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bioRxiv · 10.64898/2026.04.27.720978

Distinct Hippocampal Cellular Pathologies Influence Cognition Across Diagnostic Categories, also distinguishing Schizophrenia from Affective Psychoses

Ruby, E.·Gonen, O.·Lotan, E.·Tal, A.·Rusinek, H.·Clemente, J. C.·Robinson-Papp, J.·Karlsgodt, K. H.·Malaspina, D.
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Abstract

Introduction: Total and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses cases could be a roadblock if these differ in cellular pathology. Methods: We examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations (1H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis (Psy), including 20 schizophrenia and 13 affective psychoses (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 to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, p's<.05), although no biomarker predicted total cognition in the clinical groups. FFor NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). Opposite NP-aff, reduced myelin/membrane concentrations predicted cognitive deficits in Psy (-.514, p<.05). Separating schizophrenia from aff-P on social cognition showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) ibut higher myelin/membrane turnover and neuronal integrity concentrations in aff-P (.575, .581, p's<.05). Conclusions: Schizophrenia and affective psychosis significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different 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.

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Ruby, E., Gonen, O., Lotan, E., Tal, A., Rusinek, H., Clemente, J. C., Robinson-Papp, J., Karlsgodt, K. H., Malaspina, D.. 2026-04-29. Distinct Hippocampal Cellular Pathologies Influence Cognition Across Diagnostic Categories, also distinguishing Schizophrenia from Affective Psychoses. https://doi.org/10.64898/2026.04.27.720978

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