Distinct Hippocampal Cellular Pathologies Influence Cognition Across Diagnostic Categories and Distinguish Schizophrenia from Affective Psychoses

Abstract

Introduction: Cognitive deficits are key endophenotypes for psychosis, but targeting these in clinical trials has been unsuccessful in improving functioning. The admixture of schizophrenia and affective psychosis cases could be a roadblock if these forms of psychosis differ in cellular pathology. Methods: We examined cognitive functioning (MATRICS) and metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic resonance spectroscopic imaging (1H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 with non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis (Psy), including 20 schizophrenia and 13 affective psychosis (aff-P) cases. Results: NP-aff and HC had similar total cognition (46.64{+/-}12.01 vs 41.10{+/-}17.88), both superior to Psy (28.34{+/-} 12.34; p's<0.01). Mean metabolite concentrations were similar across all groups but showed significant within-group associations with cognitive tests. FFor HC, overall cognition, working memory, and reasoning deficits were associated with reduced neuronal integrity ({rho}=-.414, {rho}=-.422, and {rho}=-.433, respectively; all p's<.05), although no biomarker predicted overall cognition in the clinical groups. For NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits, significantly so for verbal learning deficits ({rho}=.446, p<.05), which were also associated with decreased glia ({rho}=-.503, p<.05). Opposite to NP-aff, reduced myelin/membrane concentrations predicted cognitive deficits in Psy, specifically visual learning deficits ({rho}=-.514, p<.05). Separating schizophrenia from aff-P evealed distinct abnormalities for social cognition deficits; reduced glutamate/excitation in schizophrenia ({rho}=-.673, p<.05) but increased levels of the biomarkers for myelin/membrane turnover and neuronal integrity in aff-P ({rho}=.575 and {rho}=.581, respectively; p's<.05). Conclusions: Schizophrenia and affective psychosis significantly differed in biomarkers of cellular pathology related to social cognition. Distinct underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder-based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.