In Vivo Imaging of Human Cerebral Nicotinic Acetylcholine Receptors with 2-18F-Fluoro-A-85380 and PET

Cea Leti, Grenoble, Rhône-Alpes, France
Journal of Nuclear Medicine (Impact Factor: 6.16). 03/2005; 46(2):240-7.
Source: PubMed


2-(18)F-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-(18)F-fluoro-A-85380) is a PET radioligand that is specific for nicotinic acetylcholine receptors (nAChRs) and has a high affinity for the alpha(4)beta(2) subtype. The purpose of this study was to evaluate different strategies to quantify 2-(18)F-fluoro-A-85380 binding in healthy nonsmoking human volunteers.
After intravenous injection of 189 +/- 30 MBq (0.8-5.7 nmol) of 2-(18)F-fluoro-A-85380, the first dynamic PET scan was acquired over 150 min. The second 30-min PET scan was performed 60 min later. Time-activity curves were generated from volumes of interest. 2-(18)F-Fluoro-A-85380 volume of distribution (DV) was quantified using compartmental kinetic analysis and Logan graphical analysis. In the kinetic analysis, the 1-tissue compartment model (1TCM) and the 2-tissue (2TCM) compartment model were applied. The most appropriate kinetic model was determined using the Akaike Information Criterion. The effect of reducing the PET study duration on the reliability of the DV values computed by the kinetic and the graphical analyses was evaluated.
Time-activity curves were better described by the 2TCM. The DV values ranged from 5.2 +/- 0.5 in the occipital cortex, 6.2 +/- 0.2 in the frontal cortex, and 7.3 +/- 0.4 in the putamen to 15.4 +/- 2.1 in the thalamus. These regional DV values were consistent with the distribution of nAChRs in the human brain. Logan graphical analysis provided slightly lower DV values than those of the 2TCM (from -3.5% in the occipital cortex to -6.6% in the thalamus). The minimal study duration required to obtain stable DV estimates in all regions was similar for the 2 methods: 140 min for the 2TCM and 150 min for the Logan analysis. DV estimates obtained with the 2TCM were more stable than those calculated by the Logan approach for the same scan duration.
These results show that 2-(18)F-fluoro-A-85380 can be used to assess nAChRs binding in the human brain with PET.

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    • "Using the factorial statistical parametric mapping model, a one-way ANOVA was performed to determine differences in 18 F-2FA-85380 BP RI levels between groups with gender, age and education as confounding factors. The level of significance was set at P 5 0.001 uncorrected for peak height with a cluster size larger than 100 because the regions of focus were known a priori as areas with cholinergic innervation (Gallezot et al., 2005). "
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    ABSTRACT: Nicotinic acetylcholine receptor subtype α4β2 is considered important in the regulation of attention and memory, and cholinergic degeneration is known as one pathophysiology of Alzheimer's disease. Brain amyloid-β protein deposition is also a key pathological marker of Alzheimer's disease. Recent amyloid-β imaging has shown many cognitively normal subjects with amyloid-β deposits, indicating a missing link between amyloid-β deposition and cognitive decline. To date, the relationship between the α4β2 nicotinic acetylcholine receptor and amyloid-β burden has not been elucidated in vivo. In this study we investigated the relation between α4β2 nicotinic acetylcholine receptor availability in the brain, cognitive functions and amyloid-β burden in 20 non-smoking patients with Alzheimer's disease at an early stage and 25 age-matched non-smoking healthy elderly adults by measuring levels of α4β2 nicotinic acetylcholine receptor binding estimated from a simplified ratio method (BPRI) and Logan plot-based amyloid-β accumulation (BPND) using positron emission tomography with α4β2 nicotinic acetylcholine receptor tracer (18)F-2FA-85380 and (11)C-Pittsburgh compound B. The levels of tracer binding were compared with clinical measures for various brain functions (general cognition, episodic and spatial memory, execution, judgement, emotion) using regions of interest and statistical parametric mapping analyses. Between-group statistical parametric mapping analysis showed a significant reduction in (18)F-2FA-85380 BPRI in the cholinergic projection region in patients with Alzheimer's disease with a variety of (11)C-Pittsburgh compound B accumulation. Spearman rank correlation analyses showed positive correlations of (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region with scores of the Frontal Assessment Battery (a test battery for executive functions and judgement) in the Alzheimer's disease group (P < 0.05 corrected for multiple comparison), and also positive correlations of the prefrontal and superior parietal (18)F-2FA-85380 BPRI values with the Frontal Assessment Battery score in the normal group (P < 0.05 corrected for multiple comparison). These positive correlations indicated an in vivo α4β2 nicotinic acetylcholine receptor role in those specific functions that may be different from memory. Both region of interest-based and voxelwise regression analyses showed a negative correlation between frontal (11)C-Pittsburgh compound B BPND and (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region in patients with Alzheimer's disease (P < 0.05 corrected for multiple comparison). These findings suggest that an impairment of the cholinergic α4β2 nicotinic acetylcholine receptor system with the greater amount of amyloid deposition in the system plays an important role in the pathophysiology of Alzheimer's disease.
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    • "The diversity of regions that are apparently influenced by nicotine across studies and paradigms suggests that nicotine acts on several sub-processes of attention and working memory whereby different task conditions emphasize different cortical regions. The rather uniform nicotine effect across regions is in accordance with neuroimaging and neuroanatomical studies showing a rather homogeneous density of nicotinic receptors throughout human cortex (Hellström-Lindahl et al. 1999; Gallezot et al. 2005) although one post-mortem study reported a relative increase of nicotinic binding sites in parietal cortex (Scheperjans et al. 2005). The finding from our study also fits with what is known about nicotinic/ cholinergic neurotransmission and cognition. "
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    • "Despite the wide range of disease severity in these patients , we found no correlation between the different measures of PD severity and the reduction of nAChRs density . The cerebral distribution of nAChRs in our group of elderly healthy subjects is in agreement with previous studies in nonsmoking healthy volunteers ( Gallezot et al , 2005 ; Kimes et al , 2003 ; Mitkovski et al , 2005 ; Picard et al , 2006 ) and is consistent with data obtained in vitro ( Schmaljohann et al , 2006 ) . In PD patients , there is a trend toward a mild and widespread decrease of nAChRs density . "
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