Abstract
The positron emission tomography (PET) radioligand [11C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [11C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [11C]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was studied using [11C]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [11C]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between transgenic and age-matched wild type (WT) mice. The L61 mice displayed 11–13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [11C]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18–20 months) showed lower [11C]UCB-J brain exposure than younger WT mice (8–9 months). Together, these data imply that [11C]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modelling.
Highlights
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders, and the number of patients is steadily increasing worldwide
The results showed that both genotype and region had an impact on [11C]UCB-J brain uptake
The post hoc test show no significant differences in area under the standardised uptake value (SUV) curve (AUC) in any of the studied brain regions between transgenic and wild type (WT) animals, the WT animals tended to display somewhat
Summary
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders, and the number of patients is steadily increasing worldwide. The gradual loss of functional neurons and synapses is a key characteristic in the AD and PD brain (Coleman and Yao, 2003; Esposito et al, 2012; Matuskey et al, 2020). In both disorders, neurotoxic protein aggregates are central to the pathogenesis. Positron emission tomography (PET) radioligand (R)-1-((3[ 11 C]methyl-pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin2-one, known as [11C]UCB-J, binds to synaptic vesicle glycoprotein 2A (SV2A). SV2A is a presynaptic vesicle membrane protein expressed throughout the rodent and human brain, and the amount of SV2A is correlated to the number of functional synapses (Bajjalieh et al, 1994). Clinical studies have shown that [11C]UCB-J distribution is decreased in neurodegenerative
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