Salardini Elaheh, O'Dell Ryan S, Tchorz Em, Nabulsi Nabeel B, Huang Yiyun, Carson Richard E, van Dyck Christopher H, Mecca Adam P
Alzheimer's Disease Research Unit, Yale University School of Medicine, One Church Street, 8 Floor, New Haven, CT, 06510, USA.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Alzheimers Res Ther. 2025 May 6;17(1):98. doi: 10.1186/s13195-025-01739-1.
The pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer's disease (AD). Positron emission tomography (PET) studies of mGluR5 using [F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [F]FPEB and [C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD.
Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [F]FPEB to measure mGluR5 and [C]UCB-J to measure synaptic density. Parametric distribution volume ratio (DVR) images using equilibrium methods were generated from dynamic images. For [F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region.
A strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic density in the AD group (r = 0.85, p < 0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses indicated more widespread significant positive correlations between synaptic density and mGluR5 within regions, as well as significant positive correlations between synaptic density in the temporal lobe and mGluR5 across a broader set of regions commonly affected by AD.
Our findings suggest that mGluR5 reduction in AD is closely linked to synaptic loss. Longitudinal studies are needed to clarify causality, deepen understanding of AD pathogenesis, and aid in developing novel biomarkers and treatments.
淀粉样β寡聚体（Aβo）的病理作用可能通过代谢型谷氨酸受体5（mGluR5）介导，导致阿尔茨海默病（AD）中的突触丧失。使用[F]FPEB对mGluR5进行的正电子发射断层扫描（PET）研究表明，AD患者受体结合减少，且集中在内侧颞叶。通过[C]UCB-J PET对突触囊泡糖蛋白2A（SV2A）进行定量测量得出的AD所致突触丧失也集中在内侧颞叶，但在通常受AD影响的新皮质区域有明显的广泛减少。在本研究中，我们使用[F]FPEB和[C]UCB-J PET来研究早期AD中mGluR5与突触密度之间的关系。
15名早期AD淀粉样蛋白阳性参与者和12名淀粉样蛋白阴性、认知正常（CN）的参与者接受了PET扫描，分别使用[F]FPEB测量mGluR5和[C]UCB-J测量突触密度。使用平衡法从动态图像生成参数分布体积比（DVR）图像。对于[F]FPEB PET，使用平衡法和小脑参考区域计算DVR。对于[C]UCB-J PET，使用简化参考组织模型-2和整个小脑参考区域计算DVR。
AD参与者海马体中mGluR5与突触密度之间存在强正相关（r = 0.81，p < 0.001），CN组中也存在强正相关（r = 0.74，p = 0.005）。在内嗅皮质中，AD组mGluR5与突触密度之间存在强正相关（r = 0.85，p < 0.001），但CN组中相关性较弱且无统计学意义（r = 0.36，p = 0.245）。探索性分析表明，区域内突触密度与mGluR5之间存在更广泛的显著正相关，以及在更广泛的通常受AD影响的区域中，颞叶突触密度与mGluR5之间存在显著正相关。
我们的研究结果表明，AD中mGluR5的减少与突触丧失密切相关。需要进行纵向研究以阐明因果关系，加深对AD发病机制的理解，并有助于开发新的生物标志物和治疗方法。
