Objective: To investigate longitudinal dopaminergic deficits and similarity to human Parkinson’s disease (PD) using PET imaging in the rat alpha-synuclein (a-syn) preformed fibril (PFF) model.

Background: Multiple progressive dopaminergic alterations in prodromal/manifest PD have been identified with PET. Increased dopamine (DA) turnover and a reduction in DA transporter (DAT) function have been observed. In contrast, DA synthesis and storage is relatively preserved likely reflecting synthesis upregulation contributing to the delay between disease and symptom onset. Intrastriatal injection of a-syn PFFs results in early accumulation of Lewy body-like inclusions in multiple brain regions, including the nigrostriatal system, followed by a protracted phase of nigrostriatal degeneration. The distinct stage of synucleinopathy in the α-syn PFF model provides the opportunity to determine whether dopaminergic alterations are associated with α-syn inclusion formation in the nigrostriatal system.

Method: Male Fischer 344 rats were injected unilaterally to the striatum with either a-syn PFFs or an equal volume of vehicle. PET scans with both [18F] fluoro-3,4-dihydroxyphenyl-Lalanine (FDOPA: DA synthesis, storage and turnover) and 11C-methylphenidate (¹¹C-MP for DAT: DAT density ) were conducted at 2, 4 and 6 months post-surgery.

Results: A significant progressive decrease in DAT binding in the ipsilateral striatum (65% reduction at 6 months) compared to controls was found together with a progressive decrease in EDVR (55% reduction) with relatively preserved DA synthesis and storage (15% reduction). Contralateral side values remained in the normal range.

Conclusion: These results provide the first in vivo evidence that a-syn inclusion-bearing nigrostriatal neurons undergo early axonopathy and degenerative changes in dopamine transmission prior to overt degeneration. This progressive rat model of PD shows remarkable similarities to human PD: dopaminergic deficit progression with relative preservation of DA synthesis and storage compared to DA turnover and DAT function and measurable dopaminergic deficit preceding detectable motor impairments. Synucleinopathy and degeneration induced in the a-syn PFF model may be useful to investigate disease-modifying treatments.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/alpha-synuclein-preformed-fibril-pff-triggered-synucleinopathy-recapitulates-neurochemical-features-of-human-pd-a-pet-study-in-rats/