By Roy Jones, FRCP, FFPM
In 1978, Lishman defined dementia as “an acquired global impairment of intellect, memory and personality but without impairment of consciousness.”1
Dementia is now more appropriately considered as a syndrome of acquired loss of cognitive function, behavioural changes and loss of social function.
Cognitive function includes all aspects of thinking processes and not just memory. Some degree of memory impairment is required to make the formal diagnosis of dementia, for example, as detailed in the American Psychiatric Association’s diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV).2
However, memory problems may not be prominent in the early stages of some dementing conditions, for example, subcortical dementias and dementia with Lewy bodies (DLB).
In most cases, dementia is progressive and irreversible. It can potentially be reversed or arrested (for example, by surgical treatment of normal pressure hydrocephalus) although, unfortunately, such cases are the exception rather than the rule.
Awareness of Alzheimer’s disease (AD) has altered greatly over the years. The first case, described by Alzheimer in 1907, involved a woman in her fifties. AD was for many years considered as a pre-senile dementia affecting people under the age of 65. We now know that AD is the commonest cause of dementia whatever the age of the patient and probably accounts for 50-70 per cent of all cases.
Features of the more common dementias
Memory, naming and visuospatial abilities affected early
Symptoms variable, according to site of vascular lesions. Changes may be patchy
Dementia with Lewy bodies
Mental slowing, impaired executive (planning and organisational) and visuoperceptual abilities
Executive and behavioural problems present early in the frontal form, with memory affected later. Severe aphasia an early feature of the temporal form
Prevalence and incidence
Dementia usually affects the old or the very old and its prevalence will vary according to the definition used and the population assessed. In nursing homes, as many as half of the residents will have some degree of dementia, whereas the prevalence is lower in community surveys. Whatever the population studied, there is always a marked increase in the prevalence with increasing age. Dementia affects less than 0.1 per cent of people aged 40 but 5-8 per cent of people aged over 65, 15-20 per cent of those over 75 and 25-50 per cent of those over 85.3
Despite the problems arising from methodological differences between surveys, in general there is a doubling of prevalence rates for every five-year increase in age over 60.
Prevalence studies do not make a distinction between the frequency of a disease and survival from that disease. This information is obtained from community studies assessing its incidence. For dementia, there are few such studies. Those that exist suggest an incidence rate of 1.1 to 1.6 per cent per year in people over 65 as a whole, although the incidence does rise steeply with age.
In the UK, there will be more than 700,000 cases of dementia by the year 2001, two-thirds of which will be in patients aged over 80. In both the developed and developing world the number of elderly and very elderly people is increasing. Dementing diseases like AD will, therefore, be major health problems over the coming years.
People with dementia have a lower survival rate than control subjects and this is consistent over time for all age groups. For example, two-year survival for women aged over 84 years was 60 per cent for those with dementia compared with 81 per cent for those without. The equivalent figures for men were 52 per cent and 76 per cent, respectively.4
Factors associated with reduced survival include being male, having physical illness and showing psychotic features.
In AD, the average duration from onset of symptoms to death is eight to 10 years.3
Patients with vascular dementia or DLB probably survive for a shorter time than those with AD.
Symptoms of Alzheimer’s disease
AD is characterised by an insidious onset with a gradual but relentless decline in memory and other aspects of cognitive function that is sufficient to impair activities of daily living. The rate of decline is not necessarily constant, being slower in the early and advanced stages of the disease compared with the middle stage. An early feature is memory impairment for recent events and poor retention of new information. Memory for more distant events is usually preserved in the early stages. There may be subtle changes in personality with a reduction in confidence and range of interests. A disturbance in executive function is common, causing difficulties when dealing with complex tasks, such as cooking a meal, dealing with finances or driving. Driving may also be impaired as a result of impaired spatial and visuo-perceptual ability. Language problems (aphasia) occur and are sometimes quite prominent even in the early stages of the disease. They particularly affect word fluency and cause difficulty in finding the right words or with following conversations. As AD progresses, there are increasing changes in behaviour and in more personal activities of daily living, such as dressing and eating. Loss of bladder and, later, bowel control is common.
It is important to try to obtain a history from someone who knows the patient well, otherwise the information given is likely to be inaccurate. In addition, this also provides an opportunity to offer information and support to family and friends who are often worried and stressed.
The first goal of any assessment is to decide whether the patient actually has a dementia. If so, then the second goal is to decide as accurately as possible which type of dementia it is. Unfortunately a definitive diagnosis is usually only possible by post mortem histology of the brain. There are no clear diagnostic markers, although a number of specialised scanning techniques have been suggested (for example, computed X-ray tomography of the medial temporal lobe, combined with single photon emission computerised tomography). A number of biological markers have also been evaluated, mainly by examination of the cerebrospinal fluid (CSF). In the future, it is likely that biological markers (probably in the urine or blood) will be identified and this will improve the accuracy with which AD can be diagnosed.
Dementia must be differentiated from a number of conditions, including delirium (cognitive impairment, usually of rapid onset, associated with a change in attention and consciousness), depression, impairment secondary to drug therapy (particularly drugs with anticholinergic properties) and milder forms of cognitive impairment (age-related cognitive decline and mild cognitive impairment). Other medical conditions must be dealt with carefully, including hypertension, diabetes, atrial fibrillation, and vision and hearing abnormalities.
Over the past 30-40 years, numerous compounds have been suggested for use in AD and other dementias. Until recently, most agents had not been evaluated adequately, with problems in the study design and duration as well as with the definition of the patients treated. Some of these compounds are still important in a number of countries and will be reviewed briefly here.
Co-dergocrine mesylate (Hydergine) is a combination of four dihydro derivatives of ergotoxine that has been available since 1949. Its uses have included the treatment of peripheral vascular disease, angina, hypertension and tinnitus. It is approved in the UK as an adjunct in the management of elderly patients with mild to moderate dementia and in the US for idiopathic decline in mental capacity.
The efficacy of co-dergocrine has always been uncertain. Most reviews, including a recent systematic Cochrane review, agree that there are significant effects favouring the drug in improving some patients (eg, in activities of daily living, symptoms and self-care).5
Greater effects have been seen in younger subjects and possibly with higher doses, including doses above the recommended upper limit in the US of 3mg/day. In general, the effects appear small and there is still uncertainty about the drug’s overall efficacy. The benefits may be due to effects on mood rather than as a result of a specific anti-dementia effect.
Nootropic agents, such as piracetam, do not have a well defined mechanism of action but are mentioned because of an apparent ability to improve integrative brain mechanisms associated with mental performance. They do not appear to have any particular general psychological or cardiovascular pharmacological activities.
Piracetam, the archetypal example of these compounds, is a cyclic derivative of gamma-aminobutyric acid (GABA). Piracetam’s benefit in dementias such as AD is still uncertain. Other compounds include pramiracetam, oxiracetam and aniracetam. These compounds have never been approved in the UK for the treatment of dementia, although piracetam is now approved as an adjunct for cortical myoclonus. However, they are widely available in many countries, including within Europe.
In a recent systematic review, the published evidence was not considered adequate to support piracetam’s use in the treatment of cognitive impairment or dementia because effects were only on global impression of change rather than on more specific measures.6
Naftidrofuryl Naftidrofuryl fumarate (Praxilene) has been available for many years. In the UK, it is licensed for peripheral and cerebral vascular disorders – specifically cerebral insufficiency and cerebral atherosclerosis – particularly where these manifest themselves as mental deterioration and confusion in the elderly. Its clinical actions are believed to be the result of effects on cellular metabolism, which increase adenosine triphosphate stores and regional blood flow.
Most trial results are from some years ago. Short-term studies often show modest benefits, although there do not appear to be clear improvements in cognition nor is it obvious whether there are sustained benefits.
Naftidrofuryl would seem unlikely to obtain approval as an effective antidementia therapy if re-assessed according to modern regulatory and clinical expectations.
There are a number of potential strategies that might increase acetylcholine levels within the brain and such therapies should be of value in AD. Acetylcholinesterase and butyrylcholinesterase are both found in the brain, although acetylcholinesterase predominates and exists in several forms. Acetylcholinesterase has been found in both senile plaques and neurofibrillary tangles, while butyrylcholinesterase activity also appears to be raised in AD brain, although its function is still not clear.
The only clearly successful approach to treatment of AD to date has been the use of acetylcholinesterase inhibitors. In 1993, tacrine became the first agent approved specifically for the treatment of the cognitive symptoms of AD, although it has never been marketed in the UK. Four acetylcholinesterase inhibitors – tacrine, donepezil, rivastigmine and galantamine – have already been licensed for approval in some countries (see below).
The acetylcholinesterase inhibitors are structurally distinct, with different relative specificities against acetyl- and butyryl- cholinesterase. They may thus have slightly different profiles of efficacy and adverse effects. There may also be differences in subsidiary activities, such as the allosteric modulation of nicotinic cholinergic receptors that has been reported for galantamine. Whether this translates into clinically relevant effects remains to be demonstrated.
Ginkgo biloba is a plant extract whose main actions may be as a vasodilator and as an antioxidant. There is evidence of some efficacy with regard to improved cognition, although most studies have been of poor quality. Many patients with dementia are now being given Ginkgo extracts by their family. Further carefully controlled studies are necessary to determine the level of benefit and to clarify the dosage.
There is continued interest in the place of antioxidants in the treatment of AD. A controlled trial has suggested that selegiline (5mg bd) or vitamin E (1,000IU bd) may be of value in delaying quite broad endpoints, such as institutionalisation, although the results are controversial. The American Psychiatric Association guidelines suggest that it is reasonable to consider vitamin E as a treatment option but that, at present, only conventional doses (200-800IU/day) should be used.3
Inflammation may be an important part of the AD disease process and may play a part in other dementias as well. There is epidemiological evidence supporting the possibility that non-steroidal anti-inflammatory drugs can delay the onset and/or progression of AD. A number of controlled trials are in progress, although the risk-benefit profile will need to be assessed carefully if considering treating elderly AD patients with drugs such as non-steroidal anti-inflammatory drugs. Similar comments apply to the use of oestrogens where again there has been epidemiological evidence supporting their potential benefit in AD.
Use of acetylcholinesterase inhibitors
Because of concerns about inappropriate prescribing of acetylcholinesterase inhibitors, a number of guidelines have been produced advising how the drugs should be used. In practice, many of these have been concerned more with rationing the use of the drug rather than advising on its appropriate use.14
At present, the consensus would suggest that acetylcholinesterase inhibitors should be restricted to use in patients with mild to moderately severe AD (usually with a score on the Mini Mental State Examination of 10-24).15 The Standing Medical Advisory Committee guidelines have suggested that patients selected for treatment should be similar to those included in clinical trials and that treatment should be initiated by a specialist.
In practice, the problem for general practitioners is making the diagnosis of AD. The acetylcholinesterase inhibitors are quite simple drugs to use and, in the future, it should be possible for prescribing to be initiated in general practice.
Studies are currently in progress to see whether acetylcholinesterase inhibitors are helpful in more severe dementia and in subjects with so-called mild cognitive impairment, where it is known that many will go on to develop dementia in the following few years.
Benefits of drug treatment should be assessed after a minimum of three months and efficacy judged on the basis of a formal assessment of cognition, as well as a more general assessment based on global benefits and effects on behaviour and activities of daily living. Some patients may not show a marked improvement but show a stabilisation and relative lack of deterioration. Clearly, this may sometimes be difficult to judge.
Stopping treatment can be a difficult decision. Lack of clinical benefit, behavioural disturbances and obvious progression of the disease (for example, leading to institutionalisation) may suggest that no further advantage is accruing from therapy. If so, a reduction in dose, followed, if appropriate, by withdrawal of the drug may be indicated. In some cases, this may lead to a deterioration in the patient such that therapy must be reinstated.
Tacrine (tetrahydroaminoacridine or THA) is a centrally active, non-competitive, reversible inhibitor of both acetylcholinesterase and butyrylcholinesterase. It has a number of other pharmacological effects. The pharmacokinetic parameters for tacrine show wide interindividual variation and the drug is extensively metabolised in the liver to an active metabolite, 1-hydroxytacrine.
The initial dosage of tacrine is 10mg qds, increasing every four to six weeks to a maximum of 40mg qds.
Systematic reviews involving 1,900 to 3,500 patients confirm that tacrine shows modest efficacy in some 20-30 per cent of patients with, on average, a six to 12 month delay in the cognitive deterioration that would normally be expected in AD. This is considered to be clinically relevant by the Food and Drug Administration in the US.
Tacrine improves behavioural symptoms in AD, supporting a cholinergic basis for some of these symptoms.7
Patients who take 80mg/day and higher doses for two years or more are less likely to have entered a nursing home than those on lower doses or those who discontinue the drug. Tacrine’s usefulness is limited by its frequent dosing and also by a specific, reversible hepatotoxicity. This is in addition to the cholinergic side effects that occur, to varying degrees, with all cholinesterase inhibitors.
Cholinergic side effects are usually dose-related and mainly consist of gastrointestinal symptoms (including nausea, vomiting and diarrhoea), sweating and bradycardia. Headache and myalgia have also been reported. Symptoms occur on initiating therapy and when the dose is increased and these effects are often experienced before any benefit becomes obvious.
In general, tacrine has been replaced by donepezil and rivastigmine.
The year 1997 saw the approval of donepezil, the first drug to be marketed in the UK for the symptomatic treatment of mild or moderate dementia in AD. Donepezil is a piperidine-based, highly selective, reversible inhibitor of acetylcholinesterase, with much less activity against butyrylcholinesterase, an enzyme mainly present outside the CNS. Red blood cell acetylcholinesterase inhibition of up to 90 per cent has been reported during long-term treatment with 10mg/day.
Absorption is complete and the elimination half-life is 70-80 hours, allowing once daily dosing. Neither food nor time of administration influences the rate or extent of absorption. The drug is about 95 per cent protein-bound and metabolised by the cytochrome P450 system. No significant interactions with warfarin, digoxin or cimetidine have been demonstrated but the summary of product characteristics advises caution, since it may be that some possible interactions have yet to be recorded.
To reduce the risk of side effects, all patients start on a once-daily dose of 5mg that may be increased to 10mg after at least one month.
Several efficacy studies of donepezil have now been published, involving more than 2,000 patients treated in double-blind studies for periods of 14 to 30 weeks.8
Many patients from these studies continued into open-label extension studies and have received donepezil for periods of more than two years.9
Significant improvements have been seen in the two primary endpoints: cognitive function (measured using the Alzheimer’s Disease Assessment Scale cognitive subsection, ADAS-Cog) and an independent assessment of global improvement that measures the patient’s response with input from the main caregiver (the Clinician’s Interview Based Impression of Change with carer input, CIBIC-Plus).
Some 26 per cent of patients receiving 10mg doses showed an improvement on the ADAS-Cog (in comparison with 8 per cent on placebo), equivalent to at least a six to 12-month gain in cognitive function. On the global rating, only one in 10 patients improved on placebo compared with one in four receiving donepezil.
Responder analyses (favoured by regulatory authorities) suggest that the number needed to treat (NNT) is four for a meaningful change in cognitive function and eight for improvement on the global rating.10
There appears to be a continued effect of treatment with long-term therapy. Data from clinical trials have now been supported by published studies from typical clinical practice.11
There have been significant effects on activities of daily living and beneficial effects on behaviours, such as apathy and agitation, are also emerging. Overall, it appears that about 40 per cent of patients will show a positive response to the drug.
Adverse effects are typical of the cholinergic effects described for tacrine. They are generally mild and transient, occur early in the course of treatment and often resolve despite continued therapy. It is suggested that the drug is given at night, presumably to reduce gastrointestinal disturbances. However, disturbed sleep and nightmares have been reported and these can sometimes be avoided by giving the drug in the morning. Psychiatric disturbances, such as agitation, have also been reported but these are difficult to separate from the natural progression of the disease.
Rivastigmine was licensed in the UK in 1998. It forms a carbamylated complex with acetylcholinesterase that inactivates the enzyme for about 10 hours, despite a short plasma half-life, producing “pseudo-irreversible” inhibition. It preferentially inhibits the G1 form of acetylcholinesterase, a form relatively more abundant in the brain in AD. In CSF it inhibits acetylcholinesterase and butyrylcholinesterase to the same extent.
Little detailed pharmacokinetic data have been published. Bioavailability increases with dose, while administration of the drug with food slows absorption and increases the area under the concentration-time curve by about 30 per cent. It is rapidly and extensively metabolised to a minimally active metabolite that is eliminated by the kidney. Since it is weakly protein bound (about 40 per cent) and not significantly metabolised by hepatic microsomal enzymes, there should be a minimal risk of clinically relevant drug interactions, apart from drugs that act directly on the cholinergic system.
The drug is given twice daily with food, starting at 1.5mg bd and increasing at a minimum of two-weekly intervals to achieve the effective dose range of 3-6mg bd.
The main efficacy studies, usually with treatment duration of 26 weeks, have involved over 3,300 patients, although full published data are not available for about half of the patients studied to date. Although efficacy is seen at lower doses, higher doses (6-12mg/day) are more effective and give benefits in cognition, global functioning and activities of daily living. In one study, the drug versus placebo differences in cognition (measured using the ADAS-Cog) were larger than have been reported to date for a dementia drug.12
Most of this difference was represented by a greater than usual decline in the placebo group that was not documented in another similar study with rivastigmine.13
This illustrates the difficulty of comparing studies even for the same drug. Differences have also been shown between the two main published studies for donepezil. Data from long-term, open label studies suggest that the benefits of therapy do continue and, even after two years, the cognitive decline on those receiving 6-12mg/day is less than in patients receiving placebo for six months.
Adverse events experienced with rivastigmine are generally dose-related and typical of cholinesterase inhibitors as a class. They include asthenia, anorexia, dizziness, somnolence and vomiting. Weight loss has also been seen and weight should be monitored during therapy. As with other cholinomimetic agents, care must be taken in using the drug in patients with sick sinus syndrome or other conduction defects. Titrating the dose of twice-daily rivastigmine is more complex than for once-daily donepezil, although rivastigmine is the cheaper drug.
Galantamine is likely to become available in the UK within the next few months. It is an alkaloid derived from snowdrop and daffodil bulbs, although a synthetic process is now available. It is a reversible, competitive inhibitor more active against acetylcholinesterase than butyrylcholinesterase. Galantamine is also an allosteric modulator of nicotinic cholinergic receptors and this may give it a different profile of activity, although this still needs to be confirmed clinically. Dosing will be twice daily.
Its efficacy and adverse event profile appears to be similar to donepezil and rivastigmine. No direct comparisons of any of these drugs have been completed or published.
As we learn more about the underlying processes that lead to AD and other dementias, therapeutic opportunities are appearing. The deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles are major elements in the pathology of AD and other dementias. In a minority of AD cases, genetic abnormalities cause the disease. Understanding the basis of the disease is leading to new therapies, with inhibitors of enzymes, such as gamma-secretase, that are important in amyloid deposition. Attempts are being made to immunise patients against the abnormal amyloid protein. Neurofibrillary tangles contain a hyperphosphorylated version of a protein called tau. Drugs that prevent hyperphosphorylation might be of use in AD and also in other dementias, such as frontotemporal dementia, in which tangles may be more important than amyloid deposition in the underlying disease process.
Finally, there is increasing interest in dealing more specifically with the behavioural problems associated with dementias, such as AD. Cholinesterase inhibitors may be helpful in dealing with the apathy and agitation often seen, while other approaches, such as using atypical antipsychotics like risperidone and olanzapine, may be helpful in dealing with agitation and aggression.
Dr Jones is director of the Research Institute for the Care of the Elderly, St Martin’s hospital, Bath
The Pharmaceutical Journal Vol 264 No 7099p846-850 June 3, 2000 Continuing education
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