PET studies and cholinergic therapy in Alzheimer's disease

Alzheimer's disease (AD) is one of the most devastating brain disorders of elderly humans. The last decade has witnessed a steadily increasing effort directed at discovery of the etiology of the disease and development of pha rmacological treatment stategies. Symptomatic treatment mainly focussing on cholinergic therapy has been clinical evaluated by randomized, double-blin d, placebo controlled, parallel group studies measuring performance based t ests of cognitive function, activity of daily living and behaviour. Signifi cant progress has been made in recent years to develop and apply functional brain imaging techniques allowing early diagnosis of dementia and evaluati on of treatment efficacy. Positron emission tomography (PET) is a suitable method for functional studies of pathological changes in brain which as a c linical instrument not solely reveal dysfunctional changes early in the cou rse of the disease but also may provide a deep insight into the functional mechanisms of new potential drug treatment strategies. The advantage with P ET is the capacity not only to measure changes in glucose metabolism, cereb ral blood flow but also to obtain further insight into neuronal communicati ve processes (transmitter/receptor interactions) in brain and pharmacokinet ic events and drug mechanisms. PET studies have so far revealed disturbances in some neuroreceptor systems in brain of AD patients. A significant correlation can be observed between the impairment of nicotinic receptors in the temporal cortex and the cogni tive impairment of AD patients. Cholinergic drugs including cholinesterase inhibitors such as physostigmine, tacrine, velnacrine as well as the acetyl choline releaser linopiridine have been reported to increase the cerebral b lood flow in AD patients both after acute and fairly short period of treatm ent. Increase in cerebral glucose metabolism has also been measured followi ng fairly long periods of treatment with cholinesterase inhibitors (months) The cholinergic nicotinic and muscarinic receptors do also respond to trea tment with cholinesterase inhibitors in AD patients. An improvement of the nicotinic receptors has been found in cortical regions following treatment with cholinesterase inhibitors and nerve growth factors (NGF) to AD patient s. Functional PET activation studies performed simultaneously with memory t asks will provide further valuable insight into the mechanisms of action of new drug, how they interact and can improve the efficacy of memory process es in AD brains.