In Vivo Imaging of Human Cerebral Nicotinic Acetylcholine Receptors with 2-18F-Fluoro-A-85380 and PET
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.
Available from: Hideo Tsukada
- "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). "
[Show abstract] [Hide abstract]
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.
Available from: Tracy Warbrick
- "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. "
[Show abstract] [Hide abstract]
ABSTRACT: Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double-blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers)—drawn from a larger population-based sample—performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-010-2145-8) contains supplementary material, which is available to authorized users.
Available from: Philippe Remy
- "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 . "
[Show abstract] [Hide abstract]
ABSTRACT: Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[(18)F]fluoro-3,4-dihydroxy-L-phenylalanine (6-[(18)F]fluoro-L-DOPA) to measure the dopaminergic function and another with 2-[(18)F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[(18)F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[(18)F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P <0.05) decrease of 2-[(18)F]fluoro-A-85380 DV in the striatum (-10%) and substantia nigra (-14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.