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

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 n...

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Autores principales: Sultzer, David L., Lim, Aaron C., Gordon, Hailey L., Yarns, Brandon C., Melrose, Rebecca J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819935/
https://www.ncbi.nlm.nih.gov/pubmed/35130968
http://dx.doi.org/10.1186/s13195-021-00954-w
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author Sultzer, David L.
Lim, Aaron C.
Gordon, Hailey L.
Yarns, Brandon C.
Melrose, Rebecca J.
author_facet Sultzer, David L.
Lim, Aaron C.
Gordon, Hailey L.
Yarns, Brandon C.
Melrose, Rebecca J.
author_sort Sultzer, David L.
collection PubMed
description 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-[(18)F]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.
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spelling pubmed-88199352022-02-08 Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia Sultzer, David L. Lim, Aaron C. Gordon, Hailey L. Yarns, Brandon C. Melrose, Rebecca J. Alzheimers Res Ther Research 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-[(18)F]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. BioMed Central 2022-02-07 /pmc/articles/PMC8819935/ /pubmed/35130968 http://dx.doi.org/10.1186/s13195-021-00954-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Sultzer, David L.
Lim, Aaron C.
Gordon, Hailey L.
Yarns, Brandon C.
Melrose, Rebecca J.
Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia
title Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia
title_full Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia
title_fullStr Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia
title_full_unstemmed Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia
title_short Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer’s disease dementia
title_sort cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and alzheimer’s disease dementia
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819935/
https://www.ncbi.nlm.nih.gov/pubmed/35130968
http://dx.doi.org/10.1186/s13195-021-00954-w
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