Progressive gray matter loss and changes in cognitive functioning associated with exposure to herpes simplex virus 1 in schizophrenia: a longitudinal study

Abstract

Objective: Longitudinal changes in gray matter volume and cognitive performance were evaluated among individuals exposed to neurotropic herpes simplex virus subtype 1 (HSV1). There is a replicable association of HSV1 exposure with smaller prefrontal volumes and cognitive impairments in schizophrenia.

Method: The authors concurrently examined the whole-brain longitudinal trajectory over 1 year of gray matter volumes and executive functioning measured with the Wisconsin Card Sorting Test among 26 first-episode antipsychotic-naive subjects with schizophrenia and 38 healthy subjects. Age, gender, socioeconomic status, and exposure to cytomegalovirus (another virus of the herpes family that was previously associated with cognitive impairments) were the covariates.

Results: Significant gray matter loss in the posterior cingulate gyrus was noted among the HSV1-seropositive schizophrenia subjects over 1 year but not among other groups. Prefrontal gray matter volumes did not show longitudinal changes. Binomial mixed-effects models indicated that improvement over 1 year in Wisconsin Card Sorting Test categories completed and perseverative errors occurred in significantly fewer HSV1-seropositive schizophrenia subjects than in the HSV1-seronegative schizophrenia subjects or the healthy subjects regardless of serological status. Three-way interactions of diagnosis, HSV1 status, and time were significant for both categories completed and perseverative errors. An increase in perseverative errors over 1 year, but not the change in the number of categories completed, correlated with longitudinal volume loss of the posterior cingulate gyrus.

Conclusions: These observations suggest that HSV1 exposure may be associated with longitudinal gray matter loss in the posterior cingulate gyrus and decline in executive functioning among subjects with schizophrenia.

Fig. 1

Longitudinal changes in grey matter volume among HSV1 seropositive SZ subjects. In the whole brain analysis, the left posterior cingulate gyrus showed significant grey matter volume loss over 1 year after correcting for multiple comparisons using the false discovery rate (FDR) approach (T=13.77, FDR p=0.034). The grey matter volume in the right posterior cingulate gyrus showed a trend toward significance after correcting for multiple comparisons (T=9.93, FDR p=0.07).

Fig. 2

Longitudinal changes in executive function measures. Baseline represents the median split for number of categories completed (>5) and the number of perseverative errors (>9). Bars for SZ (black) and HS (grey) represent the percentage of subjects performing above or below the median split at 1 year compared to baseline. Over 1 year, the percentage of HSV1 negative SZ subjects who could complete >5 categories increased by 57% whereas the percentage of seropositive SZ subjects who completed >5 categories fell by 40%. Similarly, the percentage of seronegative SZ subjects who committed <9 perseverative errors increased by 24.81% compared with 13.70% in seropositive SZ subjects at 1 year compared to baseline. ^aImprovement was defined as movement from below-median performance at baseline to above-median performance at 1-year follow-up. Negative values indicate movement from above-median performance at baseline to below-median performance at year 1. Perseverative errors were transformed so that higher scores indicated improvement.

Fig. 3

Correlation of change in posterior cingulate cortex volume with change in perseverative error scores over 1 year among HSV1 positive SZ patients (Pearson r=0.73, p=0.007).