Quantifying acute tau inoculations in living rats using PET

Abstract

AbstractBackgroundMonitoring tau propagation in the living brain has important pathophysiological and therapeutic implications. As tau imaging agents are dependent on tau conformations, we aimed to determine the tau species amenable to in vivo imaging. Previously we demonstrated that ex vivo tau preparations may be used to image tau seeds in living murine systems, as opposed to recombinant preparations. As such, the goal of this work is to examine the dose‐dependent relationship of patient derived AD‐tau fibrils on PET imaging outcomes.MethodA total of two 15‐month‐old (2 wild‐type, one male and one female) rats were used. All animal had a baseline scan with [18F] MK6240 before the stereotaxic injections. We tested tau PHFs from AD brains using ultracentrifugation of sarkosyl‐insoluble brain fractions. AD‐tau preparations were stereotaxically injected in the dorsal hippocampus. We tested injection volumes of 1 and 3 uL of equal concentrations (80 ng/uL). Contralateral hemispheres were injected with equivalent amounts of PBS, the solvent for tau preparations. All PET images were coregistered to the Waxholm Space Atlas of the Sprague Dawley Rat Brain sMRI using a linear transformation. The non‐displaceable binding potential (BPND) images were generated using cerebellar grey as a reference region based on Simplified Reference Tissue Method (SRTM).ResultInjection of sarkosyl‐insoluble brain fractions from AD patients displayed positive BPnd outcome in both volumes tested. Control hemispheres injected with PBS showed potential off‐target binding. Reliability of this outcome was investigated using peak normalized TACs. Hemispheres receiving AD‐tau injections showed visible divergence in retention, as compared to baseline. The hemisphere that was inoculated with 3uL of AD‐tau showed separation during washout. A similar effect was seen in the control hemisphere.ConclusionThese results continue to suggest ex vivo tau preparations may be used to image tau seeds in living murine systems. The reliability of PET and kinetic outcomes are dependent on the volume injected. Further investigation will aim to evaluate AD‐tau concentration as the dosage variable instead of injection volume. Cerebellar tissue from patients used to extract AD‐tau species should be as a control injection to account for the reagents used for protein extraction, instead of PBS alone.