This thesis describes studies of the effects on cognition of drugs that stimulate or inhibit the cholinergic system by direct or indirect mechanisms. The central question of this thesis is if the... Show moreThis thesis describes studies of the effects on cognition of drugs that stimulate or inhibit the cholinergic system by direct or indirect mechanisms. The central question of this thesis is if the integration of pharmacokinetics (PK), CNS pharmacodynamics (PD) and clinical assessments in early phase drug development is feasible for drugs for Alzheimer’s disease. All study designs included extensive pharmacodynamic testing, in various phases of drug development and in subjects with normal or impaired cognition, or in healthy volunteers with a previously pharmacologically impaired cognitive system (challenge studies). Cognitive decline is a complex process with many potential pathophysiological mechanism that allow many approaches, and we have only studied the cholinergic system. However, for all interventions it would be ideal if there were good biomarkers of the severity of the disease that were shown to respond to interventions. It is obvious that more efficient development paradigms are necessary to keep the pharmacological development trajectories economically feasible. Rapid evaluation of the most promising treatments in the right dose requires preclinical and early development, already directed towards the final clinical value based endpoint. Rapid elimination of interventions that do not work will help to focus limited resources on the more hopeful ones. Show less
The main objective of this thesis was to investigate the serotonergic and cholinergic neurotransmitter systems, and the way these are altered in older age and Alzheimer’s disease. For that purpose,... Show moreThe main objective of this thesis was to investigate the serotonergic and cholinergic neurotransmitter systems, and the way these are altered in older age and Alzheimer’s disease. For that purpose, the neuroimaging technique resting state fMRI (RS-fMRI) was used to measure whole brain functional connectivity with and without pharmacological stimulation. The first part of the thesis concerns two pharmacological RS-fMRI studies that were executed in young adults. Pharmacological challenge effects of two selective serotonin reuptake inhibitors (sertraline and citalopram) and a cholinesterase inhibitor (galantamine) on brain connectivity were examined to gain more insight into the underlying neurotransmitter systems and the mechanisms of drug action in the central nervous system. The second part of this thesis was aimed at discovering changes in brain connectivity and serotonergic and cholinergic system functioning in aging and Alzheimer’s disease, by comparing brain network connections and the pharmacological response of this measure between young and older adults and patients with Alzheimer’s disease. Show less
