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

Abstract

Background: Recent 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.

Methods: 51 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.

Results: We 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.

Conclusion: This 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.

Keywords: Blood brain barrier; Choroid Plexus; Depression; Neuroinflammation.

Fig. 1

Choroid plexus (CP) and brain-CSF-barriers (BCSFB). The CP is located at the base of each of the four brain ventricles and is composed of epithelial cells surrounded by connective stroma and blood vasculature, which forms the BCSFB. The epithelial cells are connected by tight junctions in the apical border which face the cerebrospinal fluid (CSF) and are covered by microvilli, while the basolateral border faces the blood vasculature. The ependymal cells cover the roof of the ventricles and are connected by gap junctions, which facilitate the exchange of electrolytes and some solutes between the CSF and the interstitial fluid (ISF).

Fig. 2

Choroid plexus (CP) segmentation in HCs and depressedsubject. T1-weighted MRI images with the manual segmentation of the left and right CP (red) on the axial, coronal, and sagittal planes for one representative control (A) and one depressed subject (B). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Choroid plexus (CP) volume in depressed subjects and healthy controls (HCs) Mean difference of CP volumes between HC and depressed groups (F = 5.30, p = 0.02). Error bars indicate standard error. The analysis is corrected for the intracranial volume.

Fig. 4

Correlation between the choroid plexus (CP) volume and brain inflammation in healthy controls (HCs) and depressed subjects in ACC (A), PFC (B) and INS (C). *indicates statistical significance (p-value < 0.05). ^ns indicates non-significant results.

Fig. 5

Inverse association between choroid plexus (CP) volume and CSF-blood tracer exchange measured by [¹¹C]PK11195 PET uptake (SUVR and AUC, respectively) in lateral ventricles (LV). * indicates statistical significance (p-value < 0.05).

Fig. 6

Imaging transcriptomics decoding of regional variation in the association between choroid plexus (CP) volume and TSPO. Panel A: Left - scatter plot depicting a significant positive correlation between PLS1 gene expression weights and the t-statistics quantification the association between CP volume and TSPO for each region of the left hemisphere. Right – the upper brain map depicts the cortical distribution of the t-statistics quantifying the association between CP volume and TSPO; the lower brain map depicts the cortical distribution of the weights of PLS₁. Panel B: Table showing the results of the brain cell-type gene enrichment analysis. The colours depict normalized enrichment ratios; positive ratios indicate enrichment for genes of a specific cell class among those genes with the highest positive PLS₁ weights; the reverse applies to negative enrichment ratios. White squares indicate cell classes where enrichment did not survive p_FDR < 0.05. NER – Normalized enrichment ratio; CP – Choroid plexus.