British Medical Bulletin 42:97-100 (1986)
© 1986 The British Council
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CHOLINERGIC APPROACHES TO THE TREATMENT OF ALZHEIMER'S DISEASE
Department of Psychiatry Bronx V A Medical Center New York and Department of Psychiatry and Pharmacology, Mount Sinani School of Medicine New York
Abstract
Aizheimer's disease (AD) is a major mental health problem involving abnormalities of several neurotransmitter systems in the brain. The most consistent and pervasive abnormality involves the cholmergic system, and correlates with severity of illness in AD. Pharmacological enhancement of cholinergic activity includes presynaptic agents which increase acetylcholine (ACh) synthesis and release; synaptic agents which increase ACh by limiting its breakdown; and postsynaptic agents which directly stimulate ACh receptors. Valid trials of cholinergic agents in AD require a specialized study design in which individualized optimal drug doses are tested in a large population of stringently diagnosed AD patients. Testing devices must be suitable for each patient's capabilities, and should measure alterations of function in several areas.
Clinical trials with choline and lecithin, ACh precursors, have not shown cognitive improvements in AD patients. Combination of precursors with agents that enhance the firing rate of presynaptic neurons, such as piracetam, may have some beneficial effect in a subgroup of AD patients with remaining functionally intact cholinergic neurons. Red cell-plasma choline ratio appears to be higher in treatment responders. Presynaptic approaches have the advantage of mimicking the phasic action of cholinergic cells, but require the presence of functionally intact cholinergic neurons.
Physostigmine, an acetycholinesterase (AChE) inhibitor, augments available synaptic ACh. Studies with intravenous physostigmine show significant but moderate transient improvement in memory test, but applicability is limited by short half-life. Oral, like intravenous, physostigmine has a narrow therapeutic window, necessitating the use of a dose-finding phase in study design. Oral physostigmine has yielded modest improvements in specific cognitive areas and overall functioning in a majority of AD patients. Biochemical measures of central cholinergic activity such as plasma cortisol and cerebrospinal fluid AChE activity have been correlated with symptom improvement, and may identify likely responders. Cholinergic agonists such as Rs 86, erecoline and oxotremorine have been used in preliminary trials with AD patients, yielding modest results with significant side effects. Future directions include the development of more specific, long-acting cholinergic agents with fewer side effects; differentiating M-1 and M-2 receptor sites; delineation of parameters that can predict response, and possibly the use of combined neurotransmitter enhancement treatments.
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