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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).

SUBMITTER: Seitz-Holland J

PROVIDER: S-EPMC10538303 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Seitz-Holland Johanna J Wojcik Joanne D JD Cetin-Karayumak Suheyla S Lyall Amanda E AE Pasternak Ofer O Rathi Yogesh Y Vangel Mark M Pearlson Godfrey G Tamminga Carol C Sweeney John A JA Clementz Brett A BA Schretlen David A DA Viher Petra Verena PV Stegmayer Katharina K Walther Sebastian S Lee Jungsun J Crow Tim T James Anthony A Voineskos Aristotle A Buchanan Robert W RW Szeszko Philip R PR Malhotra Anil K AK Kelly Sinead S Shenton Martha E ME Keshavan Matcheri S MS Mesholam-Gately Raquelle I RI Kubicki Marek M

Molecular psychiatry 20220818 9

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, an ...[more]

PMID: 35982257

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Project description:ImportanceEfforts to remediate the multiple cognitive function impairments in schizophrenia should consider white matter as one of the underlying neural mechanisms.ObjectiveTo determine whether altered structural brain connectivity is responsible for 2 of the core cognitive deficits in schizophrenia- reduced information processing speed and impaired working memory.Design, setting, and participantsThis cross-sectional study design took place in outpatient clinics from August 1, 2004, to August 31, 2015. Participants included 166 patients with schizophrenia and 213 healthy control individuals. These participants were from 3 independent cohorts, each of which had its own healthy control group. No participant had current or past neurological conditions or major medical conditions. Patients were diagnosed with either schizophrenia or schizoaffective disorder as defined by the DSM-IV. Controls had no Axis I psychiatric disorder.Main outcomes and measuresMediation analyses and structural equation modeling were used to analyze the associations among processing speed, working memory, and white matter microstructures. Whole-brain and regional diffusion tensor imaging fractional anisotropy were used to measure white matter microstructures.ResultsOf the study participants, the 166 patients with schizophrenia had a mean (SD) age of 38.2 (13.3) years and the 213 healthy controls had a mean (SD) age of 39.2 (14.0) years. There were significantly more male patients than controls in each of the 3 cohorts (117 [70%] vs 91 [43%]), but there were no significant differences in sex composition among the 3 cohorts. Patients had significantly reduced processing speed (Cohen d = 1.24; P = 6.91 × 10-30) and working memory deficits (Cohen d = 0.83; P = 1.10 × 10-14) as well as a significant whole-brain fractional anisotropy deficit (Cohen d = 0.63; P = 2.20 × 10-9). In schizophrenia, working memory deficit was mostly accounted for by processing speed deficit, but this deficit remained when accounting for working memory (Cohen d = 0.89; P = 2.21 × 10-17). Mediation analyses showed a significant association pathway from fractional anisotropy to processing speed to working memory (P = 5.01 × 10-7). The strength of this brain-to-cognition pathway in different white matter tracts was strongly associated with the severity of schizophrenia-associated fractional anisotropy deficits in the corresponding white matter tracts as determined by a meta-analysis (r = 0.85-0.94; all P < .001). The same pattern was observed in patients and controls either jointly or independently.Conclusions and relevanceStudy findings suggest that (1) processing speed contributes to the association between white matter microstructure and working memory in schizophrenia and (2) white matter impairment in schizophrenia is regional tract-specific, particularly in tracts normally supporting processing speed performance.

Dataset Information

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

Publications

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

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