Synaptic density in aging mice measured by [¹⁸F]SynVesT-1 PET

Synaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and in aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored. Thus, in the present study, PET ligand [¹⁸F]SynVesT-1, which binds to SV2A, was used to investigate synaptic density at different ages in healthy mice. Wild type C57BL/6 mice divided into three age groups (4-5 months (n = 7), 12-14 months (n = 11), 17-19 months (n = 7)) were PET scanned with [¹⁸F]SynVesT-1. Brain retention of [¹⁸F]SynVesT-1 expressed as the volume of distribution (V_IDIF) was calculated using an image-derived input function. Estimates of V_IDIF were derived using either a one-tissue compartment model (1TCM), a two-tissue compartment model (2TCM), or the Logan plot with blood input to find the best-fit model for [¹⁸F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers. We found that [¹⁸F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [¹⁸F]SynVesT-1 brain retention was lower in the oldest group of mice, indicating a decrease in synaptic density in this age group. However, no gradual age-dependent decrease in synaptic density at a region-specific level was observed. Immunostaining indicated that SV2A expression and neuron numbers were similar across all three age groups. In general, these data obtained in healthy aging mice are consistent with previous findings in humans where synaptic density appeared stable during aging up to a certain age, after which a small decrease is observed.