In vivo quantification of dopaminergic terminals loss in Parkinson’s Disease rat with AAV-induced overexpression of alpha-synuclein: a [18F]FMT microPET study.

Objectives: Rat models of Parkinson’s disease (PD), such as progressive neurodegeneration induced by adeno-associated virus (AAV)-mediated over-expression of human -synuclein (A53T) in midbrain dopamine neurons, are useful to evaluate novel antiparkinsonian therapies [1]. In vivo quantitative imaging of dopamine neurotransmission allows longitudinal evaluation of such PD’s rat model [2]. In this study, we investigate DA presynaptic function, with [18F]FMT PET (radiotracer of the L-aromatic amino acid decarboxylase enzyme), in the AAV A53T PD’s rat model, and correlate the results with behavioral measurements.

Methods: All animals were injected with 2 µL A53T -synuclein (n=6) or GFP (n=2) AAV2/9 in the right substantia nigra. Striatal DA presynaptic activity was assessed by dynamic PET with [18F]FMT [3] at 18 weeks post-lesion. Kinetic analysis was performed by “Patlak Reference” model, using PMOD software. Rats were monitored for motor behavior and assessed before the lesion, and at 4, 12 and 18 weeks post-lesion.

Results: As consequence of AAV-mediated A53T overexpression, significant decrease of [18F]FMT accumulation was recorded in the striatum ipsilateral to the lesion. Lesioned rats had dramatically reduced uptake constant Ki in the ipsilateral striatum compared to the contralateral striatum (p<0.001 for [18F]FMT) and to the ipsilateral striatum of sham-treated rats (p<0.001). Significant deficit in stepping adjustment was observed with the contralateral forepaw at 4, 12 and 18 weeks. Significant reduction of the time spent on the rotarod was also measured at 12 and 18 weeks.

Conclusions: Our results report good correlations between [18F]FMT PET outcomes and behavioral results. The sensitivity of the data quantification obtained in this study, confirms the interest to pursue longitudinal investigations with [18F]FMT to monitor dopaminergic dysfunction in this progressive preclinical model of PD.