Molecular Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
Neurobiology Research Unit, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
Neuroimage. 2023 Aug 15;277:120230. doi: 10.1016/j.neuroimage.2023.120230. Epub 2023 Jun 22.
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 [F]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 [F]SynVesT-1. Brain retention of [F]SynVesT-1 expressed as the volume of distribution (V) was calculated using an image-derived input function. Estimates of V 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 [F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers. We found that [F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [F]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.
某些脑结构中的突触改变与神经退行性变和衰老中的认知能力下降有关。通过正电子发射断层扫描（PET）对突触小泡糖蛋白 2A（SV2A）成像，可以观察到许多神经退行性疾病中的突触丢失。然而，SV2A PET 用于研究衰老过程中的突触变化的应用并不特别广泛。因此，在本研究中，使用与 SV2A 结合的 PET 配体 [F]SynVesT-1 来研究健康小鼠在不同年龄的突触密度。将野生型 C57BL/6 小鼠分为三组（4-5 个月（n=7）、12-14 个月（n=11）、17-19 个月（n=7）），并用 [F]SynVesT-1 进行 PET 扫描。使用图像衍生输入函数计算 [F]SynVesT-1 的脑保留量（V）表示为分布体积（V）。使用单组织室模型（1TCM）、双组织室模型（2TCM）或带血液输入的 Logan 图来估计 V，以找到最适合 [F]SynVesT-1 的模型。PET 扫描后，对组织切片进行 SV2A 和神经元标志物的免疫染色。我们发现，静脉内注射后 60 分钟采集的 [F]SynVesT-1 数据，并使用 1TCM 进行分析，可以很好地描述放射性配体在小鼠脑中的药代动力学。最年长组的 [F]SynVesT-1 脑保留量较低，表明该年龄组的突触密度降低。然而，在特定区域水平上未观察到与年龄相关的逐渐降低的突触密度。免疫染色表明，SV2A 表达和神经元数量在所有三个年龄组中相似。总的来说，这些在健康衰老小鼠中获得的数据与先前在人类中观察到的结果一致，即突触密度在一定年龄之前在衰老过程中保持稳定，之后观察到轻微下降。
