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

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.