ALTERED PATTERNS OF ASSOCIATION BETWEEN TSPO BINDING AND MGLUR5 AVAILABILITY IN VIVO IN DRUG-NAIVE PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A PRELIMINARY DUAL-TRACER PET STUDY
Authors: Kim *Jong-Hoon , Joo Yo-Han , Kim Jeong-Hee , Son Young-Don 
Published: February 2025

Abstract

Background
Based on the monoamine theory of major depressive disorder (MDD), symptoms are derived from a deficiency or imbalance in monoaminergic neurotransmission. The limitation of such a model (1) may highlight the need for alternative neurobiological constructs. Accumulating data indicate that neuroinflammation and its interactions with glutamatergic signaling may present a compelling alternative model for understanding the pathophysiology of MDD and its therapeutic approaches (2-4); however, the patterns of interregional correlations between neuroinflammation and glutamatergic signaling in MDD has not been directly investigated using in vivo positron emission tomography (PET) imaging.

Aims & Objectives
In this preliminary dual-tracer PET study, we tested for altered spatial associations between availability of ligands for the neuroinflammation marker, translocator protein (TSPO), and the metabotropic glutamate receptor-5 (mGluR5) marker in a group of MDD patients compared with matched healthy controls (HCs).

Method
Ten drug-naï ve non-smoking MDD patients without comorbidity and eight matched non-smoking HCs underwent PET scanning with the TSPO ligand [11C]PK11195 and the mGluR5 ligand [11C]ABP688. For TSPO availability, we quantified [11C]PK11195 binding potential (BPND) using a reference tissue model (5) based on the supervised cluster analysis (SVCA4) algorithm (6). For mGluR5 availability, [11 C]ABP688 BPND was obtained using the simplified reference tissue model (7) with cerebellar gray matter as a reference region. Regional BPND values were obtained from limbic brain regions that are pivotal in emotion and its regulation: prefrontal cortex, anterior cingulate cortex, parietal cortex, temporal cortex, insula, hippocampus, and amygdala. We calculated the interregional correlation coefficients between regional [11C]PK11195 BPND and [11C]ABP688 BPND values, and compared group differences in the correlation matrices using Fisher’ s z-transformation statistics. The level of statistical significance was defined as two-tailed p &lt;0.05.

Results
Regional [11C]PK11195 BPND and [11C]ABP688 BPND values showed widespread positive correlations in the HC group, but negative and attenuated positive correlations in the hippocampus and amygdala in the MDD group. The between-group comparisons of the interregional correlation coefficients showed significant differences between the [11C]PK11195 BPND in the left hippocampus and [11C]ABP688 BPND in the bilateral parietal and left temporal cortices, between the [11C]PK11195 BPND in the right hippocampus and [11C]ABP688 BPND in the bilateral prefrontal cortex, bilateral anterior cingulate cortex, bilateral parietal cortex, bilateral temporal cortex, insula, and right amygdala, and between the [11C]PK11195 BPND in the bilateral amygdala and [11C]ABP688 BPND in the right parietal cortex.

Discussion & Conclusion
Our preliminary dual-tracer PET study shows substantially different patterns of interregional correlations between the availability of TSPO and mGluR5 in MDD patients compared to HCs. The results are in line with a mechanism whereby neuroinflammation may provoke a down-regulation of a post-synaptic marker of glutamatergic transmission in limbic-cortical regions in MDD. These results call for examination in larger groups, aiming to accommodate the heterogeneity of MDD pathophysiology.

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