CASE STUDY 1 The person with Alzheimer’s disease Traci Whitfi eld CASE AIMS After examining this case study the reader should be able to: • Briefl y explain the role of neurotransmitters at a synapse. • Outline how the brain normally creates, stores and retrieves memories. • Describe the pathophysiology of Alzheimer’s disease. • Explain the three stages associated with Alzheimer’s disease. • Demonstrate an understanding of the mode of action and side- effects of donepezil • Discuss the role of the nurse in advising relatives regarding the medication.
Mr B is a 76- year- old man who was diagnosed with Alzheimer’s disease, stage one, six years ago and is being cared for at home by his wife. He has a very poor short- term memory and is unable to care for himself without assistance. He wanders around a lot and has been found outside at night several times, which causes his wife great concern. Despite living in the same house for 16 years, Mr B does not recognize his house when he wanders out and so is unable to fi nd his way home. 1 Before Mr B was diagnosed with Alzheimer’s disease, how would his neurons have communicated with each other? 2 How would Mr B’s brain have normally created, stored and retrieved his memories? 3 What is thought to be happening in Mr B’s brain in order for him to be displaying signs and symptoms of Alzheimer’s disease? 4 What will be the main effects of the disease on Mr B as it progresses through its 4 Traci Whitfi eld
Mr B is prescribed 10mg donepezil at night, but his wife feels he may be having side- effects. Mrs B has expressed concern that her husband is suffering from lack of appetite, weight loss, diarrhoea and insomnia, and as a result he has been reviewed by a specialist who has suggested Mr B should switch to memantine. 5 How do donepezil and memantine work? 6 What side- effects would you look for in Mr B while he is taking these medicines? 7 What advice would you offer to Mrs B about her husband’s medication to assist her understanding of its role in his care? Before Mr B was diagnosed with Alzheimer’s disease, how would his neurons have communicated with each other? Neurons communicate with each other across gaps or synapses that occur between them. In order for the signal to pass from one neuron to another across these synapses, the body would have produced neurotransmitters such as acetylcholine, glutamate and dopamine. Initial impulses would travel along the neurons and at the point where they meet the synapse cause vesicles containing neurotransmitters to release their contents. The neurotransmitters would then cross the synapse to the next neuron and attach to receptors on its surface in order to either excite or inhibit it. If enough excitatory neurotransmitter stimulates the receptors then a new impulse is generated and passes down that neuron. Very soon after, the neurotransmitter is removed by being broken down by an enzyme or neuronal reuptake taking place. Through this process Mr B’s brain would be able to undertake complex functional activity (Krumhardt and Alcamo 2010). How would Mr B’s brain have normally created, stored and retrieved his memories? HIPPOCAMPUS
The main area of the brain which processes new memories is located in the temporal lobes. Deep within each lobe is a banana- shaped structure called the hippocampus which is involved in transferring the newly acquired memories into long- term storage in an area of the brain known as the neocortex. The neocortex itself forms part of the cortex (or outer layer) of the cerebral hemispheres. The hippocampus communicates with the neocortex by way of other partnership structures, the most important of which is the enterhinal cortex (Amaral and Lavanex 2006; Marieb 2010). This communication method is so effective that it means the hippo campus can not only store memories but also retrieve them. Put simply, it acts in the same way as a search engine on the internet, searching quickly and effectively through the memories stored in the neocortex and retrieving those of relevance. These memories can then be used as a basis for other brain functions such as repetition, analysis, interpretation and
The person with Alzheimer’s disease 5
assimilation. Without this fundamental ability, Mr B will ultimately be unable to carry out forward planning, learn new skills or create new thoughts (Kerr 2007). TEMPORAL LOBES
The specifi c function of the hippocampus has been described above and this demonstrates the importance of the temporal lobes in learning. Naturally, the temporal lobes also have other functions which are important. Of particular note is that the right lobe stores visual memory while the left lobe stores verbal memory, whereas both lobes are associated with the sense of smell and taste. What is thought to be happening in Mr B’s brain in order for him to be displaying signs and symptoms of Alzheimer’s disease?
Evidence of two primary destructive processes is found in the brains of people with Alzheimer’s disease. Both processes are involved in the death of neurons, although the exact mechanism and sequence of events is not yet fully understood (Downey 2008). The fi rst process results in the development of beta- amyloid plaques and the second in neurofi brillary tangles. BETA- AMYLOID PLAQUES
Amyloid plaques are made up of abnormal, fi brous beta- amyloid protein fragments – degenerating neurons which have fused together with aluminium deposits (Lazenby 2011). The sticky amyloid protein material accumulates between the cells, slowing transmission of impulses (Downey 2008), but it is unclear whether the formation of the plaques is the cause of neuron damage or is the body’s response to existing damage and is intended to restrict damage by ‘walling off’ damaged cells (Janicki and Dalton 1999). Since the plaques are found mainly in the hippocampus, they mainly affect the formation of memories, and this results in diffi culty in retaining and recalling information, which presents as forgetfulness. NEUROFIBRILLARY TANGLES
Neurofi brillary tangles are found inside the neurons. The tangles consist of strands of abnor- mally twisted proteins such as tau, which destroys the neuron from the inside outwards. Tau protein in its normal state is required for growth and development of strong neuronal axons and it is only when it is hyperphosphorylated that it forms the tangles. This progressively makes it diffi cult for signals to travel across the cells in the brain (Parsons et al. 2011). In the earliest stages of Alzheimer’s, tangles are found mainly in the enterhinal cortex, and this interferes with the ‘search engine’ function of the brain described above. Later, the tangles appear in the hippocampus, which affects memory formation, and throughout the whole neocortex of the brain, affecting the function of whichever part of the brain is the host.
The net effect of cell loss is that over time the cerebral cortex atrophies: the brain tissue
itself appears shrunken, the ventricles in the brain enlarge and there is vascular degeneration. This is most noticeable in the frontal and temporal lobes (Lazenby 2011). Nerve cell loss due to the two previously outlined processes affects the production and release of neuro-transmitters in the brain. 6 Traci Whitfi eld
The neurotransmitter system most affected is the cholinergic system, which is affected by cell loss, particularly in the frontal lobes and hippocampus. This causes a marked reduction in levels of the neurotransmitter acetylcholine in the brains of sufferers. Acetylcholine is impor- tant in the formation and retrieval of memory and so its lack is also thought to lead to the functional defi cits of Alzheimer’s disease. However, reduced production of other neurotrans- mitters such as noradrenaline and serotonin is also a feature of Alzheimer’s disease which may contribute to behavioural and cognitive symptoms (Desai and Grossberg 2005).
Glutamate is the main neurotransmitter in the brain and is involved in all aspects of cognitive function. Glutamate and its receptors are involved in a process called long- term potentiation which is important in learning and memory. The activity of this system is greatly infl uenced by the activity of the cholinergic system as described above and so is adversely affected in Alzheimer’s disease (Francis 2003). One kind of glutamate receptor called N-
aspartate (NMDA) is prevalent in the brain and especially found in the same areas as the neurofi brillary tangles and amyloid plaques typical of Alzheimer’s disease.
Glutamate and its stimulation of NDMA receptors play an important role in memory
formation and learning (Clayton et al. 2002). Therefore, loss of the pyramidal neurons which produce glutamate results in a lack of glutamine and so affects both these functions. Effective functioning of the NDMA receptors at the synapse is also important. In Alzheimer’s disease, the presence of small amounts of beta-amyloid protein effectively ‘short circuit’ the synapse. This is partly because the beta amyloid causes the uptake of glutamate by the synapse to be reduced and the amount outside the synaptic terminal therefore builds up, which then increases the NDMA receptor excitability.
Although lack of glutamate causes features associated with Alzheimer’s disease, the
progression of the disease itself is actually hastened by the action of glutamate, which is a neurotoxin. In Alzheimer’s disease there is an impaired ability to maintain the normal elec-trical membrane potential of the neuron, which means the membrane potential becomes less negative. This in turn means that NDMA receptors and their associated ion channels become more easily activated and so more excitable. Glutamate causes over- excitation of the neuron in this circumstance and so causes neuronal damage and death. What will be the main effects of the disease on Mr B as it progresses through its
Alzheimer’s disease can be described in three stages:
• Stage 1 presents in the fi rst four years and the person is usually forgetful and often has
diffi culty recalling events from their short- term memory, even when reminded. They often suffer a loss of interest in what is happening around them, their environment and the people they know. They may also fi nd it diffi cult to make decisions and use their initiative. • Stage 2 can present anywhere within 2–12 years of onset and the memory loss is more
obvious and extends beyond short- term memory. The person may be unable to care for
The person with Alzheimer’s disease 7
themselves properly, to follow simple instructions or carry out simple activities. They may wander, especially at night, and become lost even in a familiar environment. The person may show signs of anxiety, anger and paranoia or act in a disinhibited manner. They may lose insight into their disease and may struggle to communicate effectively. • Stage 3 is the fi nal stage where the person with Alzheimer’s disease becomes unable to
communicate and fails to recognize close family and friends. They may stop eating and drinking, be unable to maintain their own safety, lack the ability to care for even their basic needs and become incontinent of urine and faeces (Nair and Peate 2009). How do donepezil and memantine work? DONEPEZIL
Donepezil is used to enhance the brain’s cholinergic system and so reduce the features of Alzheimer’s disease which are associated with defi ciency of the neurotransmitter acetylcho-line. It is an acetylcholinesterase inhibitor which means that it works at the synaptic junction by blocking the enzyme responsible for breaking down acetylcholine. This means that the action of acetylcholine at the cholinergic nerve synapses is prolonged and is therefore more effective. MEMANTINE
Memantine is intended primarily to reduce nerve cell death from the adverse effects of glutamine. When glutamate is present at the synapse at normal levels it enhances memory and learning. However, if the level rises excessively then glutamate seems to overstimulate the NMDA receptors, allowing a prolonged infl ux of calcium ions into the brain cell. The infl ux leads to over-
excitation of the nerve cell (excitotoxicity) which results in the
death of that cell. Memantine blocks the NMDA receptors to reduce the excitotoxicity and enables preservation of the physiological functioning of the NMDA receptors, as they can still respond appropriately to glutamate if levels of the neurotransmitter are high enough (NICE 2011). What side- effects would you look for in Mr B while he is taking these medicines? DONEPEZIL
effects of donepezil are related to the cholinergic properties of the drug.
Gastrointestinal upset such as nausea, vomiting and diarrhoea resulting in weight loss are the main side- effects. Other signifi cant side- effects include bradycardia, syncope, headache, dizzi-ness, hallucinations and aggression, with some patients reporting diffi culties in sleeping or vivid dreams (BNF 2012). MEMANTINE
Memantine is generally well tolerated but the main side- effects are constipation, dyspnoea, hypertension, dizziness, drowsiness and headache (BNF 2012). 8 Traci Whitfi eld What advice would you offer to Mrs B about her husband’s medication to assist her understanding of its role in his care?
It is important that Mrs B recognizes that Alzheimer’s disease is progressive and that Mr B will continue to deteriorate regardless of whether he is treated or not. She needs to under-stand that the medication will not cure or arrest the degenerative process as neuronal loss is ongoing, but that the decline in function may be slowed. The aim is therefore to preserve synaptic function to allow Mr B a higher functional level for longer than if he had not received treatment (Downey 2008). This should be conveyed to Mrs B in the way that she herself feels suits her best and, as with all information, it is advisable for the nurse to offer more than one form of giving information in order to allow Mrs B the opportunity to consider it in further depth later.
Mrs B should have realistic expectations of the medication. Donepezil aims to assist the
nerve to function and so may slow cognitive decline, and this in turn may delay the emergence of the behavioural features of Alzheimer’s disease (Cummings 2004). It is generally used for treatment of mild to moderate Alzheimer’s disease which is why it was originally prescribed for Mr B. Memantine aims to protect the nerve against further damage from overstimulation by one particular chemical (glutamate) and therefore may reduce deterioration in the overall condition. It does not appear to have much benefi t in mild to moderate Alzheimer’s disease (Schneider et al. 2011), therefore Mr B will only be prescribed the medication if he has moderate disease and is not tolerating the donepezil or has more severe disease which is not responding to donepezil. As his carer, Mrs B’s opinion on her husband’s condition will be sought both before starting new treatment and during the treatment because treatment should only continue if it is felt to have a worthwhile effect on Mr B (DH 2009).
Currently it is not recommended that donepezil and memantine are prescribed together
(BNF 2012), so Mr B would stop taking donepezil if prescribed memantine. Mrs B should be aware that if her husband restarts donepezil at any point he will need to start on a lower dose than he currently takes and that the dosage will be titrated back up over a period of weeks (Downey 2008).
If Mr B is prescribed memantine, his wife may notice an initial worsening of his cognitive
function due to antagonism at certain (nicotinic) acetylcholine receptors in the brain. Since these receptors soon ‘upregulate’ in response to the antagonism, long-term memantine treat-ment should have an overall positive effect (Chen and Lipton 2006). Not all those who take memantine for an extended period of time demonstrate palpable benefi ts, but those that do may show a moderate decrease in clinical deterioration and a small positive improvement in cognitive and self- care functions, as well mood and behaviour. Mrs B should be made aware that this may happen so that she knows what to expect.
Mrs B will need to know what side- effects may occur so that she can alert Mr B’s doctor
to them. When discussing donepezil the nurse should advise Mrs B that should vivid dreaming be a problem, the drug can be switched to morning administration which often improves sleep quality. In addition, Mrs B should be advised that due to the potential gastrointestinal side- effects, it is better for Mr B not to take donepezil on an empty stomach, whereas this is not an important consideration when taking memantine. Although the pharmacist will ensure that prescribed drugs are checked for interactions, Mrs B should be advised that she should check with the pharmacist about the suitability of any non- prescribed medications that Mr B might take – for example St John’s wort, which can decrease the effect of donepezil (Downey 2008).
The person with Alzheimer’s disease 9 KEY POINTS • Neurons communicate with each other across gaps or synapses that occur between • The hippocampus and temporal lobes are important in memory. • Alzheimer’s disease results in selective loss of neurons and their synapses, espe- cially in areas such as the hippocampus and neocortex. • The main pathological processes result in the development of beta- plaques and neurofi brillary tangles. • Treatment with an acetylcholinesterase inhibitor such as donepezil is recom- mended in mild to moderate Alzheimer’s disease. • Memantine is recommended for severe Alzheimer’s disease or moderate disease where acetylcholinesterase inhibitors are not tolerated. • It is important that the person’s signifi cant family members understand that Alzheimer’s disease is progressive and that their relative will continue deterio- rating regardless of whether they are treated or not. REFERENCES
Amaral, D. and Lavenex, P. (2006) Hippocampal neuroanatomy, in P. Andersen, R. Morris, D. Amaral,
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BNF (British National Formulary) (2012) BNF 63: March. London: Pharmaceutical Press. Chen, H.S. and Lipton, S.A. (2006) The chemical biology of clinically tolerated NMDA receptor antago-
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Nair, M. and Peate, I. (eds) (2009) Applied Pathophysiology: An Essential Guide for Nursing Students.
NICE (National Institute for Health and Clinical Excellence) (2011) Technology Appraisal 217:
Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer’s Disease (review). London: NICE.
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