Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis

Paulo Lizano, Olivia Lutz, Yanxun Xu, Leah H. Rubin, Lyle Paskowitz, Adam M. Lee, Seenae Eum, Sarah K. Keedy, S. Kristian Hill, James L. Reilly, Baolin Wu, Carol A. Tamminga, Brett A. Clementz, Godfrey D. Pearlson, Elliot S. Gershon, Matcheri S. Keshavan, John A. Sweeney, Jeffrey R. Bishop

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

Original languageEnglish (US)
Pages (from-to)3430-3443
Number of pages14
JournalMolecular psychiatry
Issue number7
Early online dateOct 15 2020
StatePublished - Jul 2021

Bibliographical note

Funding Information:
Acknowledgements Supported in part by NIMH grants MH-077851 (to CAT), MH-078113 (to MSK), MH-077945 (to GDP), MH-077852 (to Dr. Thaker), and MH-077862 (to JAS); MH-083888 (to JRB); the Commonwealth Research Center (grant SCDMH82101008006 to MSK); the NIH’s National Center for Advancing Translational Sciences (pilot grant to JRB supported by UL1TR000114); and a Dupont Warren and Livingston Award from Harvard Medical School (to PL). Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Poster Presentation at the American College of Neuropsychopharmacology, Orlando, FL, December 8–12, 2019.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.


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