Imaging the alpha7 nicotinic acetylcholine receptor in mild cognitive impairment

Johns Hopkins University, Baltimore MD

Investigators

Abstract

PROJECT SUMMARY This project will assess the availability of the cerebral ?7 nicotinic acetylcholine receptor (?7-nAChR) as a contributing factor in the early pathophysiology of Alzheimer's disease (AD). Converging data suggest that the ?7-nAChR promotes accumulation of A?42 in cholinergic neurons, particularly in basal forebrain and neocortical regions where the ?7-nAChR is more highly expressed. High cerebral ?7-nAChR availability (as we have observed in normal aging), promotes intracellular sequestration of A?42 in cholinergic cells, and the A?42-?7-nAChR interaction functionally antagonizes the ?7-nAChR, which may be linked to progressive, localized cell-death, synaptic loss, and aberrant neuronal activity long before spread of extracellular amyloid plaque. The A?42-?7-nAChR complex drives upregulated expression of the ?7-nAChR, fueling its further interactions with soluble A?42 species. Based on published evidence and our preliminary data, we hypothesize that higher, cerebral ?7-nAChR binding will be observed in patients with MCI, the prodrome to AD, compared to cognitively normal elderly controls using [18F]ASEM (ASEM) with positron emission tomography (PET). We further hypothesize that higher availability of ?7-nAChR in targeted brain regions will be associated with 1. lower cognitive performance and 2. higher circulating, AD-relevant, biofluid biomarkers such as ?7-nAChR autoantibodies within these participants. We will thus test for hypothesized high availability of the ?7-nAChR in MCI compared to cognitively normal individuals, and its relationship to cognitive performance (Aim 1), as well as its correlation with targeted biofluid markers that include plasma ?7- nAChR autoantibodies (Aim 2). Finally, in Aim 3, we will evaluate changes in ?7-nAChR availability using ASEM PET and its relationship to cognitive performance and these biofluid markers between baseline and two-year follow-up in a subset of participants from Aims 1 and 2. The goal of this proposal is to test for high brain availability of the ?7-nAChR in MCI and its relationship to cognition and circulating AD-relevant biomarkers - a critical step toward evaluating the ?7-nAChR as an AD imaging biomarker with diagnostic and therapeutic implications.