[18F]Nifene PET/CT Studies in Parkinson’s Disease A53T Mouse Model of a-Syncleinopathy

1615 Objectives: Nicotinic acetylcholine receptors (nAChRs) α4β2* subtype play an important role in the CNS and have been implicated in neurodegeneration. In Parkinson’s disease (PD), aggregation of misfolded α-synuclein in intracellular inclusions, Lewy bodies (LB) are some hallmarks of human PD. Our preliminary work using [18F]Nifene on postmortem human PD brain slices and other reported work suggests a potential loss of α4β2* nAChRs in PD. To study α-synucleinopathy in vivo, we have now used the transgenic Hualpha-Syn(A53T) PD mouse model which expresses the A53T mutant α-synuclein protein at six times the level of endogenous mouse of α-synuclein. Here we report our preliminary findings on [18F]Nifene PET/CT in the Hualpha-Syn(A53T) PD mouse model. Methods: Male and female hemizygous Hualpha-Syn(A53)T and no-carrier male and female (n=4) 11-month old mice from Jackson Labs were used in the study. All mice were fasted for at least 24 hours. [18F]Fluoride (from PETNET solutions) was used to prepare [18F]Nifene, which was injected intraperitoneally in normal saline (1.2 MBq in 0.1 mL) under 2% isoflurane anesthesia. Mice were then awake after [18F]Nifene injections and free to move in their cages. They were placed in the supine position in a mouse holder and anesthetized with 2% isoflurane for whole-body PET/CT imaging. All mice underwent a 15 minute-long PET scans were acquired 45 minutes after [18F]Nifene injections. All animals had a 7-minute-long CT scan before the PET scan for attenuation correction and anatomical delineation of PET images. An Inveon Multimodality (MM) CT scanner (Siemens Medical Solutions, Knoxville, TN) was used for CT acquisitions in combined PET/CT experiments. Results: The magnitude of [18F]Nifene uptake in the brain was expressed as standard uptake value (SUV) which was computed as the average [18F]Nifene activity in each volume of interest, VOI (in kBq/mL) divided by the injected dose (in MBq) times the bodyweight (Kg) of each animal (Fig-1A-C). [18F]Nifene binding in the no-carrier mouse was as expected, with the highest levels in the thalamus (Fig-1B). Hualpha-Syn(A53) mice had lower [18F]Nifene uptake in the midbrain and cortex compared to the no-carrier mice. SUV values Hualpha-Syn(A53): midbrain=0.57-0.64; cortex=0.54-0.67 versus no-carrier midbrain=1.09-1.45; cortex=1.07-1.39. The hemizygous mice develop adult-onset neurodegenerative disease between 9-16 months of age, with a progressive motoric dysfunction leading to death. [18F]Nifene SUV values in the thalamus were reduced in the Hualpha-Syn(A53) mice, while cortex was not significantly affected (Fig-1A). One Hualpha-Syn(A53) mouse, with no signs of abnormal physical activity or abnormal brain CT or abnormal [18F]FDG PET, exhibited unusually high [18F]Nifene activity in the frontal cortex (Fig-1C). Conclusion: Decreased [18F]Nifene uptake in the Hualpha-Syn(A53) PD mouse model was observed at 11 months of age. Longitudinal [18F]Nifene PET/CT studies are currently underway with more animals (n=12; Hualpha-Syn(A53) and no-carrier) to further validate these initial findings. Figure LegendFigure-1: [18F]Nifene uptake in a Parkinson’s disease alpha-synucleinopathy mouse model. Hualpha-Syn(A53T) mouse brain shows reduced thalamus (TH) [18F]Nifene uptake (A) compared to the no-carrier mouse brain shown in (B). Abnormal uptake of [18F]Nifene in the frontal cortex (FC) in a Hualpha-Syn(A53) female mouse is shown in (C).