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

Sabri, O., Meyer, P. M., Graef, S., Hesse, S., Wilke, S., Becker, G.-A., et al. (2018). Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia. Brain, 141(6), 1840-1854. doi:10.1093/brain/awy099.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-7AF9-E Version Permalink: http://hdl.handle.net/21.11116/0000-0003-9A89-5
Genre: Journal Article

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 Creators:
Sabri, Osama1, Author
Meyer, Philipp M.1, Author
Graef, Susanne2, 3, Author              
Hesse, Swen1, 4, Author
Wilke , Stephan 1, Author
Becker, Georg-Alexander1, Author
Rullmann, Michael1, 4, 5, Author              
Patt, Marianne1, Author
Luthardt, Julia1, Author
Wagenknecht, Gudrun6, Author
Hoepping, Alexander7, Author
Smits, Rene7, Author
Franke , Annegret8, Author
Sattler, Bernhard1, Author
Tiepolt, Solveig1, Author
Fischer, Steffen9, Author
Deuther-Conrad, Winnie9, Author
Hegerl, Ulrich2, Author
Barthel, Henryk1, Author
Schönknecht, Peter2, Author
Brust, Peter9, Author more..
Affiliations:
1Department of Nuclear Medicine, University of Leipzig, Germany, ou_persistent22              
2Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Germany, ou_persistent22              
3Max Planck Research Group Neurocognition of Decision Making, Max Planck Institute for Human Development, Max Planck Society, ou_2074295              
4Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Germany, ou_persistent22              
5Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_634549              
6Central Institute for Engineering, Electronics and Analytics, Research Center Jülich, Germany, ou_persistent22              
7ABX Advanced Biochemical Compounds GmbH, Radeberg, Germany, ou_persistent22              
8Clinical Trial Centre Leipzig, University of Leipzig, Germany, ou_persistent22              
9Institute of Radiopharmaceutical Cancer Research, Helmholtz Center Dresden-Rossendorf, Leipzig, Germany, ou_persistent22              

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Free keywords: (−)-18F-flubatine; PET; cognitive dysfunction; α4β2-nAChRs; Alzheimer’s dementia
 Abstract: In early Alzheimer’s dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer’s dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer’s dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (−)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer’s dementia. Fourteen non-smoking patients with mild Alzheimer’s dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (−)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer’s dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer’s dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (−)-18F-flubatine PET in patients with mild Alzheimer’s dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (−)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (−)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer’s dementia.

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Language(s): eng - English
 Dates: 2018-02-012017-11-032018-02-192018-04-172018-06-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1093/brain/awy099
PMC: PMC5972585
PMID: 29672680
 Degree: -

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Project name : -
Grant ID : 01EZ0820-3
Funding program : -
Funding organization : German Federal Ministry for Education and Research (BMBF)
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Grant ID : -
Funding program : -
Funding organization : International Max Planck Research School on Neuroscience of Communication: Function, Structure, and Plasticity (IMPRS NeuroCom)

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Title: Brain
  Other : Brain
Source Genre: Journal
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Publ. Info: London : Macmillan
Pages: - Volume / Issue: 141 (6) Sequence Number: - Start / End Page: 1840 - 1854 Identifier: ISSN: 0006-8950
CoNE: https://pure.mpg.de/cone/journals/resource/954925385135