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• W2766761509 abstract "Loss of cholinergic signaling is principally related to cognitive decline in Alzheimer's Disease (AD), and stimulation of these receptors improves cognitive performance. While acetylcholinesterase inhibitors are modestly helpful in the early stages of AD, neurodegeneration limits their effectiveness, and warrants the development of alternative cholinergic treatments. Given the high costs of drug development, it is important to obtain evidence of target engagement as early as possible. Phase 1 and 2 studies provide an opportunity not only to establish maximum tolerated doses and safety, but also to document cognitive effects in human subjects. Development of novel behavioral and brain-based measures targeting cognitive processes of interest and sensitive to the drug effects will accelerate efficacy evaluation. We report evidence from early phase drug trials using event-related potentials (ERP) and cholinergically-responsive psychomotor cognitive tasks developed in our laboratory as markers of CNS engagement. We explored whether treatment may potentiate cholinergic receptors in the CNS in humans by evaluating changes in electroencephalography (EEG) functions (e.g. altered ERPs). Oddball and memory ERP tasks were used to evaluate the cognitive impact of four-week chronic nicotine treatment on memory (indexed by increased ERP amplitudes for repeated vs. novel stimuli and better performance on a Selective Reminding Task) in aging adults with Down syndrome (DS), a single-gene model of AD. ERP passive memory testing demonstrated positive drug effects on cognitive performance compared to standard verbal memory tasks that were difficult for DS subjects to perform. In addition, computerized cognitive assessment of basic sensory and psychomotor functions utilizing critical flicker fusion and decomposition of choice reaction time detected subtle cognitive effects of cholinergic agents in volunteers. We are currently using the same ERP and sensory/psychomotor measures to examine the effects of a novel cholinergic positive allosteric modulator (PAM) to establish functional biomarkers of central target engagement in healthy young adults." @default.
• W2766761509 created "2017-11-10" @default.
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• W2766761509 date "2017-07-01" @default.
• W2766761509 modified "2023-09-28" @default.
• W2766761509 title "[P4-006]: EXPLORING NOVEL COGNITIVE AND ELECTROPHYSIOLOGICAL MARKERS OF TARGET ENGAGEMENT IN PHASE 1 AND 2 STUDIES OF PUTATIVE CHOLINERGIC COGNITIVE ENHANCERS" @default.
• W2766761509 doi "https://doi.org/10.1016/j.jalz.2017.06.1870" @default.
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