Functional brain activity in Alzheimer patients as studied by multi-tracer positron emission tomography : effects of treatment with cholinesterase inhibitors

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease accompanied by cognitive impairment and disturbances in several neurotransmitter systems, especially the cholinergic system. Studies have correlated the cognitive impairment observed in AD patients with a deficit in central cholinergic neurotransmission. The most successful therapeutic agents for symptomatic treatment of AD patients are cholinesterase inhibitors (ChEIs), e.g. donepezil, rivastigmine and galantamine, which are targeted towards enhancing cholinergic neurotransmission. One of the most valuable tools for evaluating cholinergic neurotransmission in AD patients is positron emission tomography (PET). PET with high spatial resolution, has successfully been used in the early diagnosis, differential diagnosis and evaluation of drug treatment in patients suffering from AD. The overall aim of this thesis was to utilize the multi-tracer PET technique to measure brain glucose metabolism, nicotinic acetylcholine receptor (nAChR) density, acetylcholinesterase (AChE) activity and amyloid load of patients with mild AD. These brain functional aspects were measured during the natural course of the disease or during treatment with ChEIs and/or anti-amyloid therapy in conjunction with assessment of changes in CSF biomarkers, ChE activity as well as with cognitive performance of the patients. In this thesis, it was demonstrated that cortical nAChRs as assessed by a dual tracer PET model with administration of 15O-water and (S)(-)11C-nicotine in mild AD patients (n = 27) are associated with the cognitive function of attention rather than with episodic memory. The effect of different ChEIs on cortical nAChRs was also evaluated in this thesis. Rivastigmine treated mild AD patients (n = 10) showed a significant increase of nAChRs in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of treatment. In a randomized double-blind placebo-controlled study, mild AD patients (n = 18) treated with galantamine demonstrated no change in cortical nAChRs after both short- (3 months) and long-term (12 months) treatment. However, it should be noted that individual subjects with higher plasma galantamine levels also demonstrated an increase in cortical nAChR binding. Additionally, patients treated with galantamine for 12 months demonstrated a 30–40% decrease in cortical AChE activity (as assessed by 11C-PMP-PET) and a 30-36% decrease in CSF AChEsynaptic activity. In addition to rivastigmine and galantamine, the effects of (-)-phenserine, a new ChEI, were evaluated in mild AD patients (n = 20) in a randomized double-blind placebo-controlled study. Phenserine is a tentative AD drug that demonstrates an additional mechanism of action as an inhibitor of the formation of beta-amyloid precursor protein (beta-APP). Mild AD patients treated with (-)-phenserine demonstrated an increase in cerebral glucose metabolism as evaluated by 18F-FDGPET after 3 months compared with baseline. We also observed that cortical amyloid load, measured by 11C-PIB-PET, was inversely correlated with CSF beta-amyloid (Abeta) levels, suggesting that (-)- phenserine treatment influenced both brain and CSF amyloid. After treatment with galantamine and (-)-phenserine we observed the highest level of improvement of cognitive performance up to 3 to 6 months, and maintenance of cognitive performance was observed after 12 months’ treatment, indicating stabilization of the disease. Attention was shown to be the main cognitive domain improved by the treatment. Positive correlations were also observed between the changes in number of cortical nicotinic receptors, AChE inhibition and changes in cognitive measures of attention. In conclusion, the present findings demonstrate that utilizing the multi-tracer PET method is important in the investigation of functional activity, neurotransmitters and pathology in the brains of patients with AD, in conjunction with measures of cognitive function, to evaluate the efficacy of the currently available ChEI treatments and future treatment strategies.