CHARACTERIZATION OF THK5117 BINDING IN AD BRAIN TISSUE: IMPLICATION FOR DEVELOPMENT OF PET TAU IMAGING

Background: Averting and clearing the aberrant accumulation of tau proteins in neurofibrillary tangles is the current focus of therapeutic strategies in Alzheimer’s disease (AD).New approaches for direct targeting of tau demand safe, non-invasive methods to detect and quantify tau in vivo [1, 2]. To assess tau progression together with the induced brain pathology, we longitudinally applied MRI on a conditional bigenic mouse model of tauopathy, rTg4510, in which tau expression can be supressedwith doxycycline [3].We investigated four, clinically relevant, quantitative techniques: cerebral blood flow (CBF) using arterial spin labelling (ASL); aggregated protein detection using amide proton transfer (APT); microstructural diffusion using diffusion tensor imaging (DTI), which were compared with the established gold standard structural MRI. Methods: 19 rTg4510, and 8 wild-type(WT) littermatched mice were imaged at baseline (4.5 months) using a 9.4T scanner for ASL, DTI, APT and structural data using parameters previously described [4,5]. 10 rTg4510 were then treated orally with doxycycline hyclate (10mg/kg) and maintained on a doxycycline diet for the remainder of the study to supress tau expression. The doxycycline-treated rTg4510, untreated rTg4510 and WT groups were imaged again at 5.5 and 7.5 months for longitudinal ASL, DTI, APTand structural data. During imaging, anaesthesia was maintained using 1.5-2% isoflurane and 1L/min O 2. Results:At 4.5 months, prior to doxycycline treatment, we observed marked changes in CBF, ATP and diffusion in rTg4510s due to increased tau pathology in comparison toWT controls. This was most apparent in the CBF study. Following only one month of treatment to supress tau, (imaging at 5.5 months), CBF had returned to control levels. This pattern was also observed for APT and diffusion imaging and the trend continued through to 7.5 months. Conclusions: This study demonstrates the sensitivity of multi-parametric MRI to the regulation of tau-driven pathological processes and provides an opportunity to assess novel therapeutic strategies. These approaches could give insights into the early onset of tauopathies, at a time when non-invasive imaging biomarkers are urgently needed for understanding the progressive pathology. This is the first demonstration that suppression of tau expression can be observed with the clinically relevant MRI parameters CBF, ATP and diffusion.