In vivo imaging of amyloid plaques in a transgenic mouse model of Alzheimer's disease

Background/Aim: Formation of amyloid s-plaques (As) in the brain is one of the earliest and most relevant pathophysiological processes in the development of Alzheimer's disease (AD). Modern treatment strategies are directed towards reduction of cerebral As-load. Thus, non invasive imaging of As may assist the evaluation of treatment effects. Different PET and SPECT tracers for imaging of As-load in humans are currently being evaluated in clinical trials with promising Results:. However, only a marginal retention of the lead As-radiotracers has been reported in transgenic rodent models of AD so far, despite a high expression of As detectable by means of in vitro and ex vivo binding assays. This limitation hampers preclinical As-tracer development and evaluation. The aim of the current study was to establish a feasible protocol for the in vivo As-imaging in transgenic mice, using state of the art small animal imaging technology. Methods: 11C-PIB-PET using a small-animal PET scanner (Siemens-CTI Focus 120) with 3D acquisition in list-mode (0-60 min) and cranial MRI (Philips Achieva 1.5T with 23mm microscopy coil) were performed in 10 APP/PS1 transgenic mice (age: 9 months, n=5; 23 months, n=5) and age-matched controls. MRI and PET images were manually overlaid for anatomical correlation and definition of regions of interest (ROIs). Count rates per voxel of 11C-PIB-uptake were summed up (30-35min) and ROI-ratios were calculated. The As-free cerebellum was used as a reference region. All animals also received 3H-PIB to compare the in-vivo data with ex-vivo digital autoradiography. In separate studies, the cranial and regional brain uptake of 11C-PIB was determined by means of ex-vivo biodistribution studies. Results: Ratios between As-rich cortical regions and the cerebellum revealed a significant difference (p< 0.001) between 23-months Alzheimer models and controls (mean ratio cortex/cerebellum 1.85 (Standard deviation (SD)= 0.03) in AD and 0.91 (SD = 0.11) in controls) and also between 9-months Alzheimer models and controls (mean ratio cortex/cerebellum 1.49 (SD = 0.20) in AD and 0.91 (SD = 0.06) in controls). Cortex/cerebellar ratios revealed higher values in all transgenic animals compared to healthy controls. The ex-vivo validation confirmed the in-vivo PET ratios and proved that the overlay of PET and CNS-MRI enabled accurate ROI-definition and reliable determination of specific binding. Conclusions: For the first time it has been demonstrated that by means of 11C-PIB small animal PET and a technologically advanced methodology, the amyloid beta-plaques in a transgenic rodent model can be visualized and quantified non-invasively with satisfactory Results:. The established protocol may represent a valuable screening method for As-tracer evaluation and development, and provide an important step towards translational imaging in AD-research.