Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study

Abstract

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Fig. 1. Mediation analyses utilized in the present study.

In the case of an association between whole-brain FA and cognitive performance, we conducted two additional mediation analyses (A) We tested if whole-brain FA mediates the association between group (individuals with schizophrenia versus healthy individuals) and cognitive performance (corrected for age and sex). B We explored if both whole-brain FA and processing speed mediate the association between group (individuals with schizophrenia versus healthy individuals) and cognitive performance (corrected for age and sex).

Fig. 2. Group comparisons between individuals with schizophrenia (SCZ) and healthy individuals for the eight cognitive domains investigated in the present study.

Figure 2 demonstrates that individuals with schizophrenia presented significantly (****p < 0.006, Bonferroni corrected for eight tests) lower T-scores than healthy individuals for all cognitive domains. Violin plots were chosen to display the median, the interquartile range, and single data points.