Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer’s dementia

Abstract

Whether α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) expression is reduced in early Alzheimer’s disease is controversial. Using (-)-[18F]Flubatine PET, Sabri, Meyer et al. report α4β2-nAChR deficiency in mild Alzheimer’s dementia, especially within the basal forebrain-cortical and septohippocampal cholinergic projections. Reduced α4β2-nAChR availability correlates with impaired episodic memory and executive function/working memory.

(+)-[18F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand—results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer’s disease and healthy controls

“…Thirty-six volumes of interest (VOIs) were manually drawn on three consecutive slices of the reoriented individual 3D T1w MPRAGE data (Supplementary Figure 2). The PET data was corrected for motion artifacts using Statistic Parametric Mapping 12 (SPM-Software; Wellcome Trust Centre for Neuroimaging, University College London) as described in detail elsewhere [9]. PMOD was used to co-register the dynamic PET data with the individual T1 MPRAGE MRI in order to create the time-activity curves (TACs) for the kinetic analysis.…”

“…As a reduction of α4β2 nAChRs in AD patients can be assumed based on the results of our earlier studies [9,10,13] and autoradiographic findings, one-sided t tests were performed. The entire region set was used only for kinetic modeling.…”

“…Results of first applications in humans were published for (−)-[ 18 F]Flubatine, [ 18 F]AZAN, and [ 18 F]XTRA showing favorable data for dosimetry and image quality as well as fast kinetics [5][6][7]. However, [ 18 F]AZAN and [ 18 F]XTRA are significantly metabolized [7]; (−[ 18 F]Flubatine on the other hand showed only a low amount of metabolites [5,8,9]. Due to inter-individual variability, the application of a reference region was often required to detect α4β2 nAChR differences between patients and healthy controls [9][10][11][12][13][14][15].…”

“…It is known from neuropathological studies that an alteration of the cholinergic system with loss of α4β2 nAChRs occurs in patients with Alzheimer's dementia (AD) [18,19]. Several PET and SPECT studies using 2-[ 18 F]FA-85380 or 5-[ 123 I]IA-85380 revealed a reduction of α4β2 nAChRs in both AD and MCI subjects compared with HCs in various brain regions [9][10][11][12][13].…”

Tetrapeptide Ac-HAEE-NH2 Protects α4β2 nAChR from Inhibition by Aβ

“…Existing data suggest that the interaction of Aβ with α4β2 and α7 nAChRs leads to selective loss of cholinergic neurons and cholinergic deficit, which is a hallmark of AD [ 13 ]. In mild AD, the region-specific loss of α4β2 nAChR correlates with the impairment of distinct cognitive domains [ 14 ]. Thus, compounds that prevent the interaction of Aβ with nAChRs could reduce neuronal loss and cognitive decline in AD.…”