Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer’s disease: a multi-tracer PET study

Background 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 [¹⁸F]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 [¹¹C]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 [¹⁸F]FPEB and [¹¹C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD.

Methods Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [¹⁸F]FPEB to measure mGluR5 and [¹¹C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [¹⁸F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [¹¹C]UCB-J PET, DVR was calculated with a simplified reference tissue model – 2 and a whole cerebellum reference region.

Result 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 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 within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions.

Conclusion Medial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated Aβo toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.