Dopaminergic Positron Emission Tomography Imaging in the Alpha‐Synuclein Preformed Fibril Model Reveals Similarities to Early Parkinson's Disease

BACKGROUND: Positron emission tomography (PET) imaging in early Parkinson's disease (PD) subjects reveals that increased dopamine (DA) turnover and reduced dopamine transporter (DAT) density precede decreases in DA synthesis and storage. The rat α‐synuclein preformed fibril (α‐syn PFF) model provides a platform to investigate DA dynamics during multiple stages of α‐syn inclusion‐triggered nigrostriatal degeneration. OBJECTIVES: We investigated multiple aspects of in vivo dopaminergic deficits longitudinally and similarities to human PD using translational PET imaging readouts. METHODS: Longitudinal imaging was performed every 2 months in PFF and control rats for 7 months. [(18)F]‐Fluoro‐3,4‐dihydroxyphenyl‐L‐alanine (FDOPA) imaging was performed to investigate DA synthesis and storage (K(occ)) and DA turnover, estimated by its inverse, the effective distribution volume ratio (EDVR). (11)C‐Methylphenidate (MP) was used to estimate DAT density (BP(ND)). RESULTS: Early DA turnover increases and DAT binding decreases were observed in the ipsilateral striatum of PFF rats, progressing longitudinally. EDVR decreased 26%, 38%, and 47%, and BP(ND) decreased 36%, 50%, and 65% at the 2‐, 4‐, and 6‐month time points, respectively, compared to ipsilateral control striatum. In contrast, deficits in DA synthesis and storage were not observed in the ipsilateral striatum of PFF rats compared to control injections and were relatively preserved up to 6 months (K(occ) decreased 20% at 6 months). CONCLUSIONS: The relative preservation of DA synthesis and storage compared to robust progressive deficits in DAT density and increases in DA turnover in the rat α‐syn PFF model display remarkable face validity to dopaminergic alterations in human PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society