This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This pilot project will explore the utility of combined pharmacologic manipulation and arterial spin-labeled perfusion MRI (ASL-pMRI) as an in vivo probe of cholinergic function. There is ample data that the cholinergic system plays a key role in cognition, and that cholinergic dysfunction occurs under a variety of conditions, including normal aging, dementia, and delirium. Methods to investigate cholinergic function in vivo are needed to better understand how the cholinergic system is affected in aging and in disease states. Pharmacologic MRI, by measuring the effects of drug challenges on neuronal activity, can provide an indirect measurement of neurotransmitter function with high anatomic resolution. ASL-pMRI is a technique that uses electromagnetic labeling of water in arterial blood as a diffusible tracer, rather than exogenous contrast agents or radioactivity, to generate highly accurate, non-invasive quantitative measurements of cerebral blood flow, and for these reason is ideally suited for pharmacologic MRI. We propose to use ASL-pMRI to more fully characterize the normal cerebral blood flow response to cholinergic modulation, and to correlate these changes in blood flow with cognitive performance. In this study subjects will be tested under 4 different treatment conditions using anticholinergic drugs: 1) scopolamine; 2) mecamylamine; 3) combined scopolamine and mecamylamine; and 4) placebo, in a double blind, placebo-controlled, crossover design. Under each treatment condition subjects will undergo ASL-pMRI scans and detailed cognitive testing. Comparison of global and regional brain perfusion will be made both within- and across-subjects, and correlated with performance on cognitive testing.
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