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Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study
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DOI：10.1186/s13195-025-01739-1.png)
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Abstract
En 中文
Background: The pathological effects of amyloid beta oligomers (A beta o) 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-18]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-11]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-18]FPEB and [C-11]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 [F-18]FPEB to measure mGluR5 and [C-11]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [F-18]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [C-11]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 A beta o 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.
Keywords:
Alzheimer's disease
MGluR5 binding
Synaptic density
SV2A
PET
[F-18]FPEB
[C-11]UCB-J
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1.9K
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