PT - JOURNAL ARTICLE AU - Adam Mecca AU - Ming-Kai Chen AU - Tyler Godek AU - Joanna Harris AU - Hugh Bartlett AU - Takuya Toyonaga AU - Mika Naganawa AU - Arash Salardini AU - Amy Arnsten AU - Nabeel Nabulsi AU - Keunpoong Lim AU - Soheila Najafzadeh AU - Jim Ropchan AU - Yiyun Huang AU - Richard Carson AU - Stephen Strittmatter AU - Christopher Van Dyck TI - <strong>Analysis of mGluR5 and synaptic density in Alzheimer’s disease: A multi-tracer study</strong> DP - 2019 May 01 TA - Journal of Nuclear Medicine PG - 51--51 VI - 60 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/60/supplement_1/51.short 4100 - http://jnm.snmjournals.org/content/60/supplement_1/51.full SO - J Nucl Med2019 May 01; 60 AB - 51Background: 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.1-3 Recently, we demonstrated reductions of synaptic density in the medial temporal lobe of individuals with AD compared to healthy participants using [11C]UCB-J PET.4 A similar pattern and magnitude of mGluR5 reduction was also observed with [18F]FPEB PET.5 The presence of mGluR5 may influence the regional pattern of synaptic loss, given the evidence for involvement of this receptor in AD pathogenesis. PET imaging studies with [18F]FPEB and [11C]UCB-J may be able to dissociate the regional pattern of mGluR5 and synaptic loss in early AD. Methods: [18F]FPEB and [11C]UCB-J PET were performed in 8 amyloid-positive AD and 4 amyloid-negative cognitively normal (CN) individuals that ranged in age from 59 to 81 years old. T1 weighted MRI was performed and analyzed using FreeSurfer (FS) to segment the brain into regions of interest (ROI). Images of [18F]FPEB binding to mGluR5 (BPND) were calculated by equilibrium modeling using 90 to 120 min frames and a whole cerebellum reference region. For [11C]UCB-J PET, arterial samples were used to measure the metabolite-corrected input function. VT images were produced with the one-tissue compartment model. PET images were transformed to participant MRI space using FS and 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 a linear mixed-effects model with [11C]UCB-J VT in each ROI as an outcome. The model included fixed effects for [18F]FPEB BPND, ROI, and ROI-by-[18F]FPEB BPND interaction, with participant-specific random intercepts. ROI was included as a with-subject factor. We explored the effect of diagnostic group (AD vs CN) on the patterns of tracer binding using a similar mixed-effects model. Results: 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 binding (F(1,141) = 27.5, p &lt; 0.0005) and [11C]UCB-J. There were also significant effects of ROI (F(1,132) = 9.5, p &lt; 0.005) and [18F]FPEB binding[asterisk]ROI (F(1,132) = 2.2, p = 0.019) on [11C]UCB-J VT. Post hoc analyses within each region did not reveal significant correlations between [18F]FPEB and [11C]UCB-J binding. An additional mixed-effects model demonstrated a significant effect of diagnosis (AD vs CN) (F(1,77) = 4.5, p = 0.037) and a non-significant trend for the 3-way interaction of diagnosis[asterisk]ROI[asterisk][18F]FPEB binding (F(12,133) = 1.7, 0.076) on [11C]UCB-J VT. Conclusions: Investigation of the relationship between [18F]FPEB and [11C]UCB-J binding revealed significant within-participant correlations that were largely related to regional variation. This may indicate that synaptic density is correlated with mGluR5 density within an individual’s brain. Furthermore, the relationship between regional synaptic density and mGluR5 may be altered in AD. Further study with a larger sample is needed to reveal the pattern of mGluR5 and synaptic density in AD and healthy individuals. Understanding the relationship between mGluR5 and synaptic density may expand our understanding of synaptic biology and AD pathogenesis, ultimately leading to the development of novel treatments and biomarkers for AD. Funding: NIA (P50-AG047270, K23-AG057784, R01-AG52560), NIMH (R25-MH071584), and The Dana Foundation David Mahoney Neuroimaging Grant. References 1 Renner, M. et al., Neuron, 2010. 2 Um, J. W. et al., Neuron, 2013. 3 Haas, L. T. et al., Brain, 2016. 4 Chen, M. K. et al., JAMA neurology, 2018. 5 Mecca, A. P. et al., Alzheimers Dement, 2018.