Quantitative [123I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels, but not number of nigral neurons in different mouse models of Parkinson's disease
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease. Its core clinical features result from depletion in the neurotransmitter dopamine (DA) secondary to a degeneration of dopaminergic neurons in the pars compacta of the substantia nigra (SN) (Dauer and Przedborski, 2003, Dawson and Dawson, 2003). Since the dopamine transporter (DAT) is specifically expressed in dopaminergic neurons, PET- and SPECT-based methods to image DAT-binding radiotracers ([123I]FP-CIT, [123I]β-CIT or [99mTc]TRODAT-1) are widely used to assess the integrity of the nigrostriatal projection in vivo. Such techniques are helpful to establish the diagnosis of PD or to monitor disease progression (Benamer et al., 2000, Parkinson Study Group, 2002, Ravina et al., 2005). Indeed, experiments in parkinsonian primates (Ma et al., 2002) and in PD patients (Eshuis et al., 2006) showed a strong correlation between the specific uptake of DAT-binding radiotracers in the striatum, as assessed by SPECT, and the [18F]DOPA uptake, a parameter of the DA-storage capacity of the dopaminergic nerve terminals in the striatum, as assessed by PET. Furthermore, it has been shown in rodents that the striatal [123I]FP-CIT SPECT signal in vivo correlates with the DAT protein levels (Andringa et al., 2005). Thus, SPECT with DAT-binding radiotracers appears to be a valid biomarker to assess the integrity of the striatal dopaminergic innervation in vivo. However, since DAT is a highly regulated protein with a high turnover rate (Ahlskog, 2003), and since DAT expression appears to be reduced in dopaminergic neurons in PD (Uhl et al., 1994, Counihan and Penney, 1998), it is not clear how the in vivo SPECT signal relates to functionally important parameters of the nigrostriatal system, such as the striatal DA levels and the number of dopaminergic neurons in the SN.
In recent years the development of high-resolution pinhole SPECT systems has enabled SPECT studies experimentally in small laboratory animals (Myers and Hume, 2002, Acton and Kung, 2003, Andringa et al., 2005). Several studies with gamma cameras equipped with pinhole collimators showed that the density of the DAT in the striata of rats or mice can be determined by this technique with great precision (Habraken et al., 2001, Scherfler et al., 2002, Booij et al., 2002, Andringa et al., 2005). To assess the relation of the FP-CIT SPECT signal to striatal DA levels and nigral cell numbers we studied two different mouse models of PD. We used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in a mild intoxication paradigm to model mild nigrostriatal damage and 6-hydroxydopamine (6-OHDA) model with intrastriatal toxin injection to model more advanced nigrostriatal damage (Höglinger et al., 2004). In difference to previous studies, we used a multi-pinhole collimator with ten apertures in order to increase sensitivity and decrease acquisition time and compared the striatal FP-CIT binding in vivo with postmortem histological and biochemical parameters describing the integrity of the nigrostriatal system.
Section snippets
Animals
Male C57Bl/6 mice (24–26 g) were obtained from Charles River (Sulzfeld, Germany). They were maintained on a 12:12-h light/dark cycle with lights on at 6:30 a.m. The room temperature was kept at 23 °C. Animals were permitted water and mouse chow ad libitum. All experimental procedures were approved by the Committee for Animal Care (Regierungspräsidium Giessen).
6-ODHA lesion
Mice were anesthetized using 0.42 g/kg chloralhydrate (4%) and placed into a stereotactic frame (David Kopf Instruments, USA). 6-OHDA was
SPECT imaging technique
A rotating double-headed gamma camera (Fig. 1A) equipped with a 10-pinhole aperture (Fig. 1B) yielded an excellent spatial resolution with precise visualization of the main anatomical subdivisions of the rodent brain, as shown using the radiotracer [99mTc]HM-PAO in naive mice (Fig. 1C).
Acquisition of multiple images in a time course demonstrated that the optimum time point for quantification of the specific striatal [123I]FP-CIT binding with the highest signal-to-noise ratio was 2 h after
Discussion
The present study compared the use of a [123I]FP-CIT pinhole SPECT in two different mouse models of PD, the subchronic MPTP and the intrastriatal model 6-OHDA model, at 3 different post-lesional time points. We correlated the [123I]FP-CIT binding ratios to the DA content in the striatum and the number of TH+ neurons in the SN. We demonstrated that there is an excellent correlation between the [123I]FP-CIT binding ratio measured in vivo by SPECT and the striatal DA concentration measured ex vivo
Acknowledgments
This work was supported by the German Ministry of Education and Research Grants BMBF-01GN0513 and 01GO0201 and the European Union Grant LSHM-CT-2003-503330. We thank Andreas Matusch for critically reading the manuscript.
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Have contributed equally.