Introduction
The availability of various animal models of Alzheimer's disease (AD) gives us a unique opportunity to study in detail the neuropathological processes characteristic for this disease. The triple transgenic rat model of beta-amyloid deposition, recently developed by Cephalon Inc. and Xenogen Biosciences, expressing high levels of beta-amyloid deposits in aged animals, is an excellent target for the microPET imaging due to the much larger brain size compared with mice. In our work we applied microPET with [F-18]FDDNP, a beta-amyloid binding molecular probe, to visualize the beta-amyloid deposits and to quantitate the beta-amyloid load in the living brains of these animals with the purpose of beta-amyloid load monitoring.
Methods
All animal scans were performed with a Concorde Focus microPET camera and the scan duration was 60 min after the tracer injection. The animal population consisted of 3 triple transgenic rats aged 15 months and of 2 control rats (Sprague-Dawley) aged 9 months. The data analysis was performed on the dynamic images which were reconstructed using filtered backprojection reconstruction. The dynamic images were also used to perform Logan plot graphical analysis with cerebellum as reference region and to generate the distribution volume (DV) parametric images. Regions of interest were drawn on several cortical regions and on hippocampus and were used to extract the time-activity curves from the dynamic images and DV values from the parametric images for all ROIs.
Results
We have observed the elevated levels of [F-18]FDDNP binding (compared to cerebellum) in several cortical regions but not in the subcortical regions or white matter regions (DV: frontal 1. 32±0.04, p<0.0005; hippocampus 1.23±0.05, p=0.001). This pattern of cortical signal distribution correlates well with the known distribution of beta-amyloid deposits in the brains of these rats where cortical regions have dense deposits of plaques but the subcortical areas and cerebellum either have very low level of the deposits or are free of them. As expected, the results of the experiments performed on controls animals do not show any significant signal above the cerebellar level neither in cortical nor in subcortical regions (DV: frontal 1.04 ± 0.01; hippocampus 0.99±0.04).
Conclusions
[F-18]FDDNP microPET is the first successful method for in vivo visualization of the beta-amyloid load in any rodent transgenic model of Alzheimer's disease which for the first time opens the possibility of temporal monitoring of the beta-amyloid load changes in these animals. It also opens the possibility of monitoring the beta-amyloid load changes which may result from the therapeutic interventions.