microtubules within the neuron. Plaques are an accumulation of beta amyloid fragments, snipped from an amyloid precursor protein, that are formed in between neurones in the AD brain.1
These plaques and tangles prevent the interactions between nerve cells, which will eventually cause brain cells to die and cause severe memory loss, severe behavioural imbalances and difficulty in communicating. Today in the UK, AD is the leading neuropsychiatric disease which is putting pressure on the geriatric wards of hospitals, care homes and the livelihoods of friends and relatives of those affected.
In the late 1970s - when new techniques and tools were used to explore and increase the understanding of the human body - AD research benefitted massively. In the 1980s the research was focussed towards the toxic proteins in plaques (tau) and tangles (beta-amyloid) which were affecting the interactions between nerve cells in the brains of AD patients. In the 1990s, scientists discovered the genetic link to AD in the mutated gene ApoE 4. It was this that accelerated the development of AD research. This lead to the creation of mice models and in 1992 the mutated gene was discovered in familial AD cases. By 2010, drugs such as Aricept™ (1997) Exelon™, Reminyl™ and Ebixa® (2004) had been developed and approved to help reduce the effects of dementia. These are now the four main drugs used today in the NHS.2
Today in the UK, £23 billion a year is being spent to help support AD patients, against £12 billion spent on cancer, and £8 billion on coronary heart disease (CHD). Each dementia patient costs the economy £27,647 per year compared with cancer’s £5,999 per year and CHD’s £3,455 per year. However, in terms of long-term social care systems, dementia costs
1 American Health Assistance Foundation 2009
£9 billion per year which is high compared to cancer’s £0.5 billion per year. When all of these costs are accounted for, dementia is the highest, costing 4 times more than CHD, stroke and cancer and yet the AD research funding per £1 million is only £4,882, which is approximately 26 times lower than cancer research’s £129,269 and also is far less than CHD research’s £73,153.3 In the 21stC, AD has proven to be very important new-age condition. It is mainly the ageing population who suffer from AD; 821,884 patients3 suffer from the symptoms of dementia, of
which 60,000 a year die from dementia, affecting more than 700,000 families.4 Prevention and treatment
At the moment, there is no real cure for AD, but there are therapies and treatments which are used to help reduce the effects and symptoms of dementia. These range from the use of drugs such as Aricept™; which prevents the enzyme acetylcholinesterase from hydrolysing acetylcholine in the brain allowing neuronal transmissions in the brain5 , and Ebixa® which blocks the excessive amounts of glutamate, produced by damaged neurons in AD patients, from interacting with the NMDA receptors in the brain which in turn reduces the toxicity of the excess glumate produced in the brain of AD patients6. Also creative and sensory therapies could be used which include aromatherapy and massage, drama, physical exercise, spending time in sensory rooms and reminiscence. All of these either help to reduce the growth of the toxic proteins (tau and beta-amyloid) or help to improve the neural pathways in the brain.
There are preventative measures that can be taken to help reduce the risk factor in one’s health by living a healthy lifestyle;
• Eating a healthy balanced diet, including folates found in leafy green vegetables • Avoiding smoking • Exercising regularly • Avoiding drinking excess alcohol • Staying socially active • Playing mind-stimulating games e.g. chess 7
This section will look into the factors that will help stop AD progression and the possible use of stem cells, drugs and other methods to prevent and cure AD. It is thought that there are many factors which affect the way a human thinks and processes thought and many hypotheses claim different factors are mainly responsible for the cognitive impairment in AD patients.
One theory stated by ‘PhysOrg.com’ that the neuronal cells of an AD patient are degenerated as AD progresses and may be caused by ‘inappropriate cell cycle control’. In recent research, it was found that in early stages of AD there is an ‘induction of neuronal cell cycles (CCEs)’ which instigates the growth of the disease in the brain, whereby it produces more tau protein. As a solution, non-steroidal anti-inflammatory drugs (NSAIDs), other than aspirin, were thought to help reduce and prevent AD as this was shown in mouse models. It was found in mice, that those taking ‘ibuprofen or naproxen’ had blocked further induction of new neuronal CCEs, yet the original neuronal CCEs continued to grow. This showed that using NSAIDs at an early stage of AD can help to protect against AD. The evidence suggests that this current research can be developed by performing clinical trials on humans with controlled types of NSAIDs and observe qualitatively their behaviour patterns by performing Mini-Mental State Examinations (MMSEs)8.
Current research states that the number of neuronal cells in the brain of an AD patient decreases as the disease progresses; this may be the reason why the patient would have a loss of memory and impaired communication. It was also stated by ‘ScienceDaily’ that ‘restoring destroyed neurons caused by Alzheimer’s is necessary for healthy brain functions’. This restoration of neurons could be performed by specialising stem cells into neurons, helping to increase the memory of AD patients by increasing the number of these stem cells in the hippocampus since in AD, it is these cells that degenerate and plaques start to build.9
Another cause of AD suggested by ‘BMJ’ is cerebral emboli which claim to cause AD to progress further. Cerebral embolism is the movement of a clot or matter e.g. atherosclerotic plaques in the aorta or from atrial fibrillation, from a part of the body to the brain. These emboli would cause a blockage in the artery to the brain, in particular the hippocampus, which would block the blood flow neurones need to function. This would only occur if there were spontaneous cerebral emboli (SCE) which would form small clots. When curing cerebral emboli during the mature stages, thrombolytic drug treatments and an embolectomy is now the main protocol in the NHS. SCE and the risk factors associated with it, such as poor diet and hypertension, would impair human cognition and will lead to the inevitable degeneration of neurons. Therefore the information suggests that earlier diagnosis of SCE is crucial for the patient in the future so AD can be avoided. 10
One of the causes of AD suggested by ‘De Felice FG et al’ is that beta-amyloid plaques induce tau hyper-phosphorylation. Phosphorylation occurs when a phosphate molecule attaches to a protein or organic molecule, which then either activates or deactivates an enzyme. ’De Felice FG et al’ have claimed that A beta oligomers (ADDLs) ’stimulate tau phosphorylation in mature cultures of hippocampal neurons and in neuroblastoma cells’ at the antigen binding sites where they have been ‘hyperphosphorylated in AD’. It was the ‘Src family tyrosine kinase inhibitor’ which had targeted the ADDLs and had ‘blocked their attachment to synaptic binding sites’; this in turn had prevented tau hyper-phosphorylation.
This therefore suggests that the uncontrollable tau growth in AD can now be inhibited and be prevented.11
Research into how to care for AD patients by using therapies to help prevent AD from progressing is also fundamental for the future developments of AD research. Antioxidants and amyloid drugs seem now to be the promising alternatives.
One theory suggests that amyloid production blockers work by blocking the toxic production of amyloid plaques .12 In normal brains, Amyloid Precursor Proteins (APP) are produced by healthy neurons, this then is hydrolysed by the enzyme ‘alpha-secretase’ which then produces ‘non-toxic’ proteins. In AD this protein is further hydrolysed by two other enzymes, ‘beta- and gamma secretase’ causing ‘shorter and stickier’ beta amyloid polypeptide chains to form, which can be joined together and stay soluble or fold into fibrils; both are believed to be toxic to the neurones. Having discovered these enzymes, the theory suggests that drugs can now be made to either stimulate ‘alpha-secretase’ or ‘block beta- or gamma secretase’ or even to develop drugs which inhibit ‘beta- or gamma secretase’. 12
‘AARP.org’ claims that antioxidants such as Selegiline and Vitamin E can help reduce AD as it helps to reduce the neuron degeneration in the brains of AD patients where Selegiline ‘inhibits the formation of free radicals’ in the neuronal tissue. Excitotoxins, found in the brain, are neurotransmitters which ‘stimulate communication between neurons’ yet too much excitotoxin will cause neuronal degeneration. This can be further worsened by free radicals caused by the result of neuron damage12, as they are highly reactive, causing ionisation in many types of tissues including neurons, making the excitotoxins more lethal. It is believed that these excitotoxins play some part in AD. Scientists in Columbia University found that when they tested Selegiline and Vitamin E in moderate AD patients, Selegiline and high doses of Vitamin E slowed the progression of AD. In 2002, two further studies were published which showed that those AD patients that had a diet high in Vitamin E had slowed progression of AD, despite whether the patient has the ApoE4 allele (the allele exposed in the mutated gene of some AD patients). So using this evidence, the research suggests that stronger and more powerful antioxidants could perhaps treat and prevent the disease. 12 At the moment, research is now being conducted by the National Institute on Aging to investigate whether the use of Vitamin E can safely and effectively prevent AD 13. Caution needs to be exercised with this approach, since high doses of Vitamin E can increase the risk of death e.g. if a patient suffers from haemophilia, Vitamin E can promote bleeding. 12
‘AARP.org’ suggests that ‘Ginkgo biloba’ extracts, specifically the ‘bioflavonoids’ (Natural Herbal Beauty 2009), can treat and prevent AD due to its antioxidant characteristics. It is shown in the ‘Cochraine Collaboration review’ that the effects of taking these extracts at less than 200 milligrams had improved ‘cognition, activities of daily living, and mood’ compared with those who took a placebo. Despite this, researchers do believe that these
studies of the effect on people must be re-evaluated and a larger extensive trial be taken before establishing the effectiveness of the use of ginkgo biloba in treating AD.14
Another possible preventative cure suggested by the ‘Institution on Aging’ in the University of Wisconsin claims that oestrogen therapy has the potential to expand AD research and help find the right treatment for women with AD as cures or preventative measures.15 Despite large studies indicating that oestrogen therapy after menopause increases the risk of dementia in female AD patients, ‘AARP.org’ claims that some researchers believe that there is evidence that oestrogen improves cognition in the brain. ‘Raloxifene’ is a ‘selective oestrogen receptor modulator’, which has the characteristics of oestrogen in some tissues but blocks oestrogen in other types of tissue. A trial of over 5,000 postmenopausal women with AD had found that over 66% were at less risk of developing cognitive impairment than those who took a placebo. This research continues in the University of Wisconsin where they are focussing on whether ‘raloxifene’, a drug used to cure osteoporosis and breast cancer, can improve the cognitive ability to carry out activities in daily lifestyles of female AD patients 14. Therefore, the research implies that perhaps in the future, drugs can potentially be produced to induce a more powerful form of oestrogen in female AD patients in order to improve the cognition in these people.
The hunt for a vaccine to ‘cure’ AD is one of the wonders that AD research is trying to make a reality, as ‘Cheryl A Hawkes et al’ claims that a type of immunotherapy can be devised to prevent or reduce the ‘beta-amyloid protein aggregation’. An active anti beta amyloid vaccination trial had taken place in AD patients with mild to moderate AD after the success of the use of passive and active vaccines in mice models. However, the trials came to a halt when 6% of those vaccinated had ‘developed aseptic meningoencephalitis’. Despite this, promising results had allowed this research to be continued as they indicated that the vaccine might be a possible treatment of AD, that is if the ‘harmful proinflammatory processes’ can be evaded. These results included:
• 4 of the inoculated treated with ‘AN1792’ had showed signs of plaque degeneration • Decreased T lymphocytes in 3 of the patients • An increased improvement of ‘antibody responders’ in memory tasks
In the past 10 years, there has been a development in possible immunisation tactics which help to increase more anti beta amyloid antibodies which specifically target and eradicate beta amyloid plaques without instigating ‘autoimmunity’. These methods include:
• Targeting beta amyloid epitopes • ‘antibody and adjuvant modifications’ • ‘alternative routes and mechanisms of vaccine delivery’
Currently research is still ongoing in the passive vaccination approach and will show the ‘effectiveness’ of these newly developed vaccines in these clinical trials and will also increase
the understanding of the responsibility of the beta amyloid protein in the ‘pathogenesis of the disease’. 16
All of the theories above outlined how cognition in the AD brain could be improved or suggested possible cures and treatments of AD. Only a few of these theories will be developed into treatments for AD. The most effective of these theories may be the replacement of degenerated neurones in the hippocampus of the AD brain by the use of stem cells, the use of ‘Src family tyrosine kinase inhibitor’ to block the ADDLs from binding to the synapses of neurons and the possible vaccine for AD.
The success of animal testing for AD research, by using ‘mice models’, showed that a possible cure for AD is nearing, but could these methods be used in order to help defeat AD? I suppose that with extensive research of stem cell use in the brain, research into the intake of the inhibitor and the vaccine, techniques can be developed to either slow the progression of AD or even prevent AD. This would be conducted by taking healthy stem cells from a healthy patient - possibly from a sibling or close relative with a close genetic match - and then differentiating stem cells into neurones similar to those healthy neurons in the AD patient and then simply replacing them back in the hippocampal area of the brain either by means of injection or at cellular level and controlled growth of these neurons. In this way, cognition can be regained and so will potentially reduce the effect of AD. Using the inhibitor approach, bacterial cells could be genetically modified using the human genome responsible for the synthesis of the ‘Src family tyrosine kinase’. It is the secretion of inhibitor from these bacterial cells which would be injected via the parental route or directly to the hippocampus of the AD patient. From the vaccine approach, I believe that, using passive methods, it would be possible to create ‘dead’ beta amyloid plaques by making the beta amyloid epitopes on the ‘dead’ protein. This could then be injected into the body via the veins or directly to the hippocampus where the neuron degeneration would occur in AD. This would then induce an increase in beta amyloid antibodies by the production of specific B lymphocytes which will later differentiate into memory cells which will help the patient in delayed immune response.
From this study, I would encourage all three methods to be directed towards the hippocampus in the brain with the aim of either differentiating into neurons in the brain or by blocking the ADDLs which instigate tau hyper-phosphorylation or by introducing ‘dead’ beta amyloid plaques which instigate the production of beta amyloid antibodies or by using the vaccine approach.
If a suitable and clinically-proven ‘cure’ can be devised to bring an end to AD, I think that we would be able to achieve in the UK:
• Reduced stress of carers • More people living into older age
• Having improved cognition in old age, allowing the possibility of increasing the
• Being less risk to neuropsychological diseases such as dementia • Less money being spent for care of AD patients • A decreased demand of social care and other specialist geriatric care in the UK
Moral & Ethical Issues
The ethical issues that surrounds the AD research are becoming more and more complex. This is more so when the financial constraints of AD research are added to the scenario.
The issues in AD research could be outlined as follows:
Risk: - the various researches should have minimal risk to the individual. The problem of not getting a response of how the AD patient feels in terms of clinical care, as they cannot communicate, could be a problem i.e. how to look after them in such a situation.17
Benefits: - if the research is of potential benefit to the lives of the AD patients then it could be ethically right, otherwise the ethical issues of carrying out a research would affect patient autonomy and ‘doing good to the patient’ approach.17
Consent: - will always be an issue as the patient is not competent in giving informed consent depending on the state of the illness, but if there is a consent which has already been given by the patient and is in place, then there should not be a problem to go ahead with AD research. However, the right not to get involved in the trial at any stage of the research i.e. ‘I have changed my mind’ factor will not be there, may be disadvantageous to the patient.17
Available Proxy: - making a decision by the family member or care giver, which may have conflict with the advance directive from the patient; in such cases a directive from an institutional review board would reduce the risk and could be justified in the case of AD research.17
There are some patients who have regained some cognitive function and should have their say in the decision making process. It is always expected to ensure proper safeguards are in place when the risk to the individual is involved. 17
I think that an integrated approach to the management of AD can be the cornerstone as it might help with the start of the disease; patients should be given lifestyle advice and mind-stimulating activities, together with NSIADs. This perhaps could be performed in a programme by which patients diagnosed with AD can be channelled into; which could be funded by the NHS. Stem cell research towards neuronal repair, prevention of tau protein hyper-phosphorylation and the use of antioxidants should be tried in patients with AD. Even Gingko Biloba could be used for people over 50’s for the prevention of AD. Though the costs of these regimes is potentially a large sum of money but it is worth paying as there will
be an increased number of people in the ageing population and so will be the number of AD patients in the near future.
I also think that the trials being conducted for AD research that are needed to be done need to compare treatments together so that there can be a differentiation between the different approaches to ‘curing’ AD; this could be in terms of the cost of the treatment, the effectiveness of each drug in comparison to other treatments and the ease of prescription e.g. ibuprofen could be prescribed to AD patients with ease as its very cheap to produce the drug.
Currently many AD treatments are being developed and applied in the medical profession and large amounts of research are being conducted to help find the ‘cure’ to AD. The use of stem cells, the use of the Src family Tyrosine kinase inhibitor and the possible use of a vaccine has significant potential. It is the new research that will eventually bring this potential to reality and is trying to overcome the practical, scientific, moral and ethical issues which are expressed in this paper.
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CURRICULUM VITAE Date of birth: Address: University Heart Center, Hamburg Clinic for General and Interventional Cardiology Specialty: Scientific career: 1989 - 1996 Studies of Medicine at Johannes Gutenberg-University, Mainz, Johann Wolfgang Goethe-University, Frankfurt and Mount Sinai Medical School, New York 1996 - 2002 Wissenschaftlicher Assistent (resident and f