TESTING NEUROINFLAMMATORY HYPOTHESIS OF MAJOR DEPRESSIVE DISORDER: A DOUBLE TRACER PET STUDY
Authors: Kameno *Yosuke , Yokokura Masamichi , Iwabuchi Toshiki , Murayama Chihiro , Goto Takafumi , Tamayama Taishi , Wakuda Tomoyasu , Benner Seico , Ouchi Yasuomi , Yamasue Hidenori 
Published: February 2025

Abstract

Background
Although the pathophysiology of major depressive disorder (MDD) still remains unclear, one of the promising hypotheses is the neuroinflammation hypothesis. [1] In this hypothesis, activated microglia secrete pro-inflammatory cytokines such as TNF-α and IL-1β in the brain of patients with MDD. These cytokines lead to activate serotonin transporter (5-HTT) and indoleamine 2,3-dioxygenase (IDO), decreasing the concentration of serotonin in the synaptic cleft, resulting in depressive state. However, to the best of our knowledge, no previous study tested the association between the activated microglia and upregulated 5-HTT in vivo.

Aims & Objectives
The aim of current study was to explore the associations between activated microglia and 5-HTT using positron emission tomography (PET), and their contributions to the pathophysiology of MDD.

Method
19 patients with MDD and 20 healthy controls (HC) participated in this case-control study. The participants were assessed with the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI-II), the State-Trait Anxiety Inventory (STAI), and Impact of Event Scale-Revised (IES-R). The PET scans with [11C]DPA-713 and [11C]DASB, the specific radioligands for microglia and 5-HTT respectively, were performed on the same day. The non-displaceable binding potential (BPND) levels were estimated based on simplified reference tissue models. All statistical analyses were conducted using SPSS. The threshold for statistical significance was set at p &lt;0.05. The protocol of present case-control study were reviewed and approved by the Ethics Committee of the Hamamatsu University School of Medicine. All participants provided written informed consent for themselves before participating in the study.

Results
No significant differences were found in the background information. The patients with MDD had significantly high scores on HDRS, BDI-II, IES-R, STAI-Trait anxiety, and STAI-State anxiety compared with the HC. The [11C]DASB BPND in patients with MDD was significantly lower than that in HC in the orbitofrontal cortex and the thalamus. The [11C]DPA-713 BPND in patients with MDD were significantly higher than that in HC in the superior frontal cortex, middle frontal cortex, hippocampus, anterior cingulate cortex, putamen, posterior cingulate cortex, precuneus, insula, and occipital cortex. The significant correlation of BPND between [11C]DASB and [11C]DPA-713 in the putamen was observed in the patients with MDD not in the HC.

Discussion & Conclusion
The low BPND of [11C]DASB and the high BPND of [11C]DPA-713 in patients with MDD were consistent with the previous studies.[2-5] The significant correlation between these two tracers in the putamen of patients with MDD was in line with the previous animal study showing that microglial activation induced to increase cytokines and 5-HTT in mice.[6] The present study was the first to quantitatively test the neuroinflammation hypothesis of MDD in vivo, and suggested that activated microglia and its interaction with 5-HTT play a key role in the pathophysiology of MDD.

References
1.Miller, A. H. and Raison, C. L. (2016) ‘The role of inflammation in depression: from evolutionary imperative to modern treatment target.’, Nature reviews. Immunology. 16(1), pp. 22–34.
2.Bartlett, E. A. et al. (2022) ‘Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy’, Molecular Psychiatry. 27(8), pp. 3417–3424.
3.Spies, M. et al. (2015) ‘The serotonin transporter in psychiatric disorders: Insights from PET imaging’, The Lancet Psychiatry. 2(8), pp. 743–755.
4.Gryglewski, G. et al. (2014) ‘Meta-analysis of molecular imaging of serotonin transporters in major depression.’, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 35(7), pp. 1096–1103.
5.Gritti, D. et al. (2021) ‘Neuroinflammation in Major Depressive Disorder: A Review of PET Imaging Studies Examining the 18-kDa Translocator Protein.’, Journal of affective disorders, 292, pp. 642–651.
6.Couch, Y. et al. (2013) ‘Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia.’, Brain, behavior, and immunity, 29, pp. 136–146.