Dementia Research - Prof. Gordon Wilcock

RESEARCH INTO, AND PHARMACOLOGICAL TREATMENT OF DEMENTIA,
ESPECIALLY ALZHEIMERS DISEASE

CURRENT PHARMACOLOGICAL APPROACH TO TREATING DEMENTIA

Before treating someone with dementia it is essential to make as accurate a diagnosis as possible. There are three common causes of dementia, i.e. Alzheimers disease (AD), vascular dementia (VaD) and dementia associated with Lewy Bodies (Lewy Body dementia). There are, of course, many other conditions that cause dementia but these are beyond the scope of this relatively short article.

As the reader will probably know, this is responsible for dementia in about two thirds of those afflicted, either on its own or in combination with something else. In the early and mid stages, one of the cholinesterase inhibitors (CEIs) is the drug of choice. These all act by maximising the impact of the ever-decreasing amounts of the chemical messenger, acetylcholine, that is being produced in the Alzheimer brain. The three specific treatments currently available and licensed in the UK are Reminyl (Galantamine), Aricept (Donepezil) and Exelon (Rivastigmine). They are all very similar in terms of efficacy and the choice of treatment to some extent will depend upon practical matters, e.g. the need for once daily dosage which would favour the use of Donepezil. These drugs work in about 5060% of people to whom they are given, producing benefit in some subjects who respond, and appearing to slow the deterioration or producing a period of stability in the others. We do not know why the response rate is not greater than it is, despite lots of research trying to explore this. Treatment is probably effective for 18 months 2 years in most cases where it works - but some people respond for longer. NICE, the National Institute for Clinical Excellence, recommended that withdrawal of treatment should be considered when the patient has declined to a mini-mental state of less than 12. Most of us, however, do not routinely withdraw treatment at this point but make a careful assessment as to whether this is appropriate, and institute a trial of dose reduction or withdrawal rather than using the Mini-Mental state score as an automatic cut-off. These drugs are also best prescribed using a Shared Care Protocol, with a hospital specialist instituting treatment and making the initial decision after, say, three months as to whether treatment has been worthwhile, in which case Primary Care will take on the future prescribing responsibility but with regular assessments by Secondary Care as to the suitability of continued treatment.

More recently a new type of drug has arrived on the scene. This is called Ebixa (Memantine) and works on a different chemical messenger system, a glutamate system where it protects some of the brain cells from the harmful effects of too much glutamate that is often released from injured neurones. This drug is presently licensed for moderate to severe Alzheimers disease and is, therefore, complementary to the CEIs, with a degree of overlap in the moderate stages of severity. Although there are other drugs in development and under evaluation, none of these are yet licensed but some of them are described briefly in the research section of this article.

Multiple infarct dementia is a term that is probably known to many, and implies that dementia can sometimes result from repeated small strokes. Although we know that this does happen sometimes, it is relatively infrequent, and most people who have a dementia with a vascular etiology have damage to small blood vessels, and it is partial occlusion of these, rather than an accumulation of strokes, that is responsible. There are no specific treatments currently licensed for vascular dementia, and the mainstay of treatment is the prevention of further vascular damage using a similar approach to that employed after a person has had a stroke, or a transient ischaemic attack. This means attention to relevant underlying risk factors for cerebrovascular disease, and consideration of a small dose of aspirin to facilitate blood flow through the brain.

Interestingly, many people with this type of dementia have a greater reduction in the level of acetylcholine in their brain than many patients with Alzheimers disease have. This has led to attempts to evaluate CEIs in people with Lewy body dementia, and there is accumulating evidence that they may be helpful in this context. Some authorities believe that Lewy body dementia is a variant of Alzheimers disease, where the neurofibrillary tangles are replaced by Lewy bodies instead. If one subscribes to this view, it means that it is possible to prescribe a CEI for a patient with dementia associated with Lewy bodies, as these drugs are only licensed for use in mild to moderate AD, and not for the indication of Lewy body dementia. However, if Lewy body dementia is a variant of AD, then one could argue whether or not this falls within the licensed indications for treatment with anti-Alzheimers disease drugs.

Research into the different dementias covers a wide range of topics, but not surprisingly, research into developing treatments, especially for Alzheimers disease, is one of the most extensively explored areas.

Although the CEIs have been with us now for some while, and everyone is keen to get on with evaluating newer drugs, there has been considerable additional exploration of the potential role of CEIs which may have some very useful and helpful outcomes. The initial scepticism of the value of these drugs, i.e. in improving scores on cognitive scales, has now been tempered by a significant body of evidence showing that for those people who respond to treatment there are often significant benefits for family and carers, as well as for the patients cognitive ability. This benefit extends into such basic areas as reducing, significantly, the amount of time a carer may have to spend supervising or actually assisting a person with dementia in their day-to-day activities. This in turn may prolong the time a person with dementia can stay in the community, i.e. before admission to a residential nursing home.

Further interesting facts that are beginning to emerge about CEIs from research are the breadth of conditions in which they may be useful. I have already mentioned their potential value in Lewy body dementia, but a study has recently been published showing that there are also benefits to patients who had a vascular dementia, or a mixed picture of co-existing Alzheimers disease and vascular dementia. Yet a further indication may be in relation to that of mild cognitive impairment (MCI). This is a situation where a person clearly has cognitive problems, usually, but not always, relating to memory, that is a significant deterioration from their previous level of function, but where the severity is insufficient to justify a diagnosis of dementia. A considerable proportion of people with this condition eventually develop dementia, usually AD. Treatment trials are currently under way to evaluate whether or not people with MCI are helped by a cholinesterase inhibitor, and also whether one of these drugs might slow the rate of progression from MCI to Alzheimers disease .

Substantial evidence is also emerging from clinical trials that CEIs may improve behavioural disturbance, and sometimes psychotic symptoms in people with dementia, irrespective of the underlying cause. They may therefore be an alternative to neuroleptics which have a significant side-effect profile, but we need further evidence to confirm this.

Another new area of research is whether or not these drugs all behave in the same way, and that if a person does not respond to one, that this is a class effect and they will not respond to the others. There is now a suggestion that if one CEI does not work, it is worth prescribing another, and even exploring the possibility of replacing one drug with another when a previously satisfactory level of response begins to deteriorate. Finally, and as one might expect, there are also trials under way to evaluate whether treatment with a combination of a CEI and Memantine together may be more effective than either alone.

Most people feel it is unlikely that the treatments already licensed will slow brain cell death, even if they are able to retard the development of symptoms by overcoming some of the biochemical changes that result from neuronal damage. A number of strategies are under development, and some in the early phases of evaluation, to prevent the pathological changes associated with AD from killing brain cells. These include preventing the deposition of the harmful protein, amyloid, that is formed in the Alzheimer brain, or ameliorating its effects. In addition, strategies are being developed to prevent the formation of the neurofibrillary tangles which are found inside neurones, and which interfere with intracellular transport mechanisms.

A number of other apparently protective medicines have been identified from community studies of large cohorts of people taking a variety of drugs for other conditions, and in whom Alzheimers disease appears to be less likely to occur, or occurs later in life when it does arise. These include some of the non-steroidal anti-inflammatory drugs given to treat arthritis, HRT, antioxidant drugs and vitamins, and some of the statins used to lower blood cholesterol level. Whether these work specifically as anti-Alzheimers disease agents, or whether they have a more general effect protecting brain cells from other toxic events during a persons life, and thereby maximising the number of neurones available to cope with Alzheimers disease later in life, or both, is unknown at present. So far these approaches have been less successful in trials of treatment in those who have established AD, but these studies have been of relatively short duration, and it may that any potential role of these compounds will be that of slowing neuronal death rather than improving the function of existing neurones, which would mean that much longer-term studies may be necessary to show any benefit.

Getting the diagnosis right is crucial, both in terms of evaluating new treatments and ensuring that existing treatments are prescribed appropriately. Unfortunately there are no reliable diagnostic tests that will indicate the presence of Alzheimers disease, or dementia secondary to vascular disease or Lewy bodies. A number of approaches have been shown to differentiate between conditions when explored in groups of patients, but when this knowledge has been applied to diagnosing the cause of dementia in an individual patient, the predicted value has been disappointing. It is beginning to appear, however, that in certain circumstances sequential neuroimaging may be helpful in some patients, but is not easily available in a routine clinical setting because of inadequate resources. Examination of amyloid-related compounds in the CSF, together with levels of tau, one of the proteins associated with the formation of neurofibrillary tangles, also looks promising but is not yet ready for clinical use.

We are now at an extremely exciting and positive time in terms of developing strategies for the eventual defeat of Alzheimers disease and other dementias. The drugs that are currently licensed are proving valuable to many sufferers, and there are other, possibly more effective, treatments in the pipeline. This, coupled with the expectation of reliable diagnostic testing, shows that the defeatist attitude to the dementias, that was prevalent as recently as five years ago, is a thing of a the past.