Alzheimer's and other dementias.
Dementia is an irreversible, slow deterioration in cognition. The most common form of dementia is Alzheimer's disease but other forms include vascular and fronto-temporal dementias. The greatest risk for the development of dementia is age: 40 per cent of people over the age of 85 develop dementia.
According to Alzheimer's New Zealand, there ore 44,000 people with diagnosed dementia in New Zealand, but this is likely to represent only 60 per cent of actual cases. The emotional, social and economic costs of dementia ore enormous and likely to increase as the population ages.
Dementia con be neither prevented nor cured. Our understanding of its causes has improved in recent veers, but there is still o great deal to learn. Accurate and early diagnosis is becoming increasingly important as the development of drugs end other therapies aimed at modifying or retarding the progress of the disease becomes more feasible.
Dementia describes a clinical syndrome where progressive loss of memory, cognitive and emotional function interferes with daily living and quality of life. Alzheimer's and other dementias are major causes of disability and dependence in older adulthood, more than doubting the risk of institutionalisation. (1) Worldwide, dementia prevalence in 2000 for the over-60s was 24.3 per million of population. (2) This is expected to rise to 81.1 per million by 2040, driven by increasing life expectancies in middle and low-income nations. A similar increase in prevalence is expected in New Zealand as the population ages, to 146,000 people by 2050. (3)
Rates of dementia increase with age, doubting every five wears over the age of 65. Over 85 years of age, one in three people are diagnosed with dementia. (4) However, dementia is not an inevitable outcome of ageing, and mild cognitive impairment is a separate condition. (5)
Dementia is associated with signs and symptoms that vary between individuals, and over time, but generally include: (6)
* Cognitive impairment, affecting memory, speech, language and orientation to time and place.
* Behavioural and neuropsychiatric effects: mood disorder, psychoses, agitation, wandering or incessant pacing.
* Impaired self-care: toss of ability to perform household tasks, bathing, dressing, eating.
The main cause of dementia is Alzheimer's disease, accounting for up to 60 per cent of all cases. Other causes include vascular dementia, where there is impaired blood flow to the brain, fronto-temporal dementia, Lewy body dementia (associated with Parkinson's disease), alcohol-related dementia, and Creutzfeldt-Jakob disease. Many dementias appear to have mixed aetiologies on autopsy; for example, Alzheimer's disease is often accompanied by cerebral vascular impairment and vice versa, white Lewy bodies are frequently found in association with the neurological lesions of Alzheimer's. (7)
The precise mechanisms involved in the development of dementia remain largely unknown and are subject to considerable debate. Regardless of underlying events, prolonged inflammation and oxidative damage to neurons and synapses are thought to be a significant cause of toss of function associated with all forms of dementia. (8)
PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE
German neuropathologist Alois Alzheimer and colleague Emil Kraepelin first described the plaques and tangles of Alzheimer's disease, following an autopsy of a woman with dementia at the start of the 20th century. Since then, these have been revealed as accumulations of two separate proteins in the brain: beta-amyloid peptide and tau proteins. The association of these molecules with Alzheimer's is undisputed, but their presence in the autopsied brains of up to 40 per cent of older people without dementia leaves some questions as to whether they are the cause, coincidental or a physiological response to Alzheimer's. (9)
These peptides (protein fragments) arise during normal metabolism. They are derived from amyloid precursor protein (APP), which is found in the membranes of all cells and involved in cell communication, cholesterol processing and synaptic formation and repair. APP is normally inactivated through cleavage by enzymes to form shorter beta-amyloid fragments. In the brain, these are then further degraded or taken up by microglia (immune cells in the central nervous system), or cleared across the blood-brain barrier to the general circulation.
Normal levels of beta-amyloid are thought to play a part in regulating excitatory neurotransmission in the brain, preventing hyperactivity at synapses. Insulin-degrading enzyme is one of the enzymes involved in breaking down beta-amyloid. Loss of this enzyme in mice has been shown to cause accumulation of plaques. (4) Genetic forms of Alzheimer's disease, including trisomy 21 (Down's syndrome), invariably involve mutations related to beta-amyloid.
Abnormal cleavage, or failure to dear beta-amyloid peptides, causes them to accumulate into oligomers (two to 12 peptide strands joined together), fibrils and plaques. The oligomers are toxic to neurons, causing synaptic dysfunction and neuronal cell death. (2,4) As they are taken up by the microglia, these oligomers cause abnormal inflammation and the release of reactive oxygen species that further damage neurons and trigger chronic inflammatory processes in the brain. Beta-amyloid oligomers assemble into fibrils and plaques that are insoluble and cause dysfunction by displacing neuronal processes. Accumulation of beta amyloid plaques may precede the clinical appearance of Alzheimer's by many years.
Toxic concentrations of beta-amyloid inside neurons are thought to trigger abnormal tau protein aggregations.
The tau protein is a major constituent of microtubules in neurons. Microtubules are assembled and disassembled to allow transport of macromolecules along the axons and dendrites of neurons. Lack of tau causes microtubules to become unstable and disassemble. In Alzheimer's disease, fronto-temporal dementia and some other conditions (termed tauopathies, eg Pick's disease) tau becomes phosphorylated and joins to form filaments. These are neurotoxic and eventually form neurofibrillary tangles, disrupting structure and function in the neurons. (2,4) Mutations in the gene encoding for tau protein have been detected in fronto-temporal dementia, but not in Alzheimer's disease. Accumulation of abnormal tau in Alzheimer's is attributed to beta-amyloid, oxidative stress and age-related deterioration in cellular protein repair mechanisms. (4) There is a strong correlation between high levels of phosphorylated tau in the cerebro-spinal fluid and early Alzheimer's disease.
Apolipoprotein E (ApoE)
ApoE is also implicated in the development of Alzheimer's disease. This signal molecule is involved in the normal metabolism of cholesterol, where it is found as part of the chylomicron (transporting absorbed lipids into the systemic circulation and to the liver) and intermediate density lipoproteins (IDLs) that facilitate transport of cholesterol and triglycerides both in the systemic circulation and in the brain. ApoE also plays a role in inflammation and immunity.
There are three known genetic variants of ApoE: ApoE3 is "normal", whereas ApoE2 and 4 are considered abnormal People carrying two copies for the E4 variant in their genes have up to 30 times the risk of developing Alzheimer's disease than the general population. Indeed, the presence of ApoE4 is considered the most significant risk factor for Late-onset Alzheimer's. By contrast, ApoE2 appears to provide some protection against Alzheimer's. (10)
The mechanisms by which ApoE contributes to Alzheimer's are not well understood. There are two main approaches. Firstly it is theorised that ApoE4 is toxic and causes or contributes to beta-amyloid plaque formation (possibly through an inflammatory process), or reduced clearance of beta-amyloid; secondly, that the presence of ApoE4 diminishes the beneficial functions of ApoE3. (11) ApoE3 modulates the inflammatory response in the brain and is also the main transport mechanism for cholesterol in the central nervous system. (10) The brain contains 25 per cent of the body's cholesterol, where it is essential for development and modulation of synaptic connections in the brain--plasticity that is the basis for developing and retaining memory and other higher functions.
Alpha-synuclein: Alpha-synuclein is a protein found in neurons that is thought to play key rotes in synaptic remodelling and in microtubule transport. Alpha-synucelin has been found in association with beta-amyloid plaques in Alzheimer's disease. More importantly, it is the main protein in the plaques of Lewy bodies associated with the dementia of Parkinson's disease and other neurodegenerative disorders. As with beta-amyloid, the effects of alpha-synuclein are thought to be due to either neuronal toxicity, or the triggering of prolonged and abnormal inflammation in the brain. (12)
RISK FACTORS FOR DEMENTIA
Some forms of Alzheimer's disease are caused by mutations in specific genes encoding APP and the enzymes that cleave it. However, these mutations account for only five per cent of Alzheimer's cases, where the onset is early middle-age. A genetic predisposition to late-onset dementia is shown by the 60-80 per cent hereditary risk. (10) However, a genetic predisposition does not necessarily Lead to the development of dementia, as environmental risk factors are also involved.
Modifiable risks for Alzheimer's disease include cardiovascular and cerebrovascular disease, type 2 diabetes or glucose intolerance, severe head injury, smoking, high alcohol intake and obesity. (4,5) Low cognitive reserve (a combination of level of education, occupation and mental activity) is a further modifiable factor. Lifestyle modification to reduce these risk factors, including increases in physical, mental and social activity, are suggested as strategies to reduce risk but the evidence for these is based on epidemiological studies with, as yet, little hard science to support their implementation.
DIAGNOSIS OF DEMENTIA
There are numerous conditions that may contribute to cognitive impairment in the older adult and that can be mistaken for, or contribute to, worsened impairment in dementia. Any diagnosis of dementia must have previously excluded these conditions, many of which are treatable: (7,13)
* Effect of drugs or alcohol
* Subdural haematoma, cerebral tumour or normal pressure hydrocephalus
* Vitamin B12 deficiency
For hospitalised patients, or those in long-term care, there may be some misperceptions around differences between dementia, depression and delirium. It is important to distinguish between these. Delirium or severe depression may present similarly to dementia, they may be present at the same time, and each may contribute to worsening of the other conditions. Delirium is almost always treatable and depression often so. Table 1 (see right) presents the key differences in these three conditions.
The risk of developing delirium is increased in the presence of dementia, stroke or Parkinson's disease, and with older age. Immediate causes of delirium include infection (eg sepsis, urinary tract, pneumonia), dehydration, poly-pharmacy, poor nutrition, immobility and general anaesthesia. (14) All these risk factors may be present in an older adult or in someone with dementia, so onset of delirium may be mistaken for a sudden worsening of dementia.
Early diagnosis of Alzheimer's and other dementias is seen as essential in the coming years for a number of reasons: (15)
* It allows forward planning for individuals and their families, including the ability to make decisions about future care and end-of-life treatment.
* It allows access to drug and other therapies that may slow cognitive deterioration and improve quality of Life.
* Early support can be provided for families and caregivers.
* It allows opportunities to participate in research for new dementia therapies.
* Early intervention may delay institutionalisation.
Diagnosis currently relies on the appearance of clinical features of dementia. Internationally, there is a search for simple biomarkers of Alzheimer's that would allow diagnosis very early on, or even before the appearance of the disease.
The presence of phosphorylated tau in cerebrospinal fluid is correlated to onset of Alzheimer's but this involves a high-risk procedure. Alzheimer's-specific proteins or antibodies in the blood are being sought as early markers of disease, with variable results, although there is some promise of future success. (16)
Research into treatments aimed at preventing or reversing Alzheimer's is limited by lack of knowledge about the mechanisms involved in development of the disease, and by lack of clarity about the roles of abnormal proteins such as beta-amyloid and tau. Drugs targeting these proteins have been developed but have had limited success in clinical trials. (17)
Antibodies to beta-amyloid, such as bapineuzurnab and solanezumab, are undergoing phase III clinical trials. White they reduce the amount of beta-amyloid plaques in the brain, there is, as yet, little evidence they improve cognitive function. This may be due to the delay between development of plaques, which can be present 20-30 years before symptoms, and diagnosis. (17)
Other drugs in development are aimed at the enzymes that phosphorytate tau. One of these drugs is lithium but early trials of it for treatment of Alzheimer's have been inconclusive. (17)
Therapies aimed at preserving remaining function have shown some promise. Drugs used to reduce cardiovascular risk (statins and antihypertensives) may also preserve neuronal function to some degree. (18) In the United States, a research group is administering a gene for nerve growth factor to at-risk neurons via brain surgery. This slows cognitive decline but is not a cure. (17)
The association of dementia with diabetes and insulin dysfunction in the brain has lead to some research in the field of insulin-sensitisers (eg rosiglitazone) but, like other drug therapies, results are less than conclusive.
Drugs that have been demonstrated to slow the toss of cognitive function in dementia include cholinesterase inhibitors. Neurons that use acetylchotine as a neurotransmitter appear to be particularly affected in Alzheimer's. Inhibition of the enzyme that breaks down acetylcholine (cholinesterase) may improve cognition, delay institutionalisation and reduce psychotic or behavioural symptoms in patients with mild to moderate Alzheimer's disease. (7) Donepezil is the only funded drug of this type in New Zealand.
Dysfunction of the excitatory neurotransmitter glutamate has also been implicated in development of Alzheimer's. Memantine is a drug that blocks the receptor for glutamate (the NMDA receptor) and has shown some value in increasing cognition and function and in reducing neuropsychiatric symptoms. (2)
TREATMENT OF THE BEHAVIOURAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD)
BPSD occurs in up to 80 per cent of people with dementia. It is distressing for patients and carets, and leads to increased risk of harm, reduced quality of life, earlier institutionalisation and increased use of health resources. Symptoms include aggression, agitation, anxiety, depression, wandering, repetitive vocalisation, hallucinations or delusions and sleep disturbances. (19)
While many carets rate BPSD as moderate to severe, most episodes are transient. Nevertheless, the use of antipsychotic medication to treat episodes has been prevalent, and often resulted in long-term therapy. Between 20-50 per cent of people with dementia may be prescribed antipsychotics. (20) More recently, there is recognition that antipsychotic medications, both conventional (eg haloperidol) and atypical (eg risperidone, quetiapine), have significant risks and limited benefits: for every 100 people with dementia treated with antipsychotics, there will be one death, one stroke and only 20 per cent will benefit. (29,21)
Moreover, these medications are only effective in reducing psychosis, aggression and agitation, and will not reduce BPSDs such as wandering, pacing or vocalisation. Nor do they improve cognition. (19) Aside from their cardiovascular and cerebrovascular effects, antipsychotics are also associated with increased confusion, sedation and movement disorders, such as tardive dyskinesia.
Treatment of BPSD, unless there is immediate danger to the patient, should begin with identification and removal or limitation of precipitating factors (see Table 2, p24). (19,22) Identification of the specific BPSDs that need to be addressed is essential to planning treatment. The Best Practice Advocacy Centre (BPAC) (19) suggests BPSDs be regarded as attempts by the patient to communicate an unmet need, eg pain, boredom, sadness, anxiety or loneliness.
Non-pharmacological interventions supported by research include: (7,19)
* reducing noise and other environmental stimulation, especially during care episodes;
* increasing signs and access to toilets;
* improving lighting;
* prominent placement of clocks and calendars;
* continuity with caregivers;
* meaningful and enjoyable recreational activity, eg gardening, music or art; and
* behavioural management interventions (rewarding desired behaviours).
If drug therapy for BPSD is deemed necessary, it should be targeted at specific behaviours (aggression, agitation or psychosis) where there is severe distress or the threat of harm. Documentation of the identified behaviours, risks and benefits of drug therapy, and a consent process, is essential.
Medication should be prescribed at the lowest effective dose ("start low, go slow") and for the shortest possible time. Regular reviews of the medication regime should consider effectiveness, adverse effects and potential for dose reduction and withdrawal. (21) Other common adverse effects of antipsychotic medications are constipation, sedation, and postural hypotension with increased risk of falls.
NATIONAL DEMENTIA STRATEGY
Alzheimers New Zealand, (3) a charitable trust which makes grants for dementia research, has proposed a national dementia strategy including recognition of dementia as a national health priority. It calls for increased public awareness, and development of services and support for dementia patients and their families. Care for people with dementia requires an educated and skilled workforce allowing early diagnosis, timely intervention and intensive support in the community.
The social, economic and personal costs of dementia are increasing as the population ages. Our understanding of the causes and progression of this group of diseases is poor, adversely affecting the development of treatments to prevent, reverse or cure dementia. Therapies for dementia are Limited to modifying the behavioural and psychological symptoms. Drugs in development that might treat the disease itself have had Limited success in trials. An understanding of these limitations allows nurses to support patients and family with education about treatment choices.
After reading this article and completing the accompanying online learning activities, you should be able to:
* Explain the theories underlying development of Alzheimer's and other dementias.
* Discuss diagnosis of dementia.
* Distinguish between dementia, depression and delirium.
* Outline current and prospective therapies for risk reduction, prevention and treatment of Alzheimer's and other dementias.
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(1) Alzheimer's Disease International. (2009) World Alzheimer Report 2009. Executive Summary. Alzheimer's Disease International. www.alz.co.uk/ research/world-report. Retrieved 11/6/12.
(2) Ballard, C. et al. (2011) Alzheimer's disease. Lancet; 377, pp1019-1031.
(3) Alzheimers New Zealand. (2010) National Dementia Strategy 2010-2015. Wellington: Alzheimers NZ. www.alzheimers.org.nz. Retrieved 11/6/12.
(4) Querfurth, H. & Laferla, F. (2010) Alzheimer's disease: Mechanisms of disease. New England Journal of Medicine; 362: 4, pp329-344.
(5) Mucke, L. (2009) Alzheimer's disease. Nature; 461, pp895-897.
(6) Alzheimers New Zealand. (2008) Dementia economic impact report. Wellington: Access Economics.
(7) Scottish Intercollegiate Guidelines Network (SIGN). (2006) Management of patients with dementia: A national clinical guideline, www.nzgg.org.nz/library_resources/98_management_of_patients with dementia. Retrieved 11/6/12.
(8) Glass, C. et al. (2010) Mechanisms underlying inflammation in neurodegeneration. Cell; 140: 6, pp918-934.
(9) Hardy, J. (200g) The amyloid hypothesis for Alzheimer's disease: A critical reappraisal. Journal of Neurochemistry; 110: 4, pp1129-1134.
(10) Eisenstein, M. (2011) Genetics: finding the risk factors. Nature; 475, ppS20-S22.
(11) Citron, M. (2010) Alzheimer's disease: Strategies for disease modification. Nature Reviews Drug Discovery; g, pp387-398.
(12) Jellinger, K. (2012) The role of alpha-synuclein in neurodegeneration--an update. Translational Neuroscience; 3: 2, pp75-122.
(13) Ministry of Health. (1997) Guidelines for the support and management of people with dementia. Wellington: NZ Ministry of Health. www.health.govt.nz/ publication/guidelines-support-and-management-people-dementia. Retrieved 11/6/12.
(14) Merck Manual. (2007) Overview of delirium and dementia. Merck Manual for Health Care Professionals. www.merckmanuals.com/professional/neurologic_disorders/delirium_and_dementia/ overview_of_delirium_and_dementia.html?qt=dementia&alt=sh. Retrieved 11/6/12.
(15) Alzheimer's Disease International. (2011) World Alzheimer Report 2011. Executive Summary. Alzheimer's Disease International. www.alz.co.uk/research/ world-report. Retrieved 11/6/12.
(16) Williams, R. (2011) Biomarkers: warning signs. Nature; 475, ppS5-S7.
(17) Gravitz, L. (2011) Drugs: a tangled web of targets. Nature; 475, ppS9-S11.
(18) Abbott, A. (2011) Dementia: a problem for our age. Nature; 475, ppS2-S4.
(19) Best Practice Advocacy Centre (BPAC). (2008). Antipsychotics in dementia: Best practice guide. BPACNZ. www.bpac.org.nz/a4d/resources/guide/guide. asp. Retrieved 11/6/12.
(20) Banerjee, S. (2009) Report on the prescribing of anti-psychotic drugs to people with dementia. UK Department of Health. www.dh.gov.uk/en/Publicationsandstatistics/Publications/ PublicationsPoLicyAndGuidance/DH_108303. Retrieved 11/6/12.
(21) BPAC. (2010) Antipsychotics in people with dementia--an update and reminder. BPACNZ. www.bpac.org.nz/magazine/2010/march/antipsychotics.asp. Retrieved 11/6/12.
(22) National Prescribing Service (NPS). (2007) Role of antipsychotics in managing behovioural and psychological symptoms of dementia. National Prescribing Service Ltd, Australian Department of Health and Ageing, www.nps.org.au/health_professionals/publications/prescribing_practice_review/ current/role_of_antipsychotics_in_managing_behavioural_and_psychological_ symptoms_of_dementia. Retrieved 11/6/12.
Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Table 1. Dementia, delirium and depression (14,19) DEMENTIA DELIRIUM DEPRESSION Onset Insidious, with Acute Often abrupt uncertain start Can often point identify time of onset Cause Structural brain Underlying May coincide damage conditions with significant almost always life changes present (see text) Attention Not impaired Impaired Not impaired until late in disease Memory Marked, Variable Selective/patchy loss particularly for Fluctuating recent events Level of Not impaired Variable Not impaired consciousness until late in Fluctuating disease Orientation to Impaired Variable Not impaired time and place Fluctuating Language Progressive Stowed speech; Not impaired aphasia may be incoherent/ inappropriate. Night time Sometimes Almost always No worsening worsening Disturbed sleep worse at night Sleep--early morning wakening Duration and Permanent; slow Hours to weeks Months to years; progress progression/ Usually variable and deterioration reversible uneven progression Treatment Cannot cure or Urgent to treat Treatment reverse underlying cause possible Treatment supportive only Table 2. Factors contributing to behavioural and psychological symptoms of dementia (BPSD) CAUSES EXAMPLES COMMENTS Physical Unrecognised infections Eg urinary tract cause Fluid and electrolyte Hyponatraemia disturbances Dehydration Constipation Use of diuretics Pain Check medications Hearing or vision May be difficult to assess deterioration Assess regularly Medications Antichotinergic drugs Eg amitriptyline, oxybutynin Reduce cognition Drugs that may cause Eg high-dose steroids, delirium or confusion anticonvulsants, H2 antagonists, benzodiazepines, some antibiotics Potypharmacy Environment Physical Noise, poor lighting, unfamiliar places Carers Conflict with carers, or change in primary carer Psychiatric Delirium Can aggravate BPSD diagnoses Depression May not be recognised Anxiety
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|Title Annotation:||CONTINUING PROFESSIONAL DEVELOPMENT|
|Publication:||Kai Tiaki: Nursing New Zealand|
|Date:||Jul 1, 2012|
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