THE USE OF COGNITIVE AND ERP BIOMARKERS OF CHOLINERGIC FUNCTION IN NOVEL TESTS OF MUSCARINIC POSITIVE ALLOSTERIC MODULATORS

Abstract

Introduction The decline of cholinergic functioning is associated with increased cognitive decline and the development of Alzheimer s disease (AD) pathology. At present, there is no pharmacological agent that slows the progression the disease. Muscarinic post positive allosteric modulators (PAMs) are a new class of compounds aiming to restore cholinergic functioning in patients suffering from AD pathology. PAMs of the M1 receptor can potentiate the response of the M1 receptor to acetylcholine, without inducing the harmful side-effects. This is due to the fact that PAMs do not bind at the target site, rather they boost the signal of acetylcholine when is engaged at the orthosteric receptor. The downside of using PAMs is that they have low affinity to radioactive ligands, so this reduces the utility of PET imaging. This creates a challenge in how to establish functional efficacy of the compound in both preclinical and clinical trials. Methods To address this challenge, we plan on using cognitive tasks and electroencephalography (qEEG) to identify dose-depended changes in cholinergic functioning. These functional biomarkers allow us to develop more detailed models of how M1PAMs may influence downstream cognitive processing. The cognitive and EEG measures presented have been shown to modulate cholinergic tone, therefore we should be able to identify effective target engagement. Results Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Tasks recorded by EEG tested auditory and visual discrimination using oddball tasks, and incidental memory. Conclusions These cognitive and electrophysiological results will assist in establishing functional targets for future studies using M1PAMs. This research was funded by Funding for this research comes from an Alzheimer s Association and the Alzheimer s Drug Discovery Foundation.