P2-349: association between mglur5 and synaptic density: a multi-tracer study of healthy aging and alzheimer's disease

Metabotropic glutamate subtype 5 receptors (mGluR5) modulate synaptic transmission and play an important role in Alzheimer's disease (AD) by mediating the synaptotoxic action of amyloid-beta oligomers (Haas, et al., 2016, Renner, et al., 2010,Um, et al., 2013). Synaptic density and mGluR5 are both reduced in the medial temporal lobe of individuals with AD compared to healthy participants (Chen, et al., 2018, Mecca, et al., 2018). The presence of mGluR5 may influence the regional pattern of synaptic loss. Therefore, PET imaging of mGluR5 with [18F]FPEB and synaptic density with [11C]UCB-J may be able to dissociate the regional patterns of mGluR5 and synaptic loss in early AD. [18F]FPEB and [11C]UCB-J PET were performed in 8 amyloid-positive AD and 4 amyloid-negative cognitively normal (CN) individuals (59 to 81 years old). Images of [18F]FPEB binding to mGluR5 (BPND) were calculated by equilibrium modeling. For [11C]UCB-J PET, VT images were produced with the one-tissue compartment model. Mean BPND or VT was computed for ROIs (frontal cortex, occipital cortex, parietal cortex, and temporal cortex, anterior cingulum, posterior cingulum, precuneus, hippocampus, entorhinal cortex, caudate, putamen, thalamus). The effect of mGluR5 availability on synaptic density was assessed using linear mixed-effects models. AD participants (71.0±6.7 years, CDR = 0.5-1.0) had amnestic mild cognitive impairment or mild dementia. CN participants (67.8±8.6 years) were free of clinical disease (CDR=0). There was a significant positive association between [18F]FPEB BPND (F(1,141)=27.5, p<0.0005) and [11C]UCB-J VT, as well as a significant effect of [18F]FPEB binding*ROI (F(1,132)=2.2, p=0.019) on [11C]UCB-J VT. The within region correlation between [18F]FPEB and [11C]UCB-J was strongest in the hippocampus (Pearson's r=0.530, p=0.076). Inclusion of diagnosis (CN or AD) is a separate model did not modify the relationship between [18F]FPEB and [11C]UCB-J. Investigation of the relationship between [18F]FPEB and [11C]UCB-J binding indicated that synaptic density is correlated with mGluR5 density within an individual's brain. Furthermore, the correlation between regional synaptic density and mGluR5 was strongest in the hippocampus. Further study with a larger sample is needed to reveal the pattern of mGluR5 and synaptic density in AD and healthy individuals.