Preliminary studies of muscarinic M1 receptor availability and cognition in schizophrenia

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PROJECT SUMMARY AND ABSTRACT Background: Converging lines of evidence from postmortem studies provide strong evidence that brain muscarinic M1 receptor deficit is present in a subset of schizophrenia (SZ) patients. M1 receptors are an important target for cognitive deficits in SZ. However, until now, it has not been possible to examine the heterogeneity of SZ with respect to M1 receptor availability in vivo. The development of a novel positron emission tomography (PET) ligand, [11C]EMO, at Yale PET Center provides a unique opportunity to, for the first time, examine in vivo brain muscarinic M1 receptor availability in SZ and, concurrently, elucidate the relationship of M1 receptors to cognitive deficits in SZ. The ligand has high affinity for the M1 receptor, high brain uptake, appropriate kinetics, excellent test-retest reproducibility (≤ 6% test-retest variability in cortical regions), and presence of a suitable reference region (i.e., cerebellum) demonstrated in blocking studies. This allows for a reliable estimation of specific binding to M1 receptors (BPND) using kinetic modeling. The purpose of this exploratory study is to examine M1 receptor availability in SZ patients and to relate M1 receptor availability to proximal and distal measures of cognitive performance, namely evoked ɣ oscillations in the EEG and verbal memory. Furthermore, the relationship between hippocampal [11C]EMO availability (BPND), evoked ɣ oscillations, verbal memory, and measures of illness severity will be explored. Hypotheses: SZ subjects will show lower hippocampal M1 receptor availability as measured using [11C]EMO BPND. Additionally, M1 receptor availability ([11C]EMO BPND) will correlate with verbal memory performance and EEG indices of encoding (γ power) during a verbal memory task in SZ. Methods: We will compare M1 receptor availability in SZ and age-, gender-matched healthy controls using [11C]EMO and the High Resolution Research Tomograph (HRRT), a PET scanner with high sensitivity and resolution available for human brain imaging. The relationship between hippocampal [11C]EMO binding, encoding related γ power during a verbal memory task, verbal memory, gender and serum acetylcholine level will be explored. This exploratory study will provide the necessary pilot data to conduct a larger study to fully investigate the heterogeneity of SZ with respect to M1 receptor availability.