Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer's disease dementia

Abstract

Background: Cholinergic neurotransmitter system dysfunction contributes to cognitive impairment in Alzheimer's disease and other syndromes. However, the specific cholinergic mechanisms and brain structures involved, time course of alterations, and relationships with specific cognitive deficits are not well understood.

Methods: This study included 102 older adults: 42 cognitively unimpaired (CU), 28 with mild cognitive impairment (MCI), and 32 with Alzheimer's disease (AD) dementia. Each participant underwent a neuropsychological assessment. Regional brain α4β2 nicotinic cholinergic receptor binding (V_T/fp) was measured using 2-[¹⁸F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and PET imaging. Voxel-wise analyses of group differences were performed. Relationships between receptor binding and cognition, age, and cholinesterase inhibitor medication use were assessed using binding values in six prespecified regions of interest.

Results: SPM analysis showed the group V_T/f_p binding differences in the bilateral entorhinal cortex, hippocampus, insula, anterior cingulate, thalamus, and basal ganglia (p < .05, FWE-corrected). Pairwise comparisons revealed lower binding in the AD group compared to the CU group in similar regions. Binding in the entorhinal cortex was lower in the MCI group than in the CU group; binding in the hippocampus was lower in the AD group than in the MCI group. AD participants taking cholinesterase inhibitor medication had lower 2FA binding in the bilateral hippocampus and thalamus compared to those not taking medication. In the CU group, age was negatively associated with 2FA binding in each region of interest (r_s = - .33 to - .59, p < .05 for each, uncorrected). Attention, immediate recall, and delayed recall scores were inversely associated with 2FA binding in most regions across the full sample. In the combined group of CU and MCI participants, attention was inversely associated with 2FA binding in most regions, beyond the effect of hippocampal volume.

Conclusions: Nicotinic cholinergic receptor binding in specific limbic and subcortical regions is lower in MCI and further reduced in AD dementia, compared to CU older adults, and is related to cognitive deficits. Cognitive decline with age may be a consequence of reduced cholinergic receptor density or binding affinity that may also promote vulnerability to other Alzheimer's processes. Contemporary modification of the "cholinergic deficit" of aging and AD may reveal opportunities to prevent or improve clinical symptoms.

Keywords: Alzheimer’s disease; Cholinergic receptors; Cognitive aging; Mild cognitive impairment.

Fig. 1

Results of the overall ANOVA showing the effect of diagnosis on 2FA binding (V_T/f_p values, p < .05, FWE-corrected at the voxel level). F-score is shown on the color scale

Fig. 2

SPM maps of pairwise comparisons of 2FA binding (V_T/f_p values). T-score is shown on the color scale. For CU > AD (A) and MCI > AD (B), the results are shown across the entire brain (p < .05, FWE-corrected at the voxel level). For CU > MCI (C), the results are shown within the bilateral hippocampal/entorhinal mask (p < .05, FWE-corrected using small volume correction)

Fig. 3

Mean 2FA binding in the core regions of interest in the CU, MCI, and AD diagnostic groups. L, left; R, right. *Pairwise between-group difference, p < .05, Bonferroni-corrected

Fig. 4

Exemplar scatterplot of the negative association between age and 2FA binding in right anterior cingulate in the CU group