Increased Translocator Protein Distribution Volume, A Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

By E. Setiawan, Alan A. Wilson, R. Mizrahi, P. Rusjan, L. Miler, G. Rajkowska, I. Suridjan, J. Kennedy, P. V. Rekkas, Sylvain Houle and 1 more. JAMA psychiatry, 2015

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Importance The neuroinflammatory hypothesis of major depressive disorder (MDD) is supported by several main findings: First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE) such as low mood, anhedonia, anorexia and weight loss. Second, peripheral markers of inflammation are frequently reported in MDD. Third, neuroinflammatory illnesses are associated with high rates of MDE. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence for brain inflammation during MDE. To investigate whether microglial activation, an important aspect of neuroinflammation, is present during MDE, [18F]FEPPA positron emission tomography (PET) was applied to measure translocator protein total distribution volume (TSPO VT), an index of TSPO density. Translocator protein density is elevated in activated microglia. Objective To determine whether TSPO VT, is elevated in the prefrontal cortex, anterior cingulate cortex (ACC) and insula in MDE secondary to MDD. Design Case-control study. Setting Tertiary care psychiatric hospital. Participants 20 subjects with MDE secondary to MDD and 20 healthy controls, underwent an [18F]FEPPA PET scan. MDE subjects were medication-free for at least 6 weeks. All participants were otherwise healthy, and non-smoking. Main Outcome Measure TSPO VT was measured in the prefrontal cortex, ACC, and insula. Results In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23=4.46, P=0.001).TSPO VT was increased, on average, by 30% in the prefrontal cortex, ACC and insula. In MDE, greater TSPO VT in the ACC correlated with greater depression severity (ACC: r=0.628, P=0.005). Conclusions and Relevance This finding provides the most compelling evidence to date for brain inflammation, and more specifically microglial activation, in MDE. This is important for improving treatment since it implies that therapeutics which reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT with severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors which overlap with the symptoms of MDE.

Subfields: Biological Psychiatry, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/11a05304f8b37b699393bda8ca9b8331a8217eee

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In Biological Psychiatry

1. C. Nemeroff
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4. R. Yirmiya
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In Molecular Biology

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In Neurology

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2. Eléonore Beurel
3. R. Yirmiya
4. M. Toups

Citations in the corpus

• The Bidirectional Relationship of Depression and Inflammation: Double Trouble (2020, background): “Using the [18F]FEPPATSPO ligand, elevations of TSPO volume in prefrontal cortex, insula, and anterior cingulate cortex that correlated with depression severity (Setiawan et al., 2015) and duration ( Setiawanet al.”
• Depression as a microglial disease. (2015, result): “The first PET imaging study, using the ligand [C]PK-11195, revealed no difference between depressed and control groups in any brain region [37], whereas a more recent study, using the PET ligand [F]FEPPA, reported significant depression-associated elevations in TSPO volume distribution in the prefro”