Review Treatment of Alzheimer's disease

Dementia may be caused by > 60 disorders, but currently Alzheimer's disease, a clinical syndrome involving impaired intellectual function in memory, language visuospatial skills and cognition, is thought to account for about half of all cases of dementia. No effective therapy exists and diagnosis is still a problem, often confirmed only on postmortem. The aetiology and pathogenesis also remain unknown although many precipitating factors have been suggested including genetic predisposition, protein abnormalities, infectious agents, toxins, vascular disorders and neurotransmitter deficits.

Early therapeutic strategies Initially, enhancers of cerebral blood flow and

mild psychostimulants were used. Recent studies have indicated that cerebrovascular regulatory mechanisms are maintained in the elderly and a vascular origin for Alzheimer's disease is no longer widely accepted. Many studies with vasodilators are now being conducted in patients with multi­infarct dementia. Patients with Alzheimer's disease have proved generally unresponsive to psychostimulants.

Nootropics This unique class of drugs affect mental

function; although their mechanism of action is unknown. Piracetam has produced some improvement in patients with dyslexia or alcoholism but other nootropics may be more effective in patients with cognitive deficits. The addition of choline or lecithin did not improve test results in Alzheimer's patients receiving piracetam. Synergism between piracetam and related compounds, and antiepileptics or dihydroergocristine, has been observed. Generally, promising results have been obtained in animal and preliminary clinical studies, but well designed clinical-trials have produced disappointing results.

Metabolic enhancers Metabolic enhancers affect cellular metabolism,

and in animal studies, ergoloid mesylates [codergocrine mesylate; dihydroergotoxine; dihydrogenated ergot alkaloids] have effects on local cerebral glucose uptake, central monoaminergic receptors, memory, learning, cholinergic neurotransmission, and an age and dose related effect on agonist and antagonist striatal dopamine binding. High dose ergoloid mesylates improved short term memory in mildly demented patients and also may have a positive effect on mood. They remain a world market leader despite a lack of conclusive evidence supporting their efficacy.

Cholinergic agents Although impairment of the cholinergic system

in Alzheimer's disease may account for the

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observed cognitive deficit, it is unlikely to explain the entire range of deficits observed.

Acetylcholinesterase inhibitors.· physostigmine appears to affect attention processes and may improve memory in Alzheimer's patients. However, hypertension may be a problem in some patients and the drug has a low bioavailability in humans. Miotine-related compounds appear to have a longer duration of action and greater central selectivity and may also have muscarinic receptor binding properties. Cholinergic therapy on the whole appears to improve memory function provided the dosage is individualised and addition of a precursor such as lecithin may improve results. A recent trial with tacrine (tetrahydroaminoacridine; Warner Lambert] in Alzheimer's patients preloaded with lecithin, showed considerable efficacy.

Muscarinic receptor agonists and antagonists: Cortical samples from patients with Alzheimer's disease show reductions in M2 receptor numbers and choline acetyltransferase activity. Antagonists selective for M1 or M2 muscarinic receptors have been identified but no selective agonists have been found although recent reports suggest (R)­nipecotic acid ethyl ester may be an M2-selective agonist. RS 586 (Sandoz], a muscarinic agonist, has shown some efficacy in Alzheimer's disease, with improvement of neuropsychological tests involving response speed and left hemisphere function. Another muscarinic receptor agonist, arecoline, has been shown to elevate regional cerebral metabolism in animals. However, supra­additive effects have not been observed with agonist combinations.

Other cholinergic agents include allosteric inhibitors of muscaric receptors, acetylcholine release and storage modulators, and nonspecific cholinergic agents including minaprine, bifemelane and salbutamine.

Other receptors: Nicotinic receptors may also be altered in Alzheimer's disease. Nicotine affects attention, memory and information processing and receptor numbers are reduced in Alzheimer's patients. Positive effects have been observed with nicotine administration in humans and it also stimulates acetylcholine release. Other agents that affect the cholinergic system and potentially may be useful are serotonin, amino acids, adenosine, adenylate cyclase and phosphodiesterase.

Neurotrophic factors: Nine growth factors are not reduced in Alzheimer's disease but may be involved in disease pathogenesis.

Biogenic amines Conflicting evidence has been presented as to

whether clonidine improves delayed response and cognitive performance in aged animals and normal humans. The serotonergic system may be seriously impaired in Alzheimer's disease and alaproclate [Astra], an inhibitor of neuronal serotonin reuptake, may positively influence

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emotional state in Alzheimer patients. However, zimeldine which also blocks serotonin reuptake, has no effects on memory or reaction time. Fipexide, a dopaminergic agent, may act as a cognition activator in the elderly but memantine was inactive in severe Alzheimer's disease. Selegiline [ deprenyl] enhanced episodic memory and learning task performance but knowledge memory, intrusions and other functions were not altered. Psychopathological symptoms associated with Alzheimer's disease may be managed with haloperidol, thioridazine or pimozide.

Neuropeptides A deficit in somatostatin is observed in

Alzheimer's disease but a somatostatin analogue did not improve memory in Alzheimer's patients. Vasopressin analogues may facilitate memory and learning. The corticotrophin analogue, ORG 2766 [Organon] improved attention span in patients with Alzheimer's disease but significant effects on cognitive function were not observed. Opiate antagonists, which block ,8-endorphin-induced retrograde amnesia in animals do not improve cognitive function in Alzheimers disease or after ECT, although a recent study of opioid receptor binding provides a rationale for therapeutic intervention via kappa receptors. Other neuropeptides which have been investigated include: thyrotropin releasing hormone and analogues; cholecystokinin which may indirectly influence memory; vasoactive intestinal peptide; neuropeptide Y which may inhibit memory retention in Alzheimer's disease; neurotensin which is increased in the frontal and temporal cortex in Down's syndrome; angiotensin II which facilitates learning and retention in animal models; saralasin which blocks angiotensin II effects.

Excitatory aminoacids Clinical trials with agonists and antagonists of

these compounds have not yet been performed. However, evidence is accumulating in support of an excitatory amino acid hypothesis of senile cognitive decline. Alzheimer's and Huntington's diseases have been associated with changes in L­glutamate binding and N-methyl-0-aspartate receptor distribution correlates with neurotic plaques and neurofibrillary tangles in' Alzheimer's disease. Loss of these receptors is also associated with Alzheimer's disease.

Other agents Other agents reported to affect memory

processes in animals and man include: pentoxifylline [ oxpentifylline] which reverses age­related spatial memory deficits; propentofylline [HWA 285 Hoechst] reverses cycloheximide­induced amnesia and affects cerebral metabolism in animals and affects psychomotor performance, mood and memory in man; razobazam [Hoe 175, HR 175; Hoechst] improves memory in animals; pyritinol improves learned task retention in poor learners; teniloxazine [sulfoxazine; Yoshitomo; Green Cross] protects against ECT amnesia and hypoxia in mice; buflomedil improves cognitive

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function regional blood flow and memory function in demented patients; estradiol may provide some benefit to postmenopausal women with Alzheimer's disease; cyclandelate may improve early memory disorders; glucose may modulate memory storage processing; phosphatidylserine may have positive effects in elderly patients; ST 200 [L-acetylcarnitine] may improve mental parameters in Alzheimer's disease and rolipram reverses anisomycin-induced amnesia in animals.

Animal models Valid animal models have not yet been found

for Alzheimer's disease but a number of induced behavioural models, currently used to evaluate drugs used to treat cognitive decline, include animals that have undergone specific CNS lesions or electroconvulsive shock treatment, genetic changes, oxygen deficit, aged animals, and drug­induced deficit models, and models of cognitive disorders related to immune dysfunction. The validity of these models has not been established and will probably not be determined until a drug with considerable efficacy is developed. Moos WH. Davis RE. Schwarz RD. Gamzu ER. Cognition activators. Medicinal Research Reviews 8: 353·391, No. 3, 1988 [491 references] 8009

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