Synaptic density and neuronal metabolic function measured by PET in the unilateral 6-OHDA rat model of Parkinson's disease

• Published in: bioRxiv
• Main Authors: Raval, Nakul Ravi, Gudmundsen, Frederik, Juhl, Morten, Ida Vang Andersen, Nikolaj Raahauge Speth, Videbæk, Annesofie, Petersen, Ida Nymann, Jens Damsgaard Mikkelsen, Patrick Macdonald Fisher, Herth, Matthias Manfred, Plavèn-Sigray, Pontus, Gitte Moos Knudsen, Palner, Mikael
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 09.08.2021
• Subjects: 6-Hydroxydopamine; Animal models; Autoradiography; Basal ganglia; Collaboration; Dopamine receptors; Forebrain; Medial forebrain bundle; Mesencephalon; Metabolism; Movement disorders; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Parkinson's disease; Parkinsons disease; Positron emission tomography; Prefrontal cortex; Radioisotopes; Substantia nigra; Synaptic density
• DOI: 10.1101/2021.05.27.444950

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 three 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. Competing Interest Statement MP: Compass Pathways Plc (research collaboration), GMK: H. Lundbeck A/S (research collaboration), Compas Pathways Plc (research collaboration), Elysis (research collaboration), Novo Nordisk/Novozymes/Chr. Hansen (stockholder), Sage Therapeutics and Sanos (Advisor). GMK is currently the president of the European College of Neuropsychopharmacology. All other authors declare no conflicts of interest. Footnotes * The manuscript has minor changes. Supplementary data is added with more baseline animals and autoradiography from the sham lesioned animals.