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 pharmacological treatment stategies. Symptomatic treatment mainly focussing on cholinergic therapy has been clinical evaluated by randomized, double-blind, placebo controlled, parallel group studies measuring performance based tests of cognitive function, activity of daily living and behavior. Significant progress has been made in recent years to develop and apply functional brain imaging techniques allowing early diagnosis of dementia and evaluation of treatment efficacy. Positron emission tomography (PET) is a suitable method for functional studies of pathological changes in brain which as a clinical instrument not solely reveal dysfunctional changes early in the course of the disease but also may provide a deep insight into the functional mechanisms of new potential drug treatment strategies. The advantage with PET is the capacity not only to measure changes in glucose metabolism, cerebral blood flow but also to obtain further insight into neuronal communicative processes (transmitter/receptor interactions) in brain and pharmacokinetic 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 cognitive impairment of AD patients. Cholinergic drugs including cholinesterase inhibitors such as physostigmine, tacrine, velnacrine as well as the acetylcholine releaser linopiridine have been reported to increase the cerebral blood flow in AD patients both after acute and fairly short period of treatment. Increase in cerebral glucose metabolism has also been measured following fairly long periods of treatment with cholinesterase inhibitors (months). The cholinergic nicotinic and muscarinic receptors do also respond to treatment 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 patients. Functional PET activation studies performed simultaneously with memory tasks will provide further valuable insight into the mechanisms of action of new drug, how they interact and can improve the efficacy of memory processes in AD brains.