Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson's Disease.

Nakul Ravi Raval,Patrick Macdonald Fisher,Annesofie Videbæk,Ida Nymann Petersen,Ida Vang Andersen,Jens D Mikkelsen,Gitte Moos Knudsen,Nikolaj Speth,Pontus Plavén-Sigray,Morten Juhl,Frederik Gudmundsen,Mikael Palner,Matthias Manfred Herth

doi:10.3389/fnsyn.2021.715811

Abstract

Parkinson’s disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower synaptic density and changes in neuronal metabolic function in the basal ganglia, as measured using [11C]UCB-J and [18F]FDG positron emission tomography (PET), respectively. However, the two radioligands have not been directly compared in the same PD subject or in neurodegeneration animal models. Here, we investigate [11C]UCB-J binding and [18F]FDG uptake in the CSTC circuit following a unilateral dopaminergic lesion in rats and compare it to sham lesioned rats. Rats received either a unilateral injection of 6-hydroxydopamine (6-OHDA) or saline in the medial forebrain bundle and rostral substantia nigra (n = 4/group). After 3 weeks, all rats underwent two PET scans using [18F]FDG, followed by [11C]UCB-J on a separate day. [18F]FDG uptake and [11C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [11C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [18F]FDG. Differential changes between hemispheres for [11C]UCB-J and [18F]FDG outcomes were also evident in the CSTC circuit’s cortical regions, especially in the orbitofrontal cortex and medial prefrontal cortex where higher synaptic density yet lower neuronal metabolic function was observed, following lesioning. In conclusion, [11C]UCB-J and [18F]FDG PET can detect divergent changes following a dopaminergic lesion in rats, especially in cortical regions that are not directly affected by the neurotoxin. These results suggest that combined [11C]UCB-J and [18F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders.

Highlights

Several techniques have been developed to identify diseaserelated neuronal patterns to aid early detection and differential diagnoses of Parkinson’s disease (PD)
We have previously shown that 6-OHDA lesioning lowers postsynaptic dopamine receptor density and presynaptic capacity to release amphetamine (Palner et al, 2011)
The results of our study indicate that dopaminergic lesions lead to a loss of presynaptic density in the striatal regions, as measured by [11C]UCB-J, which is similar to changes in neuronal metabolic function, as measured by [18F]FDG

Summary

Introduction

Several techniques have been developed to identify diseaserelated neuronal patterns to aid early detection and differential diagnoses of Parkinson’s disease (PD). Examples of such methods are positron emission tomography (PET) imaging to measure glucose metabolism (Loane and Politis, 2011), dopamine synthesis, transporters, or receptors (Kerstens and Varrone, 2020). The CSTC circuit connects the cortex with the basal ganglia to control and coordinate goal-directed behaviour. This circuit can be further divided into three loops: the motor, limbic, and associative circuits (Groenewegen and Trimble, 2007; Vriend et al, 2014). A model of 6-hydroxydopamine (6-OHDA) induced dopaminergic lesion leads to modulation within the CSTC, which will further help understand this circuit (Schwarting and Huston, 1996)

Methods

Results

Conclusion