Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.
Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.
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DOI：
10.1093/brain/awy099
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Brust P
中科院分区：
文献类型：
--
作者：
Sabri O;Meyer PM;Gräf S;Hesse S;Wilke S;Becker GA;Rullmann M;Patt M;Luthardt J;Wagenknecht G;Hoepping A;Smits R;Franke A;Sattler B;Tiepolt S;Fischer S;Deuther-Conrad W;Hegerl U;Barthel H;Schönknecht P;Brust P
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. 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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DOI：
10.3174/ajnr.a2070
发表时间：
2010-08
期刊：
AJNR. American journal of neuroradiology
影响因子：
--
作者：
Kantarci K;Senjem ML;Lowe VJ;Wiste HJ;Weigand SD;Kemp BJ;Frank AR;Shiung MM;Boeve BF;Knopman DS;Petersen RC;Jack CR Jr
通讯作者：
Jack CR Jr
影响因子：
2.3
作者：
Brust, Peter;Patt, Joerg Thomas;Sabri, Osama
通讯作者：
Sabri, Osama
影响因子：
--
作者：
Brody, Arthur L.;Mandelkern, Mark A.;Mukhin, Alexey G.
通讯作者：
Mukhin, Alexey G.
影响因子：
3.6
作者：
Foxe, David;Leyton, Cristian E.;Piguet, Olivier
通讯作者：
Piguet, Olivier
DOI：
10.1007/s00259-010-1644-5
发表时间：
2011-03-01
影响因子：
9.1
作者：
Kendziorra, Kai;Wolf, Henrike;Sabri, Osama
通讯作者：
Sabri, Osama