Cytomegalovirus infection associated with smaller dentate gyrus in men with severe mental illness

Dimitrios Andreou,Kjetil Nordbø Jørgensen,Stener Nerland,Kristine Engen,Robert H Yolken,Ole A Andreassen,Ingrid Agartz

doi:10.1016/j.bbi.2021.05.009

Abstract

Cytomegalovirus (CMV) infection is usually inapparent in healthy adults but persists for life. Neural progenitor/stem cells are main CMV targets, and dentate gyrus (DG) a major neurogenic niche. Smaller DG volume has been repeatedly reported in severe mental illness (SMI). Considering the suggested immune system, blood–brain barrier and DG disturbances in SMI, we hypothesized that CMV exposure is associated with smaller DG volume in patients, but not healthy controls (HC). Due to the differential male and female immune response to CMV, we hypothesized sex-dependent associations. 381 adult patients with SMI (schizophrenia spectrum or bipolar spectrum disorders) and 396 HC were included. MRI scans were obtained with 1.5T Siemens MAGNETOM Sonata scanner or 3T General Electric Signa HDxt scanner, and processed with FreeSurfer v6.0. CMV immunoglobulin G antibody concentrations were measured by solid phase immunoassay. We investigated main and interaction effects of CMV status (antibody positivity/CMV + vs. negativity/CMV-) and sex on DG in patients and HC. Among patients, there was a significant CMV-by-sex interaction on DG (p = 0.009); CMV + male patients had significantly smaller DG volume than CMV- male patients (p = 0.001, 39 mm3 volume difference) whereas no CMV-DG association was found in female patients. Post-hoc analysis among male patients showed that the CMV-DG association was present in both hemispheres and in both patients with schizophrenia spectrum and bipolar spectrum disorders, and further, that higher CMV antibody titers were associated with smaller DG. No CMV-DG association was found in HC. The results indicate a DG vulnerability to CMV infection in men with SMI.

Highlights

Cytomegalovirus (CMV) is a virus in the family Herpesviridae in the subfamily Betaherpesvirinae, with a high seroprevalence mainly depending on age, sex and socioeconomic status (Cannon et al, 2010; Voigt et al, 2016; Zuhair et al, 2019)
CMV + and CMV- patients did not significantly differ in sex, age, education years, intracranial volume (ICV), tobacco use, handedness, alcohol use disorder identification test (AUDIT) score, drug use disorder identification test (DUDIT) score, duration of illness (DOI), medication variables, Positive and Negative Syndrome Scale (PANSS) total score, Young Mania Rating Scale (YMRS) score or IDS-C score assessed with t-tests for quantitative variables and chi-square tests for categorical variables (Table 1)
Among patients with severe mental illness (SMI), we found a significant CMV immunoglobulin G (IgG) status-by-sex interaction (p = 0.009) on dentate gyrus (DG), with CMV + male patients having significantly smaller DG volume than CMV- male pa tients (p = 0.001), whereas no DG volume difference was found between CMV + and CMV- female patients (p = 0.560) (Fig. 2)

Summary

Introduction

Cytomegalovirus (CMV) is a virus in the family Herpesviridae in the subfamily Betaherpesvirinae, with a high seroprevalence mainly depending on age, sex and socioeconomic status (Cannon et al, 2010; Voigt et al, 2016; Zuhair et al, 2019). Postnatal CMV infection of immunocompetent individuals is usually inapparent, but results in lifelong latency, mainly in hematopoietic cells, that persists and is never cleared (Wills et al, 2015). This latent CMV infection is substantially more active than previously considered, with CMV gene products modifying the cellular environment, and the altered environment increasing viral reactivations (Dupont and Reeves, 2016). CMV can efficiently replicate in neural stem and progenitor cells (NSPCs) inhibiting their proliferation and differentiation (Cheeran et al, 2009; Kawasaki et al, 2017), and it has been suggested that these cells are sites of CMV latency (Belzile et al, 2014). The abundant CNS presence of NSPCs during early development may explain the susceptibility of the developing brain (Cheeran et al, 2009; Kawasaki et al, 2017)

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