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

Molecular Psychiatry volume 26, pages 3430–3443 (2021)Cite this article

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Abstract

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.

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Fig. 1: Study design and group comparisons.
Fig. 2: Exploratory factor analysis and group comparisons.
Fig. 3: Hierarchical clustering defines two cytokine-based groups (Inflammatory Subtypes).
Fig. 4: Cognition differences between inflammatory subtypes.
Fig. 5: Gray matter thickness and subcortical volume differences between inflammatory subtypes.

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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.

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Authors and Affiliations

  1. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Paulo Lizano, Olivia Lutz & Matcheri S. Keshavan

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Paulo Lizano & Matcheri S. Keshavan

  3. Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA

    Yanxun Xu & Lyle Paskowitz

  4. Department of Neurology, Psychiatry, and Epidemiology, Johns Hopkins University, Baltimore, MD, USA

    Leah H. Rubin

  5. Department of Experimental and Clinical Pharmacology and Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA

    Adam M. Lee & Jeffrey R. Bishop

  6. School of Pharmacy, Shenandoah University, Winchester, Virginia, USA

    Seenae Eum

  7. Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA

    Sarah K. Keedy & Elliot S. Gershon

  8. Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    S. Kristian Hill

  9. Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA

    James L. Reilly

  10. Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA

    Baolin Wu

  11. Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA

    Carol A. Tamminga

  12. Department of Psychology, University of Georgia, Athens, GA, USA

    Brett A. Clementz

  13. Yale School of Medicine, Hartford Hospital, Hartford, CT, USA

    Godfrey D. Pearlson

  14. Deptartment of Psychiatry, University of Cincinnati Medical Center, Cincinnati, OH, USA

    John A. Sweeney

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  1. Paulo Lizano
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Correspondence to Paulo Lizano or Jeffrey R. Bishop.

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Conflict of interest

CAT has served on the advisory board for drug development for Intra-Cellular Therapies, Inc., as an ad hoc consultant for Eli Lilly, Sunovion, Astellas, Pfizer, and Merck, has been a council member and unpaid volunteer for the National Alliance on Mental Illness, and served as deputy editor for the American Psychiatric Association. MSK has received research support from Sunovion and GlaxoSmithKline. Remaining authors report no competing interests.

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Lizano, P., Lutz, O., Xu, Y. et al. Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis. Mol Psychiatry 26, 3430–3443 (2021). https://doi.org/10.1038/s41380-020-00914-0

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