Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression

Noha Althubaity,Julia Schubert,Daniel Martins,Tayyabah Yousaf,Maria A Nettis,Valeria Mondelli,Carmine Pariante,Neil A Harrison,Edward T Bullmore,Danai Dima,Federico E Turkheimer,Mattia Veronese

doi:10.1016/j.nicl.2021.102926

Abstract

BackgroundRecent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in the interaction between the central and peripheral inflammation. Here we aimed to investigate CP volume alterations in depression and their associations with inflammation. Methods51 depressed participants (HDRS score > 13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [11C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and CP volume respectively. ResultsWe found a significantly greater CP volume in depressed subjects compared to HCs (t(76) = +2.17) that was positively correlated with [11C]PK11195 PET binding in the anterior cingulate cortex (r = 0.28, p = 0.02), prefrontal cortex (r = 0.24, p = 0.04), and insular cortex (r = 0.24, p = 0.04), but not with the peripheral inflammatory markers: CRP levels (r = 0.07, p = 0.53), IL-6 (r = -0.08, p = 0.61), and TNF-α (r = -0.06, p = 0.70). The CP volume correlated with the [11C]PK11195 PET binding in CP (r = 0.34, p = 0.005). Integration of transcriptomic data from the Allen Human Brain Atlas with the brain map depicting the correlations between CP volume and PET imaging found significant gene enrichment for several pathways involved in neuroinflammatory response. ConclusionThis result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component.

Highlights

Major Depressive Disorder (MDD) is a neuropsychiatric disorder associated with significant psychosocial impairment, recognized by the WHO as the leading cause of disability worldwide (Petralia et al, 2020).MDD is associated with mood changes such as sadness, crying, irrita bility, and anhedonia as well as psychophysiological symptoms such as insomnia, slowness of speech and action, loss of appetite, constipation, diminished sexual desire, and suicidal thoughts (Belmaker and Agam, 2008)
We demonstrated for the first time the association between choroid plexuses (CP) enlargement in depression and a reduction of brain barrier permeability reflected by blood-to-cerebrospinal fluid (CSF) radiotracer exchange parameters (SUVR)
There was no association between CP volume and peripheral inflam matory markers (CRP, IL6, and TNF- α) nor depression clinical scores (HDRS, Childhood Trauma score), but there was an association with Perceived Stress score

Summary

Introduction

Major Depressive Disorder (MDD) is a neuropsychiatric disorder associated with significant psychosocial impairment, recognized by the WHO as the leading cause of disability worldwide (Petralia et al, 2020).MDD is associated with mood changes such as sadness, crying, irrita bility, and anhedonia as well as psychophysiological symptoms such as insomnia, slowness of speech and action, loss of appetite, constipation, diminished sexual desire, and suicidal thoughts (Belmaker and Agam, 2008). MDD patients who experienced treatment resistance exhibit most of the cardinal features of inflammation, including elevations in inflam matory cytokines, acute phase proteins, chemokines, adhesion mole cules, and inflammatory mediators such as prostaglandins in peripheral blood and CSF (Miller et al, 2009). Different studies have shown sig nificant associations between inflammatory cytokines, in particular IL-1, TNF- α, and IL-6 that are markers of innate immune response, and depressive symptoms (Miller and Raison, 2016; Enache et al, 2019). Inducing acute IFN-alpha in healthy subjects results in the elevation of peripheral inflammation immune markers such as C-reactive protein, TNF-alpha, and IL-6 and is accom panied with depressive symptoms (Nettis et al, 2020). Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component

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