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Treatment of the cholinergic impairment in Alzheimer's disease
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S-13 Alzheimer's Disease
Treatment of the cholinergic impairment in Alzheimer's disease
G.K. Wilcock University Department of Care of the Elderly, Frenchay Hospital, Bristol BS16 1LE. UK Key words. Alzheimer's disease; Therapy; Anticholinesterase: Nerve growth factor Introduction There are three main therapeutic approaches to rectifying the cholinergic deficit in Alzheimer's disease. They include enhancing presynaptic production of the missing neurotransmitter; receptor agonist strategies; and the anticholinesterase approach, of which the use of anticholinesterases has been shown to be most promising. An even more fundamental approach however is the use of neurotrophic compounds to try and support the failing cholinergic ceils. This review will concentrate on the use of anticholinesterases but will also briefly describe the developing neurotrophic approach.
Physostigmine Most of the earlier attempts to try and use cholinesterase inhibition as a tool in the treatment of Alzheimer's disease used physostigmine. There are studies in the literature reporting the results of its administration orally, intravenously, and in a few instances by subcutaneous or intramuscular injection. Improvement in selected memory tasks was reported in some of the early intravenous studies, but not in all such trials. Oral physostigmine has yielded less impressive results except when higher doses have been employed. In the longer term, an oral treatment with a reasonable duration of action is clearly desirable and attempts are under way to modify physostigmine such that it meets these requirements.
Aminoacridines The aminoacridine that has received the widest publicity is of course tacrine (THA, 9-amino-l,2,3,4-tetrahydroacridine). This compound together with lecithin was the subject of the study published by Summers which generated much excitement (Summers et al., 1986) when first published, but which was subsequently much criticised. The magnitude of the benefits claimed stimulated many other studies, the earlier ones producing substantially negative or disappointing results. In most cases this was the result of the study design with inadequate numbers of subjects, too low a dose, inadequate or no wash-out periods in cross-over studies and a number of other design flaws. The hepatotoxicity and cholinergic side-effects surfaced as potentially major problems and the continued development of aminoacridines, including tacrine and velnacrine, began to look most uncertain. The first really positive study came from Raymond Levy's group (Eagger et al., 1991) in which 65 out of 89 patients completed a 7-month trial of T H A and lecithin with a significant benefit to a proportion of those included. Although subject to criticism this was the first essentially positive study following Summers' original report. There have been a number of trials of tacrine without concomitant lecithin, the better designed ones suggesting again that there is some benefit to a proportion of subjects and that concomitant lecithin is probably unnecessary. More recently three large-scale studies of tacrine have been reported. The largest included 663 patients prescribed tacrine in higher doses, up to 160 mg daily, for 30 weeks, the longest trial period reported so far. This showed clear statistically significant dose-related improvements on objective performance-based tests, and also the global evaluations of both clinician and care-giver (Knapp et al., 1994). Taking these studies together, there is a clear impression that tacrine offers significant, albeit modest, benefit to a proportion of sufferers with mild to moderate Alzheimer's disease, probably proving of some benefit to between one third and a half of such patients. Furthermore, closer scrutiny of the side-effect profile, particularly that of the hepatotoxicity, has alleviated the concern of many physicians working in this field.
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Other anticholinesterases A number of other anticholinesterases have been investigated in Alzheimer's disease, some showing promise in pilot open studies. These include galanthamine, an alkaloid derived from the bulb of the common snowdrop, metrifonate, huperzine, and E2020. Whether or not these compounds have a role will become apparent when the results of current trials are published.
Neurotrophic support to cholinergie neurons The cholinergic neurons of the basal nucleus of Meynert which are the major site of synthesis of acetylcholine in the human brain, and which are known to be depleted in Alzheimer's disease, have been shown to have the receptors for nerve growth factor (NGF). This is a small protein which is released at the target site of subcortical cholinergic neurons to whose perikaryon it is transported retrogradely. There is now a significant body of animal and tissue culture work which indicates that not just N G F but also other related members of the neurotrophin family may potentially have an important role in the treatment of a number of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, peripheral neuropathy and others. If this approach can be successfully developed it may lead to treatment that will halt or retard the progression of Alzheimer's disease (Wilcock and Dawbarn, 1994).
Conclusion Despite the early disappointments in the use of anticholinesterases as a potential treatment for Alzheimer's disease we now have a treatment that does benefit a proportion of sufferers. Although this may appear to be modest, it is nevertheless meaningful to some patients and their families. There is no other effective treatment and as the side-effect profile is manageable, the successful licensing of tacrine in the United States and France is a major step forward in those countries. Hopefully it will become available to other sufferers elsewhere before too long.
References Eagger, S.A., Levy, R. and Sahakian, B.J. (1991) Tacrine in Alzheimer's disease. Lancet 337, 989-992. Knapp, M.J., Knopman, D.S., Solomon, P.R. et al. (1994) A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. J. Am. Med. Assoc. 271,985-991. Summers, W.K., Majovski, L.V., Marsh, G.M. et al. (1986) Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer's type. New Engl. J. Med. 315, 1241-1245. Wilcock, G.K. and Dawbarn, D. (1994) Editorial review: Nerve growth factor. Int. J. Geriatr. Psychiatry (in press).
Clinically relevant measures of change in Alzheimer's patients
Gerri E. Schwartz Forest Laboratories, 150 East 58th Street, New York, N Y 10155, USA Key words'." Geriatric assessment; Psychiatric rating scales; Caretaker assessment scales
In recent years, growing interest among scientists has led to many methodological refinements and new technologies in both diagnostic and treatment outcome measures for geriatric patients. The most common evaluation of patient behavior in geriatric drug trials has been carried out by a clinician, who obtains information through interviews and rating scales. The patient is a second source of information from whom data can be obtained through psychological performance tests, such as psychometric measures of cognition or motor-skill performance. A third source of information to evaluate drug efficacy may be based on reports provided by significant others (Schwartz, 1983). Significant others, by definition, have close contact with the patient and are in a suitable position to observe the patient in the home environment. These caretakers can provide extremely valuable background information on the patient and may be in a unique position to observe changes resulting from drug treatment. Clinicians, on the other hand, may not be in a position to evaluate these areas of functioning because they rely on information obtained during an office interview. Moreover, effects of drugs that produce subtle changes in behavior may go unnoticed in the context of a clinical evaluation.
S-13 Alzheimer's Disease
Treatment of the cholinergic impairment in Alzheimer's disease
G.K. Wilcock University Department of Care of the Elderly, Frenchay Hospital, Bristol BS16 1LE. UK Key words. Alzheimer's disease; Therapy; Anticholinesterase: Nerve growth factor Introduction There are three main therapeutic approaches to rectifying the cholinergic deficit in Alzheimer's disease. They include enhancing presynaptic production of the missing neurotransmitter; receptor agonist strategies; and the anticholinesterase approach, of which the use of anticholinesterases has been shown to be most promising. An even more fundamental approach however is the use of neurotrophic compounds to try and support the failing cholinergic ceils. This review will concentrate on the use of anticholinesterases but will also briefly describe the developing neurotrophic approach.
Physostigmine Most of the earlier attempts to try and use cholinesterase inhibition as a tool in the treatment of Alzheimer's disease used physostigmine. There are studies in the literature reporting the results of its administration orally, intravenously, and in a few instances by subcutaneous or intramuscular injection. Improvement in selected memory tasks was reported in some of the early intravenous studies, but not in all such trials. Oral physostigmine has yielded less impressive results except when higher doses have been employed. In the longer term, an oral treatment with a reasonable duration of action is clearly desirable and attempts are under way to modify physostigmine such that it meets these requirements.
Aminoacridines The aminoacridine that has received the widest publicity is of course tacrine (THA, 9-amino-l,2,3,4-tetrahydroacridine). This compound together with lecithin was the subject of the study published by Summers which generated much excitement (Summers et al., 1986) when first published, but which was subsequently much criticised. The magnitude of the benefits claimed stimulated many other studies, the earlier ones producing substantially negative or disappointing results. In most cases this was the result of the study design with inadequate numbers of subjects, too low a dose, inadequate or no wash-out periods in cross-over studies and a number of other design flaws. The hepatotoxicity and cholinergic side-effects surfaced as potentially major problems and the continued development of aminoacridines, including tacrine and velnacrine, began to look most uncertain. The first really positive study came from Raymond Levy's group (Eagger et al., 1991) in which 65 out of 89 patients completed a 7-month trial of T H A and lecithin with a significant benefit to a proportion of those included. Although subject to criticism this was the first essentially positive study following Summers' original report. There have been a number of trials of tacrine without concomitant lecithin, the better designed ones suggesting again that there is some benefit to a proportion of subjects and that concomitant lecithin is probably unnecessary. More recently three large-scale studies of tacrine have been reported. The largest included 663 patients prescribed tacrine in higher doses, up to 160 mg daily, for 30 weeks, the longest trial period reported so far. This showed clear statistically significant dose-related improvements on objective performance-based tests, and also the global evaluations of both clinician and care-giver (Knapp et al., 1994). Taking these studies together, there is a clear impression that tacrine offers significant, albeit modest, benefit to a proportion of sufferers with mild to moderate Alzheimer's disease, probably proving of some benefit to between one third and a half of such patients. Furthermore, closer scrutiny of the side-effect profile, particularly that of the hepatotoxicity, has alleviated the concern of many physicians working in this field.
240
Other anticholinesterases A number of other anticholinesterases have been investigated in Alzheimer's disease, some showing promise in pilot open studies. These include galanthamine, an alkaloid derived from the bulb of the common snowdrop, metrifonate, huperzine, and E2020. Whether or not these compounds have a role will become apparent when the results of current trials are published.
Neurotrophic support to cholinergie neurons The cholinergic neurons of the basal nucleus of Meynert which are the major site of synthesis of acetylcholine in the human brain, and which are known to be depleted in Alzheimer's disease, have been shown to have the receptors for nerve growth factor (NGF). This is a small protein which is released at the target site of subcortical cholinergic neurons to whose perikaryon it is transported retrogradely. There is now a significant body of animal and tissue culture work which indicates that not just N G F but also other related members of the neurotrophin family may potentially have an important role in the treatment of a number of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, peripheral neuropathy and others. If this approach can be successfully developed it may lead to treatment that will halt or retard the progression of Alzheimer's disease (Wilcock and Dawbarn, 1994).
Conclusion Despite the early disappointments in the use of anticholinesterases as a potential treatment for Alzheimer's disease we now have a treatment that does benefit a proportion of sufferers. Although this may appear to be modest, it is nevertheless meaningful to some patients and their families. There is no other effective treatment and as the side-effect profile is manageable, the successful licensing of tacrine in the United States and France is a major step forward in those countries. Hopefully it will become available to other sufferers elsewhere before too long.
References Eagger, S.A., Levy, R. and Sahakian, B.J. (1991) Tacrine in Alzheimer's disease. Lancet 337, 989-992. Knapp, M.J., Knopman, D.S., Solomon, P.R. et al. (1994) A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. J. Am. Med. Assoc. 271,985-991. Summers, W.K., Majovski, L.V., Marsh, G.M. et al. (1986) Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer's type. New Engl. J. Med. 315, 1241-1245. Wilcock, G.K. and Dawbarn, D. (1994) Editorial review: Nerve growth factor. Int. J. Geriatr. Psychiatry (in press).
Clinically relevant measures of change in Alzheimer's patients
Gerri E. Schwartz Forest Laboratories, 150 East 58th Street, New York, N Y 10155, USA Key words'." Geriatric assessment; Psychiatric rating scales; Caretaker assessment scales
In recent years, growing interest among scientists has led to many methodological refinements and new technologies in both diagnostic and treatment outcome measures for geriatric patients. The most common evaluation of patient behavior in geriatric drug trials has been carried out by a clinician, who obtains information through interviews and rating scales. The patient is a second source of information from whom data can be obtained through psychological performance tests, such as psychometric measures of cognition or motor-skill performance. A third source of information to evaluate drug efficacy may be based on reports provided by significant others (Schwartz, 1983). Significant others, by definition, have close contact with the patient and are in a suitable position to observe the patient in the home environment. These caretakers can provide extremely valuable background information on the patient and may be in a unique position to observe changes resulting from drug treatment. Clinicians, on the other hand, may not be in a position to evaluate these areas of functioning because they rely on information obtained during an office interview. Moreover, effects of drugs that produce subtle changes in behavior may go unnoticed in the context of a clinical evaluation.