Addiction Treatment Blog

Dementia Treatment

It is not clear yet that damage to the cholinergic pathway is the central deficit in Alzheimer’s dementia. Indeed, it has recently become clear that a number of other neurotransmitters are affected in both Alzheimer’s and other cortical dementias. It is also clear that, because of the interactions between various neurotransmitter systems, it is almost impossible to manipulate one neurotransmitter systems, it is almost impossible to manipulate one neurotransmitter without affecting the others.

Finally, from the vantage point of the 1990s, it seems that many cortical dementias may involve cell protective mechanisms that have been thrown out of gear. Normally, there are a range of mechanisms within cells for neutralizing toxins of various sorts. These often involve the binding of a protein to the toxin, which labels it so that the cell’s own degredative processes destroy the offending agent. In the dementias, however, such mechanisms seem to have been stimulated to the point where the large amounts of cell-protective proteins are produced, to the point where large amounts of cell-protective proteins are produced, to the point that they themselves poison the cell. Whether the stimulus is genetic, viral, toxic (as in aluminium) or some combination of these and other factors is uncertain. The treatment options are to find compounds that will switch off the process or else compounds that will compensate for it.

At present we have no agents that might affect these mechanisms. For the most part the aim of current treatments remains largely one of giving a boost to the cholinergic system. The rationale here is not to cure the dementia but rather stimulate remaining cortical tissue. The means by which it has been hoped that this might be done include or have included the following:

• Choline. This is a precursor of the neurotransmitter acetylcholine. The rationale is that by increasing supplies of choline in the body, the brain might synthesise more acetylcholine. Initial studies supported this but more through subsequent ones have not confirmed this. Choline is also present in phosphatidylcholine, which is present in the essential fatty acid, lecithin. For this reason lecithin supplements have also been given in dementia but with little benefit.
• Piracetam / Oxiracetam / Aniracetam / Pramiracetam. In animal studies these drugs release acetylcholine within the brain. They seem to be mildly stimulant in man. Clinical studies in dementing conditions, however, have not been impressive. It has been claimed that combining them with lecithin and an anticholinesterase does give some benefit.
• Cholinesterase inhibitors. These compounds block the breakdown of acetylcholine e.g. phystostigmine. There have been some reports that this drug may bring about improvements in some subjects with Alzheimer’s on some tests of performance. However, the drug appears to have an extremely short half-life and the dose levels to which each individual may be sensitive seem to be highly variable. A dose in one person, which appears to bring about improved performances, in others may even bring about deterioration in performance. Newer, longer-acting versions of physostigmine are being synthesised.
• Tetrahydroaminoacridine (THA/tacrine). This is a longer-acting anti-cholinesterase, which has seemed in some studies to be of benefit. The findings overall have not been sufficiently robust to persuade large numbers of clinicians that a significant discovery has been made, although they have been enough for the drug to be licensed in the USA for dementia. There are suggestions that this type of compound may be of greater benefit in SDLT than in other dementias. If so, however, it is worth noting that compounds such as tacrine also block potassium channels and any therapeutic benefit may stem from such sources. The most significant problem with THA is liver toxicity. This has led to the production and clinical testing of related compounds such as velnacrine.
• Angiotensin Converting Enzyme Inhibitors (ACE inhibitors). The most recent group of drugs with effects on the cholinergic system, for which benefits have been claimed in dementia, are the ACE inhibitors. The best known of these are captopril, enalapril and lisinopril, used in the treatment of hypertension and cardiac failure. They block an enzyme called angiotensin converting enzyme with acts to produce a hormone called angiotensin, which increases blood pressure. These compounds all, however, also bring about a release of acetylcholine in the brain. The marketing of ACE inhibitors for blood pressure heavily emphasises that these drugs not only lower blood pressure but seem to give some sort of ‘zest for life’. There appears to be some, as of yet, poorly worked out stimulant quality or mild cognitive-enhancing quality to these compounds. In studies with aged rats, the ACE inhibitors seem to be able to be improve performance in a range of behavioural tasks back to the level of performance shown by young rats. It is too early to say yet whether these will be of significant benefit in the dementing disorders. A number of open studies at present have suggested that the drugs may be helpful but exactly how helpful, and for which of the many forms of dementia, remains to be determined.

Table of Contents

• Treatment of Multi-infarct Dementia
• Management of Subcortical Dementias
• Neuroprotection
• Cognitive Enhancement and Age-Associated Memory Impairment
• Smart Drugs
• Cognition and the 5-HT system
• References
• Dementia Treatment Clinic
• Do You Need Help on Dementia Treatment?

Treatment of Multi-infarct Dementia (1)

It is now believed that brain damage caused by the lack of oxygen to the brain or decreased blood perfusion to the brain, which happens most typically in strokes, occurs for a variety of reasons.

The greatest destruction of brain tissue does not happen at the first point when the stroke begins but rather happens anything over the course of several hours to one or two days later. The first insult tends to be to a very small group of nerves which release a neurotransmitter called glutamate. This increases the permeability of nerve cells in its area, which leads to both sodium and chloride entering those cells. The entry of sodium and chloride causes water also to a cell and this may cause it to swell and burst.

It has been found, however, that this process doesn’t happen if there is a low level of calcium into the cell and this causes the activation of a number of enzymes which break down proteins and fats within the cell. If this entry can be blocked the chances for survival are greatly increased. In essence, therefore, the toxicity of a stroke appears in a large part to be a question of calcium toxicity.

Efforts are now, therefore, focusing on trying to prevent calcium entry into nerve cells in the period of time immediately after the start of the stroke. This can be done in two ways. First, block a group of receptors called N-methyl-D-aspartate (NMDA) receptors, which glutamate acts on and which form one of the two principle means of calcium entry. NMDA receptors can be blocked by anaesthetic-agents such as ketamine, dextorphan and a variety of barbiturate-related compounds. The other method is to block voltage-operated calcium channels. It is these channels that drugs such as verapamil, nifedipine and diltiazem block (see The Management of Side Effects chapter) (2).

The current regimes being proposed for managing the early stages of strokes, therefore, include giving ketamine, dextorphan, aminophosphonovalerate along with diltiazem and flunarizinem which are calcium channel blockers. If these prove effective there are likely to be two consequences. One will be the survival of many more people who have strokes. Currently one-third of strokes lead to death. The other, however, will be that of those who were going to survive anyway, the prospects for something close to full recovery will be better.

Management of Subcortical Dementias

The subcortical dementias are the most treatable of dementias. sometimes, if the precise nature of the disturbance can be diagnosed, the condition can be cured entirely – this is the case for benign subcortical tumours ort hydrocephalus. If an underlying disorder cannot be identified and corrected, treatment with psychostimulants, such as dexamphetamine or pemoline, or cholinomimetrics, such as ACE-inhibitors, is worth trying and is more likely to be yield improvements than in the case of the cortical dementias. (see The Use of Psychostimulants in Schizophrenia).

Neuroprotection

The first interest centred on Parkinson’s disease and stemmed from the discovery that severe Parkinson’s like state could be precipitated by the designer drug, N-methyl-4-phenyltetrahydropyridine (MPTP), which is oxidised in the brain to the toxic N-methylyridinium ion (MPP+) by monoamine oxidase B. MPP+ seems to be responsible for the substantia nigra cell loss found after the use of MPTP. The implication was that MAO-B inhibitors, such as selegiline, might protect against such toxicity and a large study of selegiline against other treatments (the DATATOP study) (3) suggested that it did slow the progression of the disease.

Whether it does by the means outlined above or some other means is less clear. There is some evidence now to suggest that selegiline and related compounds can inhibit apoptosis. Apoptosis is the term for a recently discovered process of programmed cell death – a process that seems to be activated in cells in response to a variety of stimuli, one of which appears to be toxin overload.

Another possibility is that selegiline might work by reducing the production of what are called free radicals. These are derivatives of oxygen, which if they arise within the body may inhibit a range of enzymes, the polymerisation of proteins and the reading of DNA. The oxidation of dopamine by monoamine oxidase can in certain circumstances increase free radical production and there is some evidence of such processes at work in Parkinson’s disease. Selegiline can block a number of the enzymatic processes that might lead to increases in free radicals. Antioxidants, such as tocopherol or vitamin C are often promoted in health food shops as the natural way of cut free radicals but while these agents may reduce free radical formation in parts of the body it is not clear that they get into the parts of the brain necessary for effective action in degenerative disorders (2).

Cognitive Enhancement and Age-Associated Memory Impairment

At present, in addition to potentially finding drugs that would be useful for the various forms of dementia, manufacturers have their eyes on what may be an even larger market. As mentioned there are two ways to tackle the problem of dementia. One is to find a drug that would reserve the illness. The other is to find compounds that might enhance cognitive function of remaining brain tissues can be maximised, then the quality of life of individuals who have dementia will be improved.

However, this has led to an appreciation of a much larger issue, which is that if such drugs can be found which have these benefits for individuals with Alzheimer’s, why not give them to the population at large? Awareness of this possibility has led to a proposal that there is a condition called age-associated memory impairment (AAMI).

AAMI is a state that is proposed to affect a great number of us once we get over the age of 50 (4). Many individuals over the age of 50 complain of changes in their memory, as it is. However, formal testing with the usual tests done for dementing disorders rarely picks up anything of note. At present, therefore, it is not clear just what exactly AAMI consists of except that it is thought of as being part of normal ageing and not as being related to dementia. The notion has developed, however, that there is such a condition and that cognitive enhancers may help it. In general, in younger populations it has been difficult to show that any drugs enhance cognitive function. Any results that have been positive have tended to come from older populations.

Smart Drugs (5)

Despite this, there has been a further development in recent years, which has been the idea of using cognitive enhancers in a widespread way. This has led to the notion of ’smart drugs’. In the US, in particular, it is now common for many people to take a lot of compounds in trying to boost their cognitive performance and give themselves a competitive edge.

The compounds most commonly used are:

• Nootropics such as piracetam, oxiracetam, aniracetam, pramiracetam and pyroglutamate (see above).
• ACh precursors such as choline, lecithin and acetyl-carnitine (see above).
• Stimulants such as caffeine, pemoline or ginseng.
• Hydergine is derived from ergot, a fungus that grows on rye. It is closely related to LSD. Claims have been made that it protects brain cells from damage by low-oxygen or free radicals, that it increases blood supply to the brain, enhances brain cell metabolism and that it increases intelligence, memory-learning and recall. Some of the above metabolic effects may be true but whether hydergine has consistent effects on any mental abilities is as yet unclear. What is clear is that it is not a treatment of dementia. Nevertheless, in the USA it is used widely, often in combination with nootropics, like piracetam, with users almost invariably claiming that they feel much more alert and attentive and lively on these regimes. Cynics may say that given the amounts of money that are spent it would be unlikely that takers would claim anything other than clear benefits.
• Phenytoin (Dilantin). This drug is one of the standard treatments for epileptic convulsions. More recently, it has been claimed that in lower doses it may enhance cognitive function. At present the evidence remains anectodal.
• Vasopressin. This is a hormone secreted by the pituitary gland, also called antidiuretic hormone, which as its name implies has a role in maintaining the fluid balance of the body. It does seem to have a role in memory formation but the precise nature of this role is still unclear. It is used widely as a smart drug at the moment, usually by inhalation in the form of a nasal spray. Users typically claim to feel much more alert and attentive within seconds of taking it.
• Vitamins are used increasingly for smart drug purposes or as cerebroprotectants. Among those most commonly used are B1 (thamine), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine) and B12 (cyanocobalamin). Also used for this purpose are C and E. It is true that deficiencies of any of these compounds may cause a nervous tissue damage and affect psychological performance but there is no evidence that increasing levels of these vitamins beyond a normal dietary intake is in any way enhances cognitive functioning beyond the norm.

The smart drugs issue involves health food preparations, over-the-counter preparations or drugs for which there is little clear use being pressed into service. Individuals who are enthusiastic about cognitive enhancement are possibly spending several hundred pounds per year, if not several thousand, on these preparations. Whether they do anything at all, either to protect the brain from insult or actually to improve performance is now unproven. The suggestion from AAMI research is that if these compounds do anything, it will be for older individuals who do not have dementing processes, rather than for those who have begun to dement or for those under the age of 50 seeking some competitive edge.

Cognition and the 5-HT system (6)

While the dominant focus in dementia research and the area of cognitive enhancement, until now, has been on the cholinergic system, there is also some evidence that manipulations of the 5-HT system may have effects on memory.

Another possibility lies in connections between the 5-HT and the dopamine system. 5-HT system have direct effects on the dopamine system. It is possible therefore that many of these compounds help dopamine neurotransmission and are thereby mild psychostimulants. It is possible that some of these compounds active on the 5-HT system will prove to be cognitive-enhancing in the sense of bringing about some clear, although probably slight, improvements in the cognitive performance of some individuals, perhaps those over the age of 50 in particular.

At the very least, it would seem possible that antidepressants or anxiolytics that act on the 5-HT system will spare cognitive function compared to the traditional antidepressants, which have clear anticholinergic profiles, and compared to the benzodiazepine minor tranquillisers, which cause a marked amnesia.

References

1. Rothman S M, Olney J W: Excitatotoxicity and the NMDA receptor. Trends Neuroscience 1987, 10:299-302.
2. Mizuno Y, Mori H, Kondo T: Potential of neuroprotective therapy in Parkinson’s disease. CNS Drugs 1994, 1:45-56.
3. The Parkinson Study Group: Effect of Deprenyl on the progression of disability in early Parkinson’s disease. New England J Medicine. 1989, 321:1364-1371.
4. McEntee WJ, Crook THL Age-associated memory impairment: a role for catecholamines. Neurology 1990, 40:526-530.
5. Dean W, Morgenthaler J: Smart drugs and nutrients. Santa Cruz: B and J Publications; 1990.
6. McEntee WJ, Crook TH: Serotonin, memory and the aging brain. Psychopharmacol 1990, 103: 143-149.